WO2004030637A2 - Treatment of obesity and other disorders associated with excessive food intake - Google Patents

Treatment of obesity and other disorders associated with excessive food intake Download PDF

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Publication number
WO2004030637A2
WO2004030637A2 PCT/US2003/009717 US0309717W WO2004030637A2 WO 2004030637 A2 WO2004030637 A2 WO 2004030637A2 US 0309717 W US0309717 W US 0309717W WO 2004030637 A2 WO2004030637 A2 WO 2004030637A2
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Prior art keywords
6alkyl
pyrazol
aryl
2alkyl
phenyl
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PCT/US2003/009717
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French (fr)
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WO2004030637A3 (en
Inventor
Margaret J. Bradbury
Nicholas D. P. Cosford
Mark A. Varney
Jeffery J. Anderson
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Merck & Co., Inc.
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Priority claimed from PCT/US2002/031294 external-priority patent/WO2003029210A2/en
Priority claimed from PCT/US2002/040147 external-priority patent/WO2003051833A2/en
Priority claimed from PCT/US2002/041720 external-priority patent/WO2003051315A2/en
Priority claimed from PCT/US2002/040237 external-priority patent/WO2003053922A2/en
Priority claimed from PCT/US2002/040486 external-priority patent/WO2003059904A1/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU2003218462A priority Critical patent/AU2003218462A1/en
Publication of WO2004030637A2 publication Critical patent/WO2004030637A2/en
Publication of WO2004030637A3 publication Critical patent/WO2004030637A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • a major excitatory neurotransmitter in the mammalian nervous system is the glutamate molecule, which binds to neurons, thereby activating cell surface receptors.
  • Such surface receptors are characterized as either ionotropic or metabotropic glutamate receptors.
  • the metabotropic glutamate receptors (“mGluR”) are G protein-coupled receptors that activate intracellular second messenger systems when bound to glutamate. Activation of mGluR results in a variety of cellular responses. In particular, mGluRl and mGluR5 activate phospholipase C, which is followed by mobilizing intracellular calcium.
  • PCT Publication 99/02497 discloses pyridine derivatives useful as mGluR5 mediators.
  • PCT publication WO 02/062323 discloses mGluR5 antagonists as useful for treating pruritic conditions.
  • PCT Publication WO 01/16121 discloses particular heterocyclic compounds as modulators of the metabotropic glutamate receptors useful in treating cerebral ischemia, chronic neurodegeneration, psychiatric disorders, schizophrenia, mood disorders, emotion disorders, disorders of extrapyramidal motor function, obesity, disorders of respiration, motor control and function, attention deficit disorders, concentration disorders, pain disorders, neurodegenerative disorders, epilepsy, convulsive disorders, eating disordes, sleep disorders, sexual disorders, circadian disorders, drug withdrawal, drug addiction, compulsive disorders, anxiety, panic disorders, depressive disorders, skin disorders, retinal ischemia, retnial degeneration, glaucoma, disorders associated with organ transplantation, asthma, ischemia, astrocytomas, and the like.
  • Modulators of the mGluR5 receptor are useful in the treatment, prevention and suppression of obesity and obesity related conditions.
  • antagonists and/or inverse agonists of the mGluR5 receptor are useful in the treatment, prevention and suppression of obesity and obesity related conditions.
  • the compounds are also useful for the treatment of eating disorders by inhibiting excessive food intake and the resulting obesity and complications associated therewith.
  • the present invention is concerned with metabotropic glutamate receptor-5 modulators useful in treating, preventing and suppresing obesity and obesity-related conditions, hi particular, antagonists and/or inverse agonists of the mGluR5 receptor are useful in the treatment, prevention and suppression of obesity and obesity related conditions, as well as treating eating disorders by inhibition of excessive food intake and the resulting obesity and complications associated therewith.
  • the mGluR5 antagonists of the general Formula IA are useful in the treatment, prevention and suppression of obesity and obesity related conditions, as well as treating eating disorders by inhibition of excessive food intake and the resulting obesity and complications associated therewith.
  • the invention is also concerned with pharmaceutical formulations comprising an mGluR5 antagonist as defined above together with another agent useful for treating obesity or obesity-related conditions.
  • the present invention is concerned with metabotropic glutamate receptor-5 modulators useful in treating, preventing and suppresing obesity and obesity-related conditions.
  • antagonists and/or inverse agonists of the mGluR5 receptor are useful in the treatment, prevention and suppression of obesity and obesity related conditions, as well as treating eating disorders by inhibition of excessive food intake and the resulting obesity and complications associated therewith.
  • the mGluR5 antagonists of the general Formula IA are useful in the treatment, prevention and suppression of obesity and obesity related conditions, as well as treating eating disorders by inhibition of excessive food intake and the resulting obesity and complications associated therewith.
  • the present invention is concerned with novel substituted amides of the general Formula IA :
  • X a and Ya each independently is aryl or heteroaryl wherein at least one of X and Y a is a heteroaryl with N adjacent to the position of attachment to Aa or B a respectively; X a is optionally substituted with 1-7 independent halogen, -CN, NO2,
  • Aa is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9c ⁇ -C ⁇ -2alkyl-, -C ⁇ -2alkyl- NR9sO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5, R6, and R7 each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • R8 is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Ba is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOCO-C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlOS ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl; R9 and RlO each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl -6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl
  • Rl 1, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -C ⁇ _6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci- ⁇ alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -
  • any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
  • the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein
  • Rl, R2, and R3 each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C()-6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C()-6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • A is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9c ⁇ -C ⁇ -2alkyl- -C()-2alkyl- NR9s ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5, R ; and R7 each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl _6alkyl, -O(CQ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R8 is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • B is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C()-2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-N lOCO-C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRlOS ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R and RlO each independently is -C ⁇ -6 a lkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C
  • RU, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -C ⁇ _6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -
  • any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
  • the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein
  • Rl, R2, and R3 each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C 0 -6alkyl), -N(C 0 -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cl _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Aa is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2 ⁇ C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NR 9 CO-C ⁇ -2alkyl- -C()-2alkyl- NR 9 SO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R8 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ -6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(CQ-6 alkyl) (aryl) substituents;
  • Ba is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOCO-C ⁇ -2alkyl
  • R9 and RlO each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • Rl 1, Rl2 and Rl are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C()-6alkyl)(C3_7cycloalkyl), or -N(C ⁇ -6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
  • the compound of this is substituted
  • Rl, R2, and R3 each independently is -C ⁇ -6 a lkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C()-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6al yl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(Co_ 6alkyl)(aryl) substituents;
  • R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • A is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NR 9 CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl- NR 9 SO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • Y a is 2-pyridyl optionally substituted with 1-4 independent halogen, -
  • R7 each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R8 is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl
  • B is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOCO-C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRlOS ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9 and RlO each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7 cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
  • Rl, R2, and R3 each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R4 is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cl-6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • A is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9c ⁇ -C ⁇ -2alkyl-, -C ⁇ -2alkyl- NR9sO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5, R6, and R7 each independently is -C ⁇ -6 a lkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R8 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 lkyl)(aryl) substituents;
  • Ba is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9 and RlO each independently is -C ⁇ -6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(C()-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • Rl, R2, and R3 each independently is -C()-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ -
  • R4 is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_
  • Aa is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • Ya is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci -6alkyl, -C ⁇ _6alkenyl, -C ⁇ _6alkynyl, -OR5, -NR5R6,
  • R5, R6, and R7 each independently is -C()-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Ba is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9 and RlO each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
  • Rl, R2, and R each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(C()-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • R4 is -Ci- ⁇ alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_
  • Aa is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C()-2alkyl-S ⁇ 2-C ⁇ -
  • Y a is 2-pyridyl optionally substituted with 1-4 independent halogen, -
  • R5, R6, and R7 each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ - ⁇ alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C -7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R8 is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • B is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9 and RlO each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • Rl, R2, and R3 each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • R4 is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_
  • A is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R8 is -Ci. ⁇ alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Ba is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9 and RlO each independently is -C ⁇ -6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein
  • Rl, R2, and R3 each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ -
  • R4 is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_
  • Aa is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R5, R6 ; and R7 each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R8 is -Ci-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3
  • R9 and RlO each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
  • Rl, R2, and R3 each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Aa is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NR9c ⁇ -C ⁇ -2alkyl-, -C ⁇ -2alkyl- NR9s ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • Y is pyrazolyl optionally substituted with 1-3 independent halogen, -
  • R9 and RlO each independently is -C ⁇ -6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • Rll, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
  • Rl, R2, and R3 each independently is -C ⁇ -6 a lkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl -6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Aa is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl- NR9sO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • Y a is pyrazolyl optionally substituted with 1-2 independent halogen, -
  • Ba is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOCO-C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlOs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9 and RlO each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • Y a is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -C ⁇ _6alkyl, -C ⁇ _6alkenyl, -C ⁇ _6alkynyl, -ORl, -NR1R2, -
  • Y a is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO 2 , -C ⁇ _6alkyl, -C ⁇ _6alkenyl, -C ⁇ _6alkynyl, -ORl, -NR1R2, -
  • the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein: X a is pyridyl optionally substituted with 1-4 independent halogen, -
  • the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein: X a is phenyl optionally substituted with 1-5 independent halogen, -
  • the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein: Y a is pyrazolyl optionally substituted with 1-3 independent halogen, -
  • Rib, R2b 5 and R3b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b ; R6b, and R7b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -
  • R8b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bb is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlObs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • Rib, R2b ; and R3b each independently is -C ⁇ -6alkyl, -C3-.
  • R4b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R5b, R6b and R7b each independently is -C ⁇ -6alkyl, -C3_ 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C 3 .
  • ⁇ b is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • Rib, R2b ; and R3b each independently is -C ⁇ -6 a lkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b s -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR 9 SO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b R6b, and R7b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C 0 -6alkyl)(C 0 -6alkyl), -N(C ⁇ -6alkyl)(C 3 -7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b i s -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • ⁇ b is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOCO-C ⁇ -2
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C 0 -6alkyl), -N(C ⁇ -6alkyl)(C 3 -7cycloalkyl), -N(C 0 - 6alkyl)(aryl) substituents; one of Alb and A2b i s N, the other is CRl2b ; Rl lb and Rl2b i s each independently halogen, -C ⁇ -6alkyl, -C ⁇ -
  • Rl lband Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -C ⁇ _6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • Rib, R2b, and R3b each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9c ⁇ -C ⁇ -2alkyl- -C ⁇ -2alkyl- NR9sO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b R6b and R7b each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents; ⁇ b is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C 3 -7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; one of Alb and A2b i s N, the other is CRl2b ; Rl lb and Rl2b i s each independently halogen, -C ⁇ -6 a lkyl, -C ⁇ - ⁇ alkoxyl, or -N(C ⁇ -4alkyl)(C
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein
  • Rib, R2b and R3b each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b, R6b, and R7b each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -C ⁇ _6alkyl, -C3-7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bb is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRlObs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; one of Alb and A2b i s N, the other is CRl2b ; Rl l and Rl2b is each independently halogen, -C ⁇ -6 a lkyl, -C ⁇ -
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • Rib, R2b ; and R3b each independently is -C ⁇ -6 a lkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C 3 _ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b, R6b and R7b each independently is -C ⁇ -6alkyl, -C3. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • Bb is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlObs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9b nd RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C 0 -6alkyl), -N(C 0 -6alkyl)(C3.7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; one of Alb and A2b i s N, the other is CRl2b ; Rl lb and Rl2b i s each independently halogen, -C ⁇ -6alkyl, -C ⁇ -
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein
  • Rib, R2b, and R3b each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b R6b, and R7b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents; ⁇ b is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2al
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; one of Alb and A2b i s N, the other is CRl2b ; Rl lb and Rl2b i s each independently halogen, -C ⁇ -6alkyl, -C ⁇ - ⁇ alkoxyl, or -N(C ⁇ -4alkyl)(C ⁇ -4alkyl
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • Rib, R2b, and R3b each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b i s -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C 3 _ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b, R6b, an d R7b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bb is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlObs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C 0 -6alkyl)(C 0 -6alkyl), -N(C 0 -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; one of Alb and A2b i s N, the other is CRl2b ; Rl lb and Rl2b is each independently halogen, -C ⁇ -6 a lkyl, -C ⁇ - ⁇ alkoxyl, or -N(C ⁇ -4alkyl)
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • Rib, R2b, and R3b each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b, R6b, and R7b each independently is -C ⁇ -6alkyl, -C3. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6 lkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bb is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRlObs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9b and RlOb each independently is -C ⁇ -6 a lkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; one of Alb and A2b i s N, the other is CRl2b ; Rl lb and Rl2b is each independently halogen, -C ⁇ -6alkyl, -C ⁇ -
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein
  • Rib, R2b, and R3b each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -Ci- ⁇ alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C 0 -6alkyl), -N(C ⁇ -6alkyl)(C 3 - 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b, R6b, and R7b each independently is -C ⁇ -6 a lkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bb is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-N lObc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlObsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C 0 -6alkyl)(C ⁇ -6alkyl), -N(C 0 -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; one of Alb and A2b i s N, the other is CRl2b ; Rl lb and Rl2b i s each independently halogen, -C ⁇ -6 a lkyl, -C ⁇ -
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • Rib, R2b, and R3b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_ 7 cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -Co_2alkyl-, -C ⁇ - 2alkyl-NR9bsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b, R6b and R7b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bb is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlObs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; one of Alb and A2b i s N, the other is CRl2b ; Rl lb and Rl2b is each independently halogen, -C ⁇ -6 a lkyl, -C ⁇ -
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(ary
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2 ⁇ C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b, R6b and R7b each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -
  • R8b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bb is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRlObsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R9b and RlOb ea ch independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6al
  • Rl lb and Rl2b i s each independently halogen, -C ⁇ -6 a lkyl, -C ⁇ - 6alkoxyl, or -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cl-6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloal
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • Rib, R2b, and R3b each independently is -C ⁇ -6alkyl, -C3-
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C 0 -6alkyl), -N(C 0 -6alkyl)(C3-7cycloalkyl), -N(Q)- 6alkyl)(aryl) substituents; one of Alb an d A b i s N, the other is CRl2b ;
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • R4b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C 3 -7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl), -O(
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b, R6b, and R7b each independently is -Co ⁇ 6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -
  • R8b is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents; ⁇ b is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2alkyl-
  • Rib, R2b, and R3b each independently is -C ⁇ -6alkyl, -C3-.
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_
  • Ab is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • Yb is quinolinyl optionally substituted with 1-6 independent halogen, - CN, NO2, -C ⁇ _6alkyl, -Ci-6alkenyl, -C ⁇ _6alkynyl, -OR5b, -NR5bR6b,
  • R8b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Bb is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(ary
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b, R6b, and R7b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Co-6alkyl)(Co-6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bb is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRlObsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R9b and RlOb each independently is -C ⁇ -6 a lkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; one of Alb an d A2b i s N, the other is CRl2b;
  • Rib, R2b, and R3b each independently is -C ⁇ -6alkyl, -C3-
  • R4b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • Yb is pyrazolyl optionally substituted with 1-3 independent halogen, - CN, NO2, -Ci_6alkyl, -Ci-6alkenyl, -C ⁇ _6alkynyl, -OR5b, -NR5bR6b,
  • R8b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6al yl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bb is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
  • Rib, R2b, and R3b each independently is -C ⁇ -6alkyl, -C3-
  • R4b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(C ⁇ -6alkyl), -O(C3_
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2 ⁇ C ⁇ -
  • Yb is pyrazolyl optionally substituted with 1-3 independent halogen, - CN, NO2, -Ci-6alkyl, -C ⁇ _6alkenyl, -C ⁇ _6alkynyl, -OR5b, -NR5bR6b,
  • Bb is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b, R6b, and R7b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci- ⁇ alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7 cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents; ⁇ b is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2alky
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b;
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • Rib, R2b, and R3b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -Ci- ⁇ alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5b, R6b, and R7b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C 0 -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Bb is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlObc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlObs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alky
  • Rib, R2b and R3b each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -Ci_6alkyl, -C3-7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C 0 -6alkyl), -N(C 0 -6alkyl)(C 3 - 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ab is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9bc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR9bsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R8b is -Ci. ⁇ alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C 3 -7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -Ci. ⁇ alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl), -O(
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
  • Rib, R2b, an d R3b each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4b is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Ab is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R5b, R6b, and R7b each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8b is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -
  • R9b and RlOb each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • a compound of this invention is represented by Formula (IC):
  • Xc and Yc each independently is aryl or heteroaryl wherein at least one of X c and Y c is a heteroaryl with N adjacent to the position of attachment to Ac or B c respectively; three of Ale, A2C, A 3 C, A c, and A5c are N, the remaining are C, and one of Ale and A4c mU st be N, but not both Ale and A4c are N;
  • Rlc, R2c, and R3c each independently is -C ⁇ -6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent , halogen, -CN, -C l-6alkyl, -O(Co_6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • R4c is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_
  • Ac is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • Y c is optionally substituted with 1-7 independent halogen, -CN, NO2,
  • Be is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOcc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlOcsO2-Co-2alkyl-, or -heteroC ⁇ -4alkyl;
  • R9c and RlOc each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C 0 -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C 0 - 6alkyl)(aryl) substituents;
  • the compound of this invention is represented by Formula (IC) or a pharmaceutically acceptable salt thereof, wherein
  • Rlc, R2c, and R c each independently is -C ⁇ -6 a lkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • R4c is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_
  • Ac is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R5C, R6C, and R7c each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R8c is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents; ⁇ c is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NRlOcc ⁇ -C ⁇ -2alkyl
  • the compound of this invention is represented by Formula (IC) or a pharmaceutically acceptable salt thereof, wherein
  • R5C, R6C, and R7c each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7 cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R8c is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Be is -Co_4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-N lOcCO-C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlOcs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9c and RlOc each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any alkyl optionally substituted with 1-5 independent halogen substitutents, and any N may be an N-oxide.
  • the compound of this invention is represented by Formula (IC) or a pharmaceutically acceptable salt thereof, wherein:
  • Rlc, R2C, and R3c each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • R4c is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_ 7 cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-
  • Ac is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R5C, R6C, and R7c each independently is -C ⁇ -6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R8c is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Be is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOcc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlOcs ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9c and RlOc each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C 3 -7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any alkyl optionally substituted with 1-5 independent halogen substitutents, and any N may be an N-oxide.
  • the compound of this invention is represented by Formula (IC) or a pharmaceutically acceptable salt thereof, wherein
  • Xd and Y each independently is aryl or heteroaryl wherein at least one of X and Y is a heteroaryl with N adjacent to the position of attachment to A or ⁇ respectively;
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • A is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R5d, R6d, and R7d each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -
  • R8d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • B is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOdc ⁇ -C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRldSO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R9d and RlO ea ch independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein
  • R4d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl), -O(aryl), -O(heteroaryl), -N(C 0 -6alkyl)(C ⁇ -6alkyl), -N(C 0 -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • A is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R5d, R6d, and R7d each independently is -C ⁇ -6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bd is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOdc ⁇ -C ⁇ -2
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C 0 -6alkyl), -N(C 0 -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
  • Rid, R2d, and R3 each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4d is -Ci- ⁇ alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(CQ-6alkyl)(aryl) substituents; Ad is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl-
  • Y is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -C ⁇ _6alkyl, -C ⁇ _6alkenyl, -C ⁇ _6alkynyl, -OR5d, _NR5dR6d,
  • R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl), -O(aryl), -O(heteroaryl), -N(C 0 -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C 3 _ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bd is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2 ⁇ C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOdc ⁇ -C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRlds ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3..
  • A is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R8d is -C _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci- ⁇ alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bd is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9d and RlOd each independently is -C ⁇ -6 a lkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein
  • Rid, R2d, a d R3d each independently is -C ⁇ -6alkyl, -C3_ 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(Co-6alkyl)(aryl) substituents;
  • R4d is -C ⁇ _6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 alkyl) (aryl) substituents;
  • Ad is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRldS ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5d, Rod, and R7d each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl), -O(aryl), -O(heteroaryl), -N(C 0 -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 alkyl) (aryl) substituents;
  • Bd is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(Q)- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3. 7 cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Ad is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRl d S ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5d, R6d, and R7d each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -
  • R8d is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(Q)_6a]kyl)(C3- 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Bd is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOdc ⁇ -C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRlds ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein
  • Ad is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlds ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5d, R6d, and R7d each independently is -C ⁇ -6alkyl, -C3..
  • R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents; ⁇ d is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NRl dc ⁇ -C ⁇ -2alkyl
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C 0 -6alkyl), -N(C ⁇ -6alkyl)(C 3 -7cycloalkyl), -N(C 0 - 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C 0 -6alkyl), -N(C 0 -6alkyl)(C3- 7cycloalkyl), -N(CQ-6alkyl)(aryl) substituents; Ad is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇
  • Bd is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NRlOdc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlds ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3-
  • R4d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(C ⁇ -6alkyl), -O(C3_
  • A is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl), -O(aryl), -O(heteroaryl), -N(C 0 -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C 3 - 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • B is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2 ⁇ C ⁇ -
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3.7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4d is -C ⁇ _6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • A is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlds ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5d R6d, and R7d each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8d s -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bd is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • the compounds of this invention are represented by Formula (ED) or a pharmaceutically acceptable salt thereof, wherein:
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C 3 _7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • A is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NR 1 s ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl ;
  • R5d, R6d, a nd R7d each independently is -C ⁇ -6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -
  • R8d is -C ⁇ _6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Bd is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NRlOdc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRldSO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
  • R4 is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6 a lkyl)(aryl) substituents;
  • R4 is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O
  • A is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRldSO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5d, R6d, and R7d each independently is -C ⁇ -6 lkyl, -C3-
  • R ⁇ d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(CQ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents; ⁇ d is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOdc ⁇ -C ⁇ -2
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • Rid, R2d, a nd R3d each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • A is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2al
  • R8 is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8 is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7 cycloalkyl), -O(aryl),
  • B is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2 ⁇ C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOdc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRldSO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3_
  • R4d is -Ci- ⁇ alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_
  • Ad is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R5d, R6d, and R7d each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8d is -Ci_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bd is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(Co-6alkyl)(aryl) substituents;
  • R4d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ad is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRldsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5d, R6d, and R7d each independently is -C ⁇ -6alkyl, -C3.
  • R8d is -Ci-galkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci- ⁇ alkyl, -O(C ⁇ -6alkyl), -O(C3_
  • B is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
  • R4d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Ad is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlds ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5d R6d, and R7d ea ch independently is -C ⁇ -6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • B d is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2 ⁇ C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOdc ⁇ -C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRldsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(Co ⁇ 6alkyl)(aryl) substituents;
  • R4 is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • a d is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRl d S ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3-.
  • R4d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • A is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRldsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5d, R6d, and R7d each independently is -C ⁇ -6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • B d is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOdc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRldsO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cyclo alkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6 alkyl) (aryl) substituents; and any N may be an N-oxide.
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
  • Ad is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRldSO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5d, R6d, a nd R7d eac h independently is -Co_6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -
  • R8d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Bd is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-N ldCO-C ⁇ -2alkyl-, -Co_ 2alkyl-NRldSO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
  • R4d is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci- ⁇ alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents; Ad is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R5d, R6d, and R7d each independently is -C ⁇ -6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • ⁇ d is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -Co_2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOdc ⁇
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7 cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
  • Rid, R2d, and R3d each independently is -C ⁇ -6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R4d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • A is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2
  • R8 is -Ci_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci- ⁇ alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C ⁇ -6alkyl)(aryl) substituents;
  • R8 is -Ci_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3- 7cycloalkyl), -O(aryl),
  • Bd is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOdc ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRldSO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • Rid, R2d, a nd R3d each independently is -C ⁇ -6alkyl, -C3.
  • R4d is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_
  • Ad is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C 0 -6alkyl), -N(C 0 -6alkyl)(C3- 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Bd is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
  • Rid, R2d, and R3d each independently is -C ⁇ -6 a lkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), - N(C0-6 a lkyl)(aryl) substituents;
  • R4d is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(Co-6alkyl)(C3_ 7cycloalkyl), -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ad is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9dc ⁇ -C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRldSO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5d, Rod, and R7d each independently is -C ⁇ -6alkyl, -C3-
  • R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_
  • ⁇ d is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9d and RlOd each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents; and any N may be an N-oxide.
  • a compound of this invention is represented by Formula (IE):
  • Xc and Y e each independently is aryl or heteroaryl wherein at least one of X e and Y e is a heteroaryl with N adjacent to the position of attachment to A e or B e respectively;
  • Rle, R2e, and R3e each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), or -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R4e is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), or -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ae is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9ec ⁇ -C ⁇ -2alkyl-, -C ⁇ -2alkyl- NR9esO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • R5e, R6e, and R7e each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) substituents;
  • R8e is -C ⁇ _6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), or -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Be is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9e and RlOe each independently is -C ⁇ -6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • the compound of this invention is represented by Formula (IE) or a pharmaceutically acceptable salt thereof, wherei
  • Ae is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9ec ⁇ -C ⁇ -2alkyl-, -C ⁇ -2alkyl- NR9es ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5e, R6e, and R7e each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • R8e is -Ci- ⁇ alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_
  • Be is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9e and RlOe each independently is -C ⁇ -6 lkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C 0 -6alkyl)(C3-7cycloalkyl), -N(C 0 - 6alkyl)(aryl) substituents; Rl le and Rl2e i s each independently halogen, -C ⁇ -6alkyl, -C ⁇ -
  • the compound of this invention is represented by Formula (IE) or a pharmaceutically acceptable salt thereof, wherein:
  • Ae is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9ec ⁇ -C ⁇ -2alkyl-, -C ⁇ -2alkyl- NR9es ⁇ 2-C ⁇ -2alkyl- or -heteroC ⁇ -4alkyl;
  • R5e, R6e, and R7e each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), or -N(C ⁇ - 6alkyl)(aryl) substituents;
  • R8e is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), or -N(C ⁇ -6 a lkyl)(aryl) substituents;
  • Be is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOec ⁇ -C ⁇ -2alkyl- -C ⁇ - 2alkyl-NRlOesO2-Co-2alkyl-, or -heteroC ⁇ -4alkyl;
  • R9e and RlOe each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3-7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • Ye is not 3-cyanophenyl.
  • the compound of this invention is represented by Formula (IE) or a pharmaceutically acceptable salt thereof, wherein: X e is 2-pyridyl optionally substituted with 1-4 independent halogen, -
  • Rle, R2e, a nd R3e each independently is -C ⁇ -6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • R4e is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6 a lkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), or -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ae is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl- -C ⁇ -2alkyl-NR9ec ⁇ -C ⁇ -2alkyl-, -C ⁇ -2alkyl- NR9esO2-Co-2alkyl- or -heteroC ⁇ -4alkyl;
  • Y e is pyridyl optionally substituted with 1-4 independent halogen, -
  • R5e, R6e, and R7e each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C 0 -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C 3 -7cycloalkyl), or-N(Q)- 6alkyl)(aryl) substituents;
  • R8e is -Ci- ⁇ alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), or -N(C ⁇ -6alkyl)(aryl) substituents;
  • Be is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOec ⁇ -C ⁇ -2al
  • R9e and RlOe each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • Rle, R2e, and R3e each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), or -N( )- 6alkyl)(aryl) substituents;
  • R4e is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), or -N(C ⁇ -6alkyl)(aryl) substituents;
  • Ae is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl- -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl-, -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NR9ec ⁇ -C ⁇ -2al
  • Be is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOec ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlOesO2-Co-2alkyl-, or -heteroC ⁇ -4alkyl;
  • R9e and RlOe each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), -N(C ⁇ - 6alkyl)(aryl) substituents;
  • Xe is not 3-cyanophenyl.
  • the compound of this invention is represented by
  • Rle, R2e, and R3e each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • R4e is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_
  • Ae is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R5e, R6e, a nd R7e each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), or -N(Q)- 6 a lkyl)(aryl) substituents;
  • R8e is -Ci- ⁇ alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6al yl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3- 7cycloalkyl), or -N(C ⁇ -6alkyl)(aryl) substituents;
  • Be is -C ⁇ -4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • R9e and RlOe each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
  • Rl le and Rl2e is each independently halogen, -C ⁇ -6alkyl, -C ⁇ -
  • the compound of this invention is represented by Formula (IE) or a pharmaceutically acceptable salt thereof, wherein
  • Rle, R2e, and R3e each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci- ⁇ alkyl, -O(C ⁇ -6al yl), -O(C3_7cycloalkyl), -O(aryl), -
  • R4e is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_
  • Ae is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ -
  • NR9eSO2-Co-2alkyl- or -heteroC ⁇ -4alkyl NR9eSO2-Co-2alkyl- or -heteroC ⁇ -4alkyl
  • Y e is 2-pyridyl optionally substituted with 1-4 independent halogen, -
  • R5e, R6e, and R7e each independently is -C ⁇ -6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_7cycloalkyl), or-N(Q)- 6alkyl)(aryl) substituents;
  • R8e is -C ⁇ _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), -N(C ⁇ -6alkyl)(C3_ 7cycloalkyl), or -N(C ⁇ -6alkyl)(aryl) substituents;
  • Be is -Co-4alkyl, -C ⁇ -2alkyl-SO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-S ⁇ 2-C ⁇ - 2alkyl- -C ⁇ -2alkyl-CO-C ⁇ -2alkyl-, -C ⁇ -2alkyl-NRlOec ⁇ -C ⁇ -2alkyl-, -C ⁇ - 2alkyl-NRlOesO2-Co-2alkyl-, or -heteroC ⁇ -4alkyl;
  • R9e and RlOe each independently is -C ⁇ -6 a lkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ⁇ _6alkyl, -O(C ⁇ -6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C ⁇ -6
  • a compound of this invention is represented by Formula (IF):
  • Yf is O, or N-R4f; one of Zl, Z2 , z3 or Z optionally is N, or NH; Rlf is -OH, halogen, or -CN; or a -Ci_6alkyl, -C ⁇ _4alkoxyl, - cycloC3_6alkyl, -C ⁇ -4alkyl-phenyl, -C ⁇ -4alkyl-pyridyl, -C ⁇ -4alkyl-imidazolyl, - C ⁇ -4alkyl-pyrazolyl, -C ⁇ -4alkyl-triazolyl, -C ⁇ -4alkyl-tetrazolyl, -CQ-4alkyl- dioxolanyl, -C ⁇ -4alkyl-thiazolyl, -C ⁇ -4alkyl-piperidinyl, -C ⁇ -4alkyl-pyrrolidinyl, - C ⁇ -4alkyl-morpholinyl,
  • R2f is hydrogen, halogen, -OH, -CN, -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), - NO2; or -Ci_6alkyl, -C ⁇ _4alkoxyl, -C ⁇ -4alkyl-phenyl, or-C ⁇ _4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, -CN, or -Ci-4alkoxyl substituents;
  • R3f is hydrogen or -Ci-4alkoxyl
  • R4f is -Co-4alkyl
  • R5f is H, halogen, or -C ⁇ _4alkyl.
  • the compound of this invention is represented by Formula (IE) or a pharmaceutically acceptable salt thereof, wherein
  • Zl, Z2 z3, and Z4 are each CH;
  • Xf is N
  • Yf is O
  • Rlf is -OH, halogen, or -CN; or a -C ⁇ _6alkyl, -Ci_4alkoxyl, - cycloC3-6alkyl, -C ⁇ -4alkyl-phenyl, -C ⁇ -4alkyl-pyridyl, -C ⁇ -4alkyl-imidazolyl, - C ⁇ -4alkyl-pyrazolyl, -C ⁇ -4alkyl-triazolyl, -C ⁇ -4alkyl-tetrazolyl, -C ⁇ -4alkyl- dioxolanyl, -C ⁇ -4alkyl-thiazolyl, -C ⁇ -4alkyl-piperidinyl, -C ⁇ -4alkyl-pyrrolidinyl, - C ⁇ -4alkyl-morpholinyl, -C ⁇ -4alkyl-pyrimidinyl, -C2-6 a lkynyl-thiazolyl, or -N(
  • R2f is hydrogen, halogen, -OH, -CN, -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), - NO2; or -Ci_6alkyl, -C ⁇ _4alkoxyl, -C ⁇ -4alkyl-phenyl, or -C ⁇ _4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, -CN, or -C ⁇ _4alkoxyl substituents; R3f is hydrogen or -Ci-4alkoxyl; R4f is -Co-4alkyl; and R5f is H, halogen, or -C ⁇ _4alkyl.
  • the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
  • Zl, Z2, Z3, and Z are each CH;
  • Xf is N; Yf is O;
  • Rlf is -Ci- ⁇ alkyl, optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci-6alkyl, -C ⁇ _ 4alkoxyl, -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), -C ⁇ -4alkyl-C(O)-O-C ⁇ -4alkyl, -C ⁇ -4alkyl- morpholinyl, or -C ⁇ -4alkyl-benzoxazolyl; R2f is hydrogen, halogen, -OH, -CN, -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), -
  • R5f is H, halogen, or-C ⁇ _4alkyl.
  • the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein: Zl, Z2, Z3, and Z4 are each CH;
  • Xf is N; Yf is O;
  • Rlf is -C ⁇ _6alkyl, optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci-6alkyl, -C ⁇ _ 4alkoxyl, -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), -C ⁇ -4alkyl-C(O)-O-C ⁇ -4alkyl, -C ⁇ -4alkyl- morpholinyl, or -C ⁇ -4alkyl-benzoxazolyl;
  • R2f is -C ⁇ -4alkyl-phenyl optionally substituted with 1-3 independently halogen, -OH, -CN, or -C ⁇ _4alkoxyl substituents;
  • R3f is hydrogen or -Ci-4alkoxyl;
  • R4f is -Co-4alkyl;
  • R5f is H, halogen, or -Ci-4alkyl.
  • the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein: Zl, Z2, Z3, and Z4 are each CH; Xf is N;
  • Yf is O
  • Rlf is -Ci-galkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C ⁇ _6alkyl, -C ⁇ _4alkoxyl, - N(Co-4alkyl)(Co-4alkyl), -C ⁇ -4alkyl-C(O)-O-C ⁇ -4alkyl, -C ⁇ -4alkyl-morpholinyl, or -C ⁇ -4alkyl-benzoxazolyl;
  • R2f is hydrogen; or-Ci-6alkyl optionally substituted with 1-3 independently halogen, -OH, -CN, or-Ci_4alkoxyl substituents;
  • R3f is hydrogen or -C ⁇ _4alkoxyl; R4f is -Co-4alkyl; and
  • R5f is H, halogen, or -Ci-4alkyl.
  • the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein: Zl , Z2, Z3, and Z are each CH;
  • Xf is N
  • Yf is O
  • Rlf is -C ⁇ _6alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci- ⁇ alkyl, -Ci-4-dkoxyl, - N(Co-4alkyl)(Co-4alkyl), -C ⁇ -4alkyl-C(O)-O-C ⁇ -4alkyl, -C ⁇ -4alkyl-morpholinyl, or -C ⁇ -4alkyl-benzoxazolyl;
  • R2f is or -NO2; or -N(C ⁇ -4alkyl)(C ⁇ -4alkyl) optionally substituted with 1-3 independently halogen, -OH, -CN, or-C ⁇ _4alkoxyl substituents;
  • R3f is hydrogen or -C ⁇ _4alkoxyl; R4f is -Co-4alkyl; and
  • R5f is H, halogen, or -Ci_4alkyl.
  • the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein: Zl, Z2, z3, and Z4 are each CH;
  • Xf is N
  • Yf is O
  • Rlf is -C _6alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C ⁇ _6alkyl, -Ci-4alkoxyl, - N(Co-4alkyl)(Co-4alkyl), -Co-4alkyl-C(O)-O-Co-4alkyl, -Co-4alkyl-morpholinyl, or -C ⁇ -4alkyl-benzoxazolyl;
  • R2f is -C ⁇ _4alkoxy-phenyl optionally substituted with 1-3 independently halogen, -OH, -CN, or -Ci-4alkoxyl substituents; R f is hydrogen or -C ⁇ _4alkoxyl;
  • R4f is -Co-4alkyl
  • R5f is H, halogen, or-C ⁇ _4alkyl.
  • the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
  • Zl, Z2, Z3, and Z4 are each CH;
  • Xf is N
  • Yf is O
  • Rlf is -C ⁇ _6alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci-6alkyl, -C ⁇ _4alkoxyl, - N(Co-4alkyl)(Co-4alkyl), -Co-4alkyl-C(O)-O-Co-4alkyl, -Co-4alkyl-morpholinyl, or -C ⁇ -4alkyl-benzoxazolyl;
  • R2f is -C ⁇ _4alkoxyl optionally substituted with 1-3 independently halogen, -OH, -CN, or -C ⁇ _4alkoxyl substituents;
  • R3f is hydrogen or -C ⁇ _4alkoxyl ;
  • R4f is -Co-4alkyl
  • R5f is H, halogen, or -C ⁇ _4alkyl.
  • the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
  • Zl, Z2, Z3, and Z4 are each CH;
  • Xf is N
  • Yf is O
  • Rlf is -cycloC3_6alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci_6alkyl, -Ci- 4alkoxyl, -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), -C ⁇ -4alkyl-C(O)-O-C ⁇ -4alkyl, -C ⁇ -4alkyl- morpholinyl, or -C ⁇ -4alkyl-benzoxazolyl;
  • R2f is halogen, -OH, -CN, -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), -NO2; or -C ⁇ _ 6alkyl, -Ci_4alkoxyl, -CQ-4alkyl-phenyl, or -C ⁇ _4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or-C ⁇ _4alkoxyl substituents;
  • R3f is hydrogen or-C ⁇ _4alkoxyl
  • R4f is -Co-4alkyl
  • R5f is H, halogen, or -Ci-4alkyl.
  • the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
  • Zl, Z2, Z3, and Z4 are each CH; Xf is N;
  • Yf is O
  • Rlf is -C ⁇ -4alkyl-triazolyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci- 6alkyl, -C ⁇ _4alkoxyl, -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), -C ⁇ -4alkyl-C(O)-O-C ⁇ -4alkyl, - C ⁇ -4alkyl-morpholinyl, or -C ⁇ -4alkyl-benzoxazolyl;
  • R2f is halogen, -OH, -CN, -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), -NO2; or -Cl- 6alkyl, -C ⁇ _4alkoxyl, -C ⁇ -4alkyl-phenyl, or -C ⁇ _4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or -C ⁇ _4alkoxyl substituents; R3f is hydrogen or -C ⁇ _4alkoxyl;
  • R4f is -Co-4alkyl
  • R5f is H, halogen, or -C ⁇ _4alkyl.
  • the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
  • Zl, Z2, Z3, and Z4 are each CH;
  • Xf is N
  • Yf is O
  • Rlf is -C ⁇ -4alkyl-imidazolyl or -C ⁇ -4alkyl-pyrazolyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, - OH, -CN, -Ci-6alkyl, -Ci-4alkoxyl, -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), -C ⁇ -4alkyl-C(O)- O-C ⁇ -4alkyl, -C ⁇ -4alkyl-morpholinyl, or -C ⁇ -4alkyl-benzoxazolyl;
  • R2f is halogen, -OH, -CN, -N(C ⁇ -4alkyl)(C ⁇ -4alkyl), -NO2; or -C ⁇ _ 6alkyl, -Ci_4alkoxyl, -CQ-4alkyl-phenyl, or -C ⁇ _4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or-Ci_4alkoxyl substituents;
  • R3f is hydrogen or-Ci-4alkoxyl
  • R4f is -C ⁇ -4alkyl
  • R5 is H, halogen, or -C l -4alkyl.
  • the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
  • Zl, Z2, Z3, and Z are each CH; Xf is N;
  • Yf is O

Abstract

Modulators of metabotropic glutamate receptor-5 (mGluR5) are useful in treating disorders associated with excessive food intake, including obesity and obesity-related disorders. In particular, mGluR5 antagonists of structural formulae IA-IF are useful in treating these conditions, either as single agents or in combination with other compounds useful for treating obesity.

Description

TITLE OF THE INVENTION
TREATMENT OF OBESITY AND OTHER DISORDERS ASSOCIATED WITH
EXCESSIVE FOOD INTAKE
CROSS-REFERENCE TO RELATED APPLICATIONS Not applicable.
BACKGROUND OF THE INVENTION
A major excitatory neurotransmitter in the mammalian nervous system is the glutamate molecule, which binds to neurons, thereby activating cell surface receptors. Such surface receptors are characterized as either ionotropic or metabotropic glutamate receptors. The metabotropic glutamate receptors ("mGluR") are G protein-coupled receptors that activate intracellular second messenger systems when bound to glutamate. Activation of mGluR results in a variety of cellular responses. In particular, mGluRl and mGluR5 activate phospholipase C, which is followed by mobilizing intracellular calcium.
PCT Publication 99/02497 discloses pyridine derivatives useful as mGluR5 mediators. PCT publication WO 02/062323 discloses mGluR5 antagonists as useful for treating pruritic conditions. PCT Publication WO 01/16121 discloses particular heterocyclic compounds as modulators of the metabotropic glutamate receptors useful in treating cerebral ischemia, chronic neurodegeneration, psychiatric disorders, schizophrenia, mood disorders, emotion disorders, disorders of extrapyramidal motor function, obesity, disorders of respiration, motor control and function, attention deficit disorders, concentration disorders, pain disorders, neurodegenerative disorders, epilepsy, convulsive disorders, eating disordes, sleep disorders, sexual disorders, circadian disorders, drug withdrawal, drug addiction, compulsive disorders, anxiety, panic disorders, depressive disorders, skin disorders, retinal ischemia, retnial degeneration, glaucoma, disorders associated with organ transplantation, asthma, ischemia, astrocytomas, and the like. Modulators of the mGluR5 receptor are useful in the treatment, prevention and suppression of obesity and obesity related conditions. In particular, antagonists and/or inverse agonists of the mGluR5 receptor are useful in the treatment, prevention and suppression of obesity and obesity related conditions. The compounds are also useful for the treatment of eating disorders by inhibiting excessive food intake and the resulting obesity and complications associated therewith.
SUMMARY OF THE INVENTION The present invention is concerned with metabotropic glutamate receptor-5 modulators useful in treating, preventing and suppresing obesity and obesity-related conditions, hi particular, antagonists and/or inverse agonists of the mGluR5 receptor are useful in the treatment, prevention and suppression of obesity and obesity related conditions, as well as treating eating disorders by inhibition of excessive food intake and the resulting obesity and complications associated therewith. In particular, the mGluR5 antagonists of the general Formula IA :
Figure imgf000003_0001
(IA);
general formula IB:
Figure imgf000003_0002
(IB): general formula IC:
Figure imgf000003_0003
(IC); general formula ID:
Figure imgf000004_0001
(ID); general formula IE:
Figure imgf000004_0002
general formula IF:
Figure imgf000004_0003
(IF)
or pharmaceutically acceptable salts thereof, are useful in the methods and compositions of the present invention.
The invention is also concerned with pharmaceutical formulations comprising an mGluR5 antagonist as defined above together with another agent useful for treating obesity or obesity-related conditions.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is concerned with metabotropic glutamate receptor-5 modulators useful in treating, preventing and suppresing obesity and obesity-related conditions. In particular, antagonists and/or inverse agonists of the mGluR5 receptor are useful in the treatment, prevention and suppression of obesity and obesity related conditions, as well as treating eating disorders by inhibition of excessive food intake and the resulting obesity and complications associated therewith. In particular, the mGluR5 antagonists of the general Formula IA :
Figure imgf000005_0001
(IA);
general formula IB:
Figure imgf000005_0002
(IB): general formula IC:
Figure imgf000005_0003
(IC); general formula ID:
Figure imgf000006_0001
(ID); general formula IE:
Figure imgf000006_0002
general formula IF:
Figure imgf000006_0003
(IF)
or pharmaceutically acceptable salts thereof, are useful in the methods and compositions of the present invention.
The present invention is concerned with novel substituted amides of the general Formula IA :
Figure imgf000006_0004
(IA) or a pharmaceutically acceptable salt thereof, wherein
Xa and Ya each independently is aryl or heteroaryl wherein at least one of X and Ya is a heteroaryl with N adjacent to the position of attachment to Aa or Ba respectively; Xa is optionally substituted with 1-7 independent halogen, -CN, NO2,
-Ci_6alkyl, -Cl-6alkenyl, -Cι_6alkynyl, -ORl, -NRlR2, -C(=NR1)NR2R3, _ N(=NR1)NR2R3, -NR1COR2, -NRlCθ2R2, -NRlS02R4, -NR1CONR2R3 _SR4, -SOR4, -SO2R4, -SO2NR1R2, -CORl, -CO2Rl, -CONR1R2, -C(=NR1)R2 0r -
C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups; Rl, R2, and R3 each independently is -Cø-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - OGieteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; R4 is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C()-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Aa is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9cθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9sO2-Co-2alkyl- or -heteroCθ-4alkyl;
Ya is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cl _6alkenyl, -Cι.6alkynyl, -OR5, -NR5R6, -C(=NR5)NR6R7, -N(=NR5)NR6R7, _NR5COR6, -N 5CO2R6, -NR5SO2RS, -NR5C0NR6R7 -BRS, -SOR8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, -CONR5R6, -C(=NR5)R6, or -
C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(C()-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5, R6, and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R8 is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ba is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOCO-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; R9 and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl -6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; Rl 1, Rl2 and Rl3 is each independently halogen, -C()-6alkyl, -Cθ- βalkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of
Rl 1, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In one aspect, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein
X is 2-pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NRlR2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, -NRlCOR2, -NRlCO2R2, -NRISO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2N lR2, -COR!, -CO2RI, - CONR1R2, -C(=NR1)R2, or -C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rl, R2, and R3 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C()-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C()-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
A is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9cθ-Cθ-2alkyl- -C()-2alkyl- NR9sθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Ya is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci _6alkyl, -Cl -δalkenyl, -Ci-6alkynyl, -OR5, -NR5R6, -C(=NR5)NR6R7, -N(=NR5)NR6R7, -N 5COR6, -NR5C02R6, -NR5S02R8, - NR5CONR6R7 -SR8, -SOR8, -SO2R8, -SO2N 5R6, -COR5, -CO2R5, - CONR5R6, -C(=NR5)R6, or -C(=N0R5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5, R ; and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl _6alkyl, -O(CQ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R8 is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cø-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
B is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -C()-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-N lOCO-Cθ-2alkyl- -Cθ- 2alkyl-NRlOSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; R and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; Rl 1, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ-
6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of
RU, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryι) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In an embodiment of this one aspect, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein
Xa is 2-pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Ci-6alkynyl, -ORl, -NRlR2, - C(=NR1)NR2R3, -N(=NRl)NR2R3; -NR1C0R2 -N lCθ2R , -NRlSO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, - CONR1R2, -C(=NRl)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rl, R2, and R3 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι _6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cl _6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Aa is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2~Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9CO-Cθ-2alkyl- -C()-2alkyl- NR9SO2-Co-2alkyl- or -heteroCθ-4alkyl;
Ya is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5, -NR5R6, -C(=NR5)NR6R7, -N(=NR5)NR6R7, -NR5COR6, -NR5CO2R6, - R5sθ2R8, - NR5C0NR6R7 -SR8, -SOR8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, - CONR5R6, -C(=NR5)R6, or -C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cχ_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5, R65 and R^eeach independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(C()-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R8 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cχ-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(CQ-6 alkyl) (aryl) substituents; Ba is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOCO-Cθ-2alkyl- -Cθ- 2alkyl-NRlOSO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rll, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of
Rl 1, Rl2 and Rl are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(C()-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens. In a second aspect, the compound of this invention is represented by
Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
Xa is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci _6alkyl, -Ci_6alkenyl, -Cι_6alkynyl, -ORl, -NRlR2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, -NR1C0R2, -NRlCθ2R2, -NRlSO2R , - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, -
CONR1R2, -C(=NRl)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rl, R2, and R3 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(C()-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6al yl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Co_ 6alkyl)(aryl) substituents;
R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
A is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9CO-Cθ-2alkyl-, -Cθ-2alkyl- NR9SO2-Co-2alkyl- or -heteroCθ-4alkyl; Ya is 2-pyridyl optionally substituted with 1-4 independent halogen, -
CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5, -NR5R6, -C(=NR5)NR6R7, -N(=NR5)NR6R7, -NR5C0R6, -NR5cθ2R6, -NR5sθ2R8, - NR5C0NR6R7 -SR8, -SOR8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, - CONR5R6; -C(=NR5)R6; or -C(=N0R5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5, R6? and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl _6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; R8 is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
B is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOCO-Cθ-2alkyl- -Cθ- 2alkyl-NRlOSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι _6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rll, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of Rl 1, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Co-6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In an embodiment of this second aspect, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
Xa is pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Cl _6alkyl, -Ci -6alkenyl, -Ci-6alkynyl, -ORl, -NR1R2, - C(=NR1)NR2R3, -N(=NRl)NR2R3, -NR1C0R2, -NR1CO2R2, -NRlSO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -SO2N 1R2, -CORl, -CO2RI, -
CONR1R2, -C(=NR1)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rl, R2, and R3 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R4 is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cl-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
A is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9cθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9sO2-Co-2alkyl- or -heteroCθ-4alkyl;
Ya is 2-pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Cι_6alkyl, -Ci -6alkenyl, -Cι_6alkynyl, -OR5, -NR5R6, -C(=NR5)NR6R7, -N(=NR5)NR6R7, -NR5COR6, -NR5C02R6, -NR5SO2R8, - NR5C0NR6R7 _SR8, -SDR8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, - CONR5R6, -C(=NR5)R6; 0r -C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5, R6, and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl _6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R8 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6 lkyl)(aryl) substituents; Ba is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOCO-Cθ-2alkyl-, -Cθ- 2alkyl-NRl°SO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(C()-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(C()-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rl 1, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of Rll, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens. In a third aspect, the compound of this invention is represented by
Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
Xa is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Ci_6alkyl, -Ci-6alkenyl, -Ci_6alkynyl, -ORl, -NRlR2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, _NR1C0R2, -N lCθ2R2, -NRlSO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, -
CONR1R2, -C(=NR1)R2, or-C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rl, R2, and R3 each independently is -C()-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ-
6alkyl)(aryl) substituents;
R4 is -Cχ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Aa is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR.9cθ-Cθ-2alkyl- -C<3-2alkyl-
NR9S02-CQ-2alkyl- or -heteroC()-4alkyl; Ya is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci -6alkyl, -Cι _6alkenyl, -Cι_6alkynyl, -OR5, -NR5R6,
-C(=NR5)NR6R7, -N(=NR5)NR6R7, -NR5COR6, -NR5CO2R6, -NR5SO2R8, - NR5CONR6R7 -SR8, -SOR8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, - CONR5R6, -C(=NR5)R6, or -C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5, R6, and R7 each independently is -C()-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Ba is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOCO-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOSO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rll, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of Rl 1, R 2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(C()-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In an embodiment of this third aspect, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
X is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Ci -6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -ORl, -NR1R2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, -NR1C0R2, -N lCθ2R2, -NRlSθ2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -SO2NR1R2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rl, R2, and R each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(C()-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ-
6alkyl)(aryl) substituents;
R4 is -Ci-βalkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Aa is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -C()-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9CO-Cθ-2alkyl-, -Cθ-2alkyl-
NR9sO2-Co-2alkyl- or -heteroC()-4alkyl; Ya is 2-pyridyl optionally substituted with 1-4 independent halogen, -
CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5, -NR5R6,
Figure imgf000018_0001
-NR5S02R8, - NR5CONR6R7 -BRS, -SOR8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, - CONR5R6, -C(=NR5)R6, or -C(=N0R5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- όalkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5, R6, and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-όalkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C -7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R8 is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; B is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOCO-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rll, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cø- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of Rl 1, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C()-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens. In a fourth aspect, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
Xa is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι _6alkenyl, -Cι_6alkynyl, -ORl, -NR1R2, - C(=NR1)NR2R3, -N(=NRl)NR2R3, -NR1C0R2, -NRlCθ2R2, -NR1S02R4, - NR1CONR2R3 _SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, or-C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rl, R2, and R3 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci -6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ-
6alkyl)(aryl) substituents;
R4 is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
A is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9cθ-Cθ-2alkyl-, -Cθ-2alkyl-
NR9sO2-Co-2alkyl- or -heteroCθ-4alkyl; Ya is l,3-thiazol-2-yl optionally substituted with 1-2 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι.6alkenyl, -Cι_6alkynyl, -OR5, -NR5R6, -C(=NR5)NR6R7, -N(=NR5)NR6R7, -NR5COR6, -NR5C02R6, -NR5SO2R8, - NR5CONR6R7 -SR8, -SOR8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, - CONR5R6, -C(=NR5)R6, or -C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5, R6, and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R8 is -Ci.βalkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Ba is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOCO-Cθ-2alkyl- -Cθ- 2alkyl-NRlOSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(C0-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(C0- 6alkyl)(aryl) substituents;
Rll, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of Rl 1, Rl and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In an embodiment of this fourth aspect, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein
Xa is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Cι_6alkyl, -Cl -όalkenyl, -Ci-6alkynyl, -ORl, -NRlR2, - C(=NR1)NR2R3, -N(=NRl)NR2R3, - R1C0R2, -N- CO2R2, -NRlSO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -S02N 1R2, -CORl, -CO2R1, - CONR1R2, -C(=NR1)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rl, R2, and R3 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ-
6alkyl)(aryl) substituents;
R4 is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Aa is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9cθ-Cθ-2alkyl-, -Cθ-2alkyl-
NR9sO2-Co-2alkyl- or -heteroCθ-4alkyl;
Ya is l,3-thiazol-2-yl optionally substituted with 1-2 independent halogen, -CN, NO2, -Cι _6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5, -NR5R6; -C(=NR5)NR6R7, -N(=NR5)NR6R7, -NR5COR6, -NR5C02R6, -NR5sθ2R8, - NR5C0NR6R7 -SR8, -S0R8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, - CONR5R6, -C(=NR5)R6, or -C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5, R6; and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; R8 is -Ci-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; B is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOCO-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rll, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of RU, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aι-yl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In a fifth aspect, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
Xa is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci _6alkyl, -Cι_6alkenyl, -Ci -6alkynyl, -ORl, -NR1R2, - C(=NRl)NR2R3, -N(=NR1)NR2R3, -NR1C0R2, -NRlCθ2R2, -NRlSO2R4, - NR1CONR2R3 _SR4; -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, or -C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rl, R2, and R3 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Aa is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9cθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9sθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; Y is pyrazolyl optionally substituted with 1-3 independent halogen, -
CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5, -NR5R6, -C(=NR5)NR6R7, -N(=NR5)NR6R7, -NR5COR6, -NR5CO2R6, -NR5S02R8, - NR5CONR6R7 -SR8, -SOR8, -SO2R8, -SO2 5R6, -COR5, -CO2R5, - CONR5R65 -C(=NR5)R6, or -C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5, R6; and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; R8 is -Cl-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Ba is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOCO-Cθ-2alkyl- -Cθ- 2alkyl-NRl°SO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rll, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of
Rll, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens. In an embodiment of this fifth aspect, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
Xa is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Cι_6alkyl, -Cι _6alkenyl, -Cι_6alkynyl, -ORl, -NR1R2, - C(=NR1)NR2R3, -N(=NRl)NR2R3, _NR1C0R2, -NR1C02R2, -NRlSO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, -
CONR1R2, -C(=NR1)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cι_6 lkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rl, R2, and R3 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl -6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Aa is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9CO-Cθ-2alkyl-, -Cθ-2alkyl- NR9sO2-Co-2alkyl- or -heteroCθ-4alkyl; Ya is pyrazolyl optionally substituted with 1-2 independent halogen, -
CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Ci_6alkynyl, -OR5, -NR5R6, -C(=NR5)NR6R7, -N(=NR5)NR6R7, -NR5COR6, -NR5C02R6, -NR5sθ2R8, - NR5CONR6R7 -SR8, -SOR8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, - CONR5R6, -C(=NR5)R6, Qr -C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5, R6, and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N( )- 6alkyl)(aryl) substituents; R8 is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ba is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOCO-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rll, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of Rl 1, Rl2 and Rl are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Cχ_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aι-yl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
Thus, the compound of this invention is represented by Formula (I ) or a pharmaceutically acceptable salt thereof, wherein
Xa is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Ci_6alkyl, -Ci-6alkenyl, -Ci-6alkynyl, -ORl, -NR1R2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, -NRlCOR2, -NRlCO2R2, -NRlSO2R4, - NR1CONR2R3 _SR4, -SOR4, -SO2R , -Sθ2NRlR2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, or -C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups.
Further, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
Xa is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cl _6alkyl, -Ci_6alkenyl, -Ci_6alkynyl, -ORl, - R1R2, - C(=NRl)NR2R3, -N(=NR1)NR2R3, -NR1C0R2, -N lCθ2 2, -N lS02R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -SO2N IR2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, or -C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and
Ya is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NR1R2, -
C(=NR1)NR2R3, -N(=NR1)NR2R3, -NR1C0R2, -NRlCθ2R2, -NRlSO2R , - NR1CONR2R3 _SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups.
Still further, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
Xa is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cl_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NR1R2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, -NR1C0R2, -NRlCθ2R2, -NRlSθ2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2NRlR , -CORl, -CO2RI, - CONR1R2, -C(=NRl)R2, or -C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and
Ya is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NR1R2, -
C(=NR1)NR2R3, -N(=NRl)NR2R3, _NR1C0R2, -NR1C02R2, -NR1S02R4, - NR1CONR2R3 _SR4, -SOR4, -SO2R4, -SO2NRlR2, -CORl, -CO2Rl, -CONR1R2, -C(=NR1)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cι_ βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups.
Even further, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein: Xa is pyridyl optionally substituted with 1-4 independent halogen, -
CN, NO2, -Ci-6alkyl, -Ci-6alkenyl, -Ci_6alkynyl, -ORl, -NR1R2 _ C(=NRl)NR2R3, -N(=NR1)NR2R3, -NR1C0R2, -NR1C02R2, -NR1S02R , - NR1CONR2R3 _SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and Ya is 2-pyridyl optionally substituted with 1-4 independent halogen,
-CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORl, -NRlR2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, -NRlCOR2, -N lCO2R2, -N lSO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, - CONR1R2, -C(=NRl)R2, or -C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups. Still further, the compound of this invention is represented by Formula
(IA) or a pharmaceutically acceptable salt thereof, wherein:
Xa is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NR1R2, - C(=NR1)NR2R3, -N(=NRl)NR2R3, -NR1C0R2, -NRlCO2R2, -NRlSO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, -
CONR1R2, -C(=NR1)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- βalkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups.
Even further, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein: Xa is phenyl optionally substituted with 1-5 independent halogen, -
CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NR1R2, - C(=NR1)NR2R3, -N(=NRl)NR2R3, -NR1C0R2 -NRlCO2R2, -NRlSO2R4, - NR1CONR2R3 _SR4, -SOR4, -SO2 4, -SO2NR1R2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, 0r -C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and Ya is 2-pyridyl optionally substituted with 1-4 independent halogen,
-CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORl, -NR1R2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, -NRlCOR2, -NRlCθ2R2, -NRlSθ2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2N lR2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, 0r -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3.7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups. And, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
Ya is l,3-thiazol-2-yl optionally substituted with 1-2 independent halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NR1R2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, _NR1C0R2, -NRlCO2R2, - lSO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -SO2NRlR2, -CORl, -CO2RI, -
CONR1R2, -C(=NR1)R2, or -C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups.
Further, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein Ya is l,3-thiazol-2-yl optionally substituted with 1-2 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NRlR2, - C(=NR1)NR2R3J -N(=NR1)NR2R3, -NR1C0R2, -NRlCO2R2, -NRlSO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and Xa is phenyl optionally substituted with 1-5 independent halogen, -
CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Ci-6alkynyl, -ORl, -NRlR2, - C(=NR1)NR2R3, -N(=NRl)NR2R3, -NRlCOR2, -NRlCθ2R2, -NRlSO2R4, - NR1CONR2R3 _SR4, -SOR4, -SO2R , -SO2N 1R2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -C _6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups. And, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein:
Ya is pyrazolyl optionally substituted with 1-3 independent halogen, - CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NRlR2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, -N 1C0R2, -N lCθ2R2, -NRlSO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, -
CONRlR2, -C(=NR1)R2, or -C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups.
Further, the compound of this invention is represented by Formula (IA) or a pharmaceutically acceptable salt thereof, wherein: Ya is pyrazolyl optionally substituted with 1-3 independent halogen, -
CN, NO2, -Ci_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORl, -NR1R2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, _NR1C0R2, -NRlCO2R2, -NRlSO2R4, - NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, or -C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and Xa is phenyl optionally substituted with 1-5 independent halogen, -
CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Ci_6alkynyl, -ORl, -NRlR2, - C(=NR1)NR2R3, -N(=NR1)NR2R3, -NR1C0R2, -NRlCO2R2, -NRlSO2R4, - NR1CONR2R3 _SR4, -SOR4, -SO2R4, -SO2NR1R2, -CORl, -CO2RI, - CONR1R2, -C(=NR1)R2, or -C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups. A compound of this invention is represented by Formula (IB):
Figure imgf000032_0001
(IB) or a pharmaceutically acceptable salt thereof, wherein Xb and Yb each independently is aryl or heteroaryl wherein at least one of XD and Yb is a heteroaryl with N adjacent to the position of attachment to Ab or βb respectively;
Xb is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORlb, -NRlbR2b -C(=NRlb)NR2bR3b -N(=NRlb)NR2bR3b -NRlbCOR2b -NRlbcθ2R2b -NRlbSO2R4b, - NRlbC0NR2bR3b _SR4b, -SOR4b -SO2R4b, -SO2NRlbR2b -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2bj or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b5 and R3b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Ci-6alkynyl, -OR5b -NR5bR6b -C(=NR5b)NR6bR7b -N(=NR5b)NR6bR7b, -NR5bcOR6b -NR5bCO2R6b, -NR5bsθ2R8b, - NR5bcONR6bR7b _SR8b, -SORδb _S02R8b, -SO2N 5bR6b -COR5b -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, 0r -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b; R6b, and R7b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b;
Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Q)- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b = H and Ab = βb = Coalkyl, then Yb is not 4-methoxyphenyl or 2,5- dimethoxyphenyl.
In one aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is 2-pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Ci_6alkyl, -Ci_6alkenyl, -Ci_6alkynyl, -ORlb, -NRlb R2b _ C(=NRlb)NR2bR3b -N(=NRlb)N 2bR3b -NRlbCOR2b -NRlbCO2R2b, -NRlbSO2R4b, -NRlbCONR2bR3b _SR4b -SOR4b -SO2R4b -SO2NRlbR2b -CORlb, -CO2Rlb, -CONRlbR2b -C(=NRlb)R2b 0r -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b; and R3b each independently is -Cθ-6alkyl, -C3-.
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R4b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ-
2alkyl-NR9bsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Ci_6alkynyl, -OR5b -NR5bR6b -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b, -N 5bC0R b, -NR5bCO2R6b, -NR5bsθ2R8b, -NR5bC0NR6bR7b _SR8b, -SORδb, -SO2R8b, -SO2NR5bR6b -COR5b, -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b, R6b and R7b each independently is -Cθ-6alkyl, -C3_ 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3. 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rl lb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rl lb = Rl2b = H and Ab = βb = C0alkyl, then Y is not 4-methoxyphenyl or 2,5- dimethoxyphenyl. hi an embodiment of this one aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein
Xb is 2-pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -ORlb, -NRlbR2b _ C(=NRlb)NR2bR3b -N(=NRlb)NR2bR3b, -NRlbCOR2b -NRlbcθ2R2b, -NRlbSO2R4b, -NRlbCONR2R3b _SR4b -SOR4b -SO2R4, -SO2NRlbR2b -CORlb, -CO2Rlb, -CONRlbR2b -C(=NRlb)R2b or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
Rib, R2b; and R3b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b s -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9SO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -OR5b -NR5bR6b -C(=NR5b)NR6bR7b; -N(=NR5b)NR6bR7b -NRb5bcOR6b -N 5bcθ2R6b, -N 5bSO2R8b, -NR5bC0NR6bR7b _SR8b -SOR8b; -SO2R8b, -SO2NR5R6, -COR5, -CO2R5, -CONR5R6, -C(=NR5)R6, 0r -C(=N0R5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Co_6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Co_6alkyl)(Co_6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ- 6alkyl)(aryl) groups;
R5b R6b, and R7b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C0-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOCO-Cθ-2alkyl- -Cθ- 2alkyl-NRlOSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(C0- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rl lb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ-
6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rl lband Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N( )- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb= 2-pyridyl, Alb = N, A2b = CH, Rll = Rl2 = H and Ab = βb = C0alkyl, then Yb is not 4-methoxyphenyl or 2,5- dimethoxyphenyl.
In a second aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Ci_6alkynyl, -ORlb, -NRlbR2b _ C(=NRlb)NR2bR3b -N(=NRlb)NR2bR3b -NRlbcOR2b - RlbCO2R2b,
-NRlbSO2R4b, -NRlbCONR2bR3b -SR4b -SOR4b -SO2R4b, -SO2N lbR2b -CORlb, -CO2Rlb, -CONRlbR2b -C(=NRlb)R2b or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9cθ-Cθ-2alkyl- -Cθ-2alkyl- NR9sO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5b -NR5bR6b -C(=NR5b)NR6bR7b; -N(=NR5b)NR6bR7b _NR5bCOR6b, -NR5bcθ2R6b, -NR5bS02R8b, -NR5bC0NR6bR7b -SR8b -SOR8b, -SO2R8b, -SO2NR5bR6b, -COR5b -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, 0r -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b R6b and R7b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rl lb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- βalkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Q)- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =0, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b = H and Ab = βb = C0alkyl, then Yb is not 4-methoxyphenyl or 2,5- dimethoxyphenyl.
In a third aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein
Xb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cl-6alkenyl, -Ci_6alkynyl, -ORlb, -NRlbR2b _ C(=NRlb)NR2bR3b -N(=NRlb)NR2bR3b -NRlbcOR2b -NRlbCO2R2b,
-NRlbSO2R4b, -NRlbCONR2bR3b _SR4b -SOR4b -SO2R b, -SO2NRlbR2b -CORlb, -CO2Rlb -CONRlbR2b, -C(=NRlb)R2b or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
Rib, R2b and R3b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is 2-pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Ci_6alkynyl, -OR5b, -NR5bR6b -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b, _N 5bcOR6b, -NR5bcθ2R6b, -NR5bsθ2R8b, -NR5bcONR6bR7b _SR8b, -SORδb, -SO2R8b, -SO2NR5bR6b -COR5b, -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b 0r -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -C _6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3-7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rl l and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ-
6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b = H and Ab = βb = C0alkyl, then Y is not 4-methoxyρhenyl or 2,5- dimethoxyphenyl.
In an embodiment of the third aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -ORlb _NRlbR2b _ C(=NRlb)NR2bR3b -N(=NRlb)NR2bR3b -NRlbCOR2b, -NRlbCO2R2b,
-NRlbSO2R4b, -NRlbCONR2bR3b _SR4b _SOR4b -SO2R4b, -SO2NRlbR2b -CORlb, -CO2Rlb, -CONRlbR2b -C(=NRlb)R2b or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3.7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b; and R3b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yb is 2-pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5b -NR5bR6b -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b -NR5bCOR6b; -N 5bC02R6b, -NR5bSO2R8b, -NR5bcONR6bR7b _sR8b, -SOR8b, -SO2R8b, -SO2N 5bR6b, -COR5b -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, 0r -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
R5b, R6b and R7b each independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9b nd RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3.7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rl lb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ-
6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Q)- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b eacn independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b = H and Ab = Bb = Coalkyl, then Yb is not 4-methoxyρhenyl or 2,5- dimethoxyphenyl.
In a fourth aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein
Xb is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORlb -NRlbR2b, _ C(=NRl)NR2bR3b -N(=NRlb)NR2bR3b, -NRlbCOR2b, -NRlbcθ2R2b,
-NRlbSθ2R4b, -NRlbCONR2bR3b ,-SR4b, _SOR4b, _SO2R b, -SO2NRlbR2b -CORlb, -CO2Rlb, -CONRlbR2b -C(=NRlb)R2b, or-C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -Ci_6alkenyl, -Cl-6alkynyl, -OR5b, -NR5bR6b, -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b -N 5bcOR6b, -NR5bCO2R6b, -NR5bsθ2R8b, -NR5bcONR6bR7b,_SR8b, -SORδb, -SO2R8b, -SO2NR5bR6b -COR5b, -CO2R5 , -CONR5bR6b, -C(=NR5b)R6b, or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b R6b, and R7b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βb is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rl lb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- βalkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ- 6~alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b = H and Ab = βb = Coalkyl, then Yb is not 4-methoxyphenyl or 2,5- dimethoxyphenyl.
In an embodiment of this fourth aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Ci_6alkynyl, -ORlb, -NRlbR2b _ C(=NRlb)NR2bR3b -N(=NRlb)NR2bR3b -NRlbCOR2b, -NRlbC02R2b,
-NRlbSO2R4b, -NRlbCONR2bR3b _SR4b, -SOR4b, -SO2R4b, -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is 2-pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5b -NR5bR6b, -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b, -NR5bCOR6b, -NR5bcθ2R6b, -NR5bS02R8b, -NR5bC0NR6bR7b _SR8b -SOR8b, -SO2R8b, -SO2NR5bR6b, -COR5b, -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C0-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rl lb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- βalkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Q)- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b = H and Ab = βb = Coalkyl, then Yb is not 4-methoxyphenyl or 2,5- dimethoxyphenyl.
In a fifth aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Cι_6alkynyl, -ORlb _NRlbR2b, _ C(=NRlb)NR2bR3b -N(=NRlb)NR2bR3b -NRlbcOR2b, -NRlbCO2R2b,
-NRlbS02R4b, -NRlbCONR2bR3b _SR4b, -SOR4b, -SO2R4b, -SO2N lbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is pyrazinyl optionally substituted with 1-3 independent halogen, - CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5b, -NR5bR6b -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b -NR5bCOR6b, -N 5bcθ2R6b, -NR5bS02R8b, -NR5bC0NR6bR7b,_SR8b, -SOR8b, -SO2R8b, -SO2NR5bR6b, -COR5b -CO2R5b, -CONR5bR6b -C(=NR5b)R6b, 0r -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6 lkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bb is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rl lb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ-
6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rl lb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(C0- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b = H and Ab = βb = Coalkyl, then Yb is not 4-methoxyphenyl or 2,5- dimethoxyphenyl.
In an embodiment of this fifth aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein
Xb is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Ci-6alkyl, -Ci_6alkenyl, -Cl-6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b -NRlbC0R2b, -N lbC02R2b,
-NRlbSO2R4b, -NRlbCONR2bR3b ,_SR4b ~SOR4b, -SO2R4b, -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Ci-βalkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yb is pyrazinyl optionally substituted with 1-3 independent halogen, - CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Cι_6alkynyl, -OR5b, -NR5bR6b, -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b -NR5bcOR6b, -NR5bcθ2R6b, -N 5bsθ2R8b, -NR5bcONR6bR7b,_sR8b, -SOR8b, -SO2R8b, -SO2NR5bR6b, -COR5b, -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, 0r -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bb is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-N lObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rl lb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ-
6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b - H and Ab = βb = C0alkyl, then Yb is not 4-methoxyρhenyl or 2,5- dimethoxyphenyl.
In a sixth aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Ci_6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b -NRlbcOR2b -NRlbCO2R2b,
-NRlbSO2R4b, -NRlbCONR2bR3b ,_SR4b, -SOR4b, -SO2R4b, -SO2N lbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Co_2alkyl-, -Cθ- 2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is benzoxazolyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Ci_6alkyl, -Ci_6alkenyl, -Ci-6alkynyl, -OR5b, _NR5bR6b, -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b -N 5bcOR6b, -N 5bcθ2R6b, -NR5bS02R8b, -NR5bcONR6bR7b ,_SR8b, -SORSb, -SO2R8b, -SO2NR5bR6b, -COR5, -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, 0r -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
R5b, R6b and R7b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rl lb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ-
6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Cθ- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b = H and Ab = βb = Coalkyl, then Yb is not 4-methoxyρhenyl or 2,5- dimethoxyphenyl.
In an embodiment of the sixth aspect of the invention, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is phenyl optionally substituted with 1-5 independent halogen, -CN, NO2, -Ci-6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORlb, -NRlbR2b _ C(=NRlb)NR2bR3b _N(=NRlb)NR2bR3b -NRlbCOR2b -N lbcθ2R2b -NRlbSO2R4b, -NRlbCONR2bR3b -SR4b -SOR4b, -SO2R4b -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rib, R2b, a d R3b each independently is -Cθ-6alkyl, -C3_
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Co_6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Co~6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2~Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yb is benzoxazolyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -OR5b, -NR5bR6b, -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b -NR5bCOR6b, -NT-5bcθ2R6b, -NR5bSO2R8b, -NR5bcθNR6bR7b _SR8b -SOR8b -SO2R b, -SO2N 5bR6b, -COR5b, -CO2R5b, -CONR5bR6b, -C(=Nϊt5b)R6b, or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
R5b, R6b and R7b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl; R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b;
Rl lb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cl-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In a seventh aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci^alkyl, -Cι_6alkenyl, -Ci-βalkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b -NRlbC0R2b, -N lbC02R2b, -NRlbSO2R4b, -NRlbCONR2bR3b,_SR4b, -SOR4b, _SO2R4b, -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Co_6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)( )-6alkyl). -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Co_6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6 alkyl) (aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ-
2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is 1,3-thiazolyl optionally substituted with 1-2 independent halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Ci_6alkynyl, -OR5b, -NR5bR6b, -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b, -N 5bC0R6b, -NR5bcθ2R6b, -N 5bsθ2R b, -NR5bcONR6bR7b,_SR8b, -SOR8b, -SO2R8b, -SO2NR5bR6b, -COR5b, -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3-.
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2~Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), -N(Q)- 6alkyl)(aryl) substituents; one of Alb and A b is N, the other is CRl2b;
Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3.7cycloalkyl), or -N(C0- 6alkyl)(aryl) groups; and wherein optionally Rl lb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens. In an embodiment of the seventh aspect of the invention, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is phenyl optionally substituted with 1-5 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b -NRlbCOR2b, -NRlbCO2R2b, -NRlbSO2R4b, -NRlbCONR2bR3b ,_SR4b, -SOR4b, -SO2R4b -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Co-6alkyl)(aryl) groups; Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3_
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R4b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yb is 1,3-thiazolyl optionally substituted with 1-2 independent halogen, -CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Ci_6alkynyl, -OR5b, -NR5bR6b, -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b -NR5bcOR6b, -NR5bcθ2R6b, -N 5bS02R8b, -NR5bCONR6bR7b _SR8b, -SORδb, -SO2R8b, -SO2N 5bR6b, -COR5b, -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Cl-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b, R6b, and R7b each independently is -Co~6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl; R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3.7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b;
Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Cθ- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In an eighth aspect, the compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Xb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b, -NRlbCOR2b, -N lbCO2R2b, -NRlbSO2R4b, -NRlbCONR2bR3b,_SR4b, -SOR4b, -SO2R4b, -SO2NRlbR2b -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, 0r -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6al yl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-.
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ-
2alkyl-NR9bsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yb is quinolinyl optionally substituted with 1-6 independent halogen, - CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -OR5b, -NR5bR6b,
-C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b -NR5bcOR6b, -NR5bcθ2R6b, -NR5bS02R8b, -NR5bC0NR6bR7b ,_SR8b, -SOR8b, -SO2R8b, -SO2NR5bR6b, -COR5b -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Bb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-N lObcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rl lb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rl lb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In a ninth aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is naphthyl optionally substituted with 1-7 independent halogen, - CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORlb -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b, _NRlbCOR2b, - RlbCO2R2b, -NRlbSO2R4b, -NRlbCONR2bR3b,_SR4b, -SOR4b, -SO2R4b, _SO2N lbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rib, R2b and R3b each independently is -Cθ-6alkyl, -C3-.
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5b -NR5bR6b, -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b -NR5bC0R6b, -N 5bcθ2R6b, -NR5bS02R b, -NR5bC0NR6bR7b,_SR8b, -SOR8b, -SO2R8b, -SO2NR5bR6b, -COR5b, -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -C l-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -
O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Co-6alkyl)(Co-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b;
Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b = H and Ab = βb = Coalkyl, then Yb is not 4-methoxyphenyl or 2,5- dimethoxyphenyl .
In a tenth aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein: Xb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -Ci-6alkenyl, -Ci-6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b, -NRlbCOR2b, -N lbCO2R2b, -NRlbSO2R4b, -NRlbCONR2bR3b _SR4b, -SOR4b, -SO2R4b, -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R4b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ-
2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is pyrazolyl optionally substituted with 1-3 independent halogen, - CN, NO2, -Ci_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -OR5b, -NR5bR6b,
-C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b, -N 5bcOR6b, -N 5bC02R6b, -NR5bsθ2R8b, -NR5bcONR6bR7b,_SR8b, -SORδb, -SO2R8b, -SO2NR5bR6b, -COR5b -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5b R6b, and R7b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6al yl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Bb is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(C0- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rl lb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In an embodiment of the tenth aspect of the invention, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein: Xb is phenyl optionally substituted with 1-5 independent halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Ci_6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b -N(=NRlb)NR2bR3b -NRlbCOR2b, -N lbcθ2R2b, -NRlbSO2R4b, -NRlbcONR2bR3b _SR4b, -SOR4b -SO2R b, -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b 0r -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2~Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl- -Cθ-
2alkyl-NR9bsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yb is pyrazolyl optionally substituted with 1-3 independent halogen, - CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5b, -NR5bR6b,
-C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b -NR5bC0R6b, -NR5bcθ2R6 , -N 5bsθ2R b, -NR5bcONR6bR7b,_sR8b, -SORδb, -SO2R8, -SO2NR5R6, -COR5b, -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3-7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Bb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rl lb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rl lb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In an eleventh aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b, -NRlbcOR2b, -NRlbCO2R2b, -NRlbS02R4b, -NR1CONR2R3,-SR4, -SOR4, -SO2R4, -Sθ2N lR2, -CORl, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Q)- 6alkyl)(aryl) groups; Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R4b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is quinoxalinyl optionally substituted with 1-5 independent halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b, -NRlbC0R2b, -NRlbCO2R b, -NRlbSO2R4b, -NRlbCONR2bR3b,_SR4b, -SOR4b, -SO2R4b, -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, 0r -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b;
Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Cθ- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In an embodiment of the eleventh aspect of the invention, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is phenyl optionally substituted with 1-5 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b -NRlbCOR2b, -NRlbCO2R2b -NRlbSO2R4b -NRlbCONR2bR3b,_SR4b, -SOR4b, -SO2R4b, -SO2 RlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6aιkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Ci-βalkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is quinoxalinyl optionally substituted with 1-5 independent halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b -NRlbCOR2b, -N lbCO2R2b, -NRlbSO2R4b, -NRlbCONR2bR3b,_SR4b, -SOR4b, -SO2R4b, -SO2N lbR2b -CORlb, -CO2Rl , -CONRlbR2b, -C(=NRlb)R2b or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b;
Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or-N(Cθ- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In an twelfth aspect, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein: Xb is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-βalkyl, -Ci-6alkenyl, -Ci-6alkynyl, -ORlb, _NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b -NRlbC0R2b, -NRlbCO2R2b, -N l S02R4b, -NRlbC0NR2bR3b,_SR4b, -SOR4b, -SO2R b -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
Rib, R2b and R3b each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Ci_6alkyl, -C3-7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ab is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is pyrimidinyl optionally substituted with 1-3 independent halogen, -CN, NO2, -Ci-6alkyl, -Ci-6alkenyl, -Cι.6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b, -NRlbCOR2b, -NRlbcθ2R2b, -NRlbS02R4b, -NRlbCONR2bR3b -SR4b, -SOR4b, -SO2R4b, -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, or-C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R8b is -Ci.βalkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3.7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and R 12b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
In an embodiment of the twelfth aspect of the invention, the compound of this invention is represented by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein:
Xb is phenyl optionally substituted with 1-5 independent halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b -NRlbCOR2b -NRlbCO2R2b -NRlbSO2R4b -NRlbCONR2bR3b ,_SR4b, -SOR4b, -SO2R4b, -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4b is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl- -Cθ- 2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is pyrimidinyl optionally substituted with 1-3 independent halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Ci_6alkynyl, -ORlb, -NRlbR2b, _ C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b -NRlbCOR2b, -NRlbCO2R2b,
-NRlbSO2R4b, -NRlbCONR2bR3b ,_SR4b, -SOR4b, -SO2R4b, -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b -C(=NRlb)R2b, or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Bb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- βalkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rl lb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens.
A compound of this invention is represented by Formula (IC):
Figure imgf000076_0001
(IC) or a pharmaceutically acceptable salt thereof, wherein
Xc and Yc each independently is aryl or heteroaryl wherein at least one of Xc and Yc is a heteroaryl with N adjacent to the position of attachment to Ac or Bc respectively; three of Ale, A2C, A3C, A c, and A5c are N, the remaining are C, and one of Ale and A4c mUst be N, but not both Ale and A4c are N;
Xc is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-βalkyl, -C2-6alkenyl, -C2-6alkynyl, -ORl, -NR1CR2C, -C(=NR1C)NR2CR3C, _ N(=NR1C)NR2CR3C, -NR1CCOR2C, -NRlcC02R2c, -NRlcS02R4 , -
NR1CCONR2CR3C,_SR4C, -SOR4C, -SO2R4C, -Sθ2NRlcR2c, -CORlc, -CO2Rlc, - CONRlcR2c,
Figure imgf000077_0001
or -C(=NOR1C)R2C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to XC; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rlc, R2c, and R3c each independently is -Cθ-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent , halogen, -CN, -C l-6alkyl, -O(Co_6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Cθ-
6alkyl)(aryl) substituents;
R4c is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Ac is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ccθ-Cθ-2alkyl-, -Cθ-2alkyl-
NR9csO2-Co-2alkyl- or -heteroCθ-4alkyl; Yc is optionally substituted with 1-7 independent halogen, -CN, NO2,
-Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5c, _NR5CR6C, -C(=NR5C)NR6CR7C,
-N(=NR5C)NR6CR7C, -NR5CC0R6C, -NR5CC02R6C, -N 5CSO2R8C, -
NR5CCONR6CR7C,_SR8C, -SOR8C, -SO2R C, -SO2NR5CR6C, -COR5C, -CO2R5c, -
CONR5CR6C, -C(=NR5C)R6C, or -C(=NOR5C)R6C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yc; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5c, R6c, and R7c each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Q)- 6alkyl)(aryl) substituents; R8 is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOccθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOcsO2-Co-2alkyl-, or -heteroCθ-4alkyl;
R9c and RlOc each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(C0- 6alkyl)(aryl) substituents;
Rile is halogen, -Cθ-6alkyl, -Cθ-6alkoxyl, =O, =N(Cθ-4alkyl),or - N(Co-4alkyl)(C0-4alkyl); any alkyl optionally substituted with 1-5 independent halogen substitutents, and any N may be an N-oxide; and provided that when X is 2-pyridyl, Al and A3c are each C, A2c and A4c and A5c are each N, Ac and Be are each direct bonds, and Rile is OH, then Yc is not unsubstituted phenyl or 4-methoxyphenyl.
In one embodiment, the compound of this invention is represented by Formula (IC) or a pharmaceutically acceptable salt thereof, wherein
Xc is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORlc, -NRlcR2c, _ C(=NR1C)NR2CR3C, -N(=N 1C)NR2CR3C -NR1CCOR2C, -N 1CCO2R2C, -NRlcSO2R4c, -NR1CCONR2CR3C,_SR4C, -SOR4C, -SO2R4C, -SO2NR1CR2C, -CORlc, -Cθ2Rlc, -CONRlcR2c, -C(=NR1C)R2C, 0r -C(=NORlc)R2c substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xc; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl),
-O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rlc, R2c, and R c each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ-
6alkyl)(aryl) substituents;
R4c is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ac is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9ccθ-Cθ-2alkyl-, -Cθ-2alkyl-
NR9cSO2-Co-2alkyl- or -heteroCθ-4alkyl; Yc is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5c, _NR5CR6C, -C(=NR5C)NR6CR7C, -N(=NR5C)NR6CR7C -NR5CC0R6C, -NR5ccθ2R6c, -NR5csθ2R8c, -NR5CC0NR6CR7C -SR8C, -SOR8c, -SO2R8C, -SO2NR5CR6C, -COR5C, -Cθ2R5c, -CONR5CR6C, -C(=NR5C)R6C, or -C(=NOR5c)R6c substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to YC; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5C, R6C, and R7c each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R8c is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βc is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOccθ-Cθ-2alkyl-, -Co- 2alkyl-NRlOcsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; R9c and R Oc each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any alkyl optionally substituted with 1-5 independent halogen substitutents, and any N may be an N-oxide.
In another embodiment, the compound of this invention is represented by Formula (IC) or a pharmaceutically acceptable salt thereof, wherein
Xc is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORlc, -NR1CR2C, _ C(=NR1C)NR2CR3C, -N(=NR1C)NR2CR3C -NR1CC0R2C, -NR1CCO2R2C, -N 1CSO2R4C, -NR1CNR2CR3C,_SR4C, -SOR4C, -SO2R4C, -SO2NR1CR2C, -CORlc, -CO2Rlc, -CONRlcR2c, -C(=NR1C)R2C, or-C(=NORlc)R2c substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xc; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rlc, R2c, and R3c each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; R4c is -Cι_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Ac is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9ccθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9csO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yc is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Ci_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5c, -NR5CR6C, -C(=NR5C)NR6CR7C, -N(=NR5C)NR6CR7C -NR5CCOR6C, -NR5ccθ2R6c,
-NR5csθ2R c, -NR5CCONR6CR7C,_SR8C, -SOR8c, _SO2R8C, -SO2NR5CR6C, -COR5C, -CO2R5c, -CONR5CR6C, -C(=NR5C)R6C, or -C(=NOR5C)R6C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yc; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5C, R6C, and R7c each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R8c is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Be is -Co_4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-N lOcCO-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOcsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9c and RlOc each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any alkyl optionally substituted with 1-5 independent halogen substitutents, and any N may be an N-oxide. In still another embodiment, the compound of this invention is represented by Formula (IC) or a pharmaceutically acceptable salt thereof, wherein:
Xc is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Ci_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORlc, -NR1CR2C, _ C(=NR1C)NR2CR3C, _N(=NR1C)NR2CR3C -NRlcCOR2c, -NR1CCO2R C, -NRlcS02R4c, -NR1CCONR2CR3C,_SR4C, -SOR4C, -Sθ2R4c, -SO2NR1CR2C,
-CORlc, -CO2Rlc, -CONR1CR2C, -C(=NR1C)R2C, or -C(=NORlc)R2c substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xc; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl),
-O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rlc, R2C, and R3c each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ-
6alkyl)(aryl) substituents;
R4c is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-
7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ac is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ccθ-Cθ-2alkyl-, -Cθ-2alkyl-
NR9csθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; Yc is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5c, _NR5CR6C, -C(=NR5C)NR6CR7C, -N(=NR5C)NR6CR7C -NR5CCOR6C, -N 5ccθ2R6c, -N 5CS02R C, -NR5CCONR6CR7C,_SR8C, -SOR8c, -SO2R8C, -SO2N 5CR6C, -COR5C, -CO2R5C, -CONR5CR6C, -C(=NR5C)R6C, or -C(=NOR5C)R6C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to YC; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5C, R6C, and R7c each independently is -Cθ-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R8c is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOccθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOcsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9c and RlOc each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any alkyl optionally substituted with 1-5 independent halogen substitutents, and any N may be an N-oxide.
In another embodiment, the compound of this invention is represented by Formula (IC) or a pharmaceutically acceptable salt thereof, wherein
Xc is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORlc, _NR1CR2C, _ C(=NR1C)NR2CR3C, -N(=NR1C)NR2CR3C -NR1CCOR2C, -NRlcC02R2c,
-NRlcSO2R4c, -NR1CCONR2CR3C,_SR4C, -SOR4C, -Sθ2R4c, -Sθ2N lcR2c, -CORlc, -CO2R c, -CONR1CR2C, -C(=NR1C)R2C, or -C(=NOR1C)R2C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xc; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and
Yc is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -C l-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5c, -NR5CR6C, -C(=NR5C)NR6CR7C, -N(=NR5C)NR6CR7C -NR5CCOR6C, -NR5CCO2R6C, -NR5CS02R8C, -NR5CCONR6CR7C ,_SR8C, -SOR8c, -SO2R8C, -SO2NR5CR6C, -COR5C, -CO2R5c, -CONR5CR6C, -C(=NR5C)R6C, or -C(=NOR5C)R6C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to YC; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups. In an embodiment of the invention, the compound of this invention is represented by Formula (IC) or a pharmaceutically acceptable salt thereof, wherein Xc is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORlc, _NR1CR2C, _ C(=NR1C)NR2CR3C, -N(=NR1C)NR2CR3C -NR1CCOR2C, -NRlcC02R2c, -NRlcS02R4c, -NR1CCONR2CR3C,_SR4C, -SOR4c, -Sθ2R4c, -Sθ2NRlcR2c,
-CORlc, -CO2Rlc, -CONR1CR2C, -C(=NR1C)R2C, or -C(=NORlc)R2c substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to XC; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl),
-O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and
Yc is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5, -NR5CR6C, -C(=NR5C)NR6CR7C, -N(=NR5C)NR6CR7C _NR5CC0R6C, -NR5cCθ2R6c,
-N 5CS02R C, -NR5CC0NR6CR7C,_SR8C, -SORSC, -SO2R8C, -SO2NR5CR6C, -COR5C, -Cθ2R5c, -CONR5CR6C, -C(=NR5C)R6C, or -C(=NOR5C)R6C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to YC; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Co_6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups. In another embodiment, the compound of this invention is represented by Formula (IC) or a pharmaceutically acceptable salt thereof, wherein
Xc is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Ci_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORlc, -NR.lcR2c, _ C(=NR1C)NR2CR3C,
Figure imgf000085_0001
-NR1CCOR2C, -NRlcC02R2c, -NRlcSO2R4c, -NR1CC0NR2CR3C,_SR4C, -SOR4C, -SO2R4c, -Sθ2NRlcR2c,
-CORlc, -CO2Rlc, -CONR1CR2C, -C(=NR1C)R2C, or -C(=NOR1C)R2C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to XC; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl),
-O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and
Yc is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5c, -NR5CR6C, -C(=NR5C)NR6CR7C, -N(=NR5C)NR6CR7C _NR5CC0R6C, -NR5cC02R6c,
-N 5CSO2R8C, -NR5CC0NR6CR7C,_SR8C, -SORδc, -SO2R C, -SO2N 5CR6C, -COR5C, -CO2R5C, -CONR5CR6C, -C(=NR5C)R6C, or -C(=NOR5C)R6C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to YC; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups.
The compounds of the present invention are represented by Formula (ID):
Figure imgf000085_0002
(ID) or a pharmaceutically acceptable salt thereof, wherein
Xd and Y each independently is aryl or heteroaryl wherein at least one of X and Y is a heteroaryl with N adjacent to the position of attachment to A or β respectively;
X is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-βal yl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NRldRd2, -C(=NRld)NR2dR3d _ N(=NRld)NR2dR3d -NRldC0R2d, -NRl CO2R2 , -NRldSO2R4 - NRldCONR2dR3d,_SR4d -SOR4d, -SO2R4 , -SO2NRldR2d, -CORld, -CO2Rl , -CONRdlR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; A is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
Y is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -Cι.6alkenyl, -Cι.6alkynyl, -OR5, _NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5 cOR6d, -NR5 C02R6d, -NR5dsθ2R8d, -
NR5dC0NR6dR7d,_SR8d, -SOR8d, -SO2R8d, -SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -C ι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
B is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl; R9d and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C -7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In one aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein
X is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl _NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldC0R2d, -NRl CO2R2 ,
-N l SO2R4d, -NRldcONR2dR3d,_SR4d, -SOR4d, -SO2R4 , -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(C0-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; A is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
Y is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -OR5d, _NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -N 5 cθ2R6d,
-NR5 sθ2R8 , -NR5dcONR6dR7d _SR8d, -SORδd, -SO2R8 , -SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y ; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Bd is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide. In an embodiment of this one aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORld, -NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldCOR2d, -N l C02R2
-NRl S02R4 , -NRldC0NR2dR3d,_SR4d -SOR4d, -SO2R4 , -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, or -C(=NORl )R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
Rid, R2d, and R3 each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Ci-βalkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(CQ-6alkyl)(aryl) substituents; Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
Y is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, _NR5dR6d,
-C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -NR5 cθ2R6d, -NR5dsθ2 R8d, -NR5dC0NR6dR7d,_s R8d, -SO R8d, -Sθ2 R8 , -SO2NR5dR6d, -COR5d, -CO2R5 , -CONR5dR6d, -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y ; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Co-6alkyl)(aryl) groups; R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3.7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bd is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2~Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In a second aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein: X is aryl or heteroaryl optionally substituted with 1-7 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORld, - NRldR2d, -C(=NRld)NR2dR3d, _N(=NRld)NR2dR3d, -NRldCOR2d, -NRldCO2R2d, -NRl SO2R4d, -NRl CONR2dR3d,_SR4d, -SOR4d, -SO2R4 , -SO2NRldR2d, -CORld -CO2Rld, _C0NRldR2d, _C(=NRld)R2d, or -
C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3..
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Co-6alkyl)(aryl) substituents;
R4d is -Ci-βalkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
A is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ-
2alkyl-N ldsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Y is 2-pyridyl optionally substituted with 1-4 independent hydrogen, halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -N 5dcθR6d, -NR5 cθ2R6d, -N 5dS02 R8 , -NR5dC0NR6dR7d ,_s R8d, _sθ R8d, -SO2R8 , -SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y ; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -C _6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In a third aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein
X is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -ORld -NRldR2d, _ C(=NRld)NR2dR3d, -N(= Rld)NR2dR3d, -NRldC0R2d, -NRldCO2R2d, -NRldS02R4d, -NRl cONR2dR3d,_SR4d, -SOR4d, -SO2R4 -SO2N ldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, 0r -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, a d R3d each independently is -Cθ-6alkyl, -C3_ 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Co-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6 alkyl) (aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRldSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; Yd is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -NR5 C02R6d, _NR5dsθ2R8d, -NR5dcONR6dR7d,_SR8d, -SORδd, -SO2R8d -SO2NR5 R6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, Rod, and R7d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6 alkyl) (aryl) substituents; Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Q)- 6alkyl)(aryl) substituents; and any N may be an N-oxide. In an embodiment of the third aspect of the invention, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cl-6alkenyl, -Ci_6alkynyl, -ORld, _NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldC0R2d, -NRldcθ2R2d
-NRldSθ2R4d, -NRl CONR2dR3d _SR4d, -SOR4d, -SO2R4d, -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3.7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRl dSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yd is 2-pyridyl optionally substituted with 1-4 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Ci_6alkynyl, -OR5d _NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d, -NR5 cOR6 , -NR5dcθ2R6d, -NR5dsθ2 R8d, -NR5dcONR6dR7d ,_s R8d, -SO R8d, _SO2R8d, -SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Co-6alkyl)(aryl) groups;
R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Q)_6a]kyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In a fourth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein
Xd is aryl or heteroaryl optionally substituted with 1-7 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORld _ NRldR2d, -C(=NRld)NR2dR3d, -N(=NRl )NR2dR3d -NRldCOR2d,
-N ldCO2R2d, -NRldsθ2R4d, -NRldC0NR2dR3d,_sR4d, -SOR4d, -SO2R4d, -SO2NRldR2d, -CORld, -CO2Rld -CONRldR2d -C(=NRld)R2d, 0r-
C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rid, R2d and R3d each independently is -Cθ-6alkyl, -C3.
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R4d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yd is l,3-thiazol-2-yl optionally substituted with 1-2 independent halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, _NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -NR5dcθ2R6d, -NR5 SO2R8d R8d, -NR5dc NR6dR7d _SR8d, -SOR8d, -SO2R8d, -SO2NR5 R6, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, 0r -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3..
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRl dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(C0- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In an embodiment of this fourth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein: Xd is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORld, _NRldR2d _ C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldCOR2d, -NRl C02R2d, -N l SO2R4 , -NRldCONR2dR3d ,_SR4d, -SOR4d, -SO2R4 , -SO2NRldR2d, -CORld, -CO2Rl -CONRldR2d, -C(=NRld)R2d, or-C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3- 7cycloalkyl), -N(CQ-6alkyl)(aryl) substituents; Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Y is l,3-thiazol-2-yl optionally substituted with 1-2 independent halogen, -CN, NO2, -Cl_6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -NR5dcθ2R6 -NR5dsθ2R8d R8d, -M 5dcONR6dR7d,_SR8d, -SOR8d _SO2R8d, - SO2NR5dR6, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, 0r
-C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3.
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R8d is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In a fifth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein: Xd is 3-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Ci-6alkyl, -Ci^alkenyl, -Cι_6alkynyl, -ORld, _NRldR2d, _ C(=NRld)NR2dR3d, _N(=NRl )NR2dR3d, -NRldCOR2d, -NRl C02R2d -NRldSO2R4d, -NRldCONR2dR3d,_SR4d, -SOR4d, -SO2R4d, -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, 0r -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
A is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ-
2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yd is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -OR5d, _NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -N 5dcθ2R6d, -N 5dsθ2R8d, -NR5dC0NR6dR7d,_SR8d, -SORδd, -SO2R8d, -SO2NR5dR6d, -COR5d, -CO2R5d -CONR5dR6d, -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y ; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Co-6alkyl)(aryl) substituents;
R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; B is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2~Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In a sixth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is aryl or heteroaryl optionally substituted with 1-7 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORld, _ NRldR2d, _C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldcOR2d, -NRldCO2R2d, -NRldSO2R4d, -N ldC0NR2dR3d,_SR4d -SOR4d, -SO2R4 , -SO2NRldR2d, -CORld, -CO2Rl , -CONRldR2d, -C(=NRld)R2d, or -
C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3.7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
A is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; Yd is imidazolyl optionally substituted with 1-3 independent hydrogen, halogen, -CN, NO2, -Ci-6alkyl, -Ci_6alkenyl, -Cι_6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -NR5 cθ2R6d, -NR5 S02R8d, -NR5dcONR6dR7d _SR8d, -SOR8d, -SO2R8d, -SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, 0r -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d R6d, and R7d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d s -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide. In an embodiment of this sixth aspect, the compounds of this invention are represented by Formula (ED) or a pharmaceutically acceptable salt thereof, wherein:
X is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORld, _NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldCOR2d, -N ldcθ2R2 ,
-NRldSO2R4d, -NRl cONR2dR3d,_SR4d, -SOR4d, -SO2R d, -SO2NRldR2d, -CORld, -CO2Rl , -CONRldR2d -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
A is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR 1 sθ2-Cθ-2alkyl- or -heteroCθ-4alkyl ;
Yd is imidazolyl optionally substituted with 1-3 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d _NR5dC0R6d, -NR5dcθ2R6d -N 5dSO2R8d, -NR5dcONR6dR7d,_SR8d, -SOR8d, _SO2R8d, -SO2N 5dR6d, -COR5d -Cθ2R5d, -CONR5dR6d, _C(=NR5d)R6d, 0r -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Cι_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl; R d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In a seventh aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is aryl or heteroaryl optionally substituted with 1-7 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Cι_6alkynyl, -ORld, - NRldR2d, -C(=NRld)NR2dR3d -N(=NRld)NR2dR3d -NRldCOR2d,
-NRldCO2R2 , -N ldSO2R4d, -NRldC0NR2dR3d _SR4d, -SOR4d, -SO2R4d -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, or-
C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3_
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R4 is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
A is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yd is 1,3-oxazolyl optionally substituted with 1-2 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, _ NR5dR6d, -C(=NR5d)NRd6R7d, -N(=NR5d)NR6dR7d -NR5dC0R6d, -NR5dcθ2R6d, -NR5dsθ2R8d, -NR5dcONR6dR7d,_SR8d, -SOR8d -SO2R8d, - SO2NR5dR6d, _COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, 0r
-C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, R6d, and R7d each independently is -Cθ-6 lkyl, -C3-
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -
O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
Rδd is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(CQ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In an emdodment of this seventh aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein Xd is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl _NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldCOR2d, -N l C02R2d, -NRldSO2R4d, -N .ldC0NR2dR3d _SR4d, -SOR4d, -SO2R d, -SO2NRldR2d, -CORld -CO2Rld -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(CQ-6alkyl)(aryl) substituents; A is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
Y is 1,3 -oxazolyl optionally substituted with 1-2 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, _ NR5dR6d, -C(=NR5d)NRd6R7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -NR5dC02R6d, -NR5 sθ2R8d, -NR5dC0NR6dR7d,_SR8d, -SOR8d -SO2R8 , - SO2NR5dR6d, -COR5d, -Cθ2R5d, -CONR5dR6d, -C(=NR5d)R6d, or
-C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R8 is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
B is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2~Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In an eighth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein X is aryl or heteroaryl optionally substituted with 1-7 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORld, _ NRldR2d, -C(=NRld)NR2dR3d, _N(=NRld)NR2dR3d -NRldCOR2d, -N ldCO2R2d, -NRldsθ2R d, -NRldCONR2dR3d,_SR4d, -SOR4d, _SO2R4 , -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d _C(=NRld)R2d, 0r -
C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(C0-6alkyl)(C3-
7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3_
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R4d is -Ci-βalkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(C0-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ-
2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Y is isoxazolyl optionally substituted with 1-2 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, _NR5dR6d, -C(=NR5d)NR6dR7d -N(=NR5d)NR6dR7d; -NR5dC0R6d, -NR5dcθ2R6d, -NR5dSO2R8d, -NR5dcONR6dR7d,_SR8d, -SOR8d, -SO2R8 , -SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, 0r -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3.7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Ci_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOCO-Cθ-2alkyl-, -Cθ- 2alkyl-NRlSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(C0-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), -N(C0- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In an embodiment of this eighth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
X is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Ci-6alkynyl, -ORld, -NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldCOR2d, -NRl cθ2R2 -NRldSO2R4 -NRldcONR2dR3d _SR4d, -SOR4d, -Sθ2R4d, -SO2NRldR2d, -CORld, -Cθ2Rld, -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl),
-O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Co-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Y is isoxazolyl optionally substituted with 1-2 independent hydrogen, halogen, -CN, NO2, -Ci_6alkyl, -Ci_6alkenyl, -Cι_6alkynyl, -OR5d, _NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d -NR5dcθ2R6d, -N 5 sθ2R8d, -NR5dC0NR6dR7d,_SR8d, -SORδd, -SO2R8 , -SO2NR5dR6d, -COR5d, -C02R5d, -CONR5dR6d, -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3.
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R8d is -Ci-galkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(C0-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
B is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl~, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ-
2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl; R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In a ninth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is aryl or heteroaryl optionally substituted with 1-7 independent hydrogen, halogen, -CN, NO2, -Ci_6alkyl, -Ci-6alkenyl, -Ci_6alkynyl, -ORld, - RldR2d, -C(=NRld)NR2dR3d -N(=NRld)NR2dR3d -NRldCOR2d, -NRldCO2R2d, -NRldSO2R , -NRl CONR2dR3d,_SR4d, -SOR4d, -SO2R d, -SO2NRldR2d, -CORld, -CO2Rl -CONRldR2d, -C(=NRld)R2d, 0r-
C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3.7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R4d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Y is pyrazolyl optionally substituted with 1-3 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d _NR5dcOR6d, -NR5 CO2R6d -NR5dsθ2R8d, -NR5dcONR6dR7d,_SR8d, -SOR8d, -SO2R8 -SO2N 5dR6d, -COR5d, -CO2R5d, -CONR5dR6d _C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y ; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d R6d, and R7d each independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2~Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRldsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In an embodiment of this ninth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein: Xd is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORld, -NRldR2d, _ C(=NRld)NR2dR3d -N(=NRld)NR2dR3d -NRldCOR2d, -NRldCO2R2 , -NRldSO2R4d, -NRldCONR2dR3d,_SR4d, -SOR4d, _SO2R , -SO2N ldR2d, -CORl , -CO2Rld -CONRldR2d, -C(=NRld)R2d, or-C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O (heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C -7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Co~6alkyl)(aryl) substituents;
R4 is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yd is pyrazolyl optionally substituted with 1-3 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d -N(=NR5d)NR6dR7d -NR5dC0R6d, -NR5dcθ2R6d, -N 5 SO2R8 , -NR5dCONR6dR7d,_sR8d, _SOR8d, -SO2R8d, -SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, 0r -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3_
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In a tenth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein
X is aryl or heteroaryl optionally substituted with 1-7 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Ci_6alkynyl, -ORld, _ NRldR2d, -C(=NRld)NR2dR3d, -N(=NRl )NR2dR3d -NRldCOR2d, -N l C02R -NRl SO2R4d, -NRl C0NR2dR3d,_SR4d, -SOR4d, -SO2R4 , -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, or -
C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3-.
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R4d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
A is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yd is triazolyl optionally substituted with 1-3 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, _NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d, -NR5dC0R6d, -NR5 C02R6d, -NR5 sθ2R8 , -NR5dcONR6dR7d,_SR8d, -SORδd, -SO2R8 , -SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y ; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Co-6alkyl)(aryl) groups;
R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -C _6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3-7cyclo alkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6 alkyl) (aryl) substituents; and any N may be an N-oxide. In an embodiment of this tenth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Ci-6alkynyl, -ORld, _NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldCOR2d, -NRldCO2R2 , -N ldS02R4d, -NRldC0NR2dR3d,_SR4d, -SOR4d, _SO2R4d, -SO2NRldR2d, -CORld, -CO2Rld -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3_
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R4d is -C -βalkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
Y is triazolyl optionally substituted with 1-3 independent hydrogen, halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dC0R6d, -N 5dcθ2R6d, -NR5 S02R8 , -NR5dC0NR6dR7d,_sR8d, -SOR8d, -SO2R8 -SO2NR5 R6d, -COR5d, -CO2 5d, -CONR5dR6d, -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y ; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Co-6alkyl)(Co-6al yl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
R5d, R6d, and R7d each independently is -Co_6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-N ldCO-Cθ-2alkyl-, -Co_ 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl; R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(C"θ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In an eleventh aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is aryl or heteroaryl optionally substituted with 1-7 independent hydrogen, halogen, -CN, NO2, -Ci-βalkyl, -Ci_6alkenyl, -Cι_6alkynyl, -ORld, _ NRldR2d -C(=NRld)NR2dR3d, -N(=NRld) R2dR3d, -NRldcOR2d,
-N l CO2R2 -NRl sθ2R d, -NRldCONR2dR3d,_SR4d, -SOR4d, _SO2R4 , -SO2NRldR2d, -CORld -CO2Rld, -CONRldR2d, -C(=NRld)R2d, or -
C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(CQ-6alkyl)(aryl) groups; Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yd is pyrimidinyl optionally substituted with 1-3 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, _ NR5dR6d, -C(=MR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d,
-NR5dC02R6d, -NR5dsθ2R8 , -NR5dcONR6dR7d,_SR8d, -SORδd, -SO2R8d, - SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, or
-C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βd is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Co_2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Co_2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide. In an embodiment of this eleventh aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
X is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Ci-6alkynyl, -ORld, -NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldCOR2d, -N l CO2R2d,
-NRl SO2R4d, -NRldCONR2dR3d,_SR4d, _SOR4d, -SO2R4d, -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -C _6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; A is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yd is pyrimidinyl optionally substituted with 1-3 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Ci-6alkynyl, -OR5d, - NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -NR5dC02R6d, -NR5dsθ2R d, -NR5dcONR6dR7d,_SR8d, -SOR8d, -SO2R8d, - SO2NR5dR6d, -COR5d, -CO2R5d -CONR5dR6d, -C(=NR5d)R6d, 0r
-C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5 R6d, and R7d each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R8 is -Ci_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In a twelvth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein: Xd is aryl or heteroaryl optionally substituted with 1-7 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORld, _ NRldR2d, -C(=NRld)NR2dR3d, _N(=NRld)NR2dR3d -NRldC0R2d, -N ldCO2R2d, -N ldsθ2R4d, -NRldCONR2dR3d _SR4d, -SOR4d, _SO2R4 -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d, _C(=NRld)R2d, or -
C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3.
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R4d is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl- -Cθ-
2alkyl-NRlSO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yd is pyrazinyl optionally substituted with 1-3 independent hydrogen, halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -NR5dcθ2R6d, -NR5 S02R d, -NR5dC0NR6dR7d,_SR8d, -SOR8d, -Sθ2R8d -SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3„7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Co_ 2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
In an embodiment of this twelvth aspect, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
X is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Cχ_6alkyl, -Ci_6alkenyl, -Ci_6alkynyl, -ORld, _NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldC0R2d, -NRl CO2R2 , -NRldS02R4 , -NRldCONR2dR3d,_SR4d, -SOR4d, -SO2R4d, -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl),
-O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(C0-6alkyl)(aryl) substituents;
R4d is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Co-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
Y is pyrazinyl optionally substituted with 1-3 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d _NR5dcOR6d, -NR5 C02R6d, -N 5dsθ2R8 , -NR5dC0NR6dR7d,_SR8d, -SOR8d, -SO2R8d -SO2N 5 R6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, 0r -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
R5d, Rod, and R7d each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-N lOdcθ-Cθ-2alkyl-, -Cθ-
2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCQ-4alkyl; R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N may be an N-oxide.
Thus, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
X is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORld, _NRldR2d, _ C(=NRld)NR2dR3d -N(=NRld)NR2dR3d -NRldC0R2d, -N ldCO2R2d, -NRl sθ2R4 , -NRldCONR2dR3d _SR4d, -SOR4d, _SO2R4d, -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups. Further, the compounds of this invention are represented by Formula
(ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Cι_6alkynyl, -ORld, -NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRl )NR2dR3d -NRldC0R2d, -N ldC02R2 , -N ldSO2R4d, -NRldcONR2dR3d,_SR4d, -SOR4d, -SO2R4d, -SO2NRldR2d, -CORld, -Cθ2Rld -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl),
-O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and
Yd is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Cι_6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dC0R6d, -N 5dcθ2R6d, -NR5dSO2 R8d, -NR5dC0NR6dR7d,_s R8d, -SO R8d, -SO2 R8d, -SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, 0r -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y ; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups. Still further, the compounds of this invention are represented by
Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is aryl or heteroaryl optionally substituted with 1-7 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORld, _ NRldR2d, -C(=NRld)NR2dR3d, -N(=NRld)NR2dR3d -NRldCOR2d, -NRldGθ2R2 -NRldSO2R4d, -NRldCONR2dR3d,_SR4d, -SOR4d, -SO2R4 , -SO2NRldR2d, -CORld -CO2Rl -CONRldR2d, -C(=NRld)R2d, 0r -
C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and
Y is 2-pyridyl optionally substituted with 1-4 independent hydrogen, halogen, -CN, NO2, -Ci-6alkyl, -Ci_6alkenyl, -Cι_6alkynyl, -OR5d, _NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -NR dcθ2R6d
-N 5dsθ2 R8 , -NR5dcONR6dR7d,_s R8d _so R8d, -Sθ2R8d, -SO2NR5dR6d -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, 0r -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups. Even further, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Ci-βal yl, -Cι_6alkenyl, -Ci-6alkynyl, -ORld, _NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRl )NR2dR3d -NRldCOR2d, -N l CO2R2d,
-N ldSO2R4d, -NRl C0NR2dR3d,_SR4d, -SOR4d, -SO2R , -SO2NRldR2d, -CORld, -CO2Rl -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups.
Still further, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORld, _NRldR2d, _ C(=NRld)NR2dR3d, -N(=NRl )NR2dR3d -NRldCOR2d, -NRl cθ2R2 , -NRldSO2R4d, -NRl CONR2dR3d,_SR4d -SOR4d, -SO2R4d, -SO2NRldR2d, -CORld, -CO2R d, -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and
Y is 2-pyridyl optionally substituted with 1-4 independent hydrogen, halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Ci-6alkynyl, -OR5d, -NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dC0R6d, -N 5 cθ2R6d, -NR5dsθ2 R8d, -NR5dC0NR6dR7d,_s R8d, -SO R8d, -SO2R8 , -SO2NR5R6,
-COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, 0r -C(=NOR5d)R6dsubstituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -C 1 -6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Cθ-6alkyl)(aryl) groups.
And, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein Yd is l,3-thiazol-2-yl optionally substituted with 1-2 independent halogen, -CN, NO2, -Cι_6alkyl, -Ci_6alkenyl, -Ci-6alkynyl, -OR5d, _NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dcOR6d, -N 5dcθ2R6d, -NR5 S02R8d R8d, -NR5dcONR6dR7d,_SR8d, -SORδd, _SO2R8d, - SO2NR5dR6, -COR5d -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, 0r -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups.
Further, the compounds of this invention are represented by Formula (ID) or a pharmaceutically acceptable salt thereof, wherein:
Y is l,3-thiazol-2-yl optionally substituted with 1-2 independent halogen, -CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -OR5d, _NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d, -NR5 C0R6d, -N 5 cθ2R6d, -N 5 S02R8d R8d, -NR5dcONR6dR7d,_sR8d, -SOR8d, -SO2R8 , - SO2NR5dR6, -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d, or
-C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; and
Xd is phenyl optionally substituted with 1-5 independent hydrogen, halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -ORld -NRldR2d, _ C(=NRld)NR2dR3d, -N(=N ld)NR2dR3d -NRldCOR2d, -NRldCO2R2d, -NRldSO2R4d, -N ldCONR2dR3d,_SR4d, -SOR4d, -SO2R4 , -SO2N ldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, or-C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups.
A compound of this invention is represented by Formula (IE):
Figure imgf000127_0001
or a pharmaceutically acceptable salt thereof, wherein:
Xc and Ye each independently is aryl or heteroaryl wherein at least one of Xe and Ye is a heteroaryl with N adjacent to the position of attachment to Ae or Be respectively;
Xe is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORle, -NRleR2e, -C(=NRle)NR2eR3e, -N(=NRle)NR2eR3e, _NRleC0R2e, -NRleCO2R2e, -N leSO2R4e, - NRleCONR2eR3e,_SR4e, -SOR4e, -SO2R4e, -SO2N leR2e, -CORle, -CO2Rle, - CONRleR2e, -C(=NRle)R2e, or-C(=NORle)R2e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xe; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rle, R2e, and R3e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ- 6alkyl)(aryl) substituents;
R4e is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Ae is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ecθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9esO2-Co-2alkyl- or -heteroCθ-4alkyl;
Ye is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5e, _NR5eR6e, -C(=NR5e)NR6eR7e, -N(=NR5e)NR6eR7e, _NR5ecOR6e, -NR5eCO2R6e, -NR5esθ2R8e, - NR5eC0NR6eR7e,_SR8e, -SOR8e, -SO2R8e, -SO2NR5eR6e, -COR5e, -CO2R5e, - CONR5eR6e, -C(=NR5e)R6e, or -C(=NOR5e)R6e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- δalkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5e, R6e, and R7e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) substituents;
R8e is -Cι_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents; Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOecθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlOesO2-Co-2alkyl-, or -heteroCθ-4alkyl;
R9e and RlOe each independently is -Cθ-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rile and Rl2e is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl); any alkyl optionally substituted with 1-5 independent halogen substituents, and any N may be an N-oxide; and provided that when X = 2-pyridyl, Rl le = Rl2e = H and Ae = βe = Coalkyl, then Ye is not 3-cyanophenyl; and provided that when Ye = 2-pyridyl, Rl le = Rl2e = H and Ae = Be
= Coalkyl, then Xe is not 3-cyanophenyl.
In one aspect, the compound of this invention is represented by Formula (IE) or a pharmaceutically acceptable salt thereof, wherei
Xe is 2-pyridyl optionally substituted with 1-4 independent halogen,- CN, NO2, -Ci_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORle, -NRleR2e, _ C(=NRle)NR2eR3e, -N(=NRle)NR2eR3e -NRleCOR2e, -N leCO2R2e, -NRleSO2R4e, -NRleCONR2eR3e ,_SR4e, -SOR4e, -SO2R4e, -SO2 leR2e, -CORle, _CO2Rle, -CONRleR2e, -C(=NRle)R2e, or -C(=NORle)R2e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xe; wherein the -C _6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Co~6alkyl)(aryl) groups; Rle, R2e, and R3e each independently is -Co_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ- 6alkyl)(aryl) substituents; R4e is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Ae is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ecθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9esθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Ye is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5e, _NR5eR6e, -C(=NR5e)NR6eR7e, -N(=NR5e)NR6eR7e, _NR5eC0R6e, -NR5eCO2R6e, -NR5esθ2R e, -NR5eC0NR6eR7e ,_SR8e, _SOR8e, -SO2R8e, -SO2NR5eR6e, -COR5e, -CO2R5e, -CONR5eR6e, -C(=NR5e)R6e, or -C(=NOR5e)R6e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yβ; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Co_6al yl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5e, R6e, and R7e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Cθ-
6alkyl)(aryl) substituents;
R8e is -Ci-βalkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOecθ-Cθ-2alkyl-, -Cθ-
2alkyl-NRlOesθ2-Cθ-2alkyl-, or -heteroCθ-4alkyl; R9e and RlOe each independently is -Cθ-6 lkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), -N(C0- 6alkyl)(aryl) substituents; Rl le and Rl2e is each independently halogen, -Cθ-6alkyl, -Cθ-
6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl); any alkyl optionally substituted with 1-5 independent halogen substituents, and any N may be an N-oxide; and provided that when Rl le = Rl2e = H and Ae = βe = Coalkyl, then Ye is not 3-cyanophenyl.
In an embodiment of this one aspect, the compound of this invention is represented by Formula (IE) or a pharmaceutically acceptable salt thereof, wherein:
Xe is 2-pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORle, -NRleR2e, _ C(=NRle)NR2eR3e, -N(=NRle) R2eR3e, -NRleCOR2e, -NRlecθ2R2e, -NRleSO2R4e, -NRleCONR2eR3e,_SR4e, -SOR4e, -SO2R4e, -SO2 RleR2e, -CORle, -CO2R e, -CONRleR2e, -C(=NRle)R2e, or -C(=NORle)R2e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xe; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rle, R2e, and R3e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Coalkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) substituents; R4e is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Ae is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ecθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9esθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Ye is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5e, -NR5eR6e, -C(=NR5e)NR6eR7e, -N(=NR5e)NR6eR7e, -NR5eC0R6e, -NR5ecθ2R6e, -NR5esθ2R8e, -NR5eCONR6eR7e,_SR8e, -SORδe, -SO2R8e, -SO2NR5eR6e,
-COR5e, -CO2R5e, -CONR5eR6e, -C(=NR5e)R6e, or -C(=NOR5e)R6e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ye; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -
O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5e, R6e, and R7e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ- 6alkyl)(aryl) substituents;
R8e is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOecθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlOesO2-Co-2alkyl-, or -heteroCθ-4alkyl;
R9e and RlOe each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rile and Rl2e is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl); any alkyl optionally substituted with 1-5 independent halogen substituents, and any N may be an N-oxide; and provided that when Rl le = Rl2e = H and Ae = βe = Coalkyl, then
Ye is not 3-cyanophenyl.
In another embodiment of this one aspect, the compound of this invention is represented by Formula (IE) or a pharmaceutically acceptable salt thereof, wherein: Xe is 2-pyridyl optionally substituted with 1-4 independent halogen, -
CN, NO2, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORle, -NRleR2e, _ C(=NRle)NR2eR3e, -N(=NRle)NR2eR3e -NRleCOR2e, -NRleCO2R2e, -NRleSO2R4e, -NRleCONR2eR3e,_SR4e, -SOR4e, -SO2R4e, -SO2NRleR2e, -CORle, -CO2Rle, -CONRleR2e, -C(=NRle)R2e, or -C(=NORle)R2e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xe; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(CQ-6 alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rle, R2e, and R3e each independently is -Cθ-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Q)- 6alkyl)(aryl) substituents;
R4e is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Ae is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9ecθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9esO2-Co-2alkyl- or -heteroCθ-4alkyl; Ye is pyridyl optionally substituted with 1-4 independent halogen, -
CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5e, -NR5eR6e, -C(=NR5e)NR6eR7e, -N(=NR5e)NR6eR7e, -N 5eC0R6e, -NR5ecθ2R6e, -N 5esθ2R8e, -NR5ecONR6eR7e _SR8e, -SORδe -SO2R8e, -SO2NR5eR6e, -COR5e, -Cθ2R5e, -CONR5eR6e, -C(=NR5e)R6e, or -C(=NOR5e)R6e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ye; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5e, R6e, and R7e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or-N(Q)- 6alkyl)(aryl) substituents;
R8e is -Ci-βalkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents; Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOecθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlOesO2-Co-2alkyl-, or -heteroCθ-4alkyl;
R9e and RlOe each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rile and Rl2e is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl); any alkyl optionally substituted with 1-5 independent halogen substituents, and any N may be an N-oxide.
In a second aspect, the compound of this invention is represented by Formula (IE) or a pharmaceutically acceptable salt thereof, wherein: Xe is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORle, _NRleR2e, _ C(=NRle)NR2eR3e, -N(=NRle)NR2eR3e -NRleCOR2e, -NRleCO2R2e, -NRleSO2R4e, -NRleCONR2eR3e,_SR4e, -SOR4e, -SO2R4e, -SO2NRleR2e, -CORle, -CO2Rle, -CONRleR2e, -C(=NRle)R2e, or-C(=NORle)R2e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xe; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C -7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rle, R2e, and R3e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N( )- 6alkyl)(aryl) substituents;
R4e is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents; Ae is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ecθ-Cθ-2alkyl- -Cθ-2alkyl- NR9esO2-Co-2alkyl- or -heteroCθ-4alkyl;
Ye is 2-pyridyl optionally substituted with 1-4 independent halogen, - CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5e, -NR5eR6e, -C(=NR5e)NR6eR7e, -N(=NR5e)NR6eR7e, _N 5ecOR6e, -NR5ecθ2R6e, -NR5esθ2R8e, -NR5ecONR6eR7e,_SR8e, -SORSe, -SO2R8e, -SO2N 5eR6e, -COR5e, -CO2R5e, -CONR5eR6e, -C(=NR5e)R6e, or -C(=NOR5e)R6e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ye; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5e, R6e, and R7e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) substituents; R8e is -Ci_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOecθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOesO2-Co-2alkyl-, or -heteroCθ-4alkyl;
R9e and RlOe each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rile and Rl2e is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl); any alkyl optionally substituted with 1-5 independent halogen substituents, and any N may be an N-oxide; and provided that when Rl le = Rl2e = H and Ae = βe = Coalkyl, then
Xe is not 3-cyanophenyl. In a third aspect, the compound of this invention is represented by
Formula (IE) or a pharmaceutically acceptable salt thereof, wherein
Xe is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORle, -NRleR2e, _ C(=NRle)NR2eR3e, -N(=NRle)NR2eR3e _NRleC0R2e, -N leCO2R2e, -NRleSO2R4e, -NRleCONR2eR3e,_SR4e, -SOR4e, -SO2R4e, -SO2NRleR2e,
-CORle, -CO2Rle, -CONRleR2e, -C(=NRle)R2e, or-C(=NORle)R2e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xe; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rle, R2e, and R3e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Q)-
6alkyl)(aryl) substituents;
R4e is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Ae is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9ecθ-Cθ-2alkyl-, -Cθ-2alkyl-
NR9esO2-Co-2alkyl- or -heteroCθ-4alkyl; Ye is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5e, -NR5eR6e, -C(=NR5e)NR6eR7e, -N(=NR5e)NR6eR7e, _NR5ecOR6e, -NR5ecθ2R6e, -NR5esθ2R8e, -NR5eC0NR6eR7e,_SR8e, -SOR8e, -SO2R8e, -SO2NR5eR6e, -COR5e, -CO2R5e, -CONR5eR6e, -C(=NR5e)R6e, or -C(=NOR5e)R6e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ye; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5e, R6e, and R7e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) substituents;
R8e is -Ci-βalkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6al yl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents; Be is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOeCO-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOesθ2-Cθ-2alkyl-, or -heteroCθ-4alkyl;
R9e and RlOe each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), -N(C0-
6alkyl)(aryl) substituents;
Rl le and Rl2e is each independently halogen, -Cθ-6alkyl, -Cθ-
6alkoxyl, =0, =N(Cθ-4alkyl),or-N(Cθ-4alkyl)(Cθ-4alkyl); any alkyl optionally substituted with 1-5 independent halogen substituents, and any N may be an N-oxide; and provided that when Ye = 2-pyridyl, Rl le = Rl2e = H and Ae = Be
= Coalkyl, then Xe is not 3-cyanophenyl.
In an embodiment of this third aspect, the compound of this invention is represented by Formula (IE) or a pharmaceutically acceptable salt thereof, wherein
Xe is phenyl optionally substituted with 1-5 independent halogen, - CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORle, _NRleR2e, _ C(=NRle)NR2eR3e, -N(=NRle)NR2eR3e -NRleCOR2e, -N leC02R2e, -NRleSO2R4e, -NRleC0NR2eR3e,_SR4e, -SOR4e, -SO2R4e, -SO2NRleR2e, -CORle, -CO2Rle, -CONRleR2e, -C(=NRle)R2e, or -C(=NORle)R2e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xe; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rle, R2e, and R3e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6al yl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or-N(Cθ-
6alkyl)(aryl) substituents;
R4e is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Ae is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9eCO-Cθ-2alkyl- -Cθ-2alkyl-
NR9eSO2-Co-2alkyl- or -heteroCθ-4alkyl; Ye is 2-pyridyl optionally substituted with 1-4 independent halogen, -
CN, NO2, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5e, -NR5eR6e, -C(=NR5e)NR6eR7e, -N(=NR5e)NR6eR7e, -NR5ecOR6e, -NR5eC02R6e, -NR5esθ2R8e, -NR5ecONR6eR7e,_SR8e, -SOR8e, -SO2R8e, -SO2NR5eR6e, -COR5e, -CO2R5e, -CONR5eR6e, -C(=NR5e)R6e, or -C(=NOR5e)R6e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ye; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5e, R6e, and R7e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Q)- 6alkyl)(aryl) substituents;
R8e is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOecθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOesO2-Co-2alkyl-, or -heteroCθ-4alkyl; R9e and RlOe each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; Rl le and Rl2e is each independently halogen, -Cθ-6alkyl, -Cθ-
6alkoxyl, =O, =N(Cθ-4alkyl),or-N(Cθ-4alkyl)(Cθ-4alkyl); any alkyl optionally substituted with 1-5 independent halogen substituents, and any N may be an N-oxide; and provided that when Rl le = Rl2e = H and Ae = βe = Coalkyl, then Xe is not 3-cyanophenyl.
A compound of this invention is represented by Formula (IF):
Figure imgf000139_0001
(IF) or a pharmaceutically acceptable salt thereof, wherein: Xf is N, CH, or NH;
Yf is O, or N-R4f; one of Zl, Z2 , z3 or Z optionally is N, or NH; Rlf is -OH, halogen, or -CN; or a -Ci_6alkyl, -Cι_4alkoxyl, - cycloC3_6alkyl, -Cθ-4alkyl-phenyl, -Cθ-4alkyl-pyridyl, -Cθ-4alkyl-imidazolyl, - Cθ-4alkyl-pyrazolyl, -Cθ-4alkyl-triazolyl, -Cθ-4alkyl-tetrazolyl, -CQ-4alkyl- dioxolanyl, -Cθ-4alkyl-thiazolyl, -Cθ-4alkyl-piperidinyl, -Cθ-4alkyl-pyrrolidinyl, - Cθ-4alkyl-morpholinyl, -Cθ-4alkyl-ρyrimidinyl, -C2-6alkynyl-thiazolyl, or -N(Cθ- 4alkyl)(-Cθ-4alkyl) group, wherein any of the groups is optionally substituted with 1- 5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Cι_ 6alkyl, -Ci-4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, - Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is hydrogen, halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), - NO2; or -Ci_6alkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or-Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, -CN, or -Ci-4alkoxyl substituents;
R3f is hydrogen or -Ci-4alkoxyl;
R4f is -Co-4alkyl; and
R5f is H, halogen, or -Cι_4alkyl.
In one aspect, the compound of this invention is represented by Formula (IE) or a pharmaceutically acceptable salt thereof, wherein
Zl, Z2 z3, and Z4 are each CH;
Xf is N;
Yf is O;
Rlf is -OH, halogen, or -CN; or a -Cι_6alkyl, -Ci_4alkoxyl, - cycloC3-6alkyl, -Cθ-4alkyl-phenyl, -Cθ-4alkyl-pyridyl, -Cθ-4alkyl-imidazolyl, - Cθ-4alkyl-pyrazolyl, -Cθ-4alkyl-triazolyl, -Cθ-4alkyl-tetrazolyl, -Cθ-4alkyl- dioxolanyl, -Cθ-4alkyl-thiazolyl, -Cθ-4alkyl-piperidinyl, -Cθ-4alkyl-pyrrolidinyl, - Cθ-4alkyl-morpholinyl, -Cθ-4alkyl-pyrimidinyl, -C2-6alkynyl-thiazolyl, or -N(Cθ- 4alkyl)(-Cθ-4alkyl) group, wherein any of the groups is optionally substituted with 1- 5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Cι_ 6alkyl, -Cι_4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, - Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is hydrogen, halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), - NO2; or -Ci_6alkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, -CN, or -Cι_4alkoxyl substituents; R3f is hydrogen or -Ci-4alkoxyl; R4f is -Co-4alkyl; and R5f is H, halogen, or -Cι_4alkyl. In an embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Zl, Z2, Z3, and Z are each CH;
Xf is N; Yf is O;
Rlf is -Ci-βalkyl, optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci-6alkyl, -Cι_ 4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, -Cθ-4alkyl- morpholinyl, or -Cθ-4alkyl-benzoxazolyl; R2f is hydrogen, halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -
NO2; or -Cι_6alkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, -CN, or -Cι_4alkoxyl substituents; R3f is hydrogen or-Ci-4alkoxyl; R4f is -Co-4alkyl; and
R5f is H, halogen, or-Cι_4alkyl.
In another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein: Zl, Z2, Z3, and Z4 are each CH;
Xf is N; Yf is O;
Rlf is -Cι_6alkyl, optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci-6alkyl, -Cι_ 4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, -Cθ-4alkyl- morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is -Cθ-4alkyl-phenyl optionally substituted with 1-3 independently halogen, -OH, -CN, or -Cι_4alkoxyl substituents; R3f is hydrogen or -Ci-4alkoxyl; R4f is -Co-4alkyl; and
R5f is H, halogen, or -Ci-4alkyl.
In still another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein: Zl, Z2, Z3, and Z4 are each CH; Xf is N;
Yf is O;
Rlf is -Ci-galkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Cι_6alkyl, -Cι_4alkoxyl, - N(Co-4alkyl)(Co-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, -Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is hydrogen; or-Ci-6alkyl optionally substituted with 1-3 independently halogen, -OH, -CN, or-Ci_4alkoxyl substituents;
R3f is hydrogen or -Cι_4alkoxyl; R4f is -Co-4alkyl; and
R5f is H, halogen, or -Ci-4alkyl.
In still another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein: Zl , Z2, Z3, and Z are each CH;
Xf is N;
Yf is O;
Rlf is -Cι_6alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci-βalkyl, -Ci-4-dkoxyl, - N(Co-4alkyl)(Co-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, -Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is or -NO2; or -N(Cθ-4alkyl)(Cθ-4alkyl) optionally substituted with 1-3 independently halogen, -OH, -CN, or-Cι_4alkoxyl substituents;
R3f is hydrogen or -Cι_4alkoxyl; R4f is -Co-4alkyl; and
R5f is H, halogen, or -Ci_4alkyl.
In still another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein: Zl, Z2, z3, and Z4 are each CH;
Xf is N;
Yf is O;
Rlf is -C _6alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Cι_6alkyl, -Ci-4alkoxyl, - N(Co-4alkyl)(Co-4alkyl), -Co-4alkyl-C(O)-O-Co-4alkyl, -Co-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is -Cι_4alkoxy-phenyl optionally substituted with 1-3 independently halogen, -OH, -CN, or -Ci-4alkoxyl substituents; R f is hydrogen or -Cι_4alkoxyl;
R4f is -Co-4alkyl; and
R5f is H, halogen, or-Cι_4alkyl.
In still another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Zl, Z2, Z3, and Z4 are each CH;
Xf is N;
Yf is O;
Rlf is -Cι_6alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci-6alkyl, -Cι_4alkoxyl, - N(Co-4alkyl)(Co-4alkyl), -Co-4alkyl-C(O)-O-Co-4alkyl, -Co-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is -Cι_4alkoxyl optionally substituted with 1-3 independently halogen, -OH, -CN, or -Cι_4alkoxyl substituents; R3f is hydrogen or -C \ _4alkoxyl ;
R4f is -Co-4alkyl; and
R5f is H, halogen, or -Cι_4alkyl.
In still another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Zl, Z2, Z3, and Z4 are each CH;
Xf is N;
Yf is O;
Rlf is -cycloC3_6alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci_6alkyl, -Ci- 4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, -Cθ-4alkyl- morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -Cι_ 6alkyl, -Ci_4alkoxyl, -CQ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or-Cι_4alkoxyl substituents;
R3f is hydrogen or-Cι_4alkoxyl;
R4f is -Co-4alkyl; and R5f is H, halogen, or -Ci-4alkyl.
In another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Zl, Z2, Z3, and Z4 are each CH; Xf is N;
Yf is O;
Rlf is -Cθ-4alkyl-triazolyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci- 6alkyl, -Cι_4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, - Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -Cl- 6alkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or -Cι_4alkoxyl substituents; R3f is hydrogen or -Cι_4alkoxyl;
R4f is -Co-4alkyl; and
R5f is H, halogen, or -Cι_4alkyl.
In another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Zl, Z2, Z3, and Z4 are each CH;
Xf is N;
Yf is O;
Rlf is -Cθ-4alkyl-imidazolyl or -Cθ-4alkyl-pyrazolyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, - OH, -CN, -Ci-6alkyl, -Ci-4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)- O-Cθ-4alkyl, -Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -Cι_ 6alkyl, -Ci_4alkoxyl, -CQ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or-Ci_4alkoxyl substituents;
R3f is hydrogen or-Ci-4alkoxyl;
R4f is -Cθ-4alkyl; and R5 is H, halogen, or -C l -4alkyl.
In another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Zl, Z2, Z3, and Z are each CH; Xf is N;
Yf is O;
Rlf is -Cθ-4alkyl-tetrazolyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Cι_ 6alkyl, -Cι_4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, - Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or-Ci- 6alkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or-Ci_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or -C _4alkoxyl substituents; R is hydrogen or -C _4alkoxyl;
R4f is -Co-4alkyl; and
R5f is H, halogen, or-Ci-4alkyl.
In another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Zl, Z2, Z3, and Z4 are each CH;
Xf is N;
Yf is O;
Rlf is -Cθ-4alkyl-pyπolidinyl or -Cθ-4alkyl-piperidinyl, optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, - OH, -CN, -Ci_6alkyl, -Ci-4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)- O-Cθ-4alkyl, -Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -Cι_ 6alkyl, -Cι_4alkoxyl, -CQ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or -Cl_4alkoxyl substituents;
R3f is hydrogen or-Ci-4alkoxyl;
R4f is -Co-4alkyl; and R5f is H, halogen, or -Cι_4alkyl.
In another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Zl, Z2, Z3, and Z4 are each CH; Xf is N;
Yf is O;
Rlf is -Cθ-4alkyl-pyridyl or -Cθ-4alkyl-pyrimidinyl, optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, - OH, -CN, -Cι_6alkyl, -Ci-4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)- O-Cθ-4alkyl, -Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -Cι_ 6alkyl, -Ci-4alkoxyl, -Cθ-4alkyl-phenyl, or -Ci_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or-Ci_4alkoxyl substituents; R3f is hydrogen or -Cι_4alkoxyl;
R4f is -Co-4alkyl; and R5f is H, halogen, or -Cι_4alkyl.
In another embodiment of this one aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Zl, Z2, Z3, and Z4 are each CH; Xf is N; Yf is O;
Rlf is -Cθ-4alkyl-morpholinyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci- 6alkyl, -Cι_4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, - Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -Cι_ 6alkyl, -Ci_4alkoxyl, -CQ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or-Cι_4alkoxyl substituents;
R3f is hydrogen or -Ci-4alkoxyl;
R4f is -Co-4alkyl; and R5 is H, halogen, or -Ci-4alkyl.
In a second aspect of the invention, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein
Zl is N;
Xf is N; Yf is O;
R If is -OH, halogen, or -CN; or a -C i -δalkyl, -C 1 -4alkoxyl, - cycloC3_6alkyl, -Cθ-4alkyl-phenyl, -Cθ-4alkyl-pyridyl, -Cθ-4alkyl-imidazolyl, - Cθ-4alkyl-pyrazolyl, -Cθ-4alkyl-triazolyl, -Cθ-4alkyl-tetrazolyl, -Cθ-4alkyl- dioxolanyl, -Cθ-4alkyl-thiazolyl, -Cθ-4alkyl-piperidinyl, -Cθ-4alkyl-pyrrolidinyl, - Cθ-4alkyl-morpholinyl, -Cθ-4alkyl-pyrimidinyl, -C2-6alkynyl-thiazolyl, or -N(Cθ- 4alkyl)(-Cθ-4alkyl) group, wherein any of the groups is optionally substituted with 1- 5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci_ 6alkyl, -Cι_4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, - Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl; R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -Cι_
6alkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or -Ci-4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or -Cι_4alkoxyl substituents;
R3f is hydrogen or -Cι_4alkoxyl; R4f is -Co-4alkyl ; and
R5f is H, halogen, or -Ci-4alkyl.
In an embodiment of this second aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein Zl is N;
Xf is N;
Yf is O;
Rlf is -Cι_6alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Cι_6alkyl, -Cι_4alkoxyl, - N(Co-4alkyl)(Co-4alkyl), -Co-4alkyl-C(O)-O-Co-4alkyl, -Co-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -C\. 6alkyl, -Ci-4alkoxyl, -Cθ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or -Cι_4alkoxyl substituents;
R3f is hydrogen or -Ci_4alkoxyl; R4f is -Co-4alkyl; and R5f is H, halogen, or-Ci_4alkyl. In another embodiment of this second aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Zl is N;
Xf is N; Yf is O;
Rlf is -Cθ-4alkyl-pyridyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci-βalkyl, -Cι_ 4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, -Cθ-4alkyl- morpholinyl, or -Cθ-4alkyl-benzoxazolyl; R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -C i-
6alkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or -Cι_4alkoxyl substituents;
R3f is hydrogen or -C _4alkoxyl; R4f is -Co-4alkyl ; and
R5f is H, halogen, or -Cι_4alkyl.
In a third aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Z2 or Z3 is N; Xf is N;
Yf is O;
Rlf is -OH, halogen, or -CN; or a -Ci-6alkyl, -Cι_4alkoxyl, - cycloC3_6alkyl, -Cθ-4alkyl-phenyl, -Cθ-4alkyl-pyridyl, -Cθ-4alkyl-imidazolyl, - Cθ-4alkyl-pyrazolyl, -Cθ-4alkyl-triazolyl, -Cθ-4alkyl-tetrazolyl, -CQ-4alkyl- dioxolanyl, -Cθ-4alkyl-thiazolyl, -Cθ-4alkyl-piperidinyl, -Cθ-4alkyl-pyrrolidinyl, - Cθ-4alkyl-morpholinyl, -Cθ-4alkyl-pyrimidinyl, -C2-6alkynyl-thiazolyl, or -N(Cθ- 4alkyl)(-Cθ-4alkyl) group, wherein any of the groups is optionally substituted with 1- 5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Cχ_ 6alkyl, -Ci-4alkoxyl, -N(Co-4alkyl)(Co_4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, - Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or-Ci- 6alkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or -C 1 -4alkoxyl substituents ;
R3f is hydrogen or -Cι_4alkoxyl;
R4f is -Co-4alkyl; and
R5f is H, halogen, or -Cι_4alkyl.
In an embodiment of this third aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein
Z2 or Z3 is N;
Xf is N;
Yf is O;
Rlf is -Cθ-4alkyl-pyridyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C _6alkyl, -Cχ_ 4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, -Cθ-4alkyl- morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -Cι_ 6alkyl, -Ci_4alkoxyl, -Cθ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or -Cι_4alkoxyl substituents;
R3f is hydrogen or -Cι_4alkoxyl;
R4f is -Co-4alkyl; and
R5 is H, halogen, or -Ci_4alkyl. In a fourth aspect, the compound of this invention is represented by
Formula (IF) or a pharmaceutically acceptable salt thereof, wherein:
Zl, Z2, z3, and Z4 are CH2;
Xf is N;
Yf is O; Rlf is -OH, halogen, or -CN; or a -Cχ_6alkyl, -Cι_4alkoxyl, - cycloC3-6alkyl, -Cθ-4alkyl-phenyl, -Cθ-4alkyl-pyridyl, -Cθ-4alkyl-imidazolyl, - Cθ-4alkyl-pyrazolyl, -Cθ-4alkyl-triazolyl, -Cθ-4alkyl-tetrazolyl, -Cθ-4alkyl- dioxolanyl, -Cθ-4alkyl-thiazolyl, -Cθ-4alkyl-piperidinyl, -Cθ-4alkyl-pyrrolidinyl, - Cθ-4alkyl-morpholinyl, -Cθ-4alkyl-pyrimidinyl, -C2-6alkynyl-thiazolyl, or -N(Cθ- 4alkyl)(-Cθ-4alkyl) group, wherein any of the groups is optionally substituted with 1- 5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Cχ_ 6alkyl, -Cι_4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, - Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl; R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -Cι_
6alkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or -Ci-4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or-Cι_4alkoxyl substituents;
R3f is hydrogen or -Ci-4alkoxyl; R4fis -Co-4alkyl; and
R5f is H, halogen, or -Cι_4alkyl.
In an embodiment of this fourth aspect, the compound of this invention is represented by Formula (IF) or a pharmaceutically acceptable salt thereof, wherein: Zl, Z2, z3, and Z4 are CH2; Xf is N;
Yf is O;
Rlf is -Ci_6alkyl optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Ci-βalkyl, -Cι_4alkoxyl, - N(Co-4alkyl)(Co-4alkyl), -Co-4alkyl-C(O)-O-Co-4alkyl, -Co-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), -NO2; or -Cι_ 6alkyl, -Ci-4alkoxyl, -Cθ-4alkyl-phenyl, or -Ci-4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, - CN, or -Ci-4alkoxyl substituents; R3f is hydrogen or -Ci_4alkoxyl;
R4f is -Co-4alkyl; and
R5 is H, halogen, or -Coalkyl.
As used herein, "alkyl" as well as other groups having the prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other like terms include carbon chains containing at least one unsaturated C-C bond. The term "cycloalkyl" means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4- tetrahydronaphalene and the like. Similarly, "cycloalkenyl" means carbocycles containing no heteroatoms and at least one non-aromatic C-C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like. The term "aryl" means an aromatic substituent which is a single ring or multiple rings fused together. When formed of multiple rings, at least one of the constituent rings is aromatic. The prefeπed aryl substituents are phenyl and naphthyl groups. The term "cycloalkyloxy" unless specifically stated otherwise includes a cycloalkyl group connected by a short Cι_2alkyl length to the oxy connecting atom. The term "Cθ-6alkyl" includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. An alkyl with no carbon atoms is a hydrogen atom substituent when the alkyl is a terminal group and is a direct bond when the alkyl is a bridging group. The term "hetero" unless specifically stated otherwise includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms. The hetero atoms replace ring carbon atoms. Thus, for example, a heterocycloC5 alkyl is a five-member ring containing from 4 to no carbon atoms. Examples of heteroaryls include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl. Examples of heterocycloalkyls include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
The term "heteroCθ-4alkyl" means a heteroalkyl containing 4, 3, 2, 1, or no carbon atoms. However, at least one heteroatom must be present. Thus, as an example, a heteroCθ-4alkyl having no carbon atoms but one N atom would be a -NH- if a bridging group and a -NH2 if a terminal group. Analogous bridging or terminal groups are clear for an O or S heteroatom.
The term "amine" unless specifically stated otherwise includes primary, secondary and tertiary amines substituted with Cθ-6alkyl. The term "carbonyl" unless specifically stated otherwise includes a
Cθ-6alkyl substituent group when the carbonyl is terminal.
The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.
The term "optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring. Further, optionally substituted multiple moieties such as, for example, alkylaryl are intended to mean that the aryl and the aryl groups are optionally substituted. If only one of the multiple moieties is optionally substituted then it will be specifically recited such as "an alkylaryl, the aryl optionally substituted with halogen or hydroxyl."
Compounds described herein contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers. Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formulae IA-IF is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formulae IA-EF and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its coπesponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly prefeπed are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenedi amine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith. The terms "administration of" and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
The administration of the compound of structural formulae IA-IF in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formulae IA-IF to the subject in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors. The effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the subject suffers, the chosen route of administration other drugs and treatments which the subject may concomitantly require, and other factors in the physician's judgment. The utilities of the present compounds in these diseases or disorders may be demonstrated in animal disease models that have been reported in the literature. The following are examples of such animal disease models: a) suppression of food intake and resultant weight loss in rats (Life Sciences 1998, 63, 113-117); b) reduction of sweet food intake in marmosets (Behavioural Pharm. 1998, 9, 179-181); c) reduction of sucrose and ethanol intake in mice (Psychopharm. 1997, 132, 104- 106); d) increased motor activity and place conditioning in rats (Psychopharm. 1998, 135, 324-332; Psychopharmacol 2000, 151: 25-30); e) spontaneous locomotor activity in mice (J. Pharm. Exp. Ther. 1996, 277, 586-594); f) reduction in opiate self- administration in mice (Sci. 1999, 283, 401-404); g) bronchial hyperresponsiveness in sheep and guinea pigs as models for the various phases of asthma (for example, see W. M. Abraham et al., "0C4-Integrins mediate antigen-induced late bronchial responses and prolonged airway hypeπesponsiveness in sheep." J. Clin. Invest. 93, 776 (1993) and A. A. Y. Milne and P. P. Piper, "Role of NLA-4 integrin in leucocyte recruitment and bronchial hypeπesponsiveness in the gunea-pig." Eur. J. Pharmacol., 282, 243 (1995)); h) mediation of the vasodilated state in advanced liver ciπhosis induced by carbon tetrachloride (Nature Medicine, 2001, 7 (7), 827-832); i) amitriptyline-induced constipation in cynomolgus monkeys is beneficial for the evaluation of laxatives (Biol. Pharm. Bulletin (Japan), 2000, 23(5), 657-9); j) neuropathology of paediatric chronic intestinal pseudo-obstruction and animal models related to the neuropathology of paediatric chronic intestinal pseudo-obstruction (Journal of Pathology (England), 2001, 194 (3), 277-88).
The magnitude of prophylactic or therapeutic dose of a compound of Formulae IA-IF will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formulae IA-IF and its route of administration. It will also vary according to the age, weight and response of the individual subject. In general, the daily dose range lies within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
For use where a composition for intravenous administration is employed, a suitable dosage range is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Formulae IA-IF per kg of body weight per day and for preventive use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of Formulae IA-IF per kg of body weight per day.
In the case where an oral composition is employed, a suitable dosage range is, e.g. from about 0.01 mg to about 1000 mg of a compound of Formulae IA-IF per day, preferably from about 0.1 mg to about 10 mg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. Another aspect of the present invention provides pharmaceutical compositions which comprises a compound of Formulae IA-IF and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formulae IA-IF, additional active ingredient(s), and pharmaceutically acceptable excipients.
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
The pharmaceutical compositions of the present invention comprise a compound of Formulae IA-IF as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In particular, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The prefeπed delivery systems for inhalation are metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formulae IA-IF in suitable propellants, such as fluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol, which may be formulated as a dry powder of a compound of Formulae IA-IF with or without additional excipients. Suitable topical formulations of a compound of formulae IA-IF include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like. The topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle. Transdermal skin patches useful for administering the compounds of the present inveniton include those well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. In practical use, the compounds of Formulae IA-IF can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being prefeπed over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, the compounds of Formulae IA-IF may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion, incluidng elixirs, tinctures, solutions, suspensions, syrups and emulsions. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated, and each cachet or capsule contains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
Additional suitable means of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular and topical, with or without occlusion. Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
The dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration, the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be coπespondingly larger for the less frequent administration.
When administered via intranasal routes, transdermal routes, by rectal or vaginal suppositories, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The following are examples of representative pharmaceutical dosage forms for the compounds of Formulae IA-IF:
Injectable Suspension (I.M.) mg/mL
Compound of Formula ID 10
Methylcellulose 5.0
Tween 80 0.5 Benzyl alcohol 9.0
Benzalkonium chlori.de 1.0
Water for injection to a total volume of 1 mL
Tablet mg/tablet Compound of Formula IE 25
Microcrystalline Cellulose 415
Povidone 14.0
Pregelatinized Starch 43.5
Magnesium Stearate 2.5 500
Capsule mg/capsule
Compound of Formula IA 25 Lactose Powder 573.5 Magnesium Stearate 1.5
600 Aerosol Per canister
Compound of Formula IBb 24 mg
Lecithin, NF Liq. Cone. 1.2 mg
Trichlorofluoromethane, NF 4.025 g
Dichlorodifluoromethane, NF 12.15 g
The mGluR5 modulators, and particularly the mGluR5 antagonist compounds of formulae IA to IF may be employed with other drugs that are used in the treatment/prevention/suppression or amelioration of obesity and obesity-related conditions. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with the mGluR5 modulator compound. When the mGluR5 modulator compound is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the mGluR5 modulator compound is prefeπed. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a mGluR5 modulator compound. Examples of other active ingredients that may be combined with a mGluR5 modulator compound include, but are not limited to those agents useful in treating obesity and obesity-related conditions described below. In a further aspect of the present invention, there is provided a pharmaceutical composition comprising an mGluR5 modulator and one or more active ingredients useful in treating obesity and obesity related conditions, together with at least one pharmaceutically acceptable carrier or excipient. Thus, according to a further aspect of the present invention there is provided the use of a mGluR5 modulator compound and one or more compounds useful in treating obesity or obesity related conditions for the manufacture of a medicament for the treatment or prevention of obesity or obesity related conditions. In a further or alternative aspect of the present invention, there is therefore provided a product comprising a mGluR5 modulator compound and one or more active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of obesity or obesity-related conditions. Such a combined preparation may be, for example, in the form of a twin pack. It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents. The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a subject in need of such treatment an amount of a mGluR5 modulator compound and an amount of an anorectic agent, such that together they give effective relief.
Suitable anoretic agents for use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
A particularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof. Particularly prefeπed halogenated amphetamine derivatives of use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof. It will be appreciated that for the treatment or prevention of obesity, the mGluR5 modulator compounds may also be used in combination with a selective serotonin reuptake inhibitor (SSRI). Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine, sertraline, and imipramine, and pharmaceutically acceptable salts thereof.
It will be appreciated that for the treatment or prevention of obesity, mGluR5 modulators may also be used in combination with an opioid antagonist. Suitable opioid antagonists of use in combination with an mGluR5 modulator include: naltrexone, 3-methoxynaltrexone, naloxone and nalmefene, and pharmaceutically acceptable salts thereof.
It will be appreciated that for the treatment or prevention of diseases related to excessive food intake including obesity and obesity related conditions including diabetes, mGluR5 modulators may also be used in combination with another anti-obesity agent. The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a subject in need of such treatment an amount of an nιGluR5 modulator and an amount of another anti-obesity agent, such that together they give effective relief. Suitable anti-obesity agents of use in combination with an mGluR5 modulator, include, but are not limited to:
(a) insulin sensitizers including (i) PPARγ antagonists such as glitazones (e.g. ciglitazone; darglitazone; englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641 , and LY-300512, and the like), and compounds disclosed in WO97/10813, 97/27857, 97/28115, 97/28137, and 97/27847; (ii) biguanides such as metformin and phenformin;
(b) insulin or insulin mimetics, such as biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7) (insulintropin); and GLP-1 (7-36)-NH2);
(c) sulfonylureas, such as acetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide; glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide;
(d) α-glucosidase inhibitors, such as acarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q; salbostatin; CKD-711; MDL-25,637;
MDL-73,945; and MOR 14, and the like;
(e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, and other statins), (ii) bile acid absorbers/sequestrants, such as cholestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran; Colestid®; LoCholest®, and the like, (ii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iii) proliferator-activater receptor agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (iv) inhibitors of cholesterol absorption such as stanol esters, beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones such as ezetimibe, and the like, and (acyl CoA:cholesterol acyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide, (v) anti- oxidants, such as probucol, (vi) vitamin E, and (vii) thyromimetics;
(f) PPARα agonists such as beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; and other fibric acid derivatives, such as Atromid®, Lopid® and Tricor®, and the like, and PPARα agonists as described in WO 97/36579 by Glaxo;
(g) PPARδ agonists, such as those disclosed in WO97/28149; and
(h) antiobesity agents such as: 1) growth hormone secretagogues, such as those disclosed and specifically described in U.S. Patent 5,536,716; 2) growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, MK- 0677, SM-130686, CP-424,391, L-692,429 and L-163,255, and such as those disclosed in U.S. Patent No. 6,358,951, U.S. Patent Application Nos. 2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO 02/32888; 3) melanocortin agonists, such as Melanotan II or those described in WO 99/64002 and WO 00/74679; 4) Mc4r (melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), and those disclosed in PCT Application Nos. WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715, and WO 02/12178; 5) β-3 agonists, such as AD9677/TAK677 (Dainippon/Takeda), CL- 316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,
CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A, and such as those disclosed in U.S. Patent Application Nos. 5,705,515, and US 5,451,677 and PCT Patent Publications WO94/18161, WO95/29159, WO97/46556, WO98/04526 and WO98/32753, WO 01/74782, and WO 02/32897; 6) 5HT-2 agonists; 7) 5HT2C (serotonin receptor 2C) agonists, such as BVT933, DPCA37215, WAY161503, R- 1065, and those disclosed in U.S. Patent No. 3,914,250, and PCT Application Nos. WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; 8) orexin antagonists, such as SB- 334867-A, and those disclosed in PCT Patent Application Nos. WO 01/96302, WO 01/68609, WO 02/51232, WO 02/51838 and WO 02/090355; 9) melanin concentrating hormone antagonists; 10) melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, WO 02/51809 and WO 02/083134, and Japanese Patent Application No. JP 13226269; 11) melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists; 12) galanin antagonists; 13) CCK agonists; 14) CCK-A (cholecystokinin -A) agonists, such as AR-R 15849, Gl 181771, JMV-180, A-71378, A-71623 and SR146131, and those discribed in U.S. Patent No. 5,739,106; 15) GLP-1 agonists; 16) corticotropin- releasing hormone agonists; 17) NPY 5 antagonists, such as GW-569180A, GW- 594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384,
1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR- 120819A and JCF-104, and those disclosed in U.S. Patent Nos. 6,140,354, 6,191,160, 6,313,298, 6,337,332, 6,329,395, 6,326,375, 6,335,345, and 6,340,683, European Patent Nos. EP-01010691, and EP-01044970, and PCT Patent Publication Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; 18) NPY 1 antagonists, such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI- 264879 A, and those disclosed in U.S. Patent No. 6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; 19) histamine receptor-3 (H3) modulators; 20) histamine receptor-3 (H3) antagonists/inverse agonists, such as hioperamide, 3-(lH-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and those described and disclosed in PCT Application No. WO 02/15905, and O-[3-(lH-imidazol-4-yl)propanol]- carbamates (Kiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000)), piperidine- containing histamine H3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32 (2001), benzophenone derivatives and related compounds (Sasse, A. et al., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substituted N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)), and proxifan derivatives (Sasse, A. et al., J. Med. Chem.. 43:3335-43 (2000)); 21) β-hydroxy steroid dehydrogenase- 1 inhibitors (β-HSD-1); 22) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast; 23) phosphodiesterase-3B (PDE3B) inhibitors; 24) NE (norepinephrine) transport inhibitors, such as GW 320659, despiramine, talsupram, and nomifensine; 25) non-selective serotonin/norepinephrine transport inhibitors, such as sibutramine or fenfluramine; 26) ghrelin antagonists, such as those disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250; 27) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); 28) leptin derivatives, such as those disclosed in U.S. Patent Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283, and PCT International Publication Nos. WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, and WO 96/23520; 29) BRS3 (bombesin receptor subtype 3) agonists; 30) CNTF (Ciliary neurotrophic factors), such as Gl- 181771 (GlaxoSmithKline), SR146131 (Sanofi Synthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); 31) CNTF derivatives, such as axokine (Regeneron), and those disclosed in PCT Application Nos. WO 94/09134, WO 98/22128, and WO 99/43813; 32) monoamine reuptake inhibitors, such as those disclosed in PCT Application Nos. WO 01/27068, and WO 01/62341; 33) UCP-1 (uncoupling protein-1), 2, or 3 activators, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- napthalenyl)-l-propenyl]benzoic acid (TTNPB), retinoic acid, and those disclosed in PCT Patent Application No. WO 99/00123; 34) thyroid hormone β agonists, such as KB-2611 (KaroBioBMS), and those disclosed in PCT Application No. WO 02/15845, and Japanese Patent Application No. JP 2000256190; 35) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75; 36) DGAT1 (diacylglycerol acyltransferase 1) inhibitors; 37) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; 38) ACC2 (acetyl-CoA carboxylase-2) inhibitors; 39) glucocorticoid antagonists; 40) acyl- estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); 41) lipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferyl phosphate, and those disclosed in PCT Application No. WO 01/77094; 42) fatty acid transporter inhibitors; 43) dicarboxylate transporter inhibitors; 44) glucose transporter inhibitors; 45) phosphate transporter inhibitors; 46) serotonin reuptake inhibitors, such as those disclosed in U.S. Patent Application No. 6,365,633, and PCT Patent Application Nos. WO 01/27060, and WO 01/162341; 47) Metformin (Glucophage®); 48) Topiramate (Topimax®); and/or cannabinoid receptor 1 (CB-1) antagonist/inverse agonists, such as rimonabant (Sanofi Synthelabo), and SR-147778 (Sanofi
Synthelabo), and those disclosed in U.S. Patent Nos. 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765, WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061, WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, and EPO Application No. EP-658546.
Specific NPY5 antagonists of use in combination with an mGluR5 modulator are selected from the group consisting of: (1) 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-l(3H),4'- piperidine]-l '-carboxamide,
(2) 3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro- [isobenzofuran- 1 (3H),4' -piperidine]- 1 ' -carboxamide,
(3) N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran- 1 (3H),4' -piperidine]- 1 ' -carboxamide,
(4) trans-3 ' -oxo-N-(5 -phenyl-2-pyrimidinyl)spiro [cyclohexane- 1 , 1 ' (3 ' H)- isobenzofuran]-4-carboxamide,
(5) trans-3 ' -oxo-N- [ 1 -(3 -quinolyl)-4-imidazolyl] spiro [cyclohexane- 1 , 1 ' (3 ' H)-isobenzofuran]-4-carboxamide, (6) trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-
1 (3H), 1' -cyclohexane] -4' -carboxamide,
(7) trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5- azaisobenzofuran- 1 (3H), 1 ' -cyclohexane]-4' -carboxamide,
(8) trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5- azaisobenzofuran-l(3H), -cyclohexane]-4'-carboxamide,
(9) trans-N- [ 1 -(3 ,5-difluorophenyl)-4-imidazolyl] -3 -oxospiro [7- azaisobenzofuran-l(3H), 1 ' -cyclohexane] -4' -carboxamide,
(10) trans-3-oxo-N-(l-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran- 1 (3H), 1' -cyclohexane] -4' -carboxamide, (11) trans-N-[l-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6- azaisobenzofuran-l(3H), -cyclohexane]-4'-carboxamide,
(12) trans-3-oxo-N-(l-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran- 1 (3H), 1 ' -cyclohexane]-4'-carboxamide,
(13) trans-3-oxo-N-(2-phenyl-l,2,3-triazol-4-yl)spiro[6-azaisobenzofuran- l(3H), -cyclohexane]-4'-carboxamide, and pharmaceutically acceptable salts and esters thereof.
It will be appreciated that for the treatment or prevention of obesity, mGluR5 modulators may also be used in combination with inhibitors of the enzyme llβ-HSDl. Generally, glucocorticoid concentrations are modulated by tissue-specific llβ-hydroxysteroid dehydrogenase enzymes. The llβ-hydroxysteroid dehydrogenase type 1 enzyme (llβ-HSDl) is a low affinity enzyme that generally uses NADP+ as a cof actor rather than NAD+ (Agarwal et al, 1989). In vitro studies have shown that 11 β-HSDl is capable of acting as both a reductase and a dehydrogenase. However, 11 β-HSDl in vivo generally acts as a reductase, converting 11-ketoglucocorticoids, such as cortisone, to llβ-hydroxyglucocorticoids such as cortisol.
Excessive levels of cortisol have been associated with obesity, perhaps due to increased hepatic gluconeogenesis. Thus, the administration of an effective amount of an llβ-HSDl inhibitor in combination with an mGluR modulator may be useful in the treatment or control of obesity. Particular inhibitors of 11 β-HSDl useful in combination with the compounds of the present invention include: 3-(l- adamantyl)-4-ethyl-5-(ethylthio)-4H-l,2,4-triazole, 3-(l-adamantyl)-5-(3,4,5- trimethoxyphenyl)-4-methyl-4H-l,2,4-triazole, and 3-adamantanyl- 4,5,6,7,8,9,10,ll,12,3a-decahydro-l,2,4-triazolo[4,3-a][ll]annulene. "Obesity" is a condition in which there is an excess of body fat. The operational definition of obesity is based on the Body Mass Index (BMI), which is calculated as body weight per height in meters squared (kg/m2). "Obesity" refers to a condition whereby an otherwise healthy subject has a Body Mass Index (BMI) greater than or equal to 30 kg/m2, or a condition whereby a subject with at least one co- morbidity has a BMI greater than or equal to 27 kg/m2. An "obese subject" is an otherwise healthy subject with a Body Mass Index (BMI) greater than or equal to 30 kg/m2 or a subject with at least one co-morbidity with a BMI greater than or equal to 27 kg/m2. A "subject at risk for obesity" is an otherwise healthy subject with a BMI of 25 kg/m2 to less than 30 kg/m2 or a subject with at least one co-morbidity with a BMI of 25 kg/m2 to less than 27 kg/m2.
The increased risks associated with obesity occur at a lower Body Mass Index (BMI) in Asians. In Asian countries, including Japan, "obesity" refers to a condition whereby a subject with at least one obesity-induced or obesity-related co- morbidity that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/m2. In Asian countries, including Japan, an "obese subject" refers to a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m2. In Asian countries, a "subject at risk of obesity" is a subject with a BMI of greater than 23 kg/m2 to less than 25 kg/m2. As used herein, the term "obesity" is meant to encompass all of the above definitions of obesity.
Obesity-induced or obesity-related co-morbidities include, but are not limited to, diabetes, non-insulin dependent diabetes mellitus - type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, and infertility. In particular, co-morbidities include: hypertension, hyperlipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea, diabetes mellitus, and other obesity-related conditions.
"Treatment" (of obesity and obesity-related disorders) refers to the administration of the compounds of the present invention to reduce or maintain the body weight of an obese subject. One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds of the present invention. Another outcome of treatment may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases. The treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in subjects in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.
"Prevention" (of obesity and obesity-related disorders) refers to the administration of the compounds of the present invention to reduce or maintain the body weight of a subject at risk of obesity. One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Another outcome of prevention may be decreasing the occunence and/or severity of obesity- related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Moreover, if treatment is commenced in already obese subjects, such treatment may prevent the occunence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
The obesity-related disorders herein are associated with, caused by, or result from obesity. Examples of obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and aπythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer. The compounds of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.
The term "diabetes," as used herein, includes both insulin- dependent diabetes mellitus (i.e., IDDM, also known as type I diabetes) and non- insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type II diabetes. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type II diabetes, or insulin-independent diabetes (i.e., non-insulin-dependent diabetes mellitus), often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese. The compounds of the present invention are useful for treating both Type I and Type II diabetes. The compounds are especially effective for treating Type II diabetes. The compounds of the present invention are also useful for treating and/or preventing gestational diabetes mellitus. The method of treatment of this invention comprises a method of modulating the mGluR5 receptor and treating diseases related to excessive food intake by administering to a subject in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the mGluR5 receptor in preference to the other receptors. The term "therapeutically effective amount" means the amount the compound of structural formulae IA-IF that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated. The novel methods of treatment of this invention are for disorders known to those skilled in the art. The term "subject" generally refers to a mammal, and in a particular embodiment of the present invention is a human.
The weight ratio of the compound of the Formulae IA-IF to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formulae IA-IF is combined with a β-3 agonist the weight ratio of the compound of the Formulae IA-IF to the β-3 agonist will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formulae IA-IF and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.
Figure imgf000171_0001
Figure imgf000172_0001
ALKYL GROUP ABBREVIATIONS
Figure imgf000172_0002
Figure imgf000173_0001
The examples that follow are intended as an illustration of certain prefeπed embodiments of the invention and no limitation of the invention is implied. Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room or ambient temperature - that is, at a temperature in the range of 18-25°C. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600- 4000pascals: 4.5-30mm. Hg) with a bath temperature of up to 60°C. The course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only. Melting points are uncorrected and 'd' indicates decomposition. The melting points given are those obtained for the materials prepared as described. Polymorphism may result in isolation of materials with different melting points in some preparations. The structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data. When given, yields are for illustration only. When given, NMR data is in the form of delta (δ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300MHz, 400MHz or 500MHz using the indicated solvent. Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc. In addition, "Ar" signifies an aromatic signal. Chemical symbols have their usual meanings; the following abbreviations are used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)),mL (milliliters), g (gram(s)),mg (milligrams (s)), mol (moles), mmol (millimoles), eq (equivalent(s)).
Methods of synthesizing the mGluR5 antagonists of formula IA-IF:
Following are methods for the preparation of the mGluR5 antagonists described above. For example, many of the heterocyclic compounds described above can be prepared using synthetic chemistry techniques well known in the art (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., Pergamon Press, Oxford, 1984). Methods of Synthesis of compounds of Formula IA
Compounds of Formula IA can be prepared according to the following methods. The substituents are the same as in Formula IA except where defined otherwise, or apparent to one in the art.
In Schemes Al to A5 below, Xa and Ya are as defined above. Other variables are understood by one in the art by the context in which they are used.
Scheme Al
Figure imgf000174_0001
Thus in Scheme Al, ring system Xa ontaining an aniline moiety
(prepared using synthetic chemistry techniques well known in the art) is reacted with a 1,4-dicarbonyl or its equivalent in a suitable solvent (e.g. EtOH, THF, DME, DMF etc.) at a temperature between 30°C to 150°C for 1 to 18h to form a substituted pyrrole. In turn, the 3-position of the pyπole is derivatized with a functional group Aa, such as a halogen or trifluoromethanesulfonate and the like, which is capable of undergoing a metal-catalyzed cross-coupling reaction. For example, the group Aa may be a bromine atom which may be installed using bromotrimethylsilane (see for example Pagnoni, U.G.; Pinetti, A. J.Heterocycl.Chem. 1993, 30, 617-621).
Scheme A2
Figure imgf000174_0002
In turn, the derivatized pyπole is reacted with a moiety Ya under metal-catalyzed cross-coupling conditions (Scheme A2) where E is a metallic or metalloid species such as B(OR)2,Li, MgHal, SnR3, ZnHal, SiR3 and the like which is capable of undergoing a metal-catalyzed cross-coupling reaction. The coupling may be promoted by a homogeneous catalyst such as Pd(PPh3)4, or by a heterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g. THF, DME, toluene, MeCN, DMF, H2O etc.). Typically a base, such as K2CO3, NEt3, and the like, will also be present in the reaction mixture. Other promoters may also be used such as CsF. The coupling reaction is typically allowed to proceed by allowing the reaction temperature to warm slowly from about 0°C up to rt over a period of several hours. The reaction mixture is then maintained at rt, or heated to a temperature anywhere between 30°C to 150°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 48h, with about 18h typically being sufficient (see for example Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483). The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like. Another embodiment of the present invention is illustrated in Scheme A3. Scheme A3
Figure imgf000175_0001
Thus, the free ring nitrogen in an optionally substituted pyrrole (prepared using synthetic chemistry techniques well known in the art) is protected with a group P, where P may be a trialkyl- or triaryl silane, arylsulfonyl or alkyl carbamate protecting group and the like. In turn, the 3-position of the pyπole is derivatized with a functional group Aa, such as a halogen or trifluoromethanesulfonate and the like, which is capable of undergoing a metal- catalyzed cross-coupling reaction. For example, the group Aa may be an iodine which maybe installed using molecular iodine and mercuric acetate (see for example Bray, B. L. et al. J. Org. Chem. 1990, 55, 6317-6328). Scheme A4
Figure imgf000176_0001
In turn, the derivatized pyπole is reacted with a moiety Y under metal-catalyzed cross-coupling conditions (Scheme A4) where E is a metallic or metalloid species such as B(OR)2, ZnHal, Li, MgHal, SnR3, S1R3 and the like which is capable of undergoing a metal-catalyzed cross-coupling reaction. The coupling may be promoted by a homogeneous catalyst such as Pd(PPh3)4, or by a heterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g. THF, DME, toluene, MeCN, DMF, H2O etc.). If required a base, such as K2CO3, NEt3, and the like, will also be present in the reaction mixture. Other promoters may also be used such as CsF. The coupling reaction is typically allowed to proceed by allowing the reaction temperature to warm slowly from about 0°C up to rt over a period of several hours. The reaction mixture is then maintained at rt, or heated to a temperature anywhere between 30°C to 150°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 48h, with about 18h typically being sufficient (see for example: Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483 or Negishi, E.; Liu, F. Palladium or Nickel catalyzed Cross-coupling with Organometals Containing Zinc, Magnesium, Aluminium and Zirconium. In Metal-catalyzed Cross-coupling Reactions Diederich, F.; Stang, P.J. Eds. Wiley, Weinheim, Germany, 1998; ppl-42). The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like.
Scheme A5
Figure imgf000176_0002
As shown in Scheme A5, the pyrrole may then be coupled with a species Xa substituted with a group Ba. Ba may be a good aryl leaving group such as F, and Xa is electron deficient or has one or more electron withdrawing substituents (e.g. NO2, CN etc.), the coupling reaction may be effected thermally in a temperature range of about 60°C up to about 250°C. Typically, this reaction is carried out in the presence of base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) in a suitable solvent, such as DMSO, DMF, DMA H2O and the like, and takes from lh up to about 72h with 18h typically being sufficient (see for example Russell, S. S.; Jahangir; Synth.Commun. 1994, 24, 123-130). Alternatively, B may be a good leaving group capable of undergoing a metal-catalyzed cross-coupling reaction such as a halogen or trifluoromethanesulfonate and the like. Typically, the reaction is carried out using catalytic amounts of a copper (I) salt together with a diamine ligand and in the presence of a suitable base (e.g. K3PO4, CS2CO3, K2CO3 etc.) in a suitable solvent, such as Dioxane, DMSO, DMA, DMF (see for example Klapers, A.; Antilla, J.C.; Huang, X.; Buchwald, S.L J. Am. Chem Soc. 2001, in press).
In addition, many of the heterocyclic compounds described above can be prepared using other synthetic chemistry techniques well known in the art (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., Pergamon Press, Oxford, 1984) and references cited there within.
COMPOUND Al Synthesis of 2-(3-bromo-lH-pyrrol-l-yl)pyridine
Bromotrimethylsilane (10.9mL, 84mmol) was added to DMSO (5.7mL, 84mmol) in MeCN (200mL) at 0°C. After stirring for lOmin, 2-(lH-pyrrol-l-yl)pyridine (lOg, 70mmol) in MeCN (50mL) was added. The reaction mixture was stined at 0°C and allowed to reach rt over 3h. H2O (150mL) and EtOAc (150mL) were added and the reaction mixture was shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (3xl50mL). The combine organic layers were dried over Na2SO4 and concentrated to a brown oil. LCMS indicated good conversion to 2-(3- bromo-lH-pyrrol-l-yl)pyridine and this was used without further purification. (MS (ESI) 224 (M+Η) +
EXAMPLE Al Synthesis of 3-(l-pyridin-2-yl-lH-pyrrol-3-yl)benzonitrile
2-(3-Bromo-lH-pyrrol-l-yl)pyridine (1.34g, 2mmol), 3-cyanophenylboronic acid (0.59g, 4mmol), Pd(PPh3)4 (116mg, O.lmmol) and potassium carbonate (560mg, 4mmol) were dissolved in a mixture of DME (18mL) and Η2O (2mL) and degassed for 15min with Ar (g). The reaction mixture was then heated at 84°C for 18h. At this time, a further 0.25eq. of 3-cyanophenylboronic acid (0.15g, Immol) was added and heating was continued. After a total of 42h, the reaction mixture was cooled to rt, H2O (40mL) and EtOAc (40mL) were added and the reaction mixture shaken, the
EtOAc layer was separated and the aqueous layer shaken with EtOAc (2 x 30mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow oil. This was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (3:7) to afford a white waxy solid that was further purified by liquid chromatography on silica gel eluting with dichloromethane to afford 3-(l-pyridin-2- yl-lH-pyπol-3-yl)benzonitrile as a colorless oil. lΗ NMR (CD3CI, 300 MHz) δ 8.49 - 8.52 (IH, m), 7.66 (IH, ddd), 7.47 - 7.51 (2H, m), 7.33 - 7.39 (3H, m), 7.24 (IH, ddd), 6.91 (IH, d), 6.51 - 6.52 (IH, m), 6.43 (IH, dd). MS (ESI) 246 (M+H) +
EXAMPLE A2 Synthesis of 2-r3-(3-chlorophenyl)-lH-pyrrol-l-vnpyridine 2-(3-Bromo-lH-pyπol-l-yl)pyridine (1.34g, 2mmol), 3-chlorophenylboronic acid (0.62g, 4mmol), Pd(PPh3)4 (116mg, O.lmmol) and potassium carbonate (560mg, 4mmol) were dissolved in a mixture of DME (18mL) and Η2O (2mL) and degassed for 15min with Ar (g). The reaction mixture was then heated at 84°C for 18h. At this time, a further 0.25eq. of 3-chlorophenylboronic acid (0.16g, Immol) was added and heating was continued. After a total of 42h, the reaction mixture was cooled to rt, H2O (40mL) and EtOAc (40mL) were added and the reaction mixture shaken, the
EtOAc layer was separated and the aqueous layer shaken with EtOAc (2 x 30mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow oil. This was purified by liquid chromatography on silica gel eluting with EtOAc :hexane (3:7) to afford a white solid that was further purified by preparative HPLC to afford 2-[3-(3-chlorophenyl)-lH-pynol-l-yl]pyridine as a white solid. lΗ NMR (CD3CI, 300 MHz) δ 8.52 - 8.54 (IH, m), 7.61 (IH, ddd), 7.35 - 7.37 (IH, m),
7.28 (IH, s), 7.15 - 7.24 (3H, m), 6.99 (IH, ddd), 6.86 (IH, d), 6.47 - 6.48 (IH, m),
6.41 (IH, dd). ). MS (ESI) 255 (M+H) + EXAMPLE A3
Synthesis of 2 3-(3-methoχyphenviπH-pyrrol-l-yllpyridine
2-(3-Bromo-lH-pyrrol-l-yl)pyridine (1.34g, 2mmol), 3-methoxyphenylboronic acid (0.61g, 4mmol), Pd(PPh3)4 (116mg, O.lmmol) and potassium carbonate (560mg, 4mmol) were dissolved in a mixture of DME (18mL) and Η2O (2mL) and degassed for 15min with Ar (g). The reaction mixture was then heated at 84°C for 18h. At this time, a further 0.25eq. of 3-methoxyphenylboronic acid (0.15g, Immol) was added and heating was continued. After a total of 42h, the reaction mixture was cooled to rt, H2O (40mL) and EtOAc (40mL) were added and the reaction mixture shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (2x30mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow oil.
This was purified by liquid chromatography on silica gel eluting with EtOAc :hexane (3:7) to afford a white solid that was further purified by preparative HPLC to afford 2- [3-(3-methoxyphenyl)-lH-pyπol-l-yl]pyridine as a white solid. lΗ NMR (CD3CI, 300 MHz) δ 8.52 - 8.54 (IH, m), 7.55 (IH, ddd), 7.38 - 7.39 (IH, m), 7.15 - 7.21 (2H, m), 6.76 - 6.85 (4H, m), 6.46 - 6.48 (IH, m), 6.41 (IH, dd). MS (ESI) 251 (M+H) +
COMPOUND A2 Synthesis of S-iodo-l-CtriisopropylsilyD-lH-pyrroIe
3-Iodo-l-(triisopropylsilyl)-lH-pynole was prepared according to the method of Bray, B.L. et al. J. Org. Chem. 1990, 55, 6317-6328.
COMPOUND A3 Synthesis of 2-ri-(triisopropyIsilyl)-lH-pyrroI-3-vπpyridine
A solution of 3-iodo-l-(triisopropylsilyl)-lH-pyrrole (l.Og, 2.87mmol), triphenylphosphine (27 mg, 0.103 mmol), and tetrakis(triphenylphosphine)palladium(0) (80mg, 0.069mmol) in TΗF (20mL) was degassed with Ar (g) for 15min, then 2-bromo(pyridin-2-yl)zinc (11.5mL of 0.5M solution, 5.74mmol) was added and degassing continued a furtherl5min. The reaction was stiπed at 70°C for 5h and monitored by LC/MS. The reaction mixture was quenched with Η2O (40mL) then extracted with EtOAc (3 x 25mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and the crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:9) to afford 2-[l-(triisopropylsilyl)-lH-pyrrol-3- yl]pyridine as a clear oil which was used below without further purification.
COMPOUND A4 Synthesis of 2-(lHr-pyrrol-3-yl)pyridine
To a solution of 2-[l-(triisopropylsilyl)-lH-pyrrol-3-yl]pyridine (lg, 3.2mmol) in anhydrous TΗF (15mL) was added TBAF (3.84mL of a IM solution in TΗF, 3.84mmol). After stirring for lOmin. at rt, the reaction was complete. The reaction mixture quenched with Η2O (40mL), extracted with EtOAc (3 x 25mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and chromatographed on silica gel eluting with
EtOAc:hexane (1:1) to afford 2-(lH-pyrrol-3-yl)pyridine as a solid. lΗ NMR (CD3CI, 300 MHz) δ 8.55 (ddd, IH), 7.65 (dt, IH), 7.54 (dd, IH), 7.46-7.43 (d, IH),
7.07 (ddd, IH), 6.85 (dd, IH), 6.74 (dd, IH). MS (ESI) 145.1 (M++H).
EXAMPLE A4
Synthesis of 3-(3-pyridin-2-yl-lH-pyrrol-l-yl)benzonitrile
2-(lH-Pyπol-3-yl)pyridine (0.144g, l.Ommol), 3-fluorobenzonitrile (1.21g, lOmmol), and potassium carbonate (0.0.276g, 2mmol) were heated at 145°C in DMF (0.5mL) for 14h. After this time, the reaction mixture was cooled to rt and quenched with Η2O (30mL). The mixture was extracted with EtOAc (3x25mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and the residue was chromatographed on silica gel eluting with EtOAc:hexane (2:3) to afford a white solid which was recrystallized from dichloromethane-hexane to give 3-(3-pyridin-2-yl-lH-pynol-l-yl)benzonitrile as white crystals. lΗ NMR (CD3CI, 300 MHz) δ 8.59 (ddd, IH), 7.78-7.71 (m, 3H),
7.68 (dd, IH), 7.62-7.53 (m, 3H), 7.17-7.11 (m, 2H), 6.89 (dd, IH). MS (ESI) 246.1 (M++H).
EXAMPLE A5
Synthesis of 2-{ 1 - r3-(trifluoromethyI)phenvπ - lH-py rrol-3- yllpyridine hydrochloride
Following the procedure described in EXAMPLE A4, 2-(lH-pyrrol-3-yl)pyridine (0.072g, 0.50mmol), l-fluoro-3-(trifluoromethyl)benzene (0.82g, 5.0mmol), and potassium carbonate (0.138g, l.Ommol) were employed to obtain 2-{ l-[3- (trifluoromethyl)phenyl]-lH-pyrrol-3-yl} pyridine hydrochloride as an orange solid. lΗ-NMR (CD3OD, 300 MHz) 8.60 (d, IH), 8.49-8.46 (m, 2H), 8.36 (d, IH), 7.98-
7.94 (m, 2H), 7.80-7.71 (m, 3H), 7.62 (t, IH), 7.13 (dd, IH). MS (ESI) 289.0 (M++H).
EXAMPLE A6
Synthesis of 2-ri-(3,,5-dichlorophenyl)-lH-pyrrol-3-yl]pyridine hydrochloride
A solution of 2-(lH-ρyrrol-3-yl)pyridine (0.072 g, 0.5 mmol), l,3-dichloro-5- iodobenzene (0.163g, 0.6mmol), 1,10-phenanthroline (0.360g, 2mmol) and potassium phosphate (0.223g, 1.05mmol) in dioxane were degassed for lOmin, then copper (I) iodide (0.038g, 0.2mmol) was added and the mixture degassed a further lOmin. The mixture was heated to 110°C for 4h. The reaction mixture was quenched with brine, extracted with EtOAc (3 x 25mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and the residue was chromatographed on silica gel eluting with EtOAc:hexane (1:4) to afford a white solid. The crude material was dissolved in TΗF (5mL), 1.2eq. of IM ΗC1 in diethyl ether was added and the resulting precipitate was filtered to obtain 2-[l-(3,5- dichlorophenyl)-lH-pyπol-3-yl]pyridine hydrochloride as a white solid. lΗ-NMR (CD3OD, 300 MHz) δ 8.60 (d, IH), 8.50 (dd, IH), 8.41 (dd, IH), 8.34 (d,
IH), 7.80-7.69 (m, 3H), 7.59 (dd, IH), 7.50-7.49 (m, IH), 7.11-7.09 (dd, IH). MS (ESI) 289.0 (M++H).
EXAMPLE A7 Synthesis of 2-ri-(3-methylphenyl)-lHr-pyrrol-3-yl]pyridine hydrochloride
Following the procedure described in EXAMPLE A6, 2-(lH-pyrrol-3-yl)pyridine (0.072g, 0.50mmol) l-iodo-3-methylbenzene (0.130g, 0.6mmol), 1,10-phenanthroline (0.360g, 2mmol) and potassium phosphate (0.223g, 1.05mmol) and copper (I) iodide (0.038g, 0.2mmol) were employed to obtain 2-[l-(3-methylphenyl)-lH-pyrrol-3- yl]pyridine. Treatment of this material with 1.2eq. of IM ΗC1 in diethyl ether provided 2-[l-(3-methylphenyl)-lH-pyπol-3-yl]pyridine hydrochloride as a white solid. lΗ-NMR (CD3OD, 300 MHz) δ 8.46 (d, IH), 8.35 (dd, IH), 8.24-8.20 (m,
2H), 7.65-7.60 (m, IH), 7.41-7.38 (m, 2H), 7.34-7.32 (m, 2H), 7.17-7.14 ( , IH), 6.97 (dd, IH), 2.37 (s, 3H). MS (ESI) 235.3 (M++H). EXAMPLE A8 Synthesis of 2-ri-(3-methoxyphenyl)-lH-pyrroI-3-yl]pyridine hydrochloride
Following the procedure described in EXAMPLE A6, 2-(lH-pyrrol-3-yl)pyridine (0.072g, 0.50mmol) l-bromo-3-methoxybenzene (0.113g, 0.6mmol), 1,10- phenanthroline (0.360g, 2mmol) and potassium phosphate (0.223g, 1.05mmol) and copper (I) iodide (0.038g, 0.2mmol) were employed to obtain 2-[l-(3- methoxyphenyl)-lH-pyrrol-3-yl]pyridine. Treatment of this material with 1.2eq. of IM ΗC1 in diethyl ether provided 2-[l-(3-methoxyphenyl)-lH-pyrrol-3-yl]pyridine hydrochloride as a white solid. lΗ-NMR (CD3OD, 300 MHz) δ 8.55 (d, IH), 8.45 (dd, IH), 8.33-8.29 (m, 2H), 7.74-7.69 (m, IH), 7.51 (dd, IH), 7.48-7.42 (m, IH), 7.21-7.17 (m, 2H), 7.04 (dd, IH), 7.00-6.97 (m, IH), 3.89 (s, 3H). MS (ESI) 251.1 (M++H).
COMPOUND A5 Synthesis of 2-ri-(triisopropylsilyl)-lHr-pyrrol-3-yn-l,3-thiazole
To a solution of 3-bromo-l-(triisopropylsilyl)-lH-pyrrole (0.691g, 2.28mmol) in TΗF (lOmL) at -78°C was added t-butyllithium (2.83mL, 4.80mmol of 1.7M solution in heptane). The solution was stiπed at -78°C for 45min, then trimethylborate (2.38g, 22.8mmol) was added and stiπed at -78°C for 20min. The reaction mixture was allowed to warm to rt and then cooled again to -78°C before methanokwater
(V:V=1:1, 0.9mL) was added and the solution allowed warm to rt. The reaction mixture was quenched with brine (lOmL) and extracted with EtOAc (3 x 25mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude l-(triisopropylsilyl)-lH-pyπol-3-ylboronic acid which was used without further purification.
A solution of crude l-(triisopropylsilyl)-lH-pyπol-3-ylboronic acid, 2- bromo-l,3-thiazole (0.206g, 1.26mmol) and potassium carbonate (0.174g, 1.26mmol) in benzene (lOmL), methanol (lmL) and water (lmL) was degassed with argon for 15min. Tetrakis(triphenylphosphine)palladium(0) (40mg, 0.034mmol) was added and the reaction mixture was degassed a further 15min before stirring at 70°C for 14h. The reaction mixture was quenched with water (30mL) then extracted with EtOAc (3 x 30mL) and washed with brine. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:1) to afford 2-[l-(triisopropylsilyl)-lH- pyrrol-3-yl]-l,3-thiazole as a brown oil. lΗ NMR (CD3CI, 300 MHz) δ 7.68 (d, IH), 7.37-7.36 (m, IH), 7.08 (d, IH), 7.76-7.75 (m, IH), 6.70 (dd, IH), 1.46 (h, 3H) 1.09 (d, 18H).
COMPOUND A6 Synthesis of 2-(lH-pyrrol-3-yl)-1.3-thiazole
To a solution of 2-[l-(triisopropylsilyl)-lH-pynol-3-yl]-l,3-thiazole (0.200g, 0.671mmol) in anhydrous TΗF (2 mL) was added TBAF (lmL, Immol of a IM in TΗF) and after stirring for 20min at rt, the reaction was complete. The reaction mixture was quenched with water (40mL), extracted with EtOAc (3 x 25mL) and washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and chromatographed on silica gel eluting with EtOAc:hexane (1:1) to afford 2-(lH- pyrrol-3-yl)-l,3-thiazole as a pale solid. lΗ NMR (CD3CI, 300 MHz) δ 8.20 (br, IH)
7.63 (d, IH), 7.28 (d, IH), 7.06 (d, IH), 6.73 (dd, IH), 6.57 (dd, IH).
EXAMPLE A9 Synthesis of 3 3-(l,3-thiazol-2-vI)-lH-pyrrol-l-yl]benzonitrile
Following the procedure described in EXAMPLE A4, 2-(lH-ρyrrol-3-yl)-l,3- thiazole (O.lOOg, 0.66mmol), l-fluoro-3-(trifluoromethyl)benzene (0.805g, 6.66mmol), and potassium carbonate (0.183g, 1.33mmol) were employed to obtain 3- [3-(l,3-thiazol-2-yl)-lH-pyrrol-l-yl]benzonitrile. Treatment of this material with 1.2 eq. of IM ΗC1 in diethyl ether provided 3-[3-(l,3-thiazol-2-yl)-lH-pyrrol-l- yljbenzonitrile hydrochloride as a pale solid. lΗ-NMR (CD3OD, 300 MHz) δ 8.42
(t, IH), 8.14-8.11 (m, 2H), 8.03-7.97 (m, IH), 7.90 (m, IH), 7.81-7.71 (m, 2H), 7.63 (dd, IH), 7.03 (d, IH). MS (ESI) 252.1 (M++H).
EXAMPLE A10 to EXAMPLE A22 shown below were prepared similarly to the schemes and procedures described above (ND = not determined).
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Methods of Synthesis of Compounds of Formula IB Compounds of the present invention can be prepared according to the following methods. The substituents are the same as in Formula IB except where defined otherwise.
In Schemes BI to B9 below, XD and Yb are as defined supra. Other variables are understood by one in the art by the context in which they are used.
Scheme BI
Figure imgf000188_0001
Thus in Scheme BI, ring system Xb containing a hydrazine moiety (prepared using synthetic chemistry techniques well known in the art) is reacted with a 1,3-dicarbonyl or its equivalent in a suitable solvent (e.g. EtOH, THF, DME, DMF etc.) at a temperature between about 30°C to 150°C for about 1 to 18h to form a substituted pyrazole (see for example Sugiyarto, K. H.; Goodwin, H. A. Aust.J.Chem. 1988, 41, 1645-1664). In turn, the 4-position of the pyrazole is derivatized with a functional group Ab which is capable of undergoing a metal-catalyzed cross-coupling reaction such as a halogen or trifluoromethanesulfonate and the like. For example, the group Ab may be a bromide radical which maybe installed using molecular bromine under acidic conditions (see for example Khan, M. A.; Pinto, A. A. A. J.Heterocycl.Chem. 1981, 18, 9-14). In turn, the derivatized pyrazole is reacted with a moiety Yb under metal-catalyzed cross-coupling conditions (Scheme B2)
Scheme B2
Figure imgf000188_0002
E is a metallic or metalloid species such as B(OR)2, Li, MgHal, SnR3, ZnHal, SiR3 and the like which is capable of undergoing a metal-catalyzed cross- coupling reaction. The coupling may be promoted by a homogeneous catalyst such as Pd(PPh3)4, or by a heterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g. THF, DME, toluene, MeCN, DMF, H2O etc.). Typically a base, such as K2CO3, NEt3, and the like, will also be present in the reaction mixture. Other promoters may also be used such as CsF. The coupling reaction is typically allowed to proceed by allowing the reaction temperature to warm slowly from about 0°C up to ambient temperature over a period of several hours. The resulting reaction mixture is then maintained at ambient temperature, or heated to a temperature between about 30°C tol50°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 48 hours, with about 18 hours typically being sufficient (see for example Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483). The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like.
Another embodiment of the present invention is illustrated in Scheme B3 below.
Scheme B3
Figure imgf000189_0001
Thus a 1,3-dicarbonyl compound substituted at the 2 position with a moiety Yb (prepared using synthetic chemistry techniques well known in the art), is condensed with hydrazine in a suitable solvent (e.g. EtOH, THF, DME, DMF etc.), at a temperature between about 30°C to 150°C for about 1 to 18h to form a substituted pyrazole (see for example Brown, D. J.; Cowden, W. B.; Grigg, G. W.; Kavulak, D. Aust.J.Chem., 1980, 33, 2291-2298).
Scheme B4
Coupling
Figure imgf000189_0002
Figure imgf000189_0003
As shown in Scheme B4, the pyrazole may then be coupled with a species Xb substituted with a group B. B maybe a metalloid species such as B(OR)2, BiLn and the like and the reaction maybe promoted with stoichiometric or catalytic amounts of metal salts such as Cu(OAc)2, Cui or CuOTf and the like. Typically, a base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) will also be present and the reaction carried out in a suitable solvent (e.g. DCM, THF, DME toluene, MeCN, DMF, H2O etc.). Additionally, molecular sieves maybe used as a cocatalyst.
Alternatively, B may be a halogen or other functional group capable of undergoing a metal catalyzed N-arylation cross-coupling reaction. In that case, additional promoters such as 1,10-phenanthaline and dibenzylideneacetone may also be added to the reaction mixture. The cross-coupling reaction maybe carried out at ambient temperature or heated to a temperature anywhere between about 30°C to
150°C. The resulting reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 72 hours, with 18 hours typically being sufficient (see for example Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Cham, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944 and Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660). The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like.
In another embodiment of the present invention when B is a good aryl leaving group such as F, and Xb is electron deficient or has one or more electron withdrawing substituents (e.g. ΝO2, CN), the coupling reaction may be effected thermally in a temperature range of about 60°C up to about 250°C. Typically this reaction is carried out in the presence of base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) in a suitable solvent, such as DMSO, DMF, DMA H2O and the like, and takes from about lh up to about 72h with 18 hours typically being sufficient (see for example Russell, S. S.; Jahangir; Synth.Commun. 1994, 24, 123-130).
Another embodiment of the present invention is illustrated in Scheme B5.
Scheme B5
Coupling
Figure imgf000190_0001
Figure imgf000190_0002
Thus a 1,3-dicarbonyl compound substituted at the 2 position with a moiety Yb (prepared using synthetic chemistry techniques well known in the art (see for example Fox, J. F.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360-1370) is condensed with a species Xb substituted with a hydrazine functional group in a suitable solvent (e.g. EtOH, THF, DME, DMF, H2O etc.) at a temperature between about 30°C to 150°C for about 1 to about 24h to form a substituted pyrazole (see for example Pawar, R. A.; Heterocycles, 1984, 21, 568). Another embodiment of the present invention is illustrated in Scheme B6.
Scheme B6
Figure imgf000191_0001
Thus, a species Yb substituted with a 3-dimethylamino-2,3-unsaturated ketone is prepared using synthetic chemistry techniques well known to those skilled in the art (see for example Kepe, V.; Kocevar, M.; Polanc, S. J. Heterocyclic Chem. 1996, 33, 1707-1710). The homologated amide species is heated with hydrazine in a suitable solvent (e.g. EtOH, THF, DME, DMF, H2O etc.) at a temperature between about 30°C to 150°C for about lh up to about 24h to form a pyrazole substituted with Y (see for example Wang, F.; Schwabacher, A. W. Tetrahedron. Lett. 1999, 40, 4779- 4782).
As shown in Scheme B7, the pyrazole may then be coupled with a ring system X° substituted with a functional group B.
Scheme B7
Coupling
Figure imgf000191_0002
Figure imgf000191_0003
B may be a metalloid species such as B(OR)2, BiLn and the like and the reaction maybe promoted with stoichiometric or catalytic metal salts such as Cu(OAc)2, Cui, or CuOTf and the like. Typically, a base (e.g. pyridine, NEt3,
CS2CO3, K2CO3 etc.) will also be present and the reaction carried out in a suitable solvent (e.g. DCM, THF, DME, MeCN, DMF, H2O etc.). Additionally, molecular sieves maybe used as a cocatalyst. Alternatively B may be a halogen or other functional group capable of undergoing a metal catalyzed N-arylation cross-coupling reaction. In which case, additional promoters such as 1,10-phenanthrolene and dibenzylideneacetone may also be added to the reaction mixture. The cross-coupling reaction maybe carried out at ambient temperature or heated to a temperature between about 30°C to 150°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 72 hours, with 18 hours typically being sufficient (see for example Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Cham, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944 and Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657- 2660). The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like.
In another embodiment of the present invention, when B is a good aryl leaving group such as F, and Xb is electron deficient or has one or more electron withdrawing substituents (e.g. ΝO2, CN etc.), the coupling reaction may be effected thermally in a temperature range of about 60°C up to about 250°C. Typically, this reaction is carried out in the presence of base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) in a suitable solvent, such as DMSO, DMF, DMA H2O and the like, and takes from about lh up to about 72h with 18 hours typically being sufficient (see for example (see for example Russell, S. S.; Jahangir; Synth.Commun. 1994, 24, 123- 130).
Another embodiment of the present invention is illustrated in Scheme B8. Scheme B8
Figure imgf000192_0001
Rii^lft
Figure imgf000192_0002
Thus, moiety Xb substituted with a hydrazine functional group (prepared using synthetic chemistry techniques well known in the art) is reacted with an activated acyl enol ether moiety in a suitable solvent (e.g. THF, DME, DMF, Et2θ etc.) to form a pendant enol hydrazide. In Scheme B8, the leaving group W can be halogen, OR, SR etc. or if W = OH, the reaction is effected using typical peptide- coupling conditions (e.g using EDC etc.) that are well known to those skilled in the art at a temperature between about 0°C to 100°C for about lh to 18h. Under acidic conditions, the pendant enol hydrazide cyclizes to form the coπesponding pyrazolidone (see for example Shi, G.; Wang, Q.; Schlosser, M. Tetrahedron 1996, 52, 4403-4410). This is then converted to a pendant pyrazole substituted at the 3 position with a group Ab where Ab is a functional group capable of undergoing a metal-catalyzed cross-coupling reaction. For example, Ab may be trifluoromethanesulfonate, halogen, acyloxy, alkyl- or arylsulfonate, alkyl- or arylsulfinate, alkyl- or arylsulfide, phosphate, phosphinate and the like.
Scheme B9
Coupling
Figure imgf000193_0001
Figure imgf000193_0002
As shown in Scheme B9, the pyrazole from Scheme B8 can be coupled with a ring system Yb substituted with a group E where E is a metallic or metalloid species such as B(OR)2,Li, MgHal, SnR3, ZnHal2, SiR3 and the like which is capable of undergoing a metal-catalyzed cross-coupling reaction.. The coupling may be promoted by a homogeneous catalyst such as Pd(PPh3)4, or by a heterogeneous catalyst such as Pd on carbon in a suitable solvent, such as THF, DME, MeCN, DMF, H2O and the like. Typically, a base (e.g. K2CO3 NEI3, etc.) will also be present in the reaction mixture. Other promoters may also be used such as CsF. The coupling reaction is typically allowed to proceed by allowing the reaction temperature to warm slowly from about 0°C up to ambient temperature over a period of several hours. The reaction mixture is then maintained at ambient temperature, or heated to a temperature between about 30°C tol50°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 48 hours, with about 18 hours typically being sufficient. The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like (see for example Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483). In addition, many of the heterocyclic compounds described above can be prepared using other synthetic chemistry techniques well known in the art (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., Pergamon Press, Oxford, 1984) and references cited there within. COMPOUND BI
Synthesis of 2-(lH-pyrazol-4-yl)pyridine
2-(2-Pyridyl)-malondialdehyde (7.8g, 52mmol) and hydrazine hydrate (3.7mL) were heated at 75°C in ethanol (75mL) for 18h. After cooling to ambient temperature and concentration in vacuo, recrystallization from EtOAc/Hexane gave 2-(lH-pyrazol-4- yl)pyridine as gold crystals. MP = 136°C. lΗ NMR (CD3CI, 300 MHz) δ 6.48 - 8.51
(IH, m), 8.30 (IH, br. s), 8.07 (IH, br. s), 7.74 (IH, ddd), 7.68 (IH, d), 7.15 (IH, ddd). MS (ESI) 146 (M+H)+
EXAMPLE BI Synthesis of 3-(4-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile
To 2-(lH-pyrazol-4-yl)pyridine (292mg, 2mmol), 3-cyanoboronic acid (590mg, 4mmol), Cu(OAc)2 (547mg, 3mmol) and pyridine (0.32mL, 4mmol) in dichloromethane (4mL) was added 0.5g of 4 A molecular sieves. The resulting reaction mixture was stiπed at ambient temperature under atmospheric conditions for 48h, whereupon it was filtered through CELITE, washing with dichloromethane. The reaction mixture was concentrated onto silica gel in vacuo and purified by liquid chromatography on silica gel eluting with EtOAc:hexane (1:1 to 1:0) to afford a solid that was recrystallized from EtOΗ-Η2θ to afford 3-(4-pyridin-2-yl-lH-pyrazol-l- yl)benzonitrile as a white solid. lΗ NMR (CD3CI, 300 MHz) δ 8.63 - 8.64 (IH, m), 8.56 (IH, s), 8.23 (IH, s), 8.14 (IH, m), 8.00 - 8.05 (IH, m), 7.75 (IH, ddd), 7.57 - 7.66 (3H, m), 7.21 (IH, ddd). MS (ESI) 247 (M+H)+
EXAMPLE B2
Synthesis of 2-ri-(3-fluorophenyl)-lH-pyrazol-4-yl1pyridine To 2-(lH-pyrazol-4-yl)pyridine (292mg, 2mmol), 3-fluoroboronic acid (570mg, 4mmol), Cu(OAc)2 (547mg, 3mmol) and pyridine (0.32mL, 4mmol) in dichloromethane (4mL) was added 0.5g of 4 A molecular sieves. The resulting reaction mixture was stiπed at ambient temperature under atmospheric conditions for 48h, whereupon it was filtered through CELITE, washing with dichloromethane. The reaction mixture was concentrated onto silica gel in vacuo and purified by liquid chromatography on silica gel eluting with EtOAc:hexane (1:9 to 1:1) to afford 2-[l- (3-fluorophenyl)-lH-pyrazol-4-yl]pyridine as a white solid. lΗ NMR (CD3CI, 300
MHz) δ 8.62 - 8.63 (IH, m), 8.52 (IH, s), 8.20 (IH, s), 7.40 (IH, ddd), 7.55 - 7.59 (3H, m), 7.42 - 7.46 (IH, m), 7.19 (IH, ddd), 7.01 - 7.05 (IH, m). MS (ESI) 240 (M+H)+
EXAMPLE B3
Synthesis of 2-ri-(l-naphthyI)-lH-pyrazoI-4-yl1pyridine
To 2-(lH-pyrazol-4-yl)pyridine (292mg, 2mmol), 1-napthaleneboronic acid (690mg, 4mmol), Cu(OAc)2 (547mg, 3mmol) and pyridine (0.32mL, 4mmol) in dichloromethane (4mL) was added 0.5g of 4A molecular sieves. The resulting reaction mixture was stirred at ambient temperature under atmospheric conditions for 48h, whereupon it was filtered through CELITE, washing with dichloromethane. The reaction mixture was concentrated on to silica gel in vacuo and purified by liquid chromatography onto silica gel eluting with EtOAc:hex (2:8 to 3:7) to afford 2-[l-(l- naphthyl)-lH-pyrazol-4-yl]pyridine as a white solid. lΗ NMR (CD3CI, 300 MHz) δ
8.63 - 8.65 (IH, m), 8.39 (IH, s), 8.34 (IH, s), 7.94 - 7.99 (3H, m), 7.73 (IH, ddd), 7.53 - 7.64 (5H, m), 7.18 (IH, m). MS (ESI) 272 (M+H)+
EXAMPLE B4
Synthesis of 2-(l-pyridin-3-yl-lH-pyrazol-4-yl)pyridine
2-(lH-Pyrazol-4-yl)pyridine (292 mg, 2 mmol), 3-bromopyridine (0.23mL, 2.4mmol), Cu(OTf)2 (50mg, O.lmmol), dibenzylideneacetone (24mg, O.lmmol), CS2CO3
(780mg, 2.4mmol) and 1,10-phenanthracene (360mg, 2.4mmol) in dry o-xylene (1.5mL) under Ar (g) were heated at 115°C for 18h. After cooling to ambient temperature, NΗ4CI (20mL) and dichloromethane (20mL) were added and the reaction mixture shaken, the dichloromethane layer was separated and the aqueous layer shaken with dichloromethane (2x20mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to a brown oil. This was purified by liquid chromatography on silica gel eluting with EtOAc to give a solid that was further purified by HPLC to afford 2-(l-pyridin-3-yl-lH-pyrazol-4-yl)pyridine. lΗ NMR (CD3CI, 300 MHz) δ 9.08 (IH, d), 8.58 - 8.64 (2H, m), 8.56 (IH, s), 8.24 (IH, s), 8.12 (IH, ddd ), 7.73 (IH, ddd), 7.56 - 7.59 (IH, m), 7.45 (IH, dd), 7.19 (IH, ddd). MS (ESI) 223 (M+H)+ COMPOUND B2 Synthesis of 2-(lH-pyrazol-l-yι)pyridine
2-Hydrazinopyridine (7.6g, 70mmol), malondialdehyde-bis-(dimethylacetal) (11.5mL, 70mmol) and HCI (10M, 7mL) in EtOH (lOOmL) were heated at 75°C. After 2h, the resulting reaction mixture was cooled to ambient temperature and concentrated in vacuo to a give a brown solid. This was suspended in H2O (lOOmL) and EtOAc (lOOmL), and NaHCO3 added until there was no further effervescence.
The EtOAc layer was then separated and the aqueous layer shaken with EtOAc (3xl00mL). The combined organic layers were dried over Na2SO4 and concentrated to afford 2-(lH-pyrazol-l-yl)pyridine as a brown oil which was used without further purification. MS (ESI) 147 (M+Η)+
COMPOUND B3
Synthesis of 2-(4-bromo-lH-pyrazoI-l-yl)pyridine Bromine (10.8mL, 210mmol) in AcOH (50mL) was added carefully to a solution of 2-(lH-pyrazol-l-yl)pyridine (llg, 70mmol) in AcOΗ (lOOmL) to give a brown precipitate. After stirring at ambient temperature for 3h, the resulting reaction mixture was poured into ice and saturated aqueous Na2S2θ5 was added until the liquid phase became clear. The precipitate was removed by filtration and recrystallized from EtOΗ:Η2θ to give 2-(4-bromo-lH-pyrazol-l-yl)pyridine as beige crystals. lΗ NMR (CD3CI, 300 MHz) δ 8.61 (IH, s), 8.42 (IH, br. s), 7.94 - 7.96 (IH, m), 7.84 (IH, ddd), 7.69 (IH, s), 7.21 - 7.28 (IH, m). MS (ESI) 225 (M+H)4"
EXAMPLE B5 Synthesis of 3-(l-pyridin-2-yI-lH-pyrazol-4-yl)benzonitrile
A solution of 2-(4-bromo-lH-pyrazol-l-yl)pyridine (0.446g, 2.0mmol), 3- cyanophenylboronic acid (0.302g, 2.0mmol), potassium carbonate (0.552g, 4.0mmol) in a mixture of ethylene glycol dimethyl ether (20mL) and water (4mL) was degassed by argon bubbling for 15min., then tetrakis(triphenylphosphine)palladium(0) (20mg, 0.017mmol) was added and degassing continued a further 15min. The resulting solution was stiπed at 70°C for 14h, whereupon Η2O (30mL) was added, then extracted with EtOAc (3x30mL) and the combined extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with EtOAc :hexane (2:3) to afford a white solid which was recrystallized from EtOAc/Hexane give 3-(l-pyridin-2-yl-lH- pyrazol-4-yl)benzonitrile as a white solid. MP = 160-161°C. lH NMR (CD3CI, 300 MHz) δ 8.88 (s, IH), 8.45 (d, IH), 8.03 (s, IH), 8.01 (d, IH), 7.87 (d, IH), 7.86 (s, IH), 7.81 (d, IH), 7.57-7.48 (m, 2H), 7.25 (dd, IH). MS (ESI) 247.1 (M^+H).
EXAMPLE B6
Synthesis of 2 4-(3-chlorophenyl)-lH-pyrazol-l-yllpyridine
A solution of 2-(4-bromo-lH-pyrazol-l-yl)pyridine (0.669g, 3mmol), 3- chlorophenylboronic acid (0.468g, 3mmol) and potassium carbonate (0.828g, 6mmol) in a mixture of ethyleneglycol dimethyl ether (20mL) and Η2O (4mL) were degassed by argon bubbling for 15min., then tetrakis(triphenylphosphine) palladium(O) (20mg, 0.017mmol) was added and degasing continued a further 15min. The solution was stirred at 70°C for 14h, whereupon H2O (30mL) was added, then extracted with
EtOAc (3x30mL) and the combined extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and the crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:4) to afford a white solid which was recrystallized from EtOAc/Hexane to give 2-[4-(3-chlorophenyl)-lH- pyrazol-l-yl]pyridine. MP = 110-111°C. lΗ NMR (CD3CI, 300 MHz) δ 8.83 (d,
IH), 8.42 (dd, IH), 7.99 (s, IH), 7.99 (d, IH), 7.82 (ddd, IH), 7.57 (t, IH), 7.45 (dt, IH), 7.32 (t, IH), 7.25-7.18 (m, 2H). MS (ESI) 255.9 (M++H).
EXAMPLE B7 Synthesis of 2-r4-(3-methoxyphenvI)-lHr-pyrazol-l-yl]pyridine A solution of 2-(4-bromo-lH-pyrazol-l-yl)pyridine (0.669g, 3.0mmol), 3- methoxyphenylboronic acid (0.453g, 3.0mmol) and potassium carbonate (0.828g, ό.Ommol) in a mixture of ethyleneglycol dimethyl ether (20mL) and Η2O (4mL) were degassed by argon bubbling for 15min., then tetrakis(triphenylphosphine) palladium(O) (20mg, 0.017mmol) was added and degassing continued a further 15min. The resulting solution was stined at 70°C for 14h, whereupon H2O (30mL) was added, then extracted with EtOAc (3x30mL) and the combined extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo, and the crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:4) afford a white solid which was recrystallized from EtOAc/Hexane to give 2-[4-(3- methoxyphenyl)-lH-ρyrazol-l-yl]pyridine. MP = 89-90°C. lΗ NMR (CD3CI, 300 MHz) δ 8.84 (s, IH), 8.45 (dd, IH), 8.03 (s, IH), 8.02 (d, IH), 7.84 (dd, IH), 7.34 (t, IH), 7.23-7.15 (m, 3H), 6.84 (dd, IH) 3.87(s, 3H). MS (ESI) 252.1 (M++H).
COMPOUND B4 Synthesis of 2-(lH-pyrazol-3-yl)pyridine
2-(lH-Pyrazol-3-yl)pyridine (7.8g) was prepared according to the method of: Wang, F.; Schwabacher, A.W. Tetrahedron. Lett. 1999, 40, 4779-4782.
EXAMPLE B8 Synthesis of 3-(3-pyridin-2-yl-lH-pyrazol-l-vI)benzonitrile
2-(lH-Pyrazol-3-yl)pyridine (435mg, 3mmol), 3-fluorobenzonitrile (0.32mL, 3mmol) and K2CO3 (830mg, 6mmol) were dissolved in DMF (lOmL) under Ar (g) and heated at 145°C for 18h. After cooling to ambient temperature, Η2O (40mL) and EtOAc (40mL) were added and the reaction mixture shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (2x30mL). The combined organic layers were washed with brine (3x40mL), dried over Na2SO4 and concentrated onto silica gel. The crude material was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (1:1) to afford a solid that was recrystallized from EtOAc -hexane to give 3-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile as a solid. lΗ NMR (CD3CI, 300 MHz) δ 8.68 - 8.71 (IH, m), 8.18 (IH, m), 8.12 - 8.15 (IH, m), 8.02 - 8.06 (2H, m), 7.81 (IH, ddd), 7.60 - 7.62 (2H, m), 7.30 (IH, ddd), 7.20 (IH, d). MS (ESI) 247 (M+H) +
EXAMPLE B9 Synthesis of 2-ri-(3-chlorophenyl)-lH-pyrazol-3-yl]pyridine
2-(lH-Pyrazol-3-yl)pyridine (435mg, 3mmol), 3-fluoro-l-chlorobenzene (0.32mL, 3mmol) and K2CO3 (830mg, 6mmol) were dissolved in DMF (lOmL) under Ar (g) and heated at 145 °C for 18h. After cooling to ambient temperature, Η2O (40mL) and EtOAc (40mL) were added and the reaction mixture shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (2x30mL). The combined organic layers were washed with brine (3x40mL), dried over Na2SO4 and concentrated onto silica gel. The crude material was purified by liquid chromatography on silica gel, eluting with EtOAc:hexane (1:1) to afford 2-[l-(3- chlorophenyl)-lH-pyrazol-3-yl]pyridine as as solid. lΗ NMR (CD3CI, 300 MHz) δ 8.68 - 8.69 (IH, m), 8.13 - 8.16 (IH, m), 8.01 (IH, m), 7.88 (IH, m), 7.79 (IH, ddd), 7.66 - 7.68 (IH, m), 7.42 (IH, dd), 7.26 - 7.31 (2H, m), 7.16 (IH, d). MS (ESI) 256 (M+H)+
COMPOUND B5
Synthesis of (2E)-3-ethoxy-N'-pyridin-2-ylprop-2-enohydrazide
Ethyl vinyl ether (4.73g, 65.6mmol) was added dropwise to oxalyl chloride (12.5g, 98.4mmol) at 0°C, the resulting reaction mixture was first stirred at 0°C for 2h, and then allowed to warm to ambient temperature. After 12h GC/MS analysis indicated formation of product and the reaction mixture was concentrated in vacuo and the crude (2E)-3-ethoxyprop-2-enoyl chloride used in the next step without further purification.
To a cold (0°C) solution of 2-hydrazinopyridine (10.74g, 98.4mmol) and triethylamine (9.94g, 98.4mmol) in THF (lOOmL) was added crude (2E)-3- ethoxyprop-2-enoyl chloride (based on 100% yield of previous step) dropwise. The resulting reaction mixture was allowed to warm to ambient temperature over 2h and then heated at reflux for a further 5h. The reaction mixture was quenched with water (50mL), extracted with ΕtOAc (3x50mL) and washed with brine. The organic phase was dried over Νa2S04, concentrated in vacuo, purified using liquid chromatography on silica gel eluting with ΕtOAc to afford (2E)-3-ethoxy-N-pyridin-2-ylprop-2- enohydrazide as a brown oil. iH NMR (CD3CI, 300 MHz) δ 9.19 (br, IH), 8.08 (d,
IH), 7.59-7.44 (m, 3H), 6.75-6.69 (m, 2H), 5.34 (d, IH), 3.81 (q, 2H), 1.27 (t, 3H). MS (ΕSI) 208 (M++H).
COMPOUND B6
Synthesis of l-pyridin-2-yl-l,2-dihydro-3Hr-pyrazol-3-one
(2E)-3-Εthoxy-N-pyridin-2-ylprop-2-enohydrazide (8.5g, 41mmol) was stiπed with concentrated 37% HCI (20mL) for 3h. The resulting reaction mixture was adjusted to pH 7 using IN ΝaOH (aq) and a precipitate formed. The reaction mixture then extracted with EtOAc (3x50 mL)and washed with brine. The combined organic phase was dried over Νa2S04, concentrated in vacuo purified using liquid chromatography on silica gel eluting with EtOAc (100%) to afford l-pyridin-2-yl-l,2-dihydro-3H- pyrazol-3-one as a yellow solid. lΗ NMR (CD3CI, 300 MHz) δ 12.00 (br, IH),
8.43-8.39 (m, 2H), 7.85 (ddd, IH), 7.64 (d, IH), 7.16 (ddd, IH), 5..99 (d, IH). MS (ESI) 162 (M++H). COMPOUND B7
Synthesis of l-pyridin-2-yl-lH-pyrazol-3-yI trifluoromethanesulfonate
To a solution of l-pyridin-2-yl-l,2-dihydro-3H-pyrazol-3-one (0.161g, l.Ommol) and triethylamine (0.112g, 1. Immol) in TΗF (lOmL) at -78°C was added trifluoromethanesulfonic anhydride (0.253g, Immol) dropwise. The resulting reaction mixture was stiπed and allowed to warm to ambient temperature over 4h. The reaction was quenched by the addition of Η2O (15mL), then extracted with
EtOAc (3x20 mL) and washed with brine. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:9) to afford l-pyridin-2-yl-lH~pyrazol-3-yl trifluoromethanesulfonate as white crystals. lΗ NMR (CD3CI, 300 MHz) δ 8.57 (d,
IH), 8.43 (d, IH), 7.91-7.83 (m, 2H), 7.29-7.25 (m, IH) 6.38 (d, IH). MS (ESI) 294 (M++H).
EXAMPLE B10
Synthesis of 3-(l-pyridin-2-yl-lHr-pyrazol-3-yl)benzonitrile l-Pyridin-2-yl-lH-pyrazol-3-yl trifluoromethanesulfonate (0.21 lg, 0.72mmol), 3- fluorobenzonitrile (O.lllg, 0.76mmol) and potassium carbonate (0.209g, 1.5 Immol) in a mixture of ethyleneglycol dimethyl ether (20mL) and water (4mL) was degassed by argon bubbling for 15min., then tetrakis(triphenylphosphine) palladium(O) (20mg, 0.017mmol) was added the resulting solution degassed for a further 15min. The solution was stined at 65°C for 12h. The reaction mixture was quenched with water (30nιL), then extracted with EtOAc (3x30mL) and washed with brine. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with EtOAc :hexane (2:3) to afford a white solid which was recrystallized from EtOAc -hexane to give 3-(l-pyridin-2-yl-lH- pyrazol-3-yl)benzonitrile as a white solid. lΗ NMR (CD3CI, 300 MHz) δ 8.64 (d,
IH), 8.44 (d, IH), 8.25 (s, IH), 8.14 (d, IH), 8.10 (d, IH), 7.87 (t, IH), 7.64 (d, IH), 7.55 (t, IH), 7.24 (dd, IH), 6.80 (d, IH). MS (ESI) 247 (M++H).
COMPOUND B8 Synthesis of 2-bromo-6-hydrazinopyridine
2,5-Dibromopyridine (2.0g, 8.4mmol) was dissolved in 1,4-dioxane (2mL) and a solution of hydrazine hydrate (500mg, 8.4mmol) in 1,4-dioxane (15mL) was added dropwise by syringe pump. The reaction was heated to 80°C for 16h. The solvents were removed in vacuo and the residue was chromatographed on silica gel eluting with hexanes :EtO Ac (1:1) to afford 2-bromo-6-hydrazinopyridine as a brown solid. MS (ESI) 187.0 (M++H), 189.0(M+H+2).
EXAMPLE Bll Synthesis of 2-bromo-6-(4-pyridin-2-yI-lH-pyrazol-l-yl)pyridine 2-Bromo-6-hydrazinopyridine (500mg, 2.7mmol) was dissolved in ethanol (lOmL) and 2-(2-pyridyl)malondialdehyde(403mg, 2.7mmol) was added. The reaction was heated at 70°C for 16h. The solvents were removed the ethanol in vacuo and the residue was chromatographed on silica gel eluting with hexanes:EtOAc (1:4) to afford 2-bromo-6-(4-pyridin-2-yl-lH-pyrazol-l-yl)pyridine as a light yellow solid. lΗ- NMR (CDCI3, 300 MHz) δ 9.0 (s, IH), 8.62-8.61 (d, J=3 Hz IH), 8.27(s, IH), 7.97-
7.94 (d, J=9 Hz, IH), 7.74- 7.57 (m, 3H), 7.39-7.37(d, J=3 Hz, IH) 7.19-7.15 (t, IH). MS (ESI) 301.0 (M++H), 303.0(M+H+2).
COMPOUND B9
Synthesis of 6-fluoropyridine-2-carbonitrile
2,6 Difluoropyridine (12g, lOOmmol) was dissolved in DMSO (3mL) and sodium cyanide (1.3g, 26mmol) in DMSO (lOOmL) was added dropwise via syringe pump over 16h. The reaction was then heated at 100°C for 16h. The crude mixture was then diluted with EtOAc (500mL) and washed with a mixture of brine (200mL) and H2O (500mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes:EtOAc (4:1) to afford 6-fluoropyridine-2-carbonitrile. MS (ESI) 122.0 (M++H).
EXAMPLE B12
Synthesis of 6-(4-pyridin-2-yl-lHr-pyrazol-l-yl)pyridine-2-carbonitrile
2-(lH-Pyrazol-4-yl)pyridine (300mg, 2.0mmol) was dissolved in DMF (lOmL), potassium carbonate (566mg, 4mmol) and 6-fluoropyridine-2-carbonitrile (250mg, 2mmol) was added. The reaction was heated at 140°C for 16h. The crude mixture was cooled to rt and diluted with EtOAc (300mL) and washed with Η2O (200mL) and brine (200mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes :EtO Ac (7:3) to afford 6-(4-pyridin-2-yl-lH-pyrazol-l-yl)pyridine-2-carbonitrile. This material was dissolved in methylene chloride (5mL) and, upon treatment with IM HCI in diethyl ether (0.6mL), precipitated as the hydrochloride salt. M.P. 260-261°C. iH-NMR (CDCI3, 300 MHz) δ 9.67 (s, IH), 8.83(s, IH), 8.79-8.77 (d, J=6 Hz, IH),
8.47-8.29(m, 4H), 8.13-8.10(m,lH) 7.77-7.73 (t, IH). MS (ESI) 249 (M++H).
EXAMPLE B13 Synthesis of 2-ri-(3-bromophenyl)-lHr-pyrazol-4-ynpyridine
2-(2-Pyridyl)malondialdehyde (100 mg, 0.67 mmol) and 3- bromophenylhydrazine'hydrochloride (150 mg, 0.67 mmol) were suspended in ethanol (2 mL), and heated to 75°C for 8h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel preparative TLC eluting with hexanes:EtOAc (3:1) to afford 2-[l-(3-bromophenyl)-lH-pyrazol-4-yl]pyridine as a pale yellow solid. lΗ-NMR (CDCI3, 300 MHz) δ 8.61 (d, J=4.8 Hz, IH), 8.51 (s,
IH), 8.18 (s, IH), 7.99 (s, IH), 7.73-7.68 (m, 2H), 7.55 (d, J=7.9 Hz, IH), 7.43 (d, J=8.8 Hz, IH), 7.35 (t, J=8.1 Hz, IH), 7.17 (dd, J=4.9, 7.4 Hz, IH). MS (ESI) 300.0, 302.0 (M++H).
COMPOUND B10 Synthesis of 3-(4-bromo-lH-pyrazol-l-yl)benzonitrile 3-Fluorobenzonitrile (4.4mL, 40mmol), 4-bromopyrazole (6g, 40mmol) and potassium carbonate (llg, 80mmol) were weighed into a flask and flushed with Ar(g). Dry DMF (80mL) was added and the reaction mixture was stirred at 140°C for 18h. The reaction mixture was then cooled to rt and partitioned between EtOAc (200mL) and brine (lOOmL). The organic layer was separated and the aqueous layer was washed with EtOAc (3 x 150mL), the combined organic layers were washed with brine (3 x 50mL), dried over Na2SO4, filtered and concentrated to afford a solid. This was recrystallized from EtOAc/hexane to give 3-(4-bromo-lH-pyrazol-l- yl)benzonitrile as a beige solid.
COMPOUND Bll
Synthesis of 3-r4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yllbenzonitrile
3-(4-Bromo-lH-pyrazol-l-yl)benzonitrile (4.4g, lδmmol), bis(pinacolato)diborane (5g, 20mmol), potassium acetate (5.3g, 54mmol) and Pd(dppf)2Cl2-CΗCl3 (1.47g, l.δmmol) were weighed into a flask and flushed with Ar(g). Dry 1,4-dioxane (lOOmL) was added, the reaction mixture degassed for lOmin with Ar(g) and then heated to 80°C. Afterlδh, the reaction mixture was cooled to rt and partitioned between EtOAc (lOOmL) and brine (lOOmL) and filtered through Celite. The organic layer was separated and the aqueous layer was washed with EtOAc (3 x 70mL), dried over Na2SO4, filtered and concentrated to an oil. This was purified by chromatography on silica gel eluting with EtOAc:hexane (2:8) to afford 3-[4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]benzonitrile as an orange solid.
EXAMPLE B14 Synthesis of 3-(4-pyrazin-2-yl-lH-pyrazol-l-yl)benzonitrile
3-[4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]benzonitrile (446mg, 1.5mmol), cesium fluoride (912mg, 6mmol) and tetrakis(triρhenylphosphino) palladium (0) (173mg, 0.15mmol) were weighed into a flask and flushed with Ar(g). Dry DME (20mL) was added, the reaction mixture degassed for lOmin. with Ar(g) and then heated to 95°C. After 18h, the reaction mixture was cooled to rt and partitioned between EtOAc (50mL) and brine (50mL). The organic layer was separated and the aqueous layer was washed with EtOAc (3 x 50mL), dried over Na2SO4, filtered and concentrated onto silica gel. This was purified by chromatography on silica gel eluting with EtOAc:hexane (7:3) to give 3- (4-pyrazin-2-yl-lH-pyrazol-l-yl)benzonitrile as a white solid. This was dissolved in dichloromethane and ΗC1 (IM in Et2θ) was added to give a fine precipitate. The solvent was removed in vacuo and the residue reconstituted in Et2θ. The precipitate was removed by filtration washing with Et2θ to give the hydrochloride salt of 3-(4- pyrazin-2-yl-lH-pyrazol-l-yl)benzonitrile. lΗ-NMR (CDCI3, 300 MHz) δ9.42 (s, IH), 9.13 (s, IH), 8.66 (m, IH), 8.51-8.53 (m, 2H), 8.45 (m, IH), 8.30-8.32 (m, IH), 7.84-7.87 (m, IH), 7.77 (dd, IH). MS 248.0 (M+H)+.
COMPOUND B12 Synthesis of 3-fluoro-5-(4-iodo-lHr-pyrazol-l-yl)benzonitrile To a solution of 4-iodopyrazole (1.67 g, 8.63 mmol) in DMF (40 mL) is added NaH (9.35 mmol, 374 mg of 60% dispersion in oil). Reaction was stined for 15 min at 60°C, then 3,5-difluorobenzonitrile (1.0 g, 7.19 mmol) was added and the mixture was warmed to 125°C. After 1 hr, TLC analysis showed disappearance of starting 3,5-difluorobenzonitrile. Reaction was cooled to room temperature and poured in to a separatory funnel containing 1:1 hexanes:EtOAc (200 mL) and 10% brine (100 mL). The organic layer was washed with additional 10% brine (2X50 mL), then dried over MgSO4, filtered, and concentrated in vacuo. Residue was then dissolved in hot
EtOAc (ca. 300 mL) and allowed to cool overnight. The product-containing mother liquor was decanted away from the resulting solid material and concentrated in vacuo to afford 3-fluoro-5-(4-iodo-lH-pyrazol-l-yl)benzonitrile as a white solid. lΗ NMR (CDCI3, 500 MHz) δ 7.99 (s, IH), 7.78 (s, IH), 7.76 (s, IH), 7.68-7.72 (m, IH), 7.29-
7.31 (m, IH).
EXAMPLE B15 Synthesis of S-d'H-l^'-bipyrazol-l'-yD-S-fluorobenzonitrile
To a sealed tube containing dry, deoxygenated dioxane (1 mL) was added 3-fluoro-5- (4-iodo-lH-pyrazol-l-yl)benzonitrile (313 mg, 1.0 mmol), pyrazole (88 mg, 1.3 mmol), trαns-diaminocyclohexane (24 μL, 0.2 mmol), potassium carbonate (304 mg, 2.2 mmol), and Cui (4 mg, 0.02 mmol). The reaction was capped and heated with stirring for 48 hr at 100°C. The resulting mixture was partitioned with EtOAc (10 mL) and Η2O (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo on to a plug of silica gel, which was loaded on to a prepacked column and purified via automated flash chromatography utilizing a 5-35% EtOAc/Hexanes gradient to afford 3-(rH-l,4'-bipyrazol-r-yl)-5-fluorobenzonitrile as a white solid. lΗ NMR (CDCI3, 500 MHz) δ 8.48 (s, IH), 8.04 (s, IH), 7.96 (m, IH),
7.85-7.88 (m, 2H), 7.71 (d, IH), 7.36 (m, IH), 6.50 (m, IH). MS (ESI) 254.15 (M++H).
EXAMPLE B16 to EXAMPLE B277 shown below were prepared similarly to the schemes and procedures described above for compounds of formula IB (ND = not determined).
Figure imgf000204_0001
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Figure imgf000219_0001
Figure imgf000220_0001
Examples B93-B281 have mGluR5 inhibitory activity <30% at 3 μM concentration in the calcium flux assay and/or inhibition <50% at 100 μM concentration in the PI assay.
Figure imgf000220_0002
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Figure imgf000249_0001
Figure imgf000250_0002
Methods of Synthesis of Compounds of Formula (IC)
In Schemes Cl to CIO the substituents are the same as in Formula IC except where defined otherwise. Thus, in Scheme Cl below, Xc and Yc are as defined above.
Scheme Cl
Figure imgf000250_0001
Thus in Scheme Cl, ring system Xc containing a nitrile moiety (prepared using synthetic chemistry techniques well known in the art) is reacted with hydrazine hydrate in a suitable solvent (e.g. EtOH, MeOH, iPrOH, H2O etc.) at a temperature from 0°C to 100°C, with 25°C being presently preferred, for a sufficient period of time (typically about 12 to 18h) to form a substituted amidrazone derivative (see for example Hage, R. et al. J. Chem. Soc. Dalton Trans. 1987, 1389-1395). The resulting amidrazone is then cyclized under the appropriate conditions (e.g. hot HCO2H, or trialkylorthoformate with a catalytic amount of acid) to provide a monosubstituted 1,2,4-triazole derivative as shown (see Sugiyarto, J. H. et al. Aust. J. Chem. 1995, 48, 35-54 and Beck, J. R.; Babbitt, G. E.; Lynch, M. P. .J. Heterocyclic Chem. 1988, 25, 1467-1470). As shown in Scheme Cl, the 1,2,4-triazole may then be coupled with a species Yc substituted with a group W. W maybe a metalloid species such as B(OR)2, BiLn and the like and the reaction maybe promoted with stoichiometric or catalytic amounts of metal salts such as Cu(OAc)2, Cui or CuOTf and the like. Typically, a base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) will also be present and the reaction carried out in a suitable solvent (e.g. DCM, THF, DME, toluene, MeCN, DMF, H2O etc.). Additionally, molecular sieves may be used as a cocatalyst (see for example Fedorov, A. Y.; Finet, J-P. Tetrahedron Lett. 1999, 40, 2747-2748). Alternatively, W maybe a halogen or other functional group capable of undergoing a metal catalyzed N-arylation cross-coupling reaction. In which case, additional promoters such as 1,10-phenanthroline and dibenzylideneacetone may also be added to the reaction mixture. The cross-coupling reaction may be carried out at ambient temperature or heated to a temperature anywhere between about 30°C to 150°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 72 hours, with 18 hours typically being sufficient. The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like (see for example Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Cham, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944 and Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660).
In another embodiment of the present invention when W is a good aryl leaving group such as F, and Yc is electron deficient or has one or more electron withdrawing substituents (e.g. ΝO2, CN etc.), the coupling reaction may be effected thermally in a temperature range of about 60°C up to about 250°C. Typically, this reaction is carried out in the presence of base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) in a suitable solvent, such as DMSO, DMF, DMA H2O and the like, and takes from lh up to about 72h with 18 hours typically being sufficient (see for example Russell, S. S.; Jahangir; Synth.Commun. 1994, 24, 123-130). In another embodiment of the invention, the compounds of the present invention can be made as shown in Scheme C2 below.
Scheme C2
Figure imgf000251_0001
In Scheme C2 the same synthetic chemistry is employed as for Scheme Cl but the nitrile functional group is now attached to Yc, and W is bonded to ring system X . The product disubstituted 1,2,4-triazoles from Schemes Cl and C2 can be isolated and purified employing standard techniques, such as solvent extraction, acid-base extraction, chromatography, crystallization, distillation and the like. In another embodiment of the present invention, the compounds of the invention can be made as illustrated in Scheme C3 below. Scheme C3
Figure imgf000252_0001
Thus, 3-bromo-l,2,4-triazole, prepared using synthetic chemistry well known to those of skill in the art (see for example Bagal, L. I. et al. Kliim. Geterotsϊkl. Soedin. 1970, 6, 1701-1703), may be coupled with a species Xc substituted with a group W to provide a halogenated 1,2,4-triazole derivative. W maybe a metalloid species such as B(OR)2, BiLn and the like and the reaction maybe promoted with stoichiometric or catalytic amounts of metal salts such as Cu(OAc)2, Cui or CuOTf and the like. Typically, a base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) will also be present and the reaction carried out in a suitable solvent (e.g. DCM, THF, DME, toluene, MeCN, DMF, H2O etc.). Additionally, molecular sieves may be used as a cocatalyst (see for example Fedorov, A. Y.; Finet, J-P. Tetrahedron Lett. 1999, 40, 2747-2748).
Alternatively, W may be a halogen or other functional group capable of undergoing a metal catalyzed N-arylation cross-coupling reaction in which case additional promoters such as 1,10-phenanthroline and dibenzylideneacetone may also be added to the reaction mixture. The cross-coupling reaction maybe carried out at ambient temperature or heated to a temperature anywhere between about 30°C to 150°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 72 hours, with 18 hours typically being sufficient (see for example Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Cham, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944 and Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660).
In another embodiment of the present invention, when W is a good aryl leaving group such as F, and Yc is electron deficient or has one or more electron withdrawing substituents (e.g. ΝO2, CN etc.), the coupling reaction may be effected thermally in a temperature range of about 60°C up to about 250°C. Typically, this reaction is carried out in the presence of base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) in a suitable solvent, such as DMSO, DMF, DMA H2O and the like, and takes from lh up to about 72h with 18 hours typically being sufficient (see for example Russell, S. S.; Jahangir; SynthAommun. 1994, 24, 123-130). The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, acid-base extraction, chromatography, crystallization, distillation and the like.
In turn, the halogenated 1,2,4-triazole derivative prepared in Scheme C3 is reacted with a species Yc under metal-catalyzed cross-coupling conditions where E is a metallic or metalloid species such as B(OR)2,Li> MgHal, SnR3, ZnHal, SiR3 and the like which is capable of undergoing a metal-catalyzed cross-coupling reaction. The coupling may be promoted by a homogeneous catalyst such as Pd(PPh3)4, or by a heterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g. THF, DME, toluene, MeCN, DMF, H2O etc.). Typically a base, such as K2CO3, NEt3, and the like, will also be present in the reaction mixture. Other promoters may also be used such as CsF. The coupling reaction is typically allowed to proceed by allowing the reaction temperature to warm slowly from about 0°C up to ambient temperature over a period of several hours. The reaction mixture is then maintained at ambient temperature, or heated to a temperature anywhere between about 30°C tol50°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 48 hours, with about 18 hours typically being sufficient (see for example Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483). The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, acid-base extraction, chromatography, crystallization, distillation and the like.
In another embodiment of the present invention, the compounds of the invention are made as illustrated in Scheme C4 below.
Scheme C4
Figure imgf000253_0001
In Scheme C4, the same synthetic chemistry is employed as in Scheme C3, but the W functional group is now attached to the species Y , and E is bonded to ring system Xc. The product disubstituted 1,2,4-triazole from Scheme C4 can be isolated and purified employing standard techniques, such as solvent extraction, acid-base extraction, chromatography, crystallization, distillation and the like. Another embodiment of the present invention is illustrated in Scheme C5 below.
Scheme C5
Figure imgf000254_0001
Thus, in Scheme C5 species Xc (prepared using methods well known in the art) contains a functional group G which may be an alkynyl or a 2-nitroethenyl moiety. Species Xc is reacted with an azide moiety, such as LiN3, NaN3 or TMSN3, in a suitable solvent (e.g. toluene, benzene, xylenes etc.) at a temperature in the range of about 25°C up to about 180°C to form a monosubstituted triazole. This reaction is often performed in the presence of added catalyst such as tetrabutylammonium fluoride or dibutyltin oxide (see for example Moltzen, E. K.; Pedersen, H.; Boegesoe, K. P.; Meier, E.; Frederiksen, K. J.Med.Chem. 1994, 37, 4085-4099).
In an embodiment, the compounds of this invention can be made according to Scheme C6 below: Scheme C6
Figure imgf000254_0002
The resulting 1,2,3 -triazole from Scheme C5 may then be coupled with a species Yc substituted with a group W. W maybe a metalloid species such as B(OR) , BiLn and the like; the reaction may be promoted with stoichiometric or catalytic amounts of metal salts such as Cu(OAc)2, Cui or CuOTf and the like.
Typically, a base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) will also be present and the reaction is carried out in a suitable solvent (e.g. DCM, THF, DME toluene, MeCN, DMF, H2O etc.). Additionally, molecular sieves maybe used as a cocatalyst
(see for example Fedorov, A. Y.; Finet, J-P. Tetrahedron Lett. 1999, 40, 2747-2748). Alternatively, W may be a halogen or other functional group capable of undergoing a metal catalyzed N-arylation cross-coupling reaction. In which case, additional promoters such as 1,10-phenanthroline and dibenzylideneacetone may also be added to the reaction mixture. The cross-coupling reaction maybe carried out at ambient temperature or heated to a temperature anywhere between about 30°C to 150°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 72 hours, with 18 hours typically being sufficient (see for example Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Cham, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944 and Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660).
In another embodiment of the present invention, when W is a good aryl leaving group such as F, and Yc is electron deficient or has one or more electron withdrawing substituents (e.g. NO2, CN etc.), the coupling reaction may be effected thermally in a temperature range of about 60°C up to about 250°C. Typically, this reaction is carried out in the presence of base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) in a suitable solvent, such as DMSO, DMF, DMA H2O and the like, and takes from lh up to about 72h with 18 hours typically being sufficient (see for example Russell, S. S.; Jahangir; Synth. Commun. 1994, 24, 123-130).
The products from Scheme C6, two isomeric disubstituted 1,2,3- triazoles, can be separated and purified employing standard techniques, such as solvent extraction, acid-base extraction, chromatography, crystallization, distillation and the like. Another embodiment of the present invention is illustrated in Schemes
C7 and C8 below.
Scheme C7
Figure imgf000255_0001
Thus, in Scheme C7 species Yc (prepared using methods well known in the art) contains a functional group G which may be an alkynyl or a 2-nitroethenyl moiety. Species Yc is reacted with an azide moiety, such as LiN3, NaN3 or TMSN3, in a suitable solvent (e.g. toluene, benzene, xylenes etc.) at a temperature in the range of about 25°C up to about 180°C to form a monosubstituted triazole. This reaction is often performed in the presence of added catalyst such as tetrabutylammonium fluoride or dibutyltin oxide (see for example Moltzen, E. K.; Pedersen, H.; Boegesoe, K. P.; Meier, E.; Frederiksen, K. J.Med.Chem. 1994, 37, 4085-4099). Scheme C8
Figure imgf000256_0001
The resulting 1,2,3-rriazole from Scheme C7 may then be coupled with a species Xc substituted with a group W (Scheme C8). W may be a metalloid species such as B(OR)2, BiLn and the like and the reaction may be promoted with stoichiometric or catalytic amounts of metal salts such as Cu(OAc)2, Cui or CuOTf and the like. Typically a base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) will also be present and the reaction is carried out in a suitable solvent (e.g. DCM, THF, DME toluene, MeCN, DMF, H2O etc.). Additionally, molecular sieves maybe used as a cocatalyst (see for example Fedorov, A. Y.; Finet, J-P. Tetrahedron Lett. 1999, 40,
2747-2748).
Alternatively, W may be a halogen or other functional group capable of undergoing a metal catalyzed N-arylation cross-coupling reaction in which case additional promoters such as 1,10-phenanthroline and dibenzylideneacetone may also be added to the reaction mixture. The cross-coupling reaction maybe carried out at ambient temperature or heated to a temperature anywhere between about 30°C to
150°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 72 hours, with 18 hours typically being sufficient (see for example Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Cham,
D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944 and Kiyomori, A.;
Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660).
In another embodiment of the present invention, when W is a good aryl leaving group such as F, and Y is electron deficient or has one or more electron withdrawing substituents (e.g. ΝO2, CN etc.), the coupling reaction may be effected thermally in a temperature range of about 60°C up to about 250° C. Typically this reaction is carried out in the presence of base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) in a suitable solvent, such as DMSO, DMF, DMA H2O and the like, and takes from lh up to about 72h with 18 hours typically being sufficient (see for example Russell, S. S.; Jahangir; Synth.Commun. 1994, 24, 123-130).
The products from Scheme C8, two isomeric disubstituted 1,2,3- triazoles, can be separated and purified employing standard techniques, such as solvent extraction, acid-base extraction, chromatography, crystallization, distillation and the like.
Yet another embodiment of the present invention is illustrated in Scheme C9 below. Scheme C9
Figure imgf000257_0001
In Scheme C9, the monosubstituted triazole is prepared as in Scheme C5. The triazole is then reacted with an N-fluoropyridinium salt, which may be optionally substituted, in the presence of a suitable base (e.g. MeOΝa, EtOΝa, tBuOK and the like) for period of about 1 to 12h at a temperature in the range of -100° C to 50° C, with -78° C to 23° C being presently preferred (see for example Kiselyov, A. S. and Strekowski, L. .J. Heterocyclic Chem. 1993, 30, 1361-1364). The products from Scheme C9, isomeric 2-pyridyltriazole derivatives, can be separated and purified employing standard techniques, such as solvent extraction, acid-base extraction, chromatography, crystallization, distillation and the like.
A further embodiment of the present invention is illustrated in Scheme CIO below.
Scheme CIO
Figure imgf000257_0002
In Scheme CIO, the monosubstituted triazole is prepared as in Scheme C7. The triazole is then reacted with an N-fluoropyridinium salt, which may be optionally substituted, in the presence of a suitable base (e.g. MeOΝa, EtOΝa, tBuOK and the like) for period of about 1 to 12h at a temperature in the range of -100° C to 50° C, with -78° C to 23° C being presently preferred (see for example Kiselyov, A. S. and Strekowski, L. J. Heterocyclic Chem. 1993, 30, 1361-1364). The products from Scheme 10, isomeric 2-pyridyltriazole derivatives, can be separated and purified employing standard techniques, such as solvent extraction, acid-base extraction, chromatography, crystallization, distillation and the like.
In addition, many of the heterocyclic compounds described above can be prepared using other synthetic chemistry techniques well known in the art (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., Pergamon Press, Oxford, 1984) and references cited there within.
COMPOUND Cl Synthesis of pyridine-2-carbohvdrazonamide 2-Cyanopyridine (5.2g, 50mmol) and hydrazine hydrate (2.95g, 50mmol) were mixed and a small amount of ethanol was added to obtain a clear solution. After standing overnight at ambient temperature, the resulting white crystals were collected by filtration. The resulting product was washed with diethyl ether and dried in the air to afford pyridine-2-carbohydrazonamide. iH NMR (DMSO, 300 MHz) δ 8.49 (d, J=6.3 Hz, IH), 7.92 (d, J=9.0 Hz, IH), 7.44 (t, J=9.0 Hz, IH), 7.31 (t, J=5.7 Hz, IH), 5.74 (s, 2H), 5.30 (s, 2H). 13c NMR (CD3OD, 75 MHz) δ 151.4, 149.7, 148.8, 137.3, 124.8,
120.6.
COMPOUND C2 Synthesis of 2-(lH- 2,4-triazol 3-yl)pyridine
Pyridine-2-carbohydrazonamide (l.Og, 7.3mmol) was added in small amounts to an excess (15ml) of ice-cold formic acid. The resulting mixture was brought to, and maintained at, ambient temperature for about 30min, then heated at reflux for about 4h. Most of the excess acid was removed on a rotary evaporator, and the residual crude product was neutralized with 10% Na2CO3 solution and extracted with EtOAc (2x100 mL). The EtOAc solution was washed with H2O (lOOmL) and brine (lOOmL), then dried (MgSO4), filtered and concentrated in vacuo. The resulting crude product was crystallized from chloroform to afford 2-(lH-l,2,4-triazol 3-yl)pyridine. IH NMR (CD3OD, 300 MHz) δ 8.67 (d,lH), 8.36 (s, IH), 8.11 (d, IH), 7.95 (t, IH), 7.47 (m, IH). MS (ESI) 146.9 (M++H).
EXAMPLE Cl Synthesis of 2-ri-(3-chlorophenyl)-lH-l,2,4-triazoI-3-ynpyridine
2-(lH-l,2,4-Triazol-3-yl)pyridine (l.Og, 6.8 mmol), potassium carbonate (1.88g, 13.6 mmol) and l-chloro-3-fluorobenzene ( 0.89g, 6.8 mmol) were stirred in DMF (20 mL) at ambient temperature. The resulting reaction mixture was heated at 100°C for 16h, after which time it was quenched with H2O (50mL) and diluted with EtOAc (200mL). The EtOAc solution was washed with H2O (3x100 mL), then brine (100 mL) and dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexanes: EtOAc (40:60) to afford 2-[l- (3-chlorophenyl)-lH-l,2,4-triazol-3-yl]pyridine as a white solid which was then dissolved in dichloromethane (5mL) and precipitated as the hydrochloride salt (M.p.= 221-223 °C) upon treatment with IM ΗC1 in diethyl ether (5mL). lΗ NMR (CD3OD,
300 MHz) δ 9.45 (s, IH ), 8.91 ( d, IH), 8.79 (m, 2H), 8.17 (m, IH), 8.10 (s, IH), 7.96(d, IH), 7.60(m, 2H). 13c NMR (CD3OD, 75 MHz) δ 156.72, 148.90, 146.31,
143.66, 143.65, 143.49, 138.94, 136.73, 132.55, 130.21, 128.74, 126.02, 121.45, 119.50. MS (ESI) 257.0 (M++H).
EXAMPLE C2 Synthesis of 3-(3-pyridin-2-yl-lHr-l,2,4-triazol-l-yl)benzonitrile
2-(lH-l,2,4-Triazol-3-yl)pyridine (0.24g, l.όmmol), potassium carbonate (0.45g, 3.2mmol) and 3-fluorobenzonitrile (0.20g, 1.6mmol) were stirred in DMF (20mL) at ambient temperature. The resulting reaction mixture was heated at 145 °C for 16h, after which time it was quenched with H2O (30mL) and diluted with EtOAc (200mL). The EtOAc solution was washed with H2O (3x100 mL), then brine (lOOmL) and dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with hexane:EtOAc (40:60) to afford 3-(3- pyridin-2-yl-lH-l,2,4-triazol-l-yl)benzonitrile as a white solid. M.p.=194-195°C. lΗ NMR (CD3OD, 300 MHz) δ 8.81 (d, IH), 8.72 (s, IH), 8.24 (t, IH), 8.10 (dd, IH), 7.86 (t, IH), 7.70 (m, 2H), 7.41 (m, IH), 7.27 (s, IH). 13c NMR
(CD3OD, 75 MHz) δ 163.2, 150.3, 148.2, 141.8, 137.5, 137.0, 131.6, 130.8, 124.6,
123.8, 123.3, 122.2, 117.5, 114.5. MS (ESI) 248.1 (M++H).
COMPOUND C3 Synthesis of 3-bromo-lH-l,2,4-triazole
3-Nitro- 1,2,4 triazole (2.0g, 17.5mmol) was heated at reflux for 8h in concentrated hydrobromic acid (40mL), after which time it was cooled to ambient temperature and poured slowly into water (lOOmL). The aqueous mixture was extracted with EtOAc (500mL), then the organic phase was washed with water (2xl00mL) and brine (lOOmL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude residue was washed with EtOAc (lmL), then with hexane (8mL) to afford 3-bromo-lH-l,2,4-triazole as a yellow solid. iH NMR (CD3OD, 300 MHz) δ 8.99 (s, IH). MS (ESI) 147.95 (M++2H).
COMPOUND C4
Synthesis of 2-(3-bromo-lH-l,2,4-triazol-l-yl)pyridine
3-Bromo-lH-l,2,4-triazole (1.9g, 12.8mmol) was dissolved in anhydrous methanol (20mL). NaOMe (5 lmL of a 0.5M solution in methanol, 25.6mmol) was then added to the stirred solution and the resulting reaction mixture was cooled to -78°C in an argon blanketed flask. 1-Fluoropyridinium triflate (4.9g, 15mmol) in anhydrous methanol (20mL) was added dropwise to this stirred solution. The resulting yellow mixture was stirred at -78°C for lh under argon atmosphere, then allowed to reach ambient temperature. The mixture was stirred for 16h at ambient temperature, after which time it was concentrated in vacuo. The resulting residue was dissolved in EtOAc (lOOmL), the EtOAc solution washed with H2O (lOOmL), then brine (lOOmL), dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane:EtOAc (90:10) to afford 2-(3- bromo-lH-l,2,4-triazol-l-yl)pyridine as a white solid. iH NMR (CD3OD, 300 MHz) δ 9.27 (s, IH), 8.51 (d, IH), 8.03 (t, IH), 7.88 (d, IH), 7.45 (t, IH). MS (ESI) 224.9 (M++2H).
EXAMPLE C3 Synthesis of 3-(l-pyridin-2-yl-lH-l,2,4-triazol-3-yl)benzonitrile
2-(3-Bromo-lH-l,2,4-triazol-l-yl)pyridine ( 0.25g, 1.12mmol) and 3- cyanophenylboronic acid (0.33g , 2.23mmol) were dissolved in toluene (20mL) and methanol (2mL), then deoxygenated via argon bubbling for lOmin. Potassium carbonate (0.23g, 1.6mmol) and tetrakis(triphenylphosphine)palladium (129mg, 0.1 Immol) were then added to the stirred solution. The reaction flask was fitted with a reflux condenser and the mixture stirred at 90°C for 16h, after which time it was cooled to ambient temperature and poured into a separatory funnel containing EtOAc (lOOmL). The EtOAc solution was washed with H2O (2xl00mL), then brine (lOOmL) and the organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude residue was chromatographed on silica gel eluting with hexanes: EtOAc (40:60)to afford 3-(l-pyridin-2-yl-lH-l,2,4-triazol-3-yl)benzonitrile as a white solid which was then dissolved in dichloromethane (lOmL) and precipitated as the hydrochloride salt (M.p.=185-188 °C) upon treatment with IM HCI in diethyl ether (lmL). iH NMR (CD3OD, 300 MHz) δ 9.42 (s, IH), 8.49 (d,
IH), 8.37 (s, IH), 8.34 (d, IH), 8.04 (dt, IH), 7.90 (t, 2H), 7.68 (t, IH), 7.44 (dt, IH). 13C NMR (CD3OD, 75 MHz) δ 160.5, 148.7, 148.6, 143.4, 140.1, 133.3, 131.1, 130.5, 130.3, 129.3, 123.8, 118.2, 113.0, 112.12. MS (ESI) 248.1 (M++H).
EXAMPLE C4 Synthesis of 2-r3-(3-chIorophenyl)-lJ-f-l,2,4-triazol-l-ynpyridine
2-(3-Bromo-lH-l,2,4-triazol-l-yl)pyridine (0.25g, 1.12mmol) and 3- chlorophenylboronic acid (0.35g , 2.23mmol) were dissolved in toluene (20mL) and methanol (2mL), then deoxygenated via argon bubbling for 10 min. Potassium carbonate (0.23g, 1.6mmol) and tetrakis(triphenylphosphine)palladium (129mg, 0.1 Immol) were added to this stirred solution. The reaction container was fitted with a reflux condenser and stirred at 90°C for 16h, after which time it was cooled to ambient temperature and poured into a separatory funnel containing EtOAc (lOOmL). The EtOAc solutoin was washed with H2O (2xl00mL), then brine (lOOmL) and the organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude residue was chromatographed on silica gel eluting with hexanes:EtOAc (8:2) to afford 2-[3-(3-chlorophenyl)-lH-l,2,4-triazol-l-yl]pyridine as a white powder which was dissolved in dichloromethane (lOmL) and precipitated as the hydrochloride salt (M.p.=125-128°C) upon treatment with IM ΗC1 in diethyl ether (lmL). lΗ NMR (CD3OD, 300 MHz) δ 9.35(s, IH), 8.51 (d, IH), 8.14 (s, IH), 8.07 (m, 3H), 7.46 (m, 3H). 13C NMR (CD3OD, 75 MHz) δ 163.0, 150.6, 149.8, 144.0, 141.0, 135.8, 133.5, 131.5, 130.9, 127.4, 125.8, 124.7, 114.2. MS (ESI) 257.5 (M++H).
COMPOUND C5
Synthesis of 3-(l-hydroxy-2-nitroethyl)benzonitrile
3-Cyanobenzaldehyde (3.0g, 22.9mmol), nitromethane (4.2g, 68.7mmol) and diethylamine (167mg, 2.29mmol) were stirred for 48h in THF at 55°C in the presence of 4 A molecular sieves. The resulting reaction mixture was filtered through celite and the resulting solution was concentrated in vacuo, then partitioned between EtOAc (200mL) and H2O (lOOmL). The EtOAc layer was washed with H2O (2x75mL) and brine (lx50mL), then dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was filtered through silica gel, eluting with hexanes:EtOAc (2:1) to obtain 3-(l-hydroxy-2-nitroethyl)benzonitrile as a pale yellow solid. MS (ESI) 193.1 (M++H).
COMPOUND C6 Synthesis of 3-f (E)-2-nitroethenvπbenzonitrile
3-(l-Hydroxy-2-nitroethyl)benzonitrile (3.32g, 17.3mmol) and triethylamine (4.37g, 43.2mmol) were stirred in anhydrous dichloromethane (lOOmL) at 0°C. To the resulting solution was added methanesulfonyl chloride (2.77g, 24.2mmol) dropwise via syringe, after which time the reaction was warmed to ambient temperature and stirred for 15min. The resulting reaction mixture was diluted with additional dichloromethane (200mL) and partitioned with H2O (lOOmL). The dichloromethane layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude residue was filtered through silica gel eluting with hexane:EtOAc (4:1) to afford 3- [(E)-2-nitroethenyl]benzonitrile as a yellow solid. iH-NMR (CDCI3, 300 MHz) δ 7.99 (d, IH), 7.86 (s, IH), 7.78-7.82 (m, 2H), 7.65 (s, IH), 7.62 (dd, IH).
COMPOUND C7 Synthesis of 3-(lHr-l,2,3-triazol-4-yl)benzonitriIe
3-[(E)-2-Nitroethenyl]benzonitrile (2.79g, 16.0mmol) and azidotrimethylsilane (2.76g, 24.0mmol) was stirred in anhydrous DMF (lOOmL) at 50°C. To this was added tetrabutylammonium fluoride (17.6mL of a 1.0M solution in THF, 17.6mmol) via syringe pump over 20min. The resulting reaction was quenched with MeOH (25mL) and concentrated in vacuo to a volume of ca. 30mL. The resulting crude mixture was dissolved in ΕtOAc (300mL) and washed with H2O (2xl00mL). The product was then extracted from the ΕtOAc layer with IM aqueous NaOH (4x75mL). The combined basic aqueous portions were treated with 4M HCI to obtain an endpoint of pH=4, and the product was extracted into ΕtOAc (4xl00mL). The combined ΕtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to obtain 3-
(lH-l,2,3-triazol-4-yl)benzonitrile as a tan solid. MS (ΕSI) 171.1 (M++Η).
EXAMPLE C5 and EXAMPLE C6
Synthesis of 3-(2-pyridin-2-yl-2H-l,2,3-triazol-4-yl)benzonitrile and 3-(l-pyridin-
2-yl-lH-l,2,3-triazol-4-yl)benzonitriIe
3-(lH-l,2,3-Triazol-4-yl)benzonitrile (1.82g, 10.69mmol) was suspended in anhydrous MeOΗ (25mL) under argon at ambient temperature. To this was added NaOMe (21.4mL of 0.5M solution in MeOH, 10.69mmol), and the resulting reaction mixture was cooled to -78°C. A solution of N-fluoropyridinium triflate (2.95g, 8.91mmol) in anhydrous MeOH (5mL) was then added dropwise via syringe. The reaction mixture was stirred at -78°C for 30min, then warmed to ambient temperature and stirred for an additional 18h. The reaction mixture was partitioned between
EtOAc (300mL) and IN aqueous ΝaOH (lOOmL). The EtOAc layer was washed with additional IN aqueous ΝaOH (6x50mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude material was then chromatographed on silica gel eluting with hexanes:EtOAc (2:1) to afford EXAMPLE C5 3-(2-pyridin-2-yl-2H-l,2,3-triazol-4-yl)benzonitrile as a tan solid. lΗ-ΝMR (CDCI3, 300 MHz) δ 8.65 (d, IH), 8.27 (s, IH), 8.14-8.21 (m, 3H), 7.92-
7.98 (m, IH), 7.70 (d, IH), 7.59 (dd, IH), 7.37-7.41 (m, IH). MS (ESI) 248.1 (M++H).
The reaction also yielded EXAMPLE C6 3-(l-pyridin-2-yl-lH-l,2,3- triazol-4-yl)benzonitrile as a tan solid. lΗ-ΝMR (CDCI3, 300 MHz) δ 8.90 (s, IH),
8.54 (d, IH), 8.16-8.27 (m, 3H), 7.97 (dd, IH), 7.56-7.68 (m, 2H), 7.41 (m, IH). MS (ESI) 248.1 (M++H).
COMPOUND C8 Synthesis of 2-(2H-l,2,3-triazol-4-yl)pyridine
2-Ethynylpyridine (3.1g, 30mmol) and trimethylsilylazide (7.9mL, 60mmol) were combined under Ar (g) and heated at 95°C for 18h. After cooling to ambient temperature, Et O (50mL) and H2O (2mL) were added and the resulting reaction mixture was stirred for 2h. The reaction mixture was then extracted with H2O (3x50mL) and the organic layer extracted with IM KOH (3x30mL). The two aqueous layers were combined and the pH adjusted to 7 with HCI (2M), extracted with EtOAc (3x50mL), dried over Na2SO4 and concentrated in vacuo to afford 2-(2H-l,2,3- triazol-4-yl)pyridine as a brown solid that was used without further purification. lΗ NMR (CD3CI, 300 MHz) δ 8.59 - 8.60 (IH, m), 8.28 (IH, s), 8.06 (IH, d), 7.87 (IH, ddd), 7.34 (IH, ddd).
EXAMPLE C7 and EXAMPLE C8 Synthesis of 3-(4-pyridin-2-yI-2Hr-l,2,3-triazol-2-yl)benzonitrile and 3-(4-pyridin- 2-yl-lH-l,2,3-triazol-l-yI)benzonitrile 2-(2H-l,2,3-Triazol-4-yl)ρyridine (510mg, 3.5mmol), 3-fluorobenzonitrile (0.37mL, 3.5mmol) and K2CO3 (lg, 7mmol) were dissolved in DMF (lOmL) under Ar (g) and heated at 140°C for 18h. After cooling to ambient temperature, Η2O (40mL) and
EtOAc (40mL) were added and the resulting reaction mixture shaken. The EtOAc layer was separated and the aqueous layer shaken with EtOAc (2x30mL). The combined organic layers were washed with brine (3x40mL), dried over Na2SO4 and concentrated onto silica gel. This was purified by liquid chromatography on silica gel eluting with EtOAc :hexane (1:1) to afford:
A) A white solid. This solid was dissolved in Et2θ/dichloromethane (20mL/5mL) and HCI (IM in Et2θ, 1.2mL) was added. The resulting fine precipitate was filtered, and washed with dichloromethane to afford EXAMPLE C7 3-(4- pyridin-2-yl-2H-l,2,3-triazol-2-yl)benzonitrile hydrochloride. lΗ NMR (CD3CI, 300
MHz) δ 8.79 (IH, s), 8.75 - 8.78 (IH, m), 8.49 - 8.51 (IH, m), 8.38 - 8.43 (IH, m), 8.18 - 8.25 (IH, m), 8.11 (IH, ddd), 7.91 - 7.95 (IH, m), 7.80 (IH, dd), 7.57 (IH, ddd). MS (ESI) 248 (M+H) +
B) A second white solid. This solid was recrystallized from EtOAc/Hexane to afford white crystals which were dissolved in Et2θ/ dichloromethane (20mL/5mL). HCI (IM in Et2θ, 0.3mL) was added. The resulting fine precipitate was filtered, washing with dichloromethane to afford EXAMPLE C8 3-(4-pyridin-2-yl-lH-l,2,3-triazol-l-yl)benzonitrile. lΗ NMR (CD3CI, 300 MHz) δ
9.64 (IH, s), 8.66 - 8.68 (IH, m), 8.51 (IH, m), 8.35 - 8.39 (IH, m), 8.16 - 8.24 (IH, m), 8.14 (IH, ddd), 7.94 - 8.00 (IH, m), 7.81 (IH, dd), 7.54 (IH, ddd). MS (ESI) 248 (M+H) +
EXAMPLE C9 AND EXAMPLE CIO
Synthesis of 2-r2-(3-chlorophenyl)-2H-l,2,3-triazol-4-yllpyridine and 2-H-(3- chlorophenyl)-lHr-l,2,3-triazol-4-yllpyridine
2-(2H-l,2,3-Triazol-4-yl)pyridine (500mg, 3.5mmol), 3-fluorochlorobenzene (459mg, 3.5mmol) and K2CO3 (lg, 7mmol) were dissolved in DMF (lOmL) under Ar (g) and heated at 140°C for 42h. After cooling to ambient temperature, Η2O (40mL) and EtOAc (40mL) were added and the resulting reaction mixture shaken. The EtOAc layer was separated and the aqueous layer shaken with EtOAc (2x30mL). The combined organic layers were washed with brine (3x40mL), dried over Na2SO4 and concentrated onto silica gel. This was purified by liquid chromatography on silica gel eluting with EtOAc:Hexane (1 : 1) to afford: A) A white solid. This was dissolved in Et2θ (lOmL) and HCI (IM in Et2θ, 0.3mL) was added. The resulting fine precipitate was filtered, and washed with Et2θ to afford EXAMPLE C9 2-[2-(3-chlorophenyl)-2H-l,2,3-triazol-4-yl]pyridine. lΗ NMR (CD3CI, 300 MHz) δ 8.71 - 8.72 (IH, m), 8.67 (IH, s), 8.13 - 8.16 (2H, m), 8.07 - 8.11 (IH, m), 8.00 (IH, ddd), 7.66 (IH, dd), 7.54 - 7.57 (IH, m), 7.50 (IH, ddd). MS (ESI) 257 (M+H) +
B) A second white solid. This was further purified by HPLC to give a white solid which was dissolved in Et2θ (lOmL) and HCI (IM in Et2θ, 0.2mL) was added. The resulting fine precipitate was filtered, and washed with Et2θ to afford
EXAMPLE CIO 2-[l-(3-chlorophenyl)-lH-l,2,3-triazol-4-yl]pyridine. lΗ NMR (CD3CI, 300 MHz) δ 9.47 (IH, s), 6.67 - 6.69 (IH, m), 8.19 (IH, dd), 8.12 - 8.15
(IH, m), 7.99 (IH, ddd), 7.59 - 7.69 (2H, d), 7.43 - 7.47 (IH, m). MS (ESI) 257 (M+H) +
EXAMPLE Cll to EXAMPLE C26 shown below were prepared similarly to the schemes and procedures described above (ND = not determined).
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0002
Methods of Synthesis of Compounds of Formula ID
Compounds of the present invention can be prepared according to the following methods. The substituents are the same as in Formula ID except where defined otherwise. In Schemes DI to D3 below, Xd, yd, Rid and R2d are as defined above for Formula (ID).
Scheme DI
Figure imgf000271_0001
Referring to Scheme DI, ring system Yd containing an aldehyde moiety (prepared using synthetic chemistry techniques well known in the art) is reacted with an arylsulfonylhydrazide in a suitable solvent (e.g. EtOΗ, MeOΗ, TΗF, DME, DMF etc.) at a temperature between 0°C to 100°C for 5 to 60min to form an arylsulfonylhydrazone. An amine-substituted Xd is treated with nitrous acid, at a temperature of -10°C to 0°C, in a suitable solvent such as, for example, water. In this manner an arenediazonium species is generated which then reacts with an arylsulfonylhydrazone in a 1,3-dipolar cycloaddition reaction to form a substituted tetrazole as shown (for example, see A.S. Shawali et al., J. Heterocyclic Chem. 1979, 16, 123-128). The product from Scheme DI, a disubstituted tetrazole, can be isolated and purified employing standard techniques, such as solvent extraction, acid-base extraction, chromatography, crystallization, distillation and the like. Scheme D2
Figure imgf000272_0001
As shown in Scheme D2 above, Yd substituted with a nitrile functional group (prepared using methods well known in the art) is reacted with an azide moiety, such as LiN3, N-1N3 or TMSN3, in a suitable solvent (e.g. toluene, benzene, xylenes etc.) at a temperature in the range of about 25°C to 180°C to form a monosubstituted tetrazole. This reaction can conveniently be performed with an added catalyst such as dibutyltin oxide. The resulting tetrazole may then be coupled with Xd substituted with a group W. W maybe a metalloid species such as B(OR)2,
BiLn and the like and the reaction may be promoted with stoichiometric or catalytic amounts of metal salts such as Cu(OAc)2, Cui or CuOTf and the like. Conveniently, a base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) will also be present and the reaction is carried out in a suitable solvent (e.g. DCM, THF, DME toluene, MeCN, DMF, H2O etc.). Additionally, molecular sieves may be used as a cocatalyst (see for example Fedorov, A. Y.; Finet, J-P. Tetrahedron Lett. 1999, 40, 2747-2748).
Alternatively W may be a halogen or other functional group capable of undergoing a metal catalyzed N-arylation cross-coupling reaction in which case additional promoters such as 1,10-phenanthrolene and dibenzylideneacetone may also be added to the reaction mixture. The cross-coupling reaction maybe carried out at ambient temperature or heated to a temperature between about 30°C to 150°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 to 72 hours, with 18 hours typically being sufficient (see for example Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Cham, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944 and Kiyomori, A.; Marcoux, J. F.;
Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660). The product from Scheme D2, a disubstituted tetrazole, can be isolated and purified employing standard techniques, such as solvent extraction, acid-base extraction, chromatography, crystallization, distillation and the like.
Scheme D3
Figure imgf000273_0001
Referring fc to Sch®eme D-3,y the m-onosubst tuted tetrazole is prepared as described in Scheme D2 from a suitable nitrile-substituted precursor. The tetrazole is then reacted with an N-fluoropyridinium salt, which may be optionally substituted, in the presence of a suitable base (e.g. MeOΝa, EtOΝa, tBuOK and the like) for a period of time sufficient for the reaction to proceed to completion, typically from about 1 to 12h, at a temperature in the range of about -100°C to 50°C, with -78°C to 23°C being advantageous (see for example Kiselyov, A. S. and Strekowski, L. J. Heterocyclic Chem. 1993, 30, 1361-1364). The product from Scheme 3, a 2-pyridyltetrazole derivative, can be isolated and purified employing standard techniques, such as solvent extraction, acid-base extraction, chromatography, crystallization, distillation and the like.
In addition, many of the heterocyclic intermediate compounds described above can be prepared using other synthetic chemistry techniques well known in the art (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., Pergamon Press, Oxford, 1984) and references cited there within.
EXAMPLE DI 2-[2-(3-chIorophenyl)-2H-tetrazol-5-yl]pyridine 3-Chloroaniline (762mg, 6.0mmol) was dissolved in 6Ν HCI (3.55mL, 21.3mmol), cooled to 0°C, and a solution of NaNO2 (443mg, 6.42mmol) in H2O (2mL) was added dropwise. The internal reaction temperature was maintained at <5°C by the addition of ice chips to the flask.
Separately, 2-pyridyl carboxaldehyde (643mg, 6.0mmol) and toluenesulfonyl hydrazide (1.12g, 6.0mmol) were combined in ethanol (15mL). The resulting reaction mixture was stirred at ambient temperature for 15min and monitored by TLC for the disappearance of aldehyde (2,4-DNP stain). NaOH pellets (1.2g, 30.0mmol) were then added along with H2O (40mL) and the reaction mixture was cooled to 0°C with an ice bath. The 3-chloroaniline diazotization reaction contents were then added dropwise via pipet. The resulting reaction was stirred for an additional lOmin at 0°C, then the cooling bath was removed and the reaction was allowed to warm to ambient temperature. The crude mixture was diluted with EtOAc (300mL) and washed with H2O (3xl00mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes.ΕtOAc (3:1) to afford 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine as a pale orange solid. lΗ-NMR (CDCI3, 300 MHz) δ 8.85 (d, J=4.9 Hz, IH), 8.35 (m,
2H), 8.19 (d, J=7.29 Hz, IH), 7.92 (dd, J=7.8 Hz, 7.7 Hz, IH), 7.5 (m, 3H). MS (ESI) 258.0 (M++H).
EXAMPLE D2 3-(5-pyridin-2-yI-2H-tetrazol-2-yl)benzonitriIe
By following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, except that 3-amino benzonitrile (709mg, 6.0mmol) and 2-pyridyl carboxaldehyde (642mg, 6.0mmol) were employed, 3-(5- pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile was obtained as an orange solid. lΗ-NMR (CDCI3, 300 MHz) δ 8.86 (d, J=3.9 Hz, IH), 8.62 (s, IH), 8.56 (d, J=8.2 Hz, IH),
8.36 (d, J=7.9 Hz, IH), 7.94 (dd, J=7.8 Hz, 7.7 Hz, IH), 7.73-7.84 (m, 2H), 7.48 (m, IH). MS (ESI) 249.1 (M++H).
EXAMPLE D3 2-(2-pyridin-3-yI-2H-tetrazol-5-yl)pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, but using 3-amino pyridine (565mg, 6.0mmol) and 2-pyridyl carboxaldehyde (642mg, 6.0mmol), 2-(2-pyridin-3-yl-2H- tetrazol-5-yl)pyridine was obtained as an off white solid. lΗ-NMR (CDCI3, 300 MHz) δ 9.57 (s, IH), 8.86 (d, J=4.4 Hz, IH), 8.79 (d, J=4.8 Hz, IH), 8.57 (m, IH), 8.36 (d, J=7.9 Hz, IH), 7.93 (dd, J=7.8 Hz, 7.7 Hz, IH), 7.58 (m, IH), 7.48 (m, IH). MS (ESI) 225.1 (M++H).
COMPOUND DI (2-methyl-l,3-thiazoI-4-yl)methanoI
Ethyl 2-methyl-l,3-thiazole-4-carboxylate (15 g, 60mmol) was slurried in THF (40mL) and cooled to 0°C. Lithium aluminum hydride (60mL of a IM solution in THF) was added slowly and the resulting reaction mixture was allowed to warm to 25°C. After 16h the reaction was quenched by the dropwise addition of water (2.28mL), 15% NaOH solution (2.28mL) and more water (6.84mL). Ethyl acetate (lOOmL) was added, the reaction mixture filtered, and the filtrate was concentrated in vacuo. The crude residue was chromatographed on silica gel with EtOAc:hexane (1:1) as eluant to afford (2-methyl-l,3-thiazol-4-yl)methanol as an oil. iH NMR (CD3OD,
300 MHz) δ 7.21 (s,lH), 4.53 (s, 2H), 2.67(s, 3H ).
COMPOUND 2
4-(2-methyl thiazole) carboxaldehyde
(2-Methyl-l,3-thiazol-4-yl)methanol (4.4g, 34mmol) was dissolved in CH2CI2
(400mL). Magtrieve™ (44g) was added and the reaction was heated under reflux for 24h. The resulting mixture was filtered through Celite™, and the filter pad was washed thoroughly with CH2CI2. The filtrate was concentrated in vacuo to afford 2- methyl-l,3-thiazole-4-carbaldehyde as a yellow oil which was used in EXAMPLE D4 without further purification. iH NMR (CDCI3, 300 MHz) δ 9.98 (s, IH), 8.06 (s,
IH,), 2.79 (s, 3H,). MS (El ionization) 127 (hit).
EXAMPLE D4
2-(3-chlorophenyl)-5-(2-methyl-l,3-thiazol-4-yl)-2H-tetrazole
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-chloro aniline (565mg, 6.0mmol) and 4- (2-methyl thiazole) carboxaldehyde (508mg, 4.0mmol) were employed to obtain 2-(3- chlorophenyl)-5-(2-methyl-l,3-thiazol-4-yl)-2H-tetrazole as an orange solid. lΗ- NMR (CDCI3, 300 MHz) δ 8.28 (s, IH), 8.14 (m, IH), 8.08 (s, IH), 7.44-7.52 (m,
2H), 2.85 (s, 3H). MS (ESI) 278.0 (M++H).
EXAMPLE D5
3-[5-(2-methyl-l,3-thiazol-4-yl)-2H-tetrazol-2-yl]benzonitriIe
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-amino benzonitrile (651mg, 5.5mmol) and 4-(2-methyl thiazole) carboxaldehyde (700mg, 5.5mmol) were employed to obtain 3- [5-(2-methyl-l,3-thiazol-4-yl)-2H-tetrazol-2-yl]benzonitrile as an orange solid. lΗ- NMR (CDCI3, 300 MHz) δ 8.60 (s, IH), 8.53 (d, IH), 8.13 (s, IH), 7.68-7.82 (m,
2H). MS (ESI) 269.0 (M++H).
COMPOUND D3 5-(3-bromophenyI)-2H-tetrazole 3-Bromobenzonitrile (2.49g, 13.7mmol) and azidotrimethylsilane (3.14g, 27.3mmol) were stirred in anhydrous toluene (lOOmL) under argon at ambient temperature. To this was added dibutyltin oxide (341mg, 1.37mmol) and the resulting reaction was fitted with a reflux condenser and heated with stirring at 110°C for 3h. Upon cooling, the reaction mixture was concentrated in vacuo, and then concentrated to dryness twice following the addition of MeOH (ca. 25mL each). The crude reaction mixture was dissolved in EtOAc (300mL) and washed with H2O (2xl00mL). The organic phase was washed with IN aqueous NaOH (4x75mL), the combined basic aqueous portions were treated with 4N HCI to obtain an endpoint of pH=4 and the acidic aqueous phase was extracted with EtOAc (4xl00mL washes). The combined EtOAc layers were dried (MgSO4), filtered, and concentrated in vacuo to obtain 5-(3- bromoρhenyl)-2H-tetrazole as a white solid. MS (ESI) 225.0 (M++Η).
EXAMPLE D6 2-[5-(3-bromophenyl)-2H-tetrazoI-2-yl]pyridine
5-(3-Bromophenyl)-2H-tetrazole (448mg, 2.0mmol) was stirred in anhydrous MeOΗ (15mL) under argon at ambient temperature. To this was added NaOMe (4mL of 0.5M solution in MeOΗ, 2.0mmol), and the reaction flask was cooled to -78°C. A solution of N-fluoropyridinium triflate (33 lmg, l.Ommol) in anhydrous MeOΗ (2mL) was then added dropwise via syringe. The resulting reaction mixture was stirred at - 78°C for 30min, then warmed to ambient temperature and stirred for an additional 3h. The reaction mixture was partitioned between EtOAc (150mL) and 10% aqueous ΝaΗCθ3 (50mL). The EtOAc layer was washed with additional 10% aqueous NaHCO3 (2x50mL), and the combined aqueous layers were back extracted with EtOAc (lOOmL). The EtOAc layers were combined, dried (MgSO4), filtered and concentrated in vacuo. The crude material was then chromatographed on silica gel eluting with hexanes:EtOAc (3:1) to afford 2-[5-(3-bromophenyl)-2H-tetrazol-2- yl]pyridine as a white solid. lΗ-NMR (CDCI3, 300 MHz) δ 8.73 (d, IH), 8.49 (s,
IH), 8.24 (m, 2H), 8.03 (dd, IH), 7.64 (d, IH), 7.52 (dd, IH), 7.41 (dd, IH). MS (ESI) 324.0 (M*+Na).
EXAMPLE D7 2-[5-(3-chlorophenyl)-2H-tetrazoI-2-yI]pyridine Following the procedure in COMPOUND D3 for the synthesis of intermediate 5-(3- bromophenyl)-2H-tetrazole, 3-chlorobenzonitrile (1.88g, 13.67mmol) was employed to obtain 5-(3-chlorophenyl)-2H-tetrazole. MS (ESI) 181.1 (M++Η).
This material (500mg, 2.78mmol) was then carried on following the procedure in EXAMPLE D6 for the synthesis of 2-[5-(3-bromophenyl)-2H-tetrazol- 2-yl]pyridine to obtain 2-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]pyridine as an off- white solid. lΗ-NMR (CD3OD, 300 MHz) δ 8.66 (d, IH), 8.10-8.24 (m, 4H), 7.61
(dd, IH), 7.40-7.52 (m, 2H). MS (ESI) 280.0 (M++Na).
EXAMPLE D8
3-(2-pyridin-2-yI-2H-tetrazol-5-yl)benzonitrile
Following the procedure in COMPOUND D3 for the synthesis of 5-(3- bromophenyl)-2H-tetrazole, 1,3-dicyanobenzene (2.0 g, 15.63mmol) was employed to obtain 3-(2H-tetrazol-5-yl)benzonitrile. MS (ESI) 172.1 (M÷+Η). This material was then carried on following the procedure in
EXAMPLE D6 for the synthesis of 2-[5-(3-bromophenyl)-2H-tetrazol-2-yl]pyridine to obtain 3-(2-pyridin-2-yl-2H-tetrazol-5-yl)benzonitrile as an off-white solid. lΗ- NMR (CDCI3, 300 MHz) δ 8.75 (d, IH), 8.64 (s, IH), 8.57 (d, IH), 8.27 (d, IH), 8.07
(dd, IH), 7.81 (d, IH), 7.68 (dd, IH), 7.56 (dd, IH). MS (ESI) 271.0 (M +Na).
EXAMPLE D9
2-[2-(3,5-difluorophenyl)-2H-tetrazol-5-yl]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3,5-difluoroaniline (13 lmg, l.Ommol) and pyridine-2-carboxaldehyde (109mg, l.Ommol) were employed to obtain 2-[2-(3,5- difluorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300
MHz) δ 8.87 (d, IH), 8.37 (d, IH), 7.90-7.97 ( , 3H), 7.46-7.51 (m, IH), 6.97-7.03 (m, IH). MS (ESI) 260.0 (M++H).
EXAMPLE DIP
2-[2-(3-methoxyphenyI)-2H-tetrazol-5-yI]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, -anisidine (135mg, 1. Immol) and pyridine-2-carboxaldehyde (118mg, 1. Immol) were employed to obtain 2-[2-(3- methoxyphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300 MHz) δ 8.84-8.86 (m, IH), 8.34-8.38 (m, IH), 7.80-7.94 (m, 3H), 7.43-7.50 (m, 2H), 7.04-7.07 (m, IH), 3.93 (s, 3H). MS (ESI) 254.0 (M++H).
EXAMPLE Dll 2-[2-(3-trifluoromethylphenyl)-2H-tetrazol-5-yl]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-trifluoromethylaniline (195mg, 1.2mmol) and pyridine-2-carboxaldehyde (128 mg, 1.2mmol) were employed to obtain 2-[2-(3- trifluoromethylphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300 MHz) δ 8.87 (d, IH), 8.60 (s, IH), 8.52 (d, IH), 8.39 (d, IH), 7.91-7.97
(m, IH), 7.72-7.81 (m, 2H), 7.46-7.50 (m, IH). MS (ESI) 292.0 (M++H).
EXAMPLE D12 2- [2- (3-iodophenyl)-2H-tetrazol-5-yI]pyridine Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-iodoaniline (263mg, 1.2mmol) and pyridine-2-carboxaldehyde (128 mg, 1.2mmol) were employed to obtain 2-[2-(3- iodophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300
MHz) δ 8.85-8.87 (m, IH), 8.68-8.69 (m, IH), 8.26-8.38 (m, 2H), 7.84-7.95 (m, 2H), 7.44-7.49 (m, IH), 7.27-7.35 (m, IH). MS (ESI) 350.0 (M'+H).
EXAMPLE D13 2-[2-(3-bromophenyl)-2H-tetrazol-5-yI]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-bromoaniline (223mg, 1.3mmol) and pyridine-2-carboxaldehyde (135mg, 1.3mmol) were employed to obtain 2-[2-(3- bromophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300
MHz) δ 8.85-8.87 (m, IH), 8.50-8.51 (m, IH), 8.35-8.38 (m, IH), 8.23-8.27 (m, IH), 7.90-7.94 (m, IH), 7.64-7.67 (m, IH), 7.44-7.49 (m, 2H). MS (ESI) 303.0 (M++H).
EXAMPLE D14 2-[2-(3-MethylmercaptophenyI)-2H-tetrazol-5-yl]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-mercaptophenylaniline (41.8mg, 0.3mmol) and 2-pyridinecarboxaldehyde (32. lmg, 0.3mmol) were employed to obtain 2-[2-(3-Methylmercaptophenyl)-2H-tetrazol-5-yl]ρyridine as an orange solid. lΗ- NMR (CDCI3, 300 MHz) δ 8.86 (d, IH), 8.36 (d, IH), 8.14 (t, IH), 8.02 (d, IH), 7.92
(t, IH), 7.50-7.43 (m, 2H), 7.36 (d, IH), 2.59 (s, 3H). MS (ESI) 270.0 (M++H).
EXAMPLE D15 2-[2-(4-fluorophenyl)-2H-tetrazol-5-yl]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 4-fluorophenylaniline (33.3mg, 0.3mmol) and 2-pyridinecarboxaldehyde (32. lmg, 0.3mmol) were employed to obtain 2-[2-(4- fluorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300
MHz) δ 8.85 (d, IH), 8.35 (d, IH), 8.28 (m, 2H), 7.92 (t, IH), 7.49-7.44 (m, IH), 7.29 (t, 2H). MS (ESI) 242.1 (M++H).
EXAMPLE D16
2-[2-(3-fluorophenyI)-2H-tetrazol-5-yl]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-fluorophenylaniline (33.3mg, 0.3mmol) and 2-pyridinecarboxaldehyde (32. lmg, 0.3mmol) were employed to obtain 2-[2-(3- fluorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300
MHz) δ 8.85 (d, IH), 8.35 (d, IH), 8.10 (d, IH), 8.03 (d, IH), 7.92 (t, IH), 7.57 (q, IH), 7.47 (m, IH), 7.25 (t, IH). MS (ESI) 242.1 (M++H).
EXAMPLE D17 2- [2- (2-methoxyphenyI)-2H-tetrazoI-5-yl]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 2-methoxyphenylaniline (36.9mg, 0.3mmol) and 2-pyridinecarboxaldehyde (32. lmg, 0.3mmol) were employed to obtain 2-[2-(2- methoxyphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300 MHz) δ 8.82 (d, IH), 8.33 (d, IH), 7.89 (t, IH), 7.63 (d, IH), 7.55 (t, IH), 7.45-7.41 (m, IH), 7.14 (d, IH), 7.13 (t, IH), 3.88 (s, 3H). MS (ESI) 254.1 (M++H).
EXAMPLE D18 2-[2-(3-ethyIphenyl)-2H-tetrazol-5-yl]pyridine Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-ethylphenylaniline (36.4mg, 0.3mmol) and 2-pyridinecarboxaldehyde (32. lmg, 0.3mmol) were employed to obtain 2-[2-(3- ethylphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300 MHz) δ 8.84 (d, IH), 8.36 (d, IH), 8.13 (s, IH), 8.08 (d, IH), 7.91 (t, IH), 7.51-7.42 (m, 2H), 7.35 (d, IH), 2.78 (q, 2H), 1.32 (t, 3H). MS (ESI) 252.2 (NT+H).
EXAMPLE D19 2-[2-(3-methylphenyI)-2H-tetrazol-5-yI]pyridine Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-methylphenylaniline (32. lmg, 0.3mmol) and 2-pyridinecarboxaldehyde (32. lmg, 0.3mmol) were employed to obtain 2-[2-(3- ethylphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300
MHz) δ 8.85 (d, IH), 8.36 (d, IH), 8.12 (s, IH), 8.07 (d, IH), 7.91 (t, IH), 7.48-7.42 (m, 2H), 7.32 (d, IH), 2.49 (s, 3H). MS (ESI) 238.1 (M++H).
EXAMPLE D20
2- [2- (2-chloro-3-pyridyι)-2H-tetrazol-5-yl]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-amino-2-chloropyridine (38.6mg,
0.3mmol) and 2-pyridinecarboxaldehyde (32. lmg, 0.3mmol) were employed to obtain 2-[2-(2-chloro-3-pyridyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300 MHz) δ 8.84 (d, IH), 8.67 (d, IH), 8.36 (d, IH), 8.12 (d, IH), 7.94 (t,
IH), 7.55 (m, IH), 7.50-7.46 (m, IH). MS (ESI) 259.0 (M÷+H).
EXAMPLE D21
2-[2-(3,5-dichlorophenyI)-2H-tetrazol-5-yl]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3,5-dichloroaniline (48.6mg, 0.3mmol) and 2-pyridinecarboxaldehyde (32. lmg, 0.3mmol) were employed to obtain 2-[2-(3,5- dichlorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300
MHz) δ 8.86 (d, IH), 8.36 (d, IH), 8.25 (d, 2H), 7.93 (t, IH), 7.51-7.44 (m, 2H). MS (ESI) 292.0 (M++H).
EXAMPLE D22 2-[2-(2-chlorophenyl)-2H-tetrazoI-5-yl]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 2-chloroaniline (38.27mg, 0.3mmol) and 2- pyridinecarboxaldehyde (32. lmg, 0.3mmol) were employed to obtain 2-[2-(2- chlorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300
MHz) δ 8.84 (d, IH), 8.34 (d, IH), 7.92 (t, IH), 7.71 (d, IH), 7.66 (d, IH), 7.59-7.43 (m, 3H). MS (ESI) 258.0 (M++H).
EXAMPLE D23 2-[2-(4-methoxyphenyl)-2H-tetrazol-5-yl]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 4-methoxyaniline (41.8mg, 0.3mmol) and 2- pyridinecarboxaldehyde (32. lmg, 0.3mmol) were employed to obtain 2-[2-(4- methoxyphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300 MHz) δ 8.84 (d, IH), 8.34 (d, IH), 8.19 (d, 2H), 7.90 (t, IH), 7.46-7.42 (m, IH), 7.07 (d, 2H), 3.90 (s, 3H). MS (ESI) 254.1 (M++H).
EXAMPLE D24 2-[2-(4-pyridyl)-2#-tetrazoI-5-yl]pyridine Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 4-aminopyridine (56.5mg, 0.6mmol) and 2- pyridinecarboxaldehyde (64.2mg, 0.6mmol) were employed to obtain 2-[2-(4- pyridyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDCI3, 300 MHz) δ
8.89 (d, IH), 8.88 (d, 2H), 8.38 (d, IH), 8.22 (d, 2H), 7.94 (t, IH), 7.51-7.47 (m, IH). MS (ESI) 225.1 (M++H).
EXAMPLE D25 2-[2-(3,5-dimethylphenyl)-2H-tetrazol-5-yl]pyridine
Following the procedure described in EXAMPLE DI for the synthesis of 2-[2-(3- chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3,5-dimethylaniline (72.7mg, 0.6mmol) and 2-pyridinecarboxaldehyde (64.2mg, 0.6mmol) were employed to obtain 2-[2-(4- pyridyl)-2H-tetrazol-5-yl]pyridine as an orange solid. lΗ-NMR (CDC13, 300 MHz) δ 8.84 (d, IH), 8.35(d, IH), 7.91 (s, 2H), 7.45-7.41 (m, IH), 7.13 (s, IH), 2.42 (s, 6H). MS (ESI) 252.1 (M++H). EXAMPLE D26 to EXAMPLE D206 shown below were prepared similarly to the schemes and procedures described above (ND = not determined).
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
Examples D207-D236 have mGluR5 inhibitory activity greater than 10 μM in the calcium flux assay or inhibition <50% at 100 μM concentration in the PI assay.
Figure imgf000321_0002
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Methods of Synthesis of Compounds of Formula IE Compounds of the present invention can be prepared according to the following methods. The substituents are the same as in Formula (IE) except where defined otherwise, or apparent to one in the art.
In Schemes El to E5 below, Xe and Ye are as defined above. Other variables are understood by one in the art by the context in which they are used. Scheme El
Figure imgf000328_0001
Thus in Scheme El, a suitably substituted imidazole containing a functional group Ae , which is capable of undergoing a metal-catalyzed cross- coupling reaction, such as a halogen or trifluoromethanesulfonate and the like (prepared using synthetic chemistry techniques well known in the art) may be coupled with a species Xe substituted with a group Be- Be may be a metalloid such as B(OR)2, BiLn or related species and the reaction may be promoted with stoichiometric or catalytic amounts of metal salts such as Cu(OAc)2, Cui, [Cu(OH)TMEDA]2Cl2 or CuOTf and the like. Typically a base (e.g. pyridine, NEt3, CS2CO3, K^PO-i, K2CO3 etc.) will also be present and the reaction carried out in a suitable solvent (e.g. DCM, THF, DME, dioxane, toluene, MeCN, DMF, H2O etc.). Additionally, molecular sieves may be used as a cocatalyst and an atmosphere of oxygen may be required. The cross-coupling reaction may be carried out at rt or heated to a temperature between about 30°C to 150°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 72h, with 18h typically being sufficient (see for example Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Cham, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944 and Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660 and Collman, J.P.; Zhong, M. Org. Lett. 2000, 2, 9, 1233-1236). The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like.
In another embodiment of the present invention when Be is a good leaving group such as F, and Xe is electron deficient or has one or more electron withdrawing substituents (e.g. NΟ2, CN), the coupling reaction may be effected thermally in a temperature range of about 60°C up to about 250°C. Typically, this reaction is carried out in the presence of base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) in a suitable solvent, such as DMSO, DMF, DMA H2O and the like, and takes from lh up to about 72h with 18h typically being sufficient (see for example Davey, D. D.; Erhardt, P. W.; Cantor, E. H.; Greenberg, S. S.; Ingebretsen, W. R.; Wiggins; J.MedChem. 1991, 34, 9, 2671-2677).
In turn the derivatized imidazole is reacted with a moiety Ye under metal-catalyzed cross-coupling conditions (Scheme E2)
Scheme E2
Figure imgf000329_0001
where Ee is a metallic or metalloid species such as B(OR)2, Li, MgHal, SnR3, ZnHal, SiR3 and the like which is capable of undergoing a metal-catalyzed cross-coupling reaction. The coupling may be promoted by a homogeneous catalyst such as Pd(PPh3)4, or by a heterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g. THF, DME, toluene, MeCN, DMF, H2O etc.). Typically a base, such as K2CO3, NEt3, and the like, will also be present in the reaction mixture. Other promoters may also be used such as CsF. The reaction mixture is maintained at rt, or heated to a temperature between 30°C tol50°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 48h, with about 18h typically being sufficient (see for example Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483). The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like.
Another embodiment of the present invention is illustrated in Scheme E3:
Scheme E3
Figure imgf000329_0002
Thus, a suitably substituted imidazole containing a functional group Ae, which is capable of undergoing a metal-catalyzed cross-coupling reaction, such as a halogen or trifluoromethanesulfonate and the like (prepared using synthetic chemistry techniques well known in the art) may be coupled with a species Ye substituted with a group Ee where Ee is a metallic or metalloid species such as B(OR)2,Li, MgHal, SnR3, ZnHal, SiR3 and the like. The coupling may be promoted by a homogeneous catalyst such as Pd(PPh3)4, or by a heterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g. THF, DME, toluene, MeCN, DMF, H2O etc.). Typically a base, such as K2CO3, NEt3, and the like, will also be present in the reaction mixture. Other promoters may also be used such as CsF. The reaction mixture is maintained at rt, or heated to a temperature between about 30°C tol50°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4h up to 48h, with about 18h typically being sufficient (see for example Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483 or Negishi, E., Liu, F., Palladium or Nickel catalyzed Cross-coupling with Organometals Containing Zinc, Magnesium, Aluminium and Zirconium in Metal-catalyzed Cross-coupling Reactions Diederich, F.; Stang, P.J. Eds. Wiley, Weinheim, Germany, 1998; ppl-42). The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like.
Another embodiment of the present invention is illustrated in Scheme E4:
Scheme E4
Figure imgf000330_0001
Thus a suitably substituted species Ye containing a pendant aldehyde group (prepared using synthetic chemistry techniques well known in the art) may be converted to a substituted imidazole in a two step procedure. First, the aldehyde is converted to an intermediate substituted oxazole using tosylmethylisocyanide in a suitable solvent (e.g. THF, EtOH, dioxane, DCM, toluene etc.) in the presence of a suitable base (such as NaH, KOtBu, KCN, K2CO3 etc.). The reaction mixture is then maintained at rt, or heated to a temperature between about 30°C to 100°C. The reaction mixture is then maintained at the required temperature for a time in the range of about 2h up to 48h, with about 6h typically being sufficient. The intermediate oxazole is then heated with ammonia in a suitable solvent (e.g. THF, MeOH, DCM, toluene, dioxane etc.). The reaction mixture is then maintained at ambient temperature, or heated to a temperature anywhere between 30°C tol50°C. The reaction mixture is then stirred for a time in the range of about 2 up to 48h, with about 24h typically being sufficient. The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like (see for example Wang, F.; Schwabacher, A. W. Tetrahedron. Lett. 1999, 40, 4779-4782). As shown in Scheme E5, the imidazole may then be coupled with a ring system Xe substituted with a functional group Be.
Scheme E5
Figure imgf000331_0001
Be may be a metalloid species such as B(OR)2, BiLn or the like and the reaction may be promoted with stoichiometric or catalytic amounts of metal salts such as Cu(OAc)2, Cui, [Cu(OH)TMEDA]2Cl2 or CuOTf and the like. Typically, a base (e.g. pyridine, NEt3, CS2CO3, K3PO4iK2CO3 etc.) will also be present and the reaction carried out in a suitable solvent (e.g. DCM, THF, DME, dioxane, toluene, MeCN, DMF, H2O etc.). Additionally, molecular sieves may be used as a cocatalyst and an atmosphere of oxygen may be required. The cross-coupling reaction may be carried out at ambient temperature or heated to a temperature anywhere between 30°C to 150°C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 72h, with 18h typically being sufficient (see for example Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Cham, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944 and Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660 and Collman, J.P.; Zhong, M. Org. Lett. 2000, 2, 9, 1233-1236). The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation and the like. Alternatively, Be may be a leaving group capable of undergoing a metal-catalyzed cross-coupling reaction such as a halogen or trifluoromethanesulfonate and the like. Typically, the reaction is carried out using catalytic amounts of a copper (I) salt together with a di-amine ligand and in the presence of a suitable base (e.g. K3PO4, CS2CO3, K2CO3 etc.) in a suitable solvent, such as dioxane, DMSO, DMA, DMF (see for example Klapars, A.; Antilla, J.C.; Huang, X.; Buchwald, S.L J. Am. Chem Soc. 2001, 123(31); 7727-7729). Additionally, when Be is a good aryl leaving group such as F, and Xe is electron deficient or has one or more electron withdrawing substituents (e.g. NO2,
CN), the coupling reaction may be effected thermally in a temperature range of about 60°C up to about 250°C. Typically, this reaction is carried out in the presence of base (e.g. pyridine, NEt3, CS2CO3, K2CO3 etc.) in a suitable solvent, such as DMSO, DMF, DMA H2O and the like, and takes from lh up to about 72h with 18h typically being sufficient (see for example Davey, D. D.; Erhardt, P. W.; Cantor, E. H.; Greenberg, S. S.; Ingebretsen, W. R.; Wiggins; J.Med.Chem. 1991, 34, 9, 2671-2677). In addition, many of the heterocyclic compounds described above can be prepared using other synthetic chemistry techniques well known in the art (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., Pergamon Press, Oxford, 1984) and references cited there within.
COMPOUND El Synthesis of 2-(4-bromo-lH-imidazoI-l-yl)pyridine
2-Bromopyridine (1.3mL, 14mmol) and 4-bromo-lH-imidazole (2g, 14mmol) were heated in dry NMP (15mL) under an atmosphere of Ar (g) at 165°C for 18h. After cooling to rt, H2O (40mL) and EtOAc (40mL) were added and the reaction mixture shaken, the EtOAc layer was separated, and the aqueous layer shaken with EtOAc (2 x 30mL). The combined organic layers were dried over Na2SO4 and concentrated to a brown oil. This was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (4:6) to afford 2-(4-bromo-lH-imidazol-l-yl)pyridine as a white solid. lΗ NMR (CD3CI, 300 MHz) δ 8.50 - 8.52 (IH, m), 8.25 (IH, d), 7.87 (IH, ddd),
7.64 (IH, d), 7.28 - 7.36 (2H, m). MS (ESI) 224 (M+H) +
EXAMPLE El
Synthesis of 2-r4-(3-chIorophenyl)-lH-imidazol-l-yl1pyridine
2-(4-Bromo-lH-imidazol-l-yl)pyridine (225mg, Immol), 3-chlorophenylboronic acid (173mg, 1. Immol), Pd(PPh3)4 (58mg, 0.05mmol) and potassium carbonate (276mg, 2mmol) were dissolved in a mixture of DME (9mL) and Η2O (lmL) and degassed for
15min. with Ar (g). The reaction mixture was then heated at 80°C for 18h. After cooling to rt, H2O (40mL) and EtOAc (40mL) were added and the reaction mixture shaken, the EtOAc layer was separated, and the aqueous layer shaken with EtOAc (2 x 30mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow oil. This was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (4:6) to afford 2-[4-(3-chlorophenyl)-lH-imidazol-l-yl]pyridine as a white solid. lΗ NMR (CDCI3, 300 MHz) δ 8.52 - 8.54 (IH, m), 8.40 (IH, d), 7.99
(IH, d), 7.85 - 7.91 (2H, m), 7.74 - 7.77 (IH, m), 7.43 (IH, d), 7.25 - 7.38 (3H, m). MS (ESI) 257 (M+H) +
EXAMPLE E2 Synthesis of 2-(4-pyridin-3-yI-lH-imidazol-l-yI)pyridine
2-(4-Bromo-lH-imidazol-l-yl)pyridine (225mg, Immol), diethyl-(3-pyridyl)-borane (162mg, 1. Immol), Pd(PPh3)4 (58mg, 0.05mmol) and potassium carbonate (276mg, 2mmol) were dissolved in a mixture of DME (9mL) and Η2O (lmL) and degassed for
15min. with Ar (g). The reaction mixture was then heated at 80°C for 18h. After cooling to rt, H2O (40mL) and EtOAc (40mL) were added and the reaction mixture shaken, the EtOAc layer was separated ,and the aqueous layer shaken with EtOAc (2 x 30mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow oil. This was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (2:1) to afford 2-(4-pyridin-3-yl-lH-imidazol-l-yl)pyridine as a white solid. lΗ NMR (CDCI3, 300 MHz) δ 9.10 (IH, m), 8.54 - 8.56 (2H, m), 8.44 (IH, s),
8.20 (IH, ddd), 8.06 (IH, s), 7.91 (IH, ddd), 7.47 (IH, d), 7.30 - 7.39 (2H, m). MS (ESI) 223 (M+H) +
COMPOUND E2 Synthesis of 2-(lH-imidazol-4-yl)pyridine
2-(lH-Imidazol-4-yl)pyridine was prepared according to the method of Wang, F.; Schwabacher, A. W. Tetrahedron. Lett. 1999, 40, 4779-4782.
EXAMPLE E3
Synthesis of 2-ri-(3-chlorophenyl)-lH-imidazoI-4-yllpyridine
2-(lH-Imidazol-4-yl)pyridine (0.145 g, 1 mmol), 3-chlorophenylboronic acid (0.312g, 2 mmol), pyridine (0.158g, 2 mmol), copper (Η) acetate (0.313g, 1.5mmol) and molecular sieves lOOmg were mixed in dichloromethane (10 mL). The mixture was stirred at ambient temperature for 48 h. The reaction mixture was concentrated onto silica gel in vacuo, the crude residue was chromatographed on silica gel eluting with EtOAc:hexane (3:2) to afford 2-[l-(3-chlorophenyl)-lH-imidazol-4-yl]pyridine as a colorless solid. iH NMR (CD3CI 300 MHz) δ 8.51-8.48 (m, 2H), 7.78-7.72 (m, 2H), 7.52 (d, IH), 7.46-7.41 (m, IH), 7.38-7.35 (m, 2H), 7.31-7.19 (m, 2H). MS (ESI) 256.0 (M++H).
COMPOUND E3
Synthesis of 3-(3-bromo-5-fluorophenoxy)pyridine
1-Bromo 3,5-difluorobenzene (10 g, 51.8 mmol) and potassium carbonate(10g, 76 mmol) were combined in DMF (100 mL) under argon and heated to 100° C. 3- Hydroxypyridine (4.9 g, 51.8 mmol) in DMF ( 50 ml) was added to the reaction mixture by syringe pump over night . The reaction was allowed to cool to ambient temperature. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (600 mL), and washed with H2O (3 x 300 mL), brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil. The crude product was purified by column chromatography eluting with CH2H2:pentane (1:9) to afford 3-(3-bromo-5-fluorophenoxy)pyridine as a yellow oil. iH NMR
(CDCI3, 300 MHz) 6 8.47-8.43 (m, 2H), 7.36-7.34 (m, 2H), 7.03-7.02(d, IH), 7.03 (s,
IH), 6.67-6.65 (d, IH). MS (ESI) 269.9 (M++2H).
EXAMPLE E4 Synthesis of 2-{l-r3-fluoro-5-(pyridin-3-yloxy)phenyn-lH-imidazoI-4-yl}pyridine
2-(lH-Imidazol-4-yl)pyridine (300 mg, 2 mmol) , 3-(3-bromo-5- fluorophenoxy)pyridine (641 mg, 2.4 mmol), sodium t-butoxide (385 mg, 4 mmol), Cui (20 mg, 0.1 mmol) and 1,10-phenanthroline (72 mg, 0.4mmol) were combined in DMF (25 mL) under argon. The reaction mixture was heated at 120° C overnight. The reaction mixture was allowed to cool to ambient temperature. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (300 mL), and washed with Η2O (3 x 100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil which partially solidified when pumped down under high vacuum. The crude product was purified by column chromatography eluting with EtOAc:hexane (7:3) to afford 2-{ l-[3-fluoro-5-(pyridin-3-yloxy)phenyl]- lH-imidazol-4-yl}pyridine as a yellow solid. lΗ NMR (CDCI3, 300 MHz) δ 8.57-
8.56 (d, IH), 8.52-8.49 (m, 2H),8.10-8.08 (d, IH), 7.93 (s, IH), 7.89( s, IH), 7.77- 7.74 ( m, IH), 7.44-7.36 (m, 2H), 7.20-7.17(m, IH), 6.99-6.97 (d, 1H)6.93 (s, IH), 6.72-6.70 (d, IH). MS (ESI) 333.2 (M++H). Methods of Synthesis of Compounds of Structural Formula (IF)
Compounds of the present invention can be prepared according to the following methods. The substituents are the same as in Formula IF except where defined otherwise. In the following schemes FI to F9 , Rl represents Rlf; R2 represents R2f; R3 represents R3 ; R4 represents R4 . Scheme FI:
Figure imgf000335_0001
Scheme F2:
Figure imgf000336_0001
3) PTSA, Toluene, Heat
Pd/C, H2, EtOH/EtOAc NC r^r^»
H„N
Scheme F3:
Figure imgf000336_0002
Scheme F4:
Figure imgf000337_0001
Scheme F5:
Figure imgf000337_0002
Scheme F6:
Figure imgf000338_0001
Scheme F7:
Figure imgf000338_0002
1)nBuLi, ZnCI2,THF,
Figure imgf000338_0003
Scheme F8:
Figure imgf000339_0001
3) POCI3,Heat
Scheme F9:
Figure imgf000339_0002
Example FI r4-(l,3-Benzoxazol-2-yl)-2-bromophenynacetonitrile
Figure imgf000339_0003
A mixture of 3-bromo-4-methylbenzoic acid (l.Og, 4.7mmol) and thionyl chloride (18mL) was refluxed for lh and then cooled to rt. The excess thionyl chloride was removed in vacuo, the residue was dissolved in THF (lOmL), and was added to a cooled (0°C) mixture of 2-aminophenol (510mg, 4.7mmol) and diisopropylethylamine (0.90mL, 5. Immol) in THF (18mL). The resulting mixture was stirred at rt for 4h. The solvent was then removed and the residue was purified by flash chromatography on silica gel eluting with EtOAchexane (1:5 to 1:4) to afford 3-bromo-N-(2- hydroxyphenyl)-4-methylbenzamide.
A mixture of 3-bromo-N-(2-hydroxyphenyl)-4-methylbenzamide (550mg, 1.8mmol),/?-toluenesulfonic acid (2.4g, 12.7mmol) in toluene (50mL) was refluxed for 4h, cooled to rt, and filtered through a Celite pad. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica gel using a gradient of EtOAchexane (0 to 30min: 0 to 15% EtOAc) to afford 2-(3- bromo-4-methylphenyl)-l,3-benzoxazole as a colorless solid. MS (ESI) 288 (M + H)+.
A mixture of 2-(3-bromo-4-methylphenyl)-l,3-benzoxazole (240mg, 0.83mmol), n-bromosuccinimide (180mg, 0.99mmol), and benzoyl peroxide (lOmg, 0.041mmol) in carbon tetrachloride (15mL) was refluxed for 3h. The white precipitate was filtered and the filtrate was evaporated to dryness. The resulting solid was purified by flash chromatography on silica gel eluting with EtOAchexane (1:5) to afford 2-[3-bromo-4-(bromomethyl)phenyl]-l,3-benzoxazole as a yellow solid. A mixture of 2-[3-bromo-4-(bromomethyl)phenyl]-l,3-benzoxazole (156mg, 0.42mmol), and sodium cyanide (41mg, 0.84mmol) in DMF:H2θ (3:1,
16mL) was stirred at rt for 18h. Water (50mL) was added to the reaction mixture and it was extracted with EtOAc (3x). The organics were combined, washed with brine (2x), dried over Νa2Sθ4, and evaporated to dryness to give an orange oil. The crude oil was purified by flash chromatography eluting with a gradient of EtOAc :hexane (0 to 30min: 0 to 20% EtOAc) to afford the desired [4-(l ,3-benzoxazol-2-yl)-2- bromophenyl] acetonitrile as a yellow solid (M.p. 190-191°C). iH NMR (CDCI3,
300MHz) δ 8.50 (s, IH), 8.22 (dd, IH), 7.78 (m, IH), 7.70 (d, 1H), 7.60 (m, IH), 7.39 (m, 2H), 3.91 (s, 2H). MS (ESI) 313 (M)+.
Example F2 rS-d^-Benzoxazol^-vD^'^'-dimethoxy-U'-biphenyl^-vnacetonitrile
Figure imgf000341_0001
A mixture of 2,4-dimethoxyphenylboronic acid (175mg, 0.96mmol), [4-(l,3- benzoxazol-2-yl)-2-bromophenyl]acetonitrile (example FI) (200mg, 0.64mmol), dichlorobis(triphenylphosphine)palladium(II) (22mg, 0.032mmol), triphenylphosphine (17mg, 0.064mmol), and potassium carbonate (177mg, 1.3mmol) in degassed DME/H2O (5:1, 12mL) was heated at 83°C for 18h. The mixture was cooled to rt, the two layers were separated and the aqueous layer was extracted with EtOAc (3x). The organics were combined, dried over N 2SO4 and evaporated to dryness to give an orange solid. Purification of the crude by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 40min: 0 to 20% EtOAc, 40 to 50min: 50% EtOAc) afforded [5-(l,3-benzoxazol-2-yl)-2\4'-dimethoxy-l,l'- biphenyl-2-yl]acetonitrile as a yellow solid. iH NMR (CDCI3, 300MHz) δ 8.26 (dd,
IH), 8.15 (s, IH), 7.77 (m, IH), 7.70 (d, IH), 7.57 (m, IH), 7.36 (m, 2H), 7.16 (d, IH), 6.62 (dd, IH), 6.57 (s, IH), 3.88 (s, 3H), 3.78 (s, 3H), 3.64 (q, 2H). MS (ESI) 371 (M + H)+.
Example F3 r4-(l,3-Benzoxazol-2-yl)-2-methyIphenvπacetonitriIe
Figure imgf000341_0002
A mixture of methane boronic acid (57.6mg, 0.96mmol), [4-(l,3-benzoxazol-2-yl)-2- bromophenyl] acetonitrile (example FI) (200mg, 0.64mmol), dichlorobis
(triphenylphosphine)palladium(II) (22.4mg, 0.032mmol), triphenylphosphine (17mg, 0.064mmol), and potassium carbonate (177mg, 1.3mmol) in degassed DME/H2O
(5:1, 12mL) was heated at 80°C for 18h. The mixture was cooled to rt, the two layers were separated and the aqueous layer was extracted with EtOAc (3x). The organics were combined, dried over Na2SO4 and evaporated to dryness to give a brown solid.
Purification of the crude solid by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 40min: 0 to 25% EtOAc) afforded the desired [4- (l,3-benzoxazol-2-yl)-2-methylphenyl]acetonitrile as a yellow solid. lH NMR
(CDCI3, 300MHz) δ 8.14 (s, IH), 8.11 (d, IH), 7.78 (m, IH), 7.60 (m, IH), 7.54 (d,
IH), 7.38 (m, 2H), 3.76 (s, 2H), 2.45 (s, 3H). MS (ESI) 249 (M + H)+.
Example F4 5,-(l,3-BenzoxazoI-2-yl)-2'-(cyanomethyl)-l,l'-biphenvI-3-carbonitrile
Figure imgf000342_0001
A mixture of 3-bromo-4-methylbenzoic acid (l.Og, 4.7mmol) and thionyl chloride (18mL) was refluxed for lh and then cooled to rt. The excess thionyl chloride was removed in vacuo, the residue was dissolved in THF (lOmL), and it was added to a cooled (0°C) mixture of 2-aminophenol (507mg, 4.7mmol) and diisopropylethylamine (0.90mL, 5. Immol) in THF (18mL). The resulting mixture was stirred at rt for 4h. The solvent was then removed and the residue was purified by flash chromatography on silica gel eluting with EtOAc:hexanes (1:5 to 1:4) to afford 3-bromo-N-(2- hydroxyphenyl)-4-methylbenzamide . A mixture of 3-bromo-N-(2-hydroxyphenyl)-4-methylbenzamide
(554mg, 1.8mmol), p-toluenesulfonic acid (2.41g, 12.7mmol) and toluene (50mL) was refluxed for 4h, cooled to rt, and filtered through a Celite pad. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica gel using a gradient of EtOAc:hexanes (0 to 30min:0 to 15% EtOAc) to afford 2-(3- bromo-4-methylphenyl)-l,3-benzoxazole as a colorless solid. MS (ESI) 288 (M "). A mixture of 3-cyano-phenylboronic acid (183mg, 1.3mmol), 2-(3- bromo-4-methylphenyl)-l,3-benzoxazole (300mg, 1.04mmol), dichlorobis(triphenylphosphine) palladium(IT) (36.5mg, 0.052mmol), triphenylphosphine (27mg, 0.104mmol), and potassium carbonate (287mg, 2.08mmol) in degassed DME/H2O (5:1, 18mL) was heated to 80°C for 18h. The mixture was cooled to rt and the two layers were separated and the aqueous layer was extracted with EtOAc (3x). The organics were combined, dried over Na2SO4, and evaporated to dryness to give a clear solid. Purification of the crude by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 30min: 0 to 20% EtOAc) afforded 5'-(l,3-benzoxazol-2-yl)-2'-methyl-l,l'-biphenyl-3- carbonitrile a colorless solid.
A mixture of 5'-(l,3-benzoxazol-2-yl)-2'-methyl-l,l'-biphenyl-3- carbonitrile (229mg, 0.74mmol), 7z-bromosuccinimide (145mg, 0.8 Immol), and benzoyl peroxide (9mg, 0.037mmol) in carbon tetrachloride (15mL) was refluxed for 5h. The solvent was evaporated to dryness and the crude was purified by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 30min: 0 to 20% EtOAc, 30 to 40min: 50% EtOAc) to afford 5'-(l,3-benzoxazol-2-yl)-2'- (bromomethyl)-l, -biphenyl-3-carbonitrile as a colorless solid. A mixture of 5'-(l,3-benzoxazol-2-yl)-2'-(bromomethyl)-l,l '- biphenyl-3-carbonitrile (183mg, 0.47mmol) and sodium cyanide (46mg, 0.94mmol) in DMF:H2θ (5:1, 18mL) and DMF (20mL) was stirred at rt for 3h. H2O was added to the reaction mixture and it was extracted with EtOAc (3x). The organics were combined, washed with brine (2x), dried over Na2SO4, and evaporated to dryness to give an orange oil. The crude was purified by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 30min: 0 to 20% EtOAc) to afford the desired 5'-(l,3-benzoxazol-2-yl)-2'-(cyanomethyl)-l, -biphenyl-3-carbonitrile as a colorless solid (M.p. 175-176°C). iH NMR (CDCI3, 300MHz) δ 8.34 (dd, IH), 8.18
(s, IH), 7.77 (m, 3H), 7.67 (m, 3H), 7.60 (m, IH), 7.40 (m, 2H), 3.69 (s, 2H). MS (ESI) 336 (M + H)+.
Example F5 T4- (1 ,3-Benzoxazol-2-yl)-2- (trifluoromethyDphenyllacetonitrile
Figure imgf000343_0001
A mixture of 4-methyl-3-(trifluoromethyl)benzoic acid (l.Og, 4.9mmol) and thionyl chloride (15mL) was refluxed for 3h and then stirred at rt overnight. The excess thionyl chloride was removed in vacuo, the residue was dissolved in THF (20mL), and it was added to a cooled (0°C) solution of 2-aminophenol (0.53g, 4.9mmol) and diisopropylethylamine (LOmL, 5.9mmol) in anhydrous THF (15mL). The resulting brownish mixture was stirred at rt for 3h. The solvent was then removed and - toluenesulfonic acid (3.7g, 19.6mmol) and toluene (20mL) were added to the dark oil. The mixture was then refluxed for 3h and the mixture was cooled to rt. The excess p- toluenesulfonic acid was filtered through Celite and the filtrate was evaporated to dryness. The crude was purified by flash chromatography on silica gel eluting with EtOAc:hexanes (1:9) to afford 2-[4-methyl-3-(trifluoromethyl)phenyl]-l,3- benzoxazole as a colorless solid.
A mixture of 2-[4-methyl-3-(trifluoromethyl)phenyl]-l,3-benzoxazole (600mg, 2.2mmol), n-bromosuccinimide (579mg, 3.25mmol), benzoyl peroxide (26mg, 0.1 Immol) in carbon tetrachloride (15mL) was refluxed for 3h and then cooled to rt. The white precipitate was filtered and the filtrate was concentrated to dryness. The crude was purified by flash chromatography on silica gel eluting with EtOAc:hexanes (1:1) to afford 2-[4-(bromomethyl)-3-(trifluoromethyl)phenyl]-l,3- benzoxazole. To a suspension of 2-[4-(bromomethyl)-3-(trifluoromethyl)phenyl]-
1,3-benzoxazole (528mg, 1.5mmol) and cyanotrimethylsilane (0.30mL, 2.2mmol) in acetonitrile (19mL) was added TBAF (1.0M in THF, 2.2mL, 2.2mmol) and the mixture was stirred at rt for 2h. The solvent was removed in vacuo and the crude was purified by flash chromatography eluting with EtOAc: hexanes (1:9) to afford the desired [4-(l,3-benzoxazol-2-yl)-2-(trifluoromethyl)phenyl]acetonitrile as a colorless solid. IH NMR (CDCI3, 300MHz) δ 8.60 (s, IH), 8.48 (d, IH), 7.88 (d, IH), 7.82
(m, IH), 7.63 (m, IH), 7.43 (m, 2H), 4.05 (s, 2H). MS (ESI) 303 (M + H)+.
Example F6 r4-(l,3-Benzoxazol-2-yl)-2-nitrophenynacetonitrile
Figure imgf000345_0001
A mixture of 4-fluoro-3-nitrobenzoic acid (2.1g, 11.3mmol) and thionyl chloride (20mL) was refluxed for 3h and then cooled to rt. The excess thionyl chloride was removed and the residue dissolved in lOmL of THF was added to a cooled (0°C) solution of 2-aminophenol (1.24g, 11.3mmol) and diisopropylethylamine (2.4mL,
13.6mmol) in anhydrous THF (20mL). The resulting mixture was refluxed for 4h and then cooled to rt. The solvent was removed and p-toluenesulfonic acid (8.63g, 45.4mmol) and toluene (50mL) were added to afford a dark mixture that was refluxed overnight. The solvent was removed and the crude was purified by flash chromatography on silica gel eluting with hexanes:CH2Cl2 (L5) to afford 2-(4- fluoro-3-nitrophenyl)-l,3-benzoxazole as a colorless solid.
2-(4-fluoro-3-nitrophenyl)-l,3-benzoxazole (200mg, 0.77mmol) was dissolved in DMSO (5mL) and K2CO3 (267mg, 1.94mmol) was added. The resulting yellow mixture was warmed to 65°C and tert-butylcyanoacetate (137mg, 0.97mmol) was added dropwise. The dark red mixture was heated to 65°C for 30min, cooled to rt, and poured into H2O. The aqueous layer was acidified to pH 3 (with a 10% aqueous HCI solution) and it was extracted with EtOAc (3x). The organics were combined, washed with brine (2x), dried over Na2SO4, and evaporated to dryness.
The yellow residue and p-toluenesulfonic acid (29.5mg, 0.15mmol) were dissolved in toluene (15mL) and the mixture was refluxed for 20h. After cooling to rt, the mixture was poured in H2O and the two layers were separated. The aqueous was extracted with EtOAc (3x), the organics were combined, dried over Na2SO4, and evaporated to dryness. Purification of the residue by flash chromatography on silica gel eluting with EtOAc:hexanes (3:7 to 2:3 to 1:1) afforded the desired [4-(l,3-benzoxazol-2-yl)-2- nitrophenyl] acetonitrile as an orange solid (M.p. 203°C). iH NMR (CDCI3,
300MHz) δ 8.79 (s, IH), 8.57 (dd, IH), 7.97 (d, IH), 7.86 (m, 2H), 7.54-7.44 (m, 2H), 4.50 (s, 2H). MS (ESI) 280 (M + H)+.
Example F7 r2-Amino-4-(l,3-benzoxazol-2-yl)phenyllacetonitrile
Figure imgf000346_0001
A suspension of [4-(l,3-benzoxazol-2-yl)-2-nitrophenyl]acetonitrile (lOOmg, 0.36mmol) and Pd/C (20mg) in EtOH/EtOAc (5:1, 60mL) was hydrogenated (35psi) over 2d. The resulting reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The yellow solid obtained was purified by flash chromatography on silica gel eluting with MeOH:CH2θ2 (1:19) to afford [2-amino-
4-(l,3-benzoxazol-2-yl)phenyl]acetonitrile as an orange solid (M.p.l98-199°C). iH NMR (CDCI3, 300MHz) δ 7.77 (m, IH), 7.71-7.66 (m, 2H), 7.58 (m, IH), 7.40-7.34
(m, 3H), 3.88 (s, 2H), 3.66 (s, 2H). MS (ESI) 250 (M + H)+.
Example F8 r4-(l,3- Benzoxazol-2-yl)-2-fluorophenyn acetonitrile
Figure imgf000346_0002
To a stirred solution of 4-bromo-2-fluoro benzyl bromide (1.5g, 5.6mmol) in DMF (50mL) was added sodium cyanide (0.8g, 17mmol). The reaction mixture was stirred at 90°C for lh, cooled to rt and quenched with brine (50mL). After extraction with EtOAc (3 x lOOmL), the organic layers were combined, washed with brine (50mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexanes:EtOAc 5:1) to afford 4-bromo-2-fluoro benzyl cyanide as yellow solid. MS (ESI) 307 (M + H)+.
To a stirred solution of benzoxazole (153mg, 1.3mmol) in 5mL THF at -78°C, was added π-Butyllithium (640μL, 2.5M in hexanes, 1.6mmol). The reaction mixture was stirred for 15min at -78°C and ZnCl2 (3.9mL, 1.0M solution in Et2θ,
3.9mmol) was added via a syringe. The reaction was then warmed to 0°C for lh and a solution of 4-bromo-2-fluoro benzyl cyanide (214mg, l.Ommol) in THF (2mL) was added, along with Pd (a fine suspension prepared as follows: 200μL ?z-Butyllithium, 2.5M in hexanes added to 144mg PdCl2(PPh3)2 in 5mL of THF). The reaction mixture was then stirred at reflux overnight, quenched with sat. NaHCO3 (50mL) and diluted with EtOAc (300mL). The resulting organic layer was washed with H2O (1 x 50mL), dried (MgSO4) and concentrated in vacuo. The residue purified by flash chromatography (silica gel, hexanes:EtOAc 5:1) to afford the desired [4-(l,3- benzoxazol-2-yl)-2-fluorophenyl] acetonitrile as a yellow solid. iH NMR (CD3OD,
300MHz) δ 8.14 (q, IH), 8.2 (q, IH), 7.82 (m, IH), 7.63 (m,2H), 7.42 (m,2H), 3.85 (s, 2H). MS (ESI) 253 (M + H)+.
Example F9 r2-Fluoro-4-(6-methyl-l,3- benzoxazol-2-yl)phenyl1 acetonitrile
Figure imgf000347_0001
To a stirred solution of 4-bromo-2-fluoro benzyl bromide (1.5g, 5.6mmol) in DMF (50mL) was added sodium cyanide (0.8g, 16.8mmol). The reulting reaction mixture was stirred at 90°C for lh, cooled to rt, quenched with brine (50mL) and extracted with EtOAc (3 x lOOmL). The organic layers were combined, washed with brine
(50mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column (silica gel, hexanes :EtO Ac 5:1) to afford 4-bromo-2-fluoro benzyl cyanide as yellow solid. MS (ESI) 307 (M + H)+.
To a stirred solution of 6-methylbenzoxazole (173mg, 1.3mmol) in THF (5mL) at -78 °C, was added rc-Butyllithium (640μL, 2.5M in hexanes,
1.6mmol). The resulting reaction mixture was stirred for 15min at -78 °C and ZnCl2 (3.9mL, IM in Et2θ, 3.9mmol) was added via a syringe. After warming up the reaction mixture at 0°C for lh, a solution of 4-bromo-2-fluoro benzyl cyanide (214mg, l.Ommol) in THF (2mL) was added, along with PdO (a fresh suspension prepared as follows: 200μL 7?-Butyllithium, 2.5M in hexanes added to 144mg of
PdCl2(PPh3)2 in 5mL of THF). The mixture was then heated under reflux overnight. The mixture was hydrolized with sat. NaHCO3 (50mL) and extracted with EtOAc (3 x 150mL). The organic layers were combined, washed with H2O (50mL), dried (MgSO ) and concentrated in vacuo. The residue was purufied by chromatography on silica gel using a mixture of hexanes :EtO Ac (5: 1) as eluant to afford [2-fluoro-4-(6- methyl-1,3- benzoxazol-2-yl)phenyl] acetonitrile as yellow solid. iH NMR (CD3OD, 300MHz), δ8.07 (d, IH), 7.95(d, IH), 7.64(m, 2H), 7.40(s, IH), 7.20(d, IH), 3.90(s, IH). MS (ESI) 267 (M + H)+.
Example F10 r2-Fluoro-4-(5-methyl-l,3- benzoxazol-2-yl)phenyll acetonitrile
Figure imgf000348_0001
To a stirred solution of 4-bromo-2-fluoro benzyl bromide (1.5g, 5.6mmol) in DMF (50mL) was added sodium cyanide (0.8g, 16.8mmol). The resulting mixture was stirred at 90°C for lh, cooled at rt and quenched with brine (50mL). After extraction with EtOAc (3 x 50mL), the organic layers were combined, washed with brine (50mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexanes:EtOAc (5:1) to afford 4- bromo-2-fluoro benzyl cyanide as yellow solid. MS (ESI) 307 (M + H)+.
To a stirred solution of 5-methylbenzoxazole (173mg, 1.3mmol) in THF (5mL) at -78 °C was added n-Butyllithium (640μL, 2.5M in hexanes, l.όmmol). The reaction mixture was stirred for 15min at -78°C followed by the addition of ZnCl2 (3.9mL, IM in Et2θ, 3.9mmol) via a syringe. The reaction mixture was warmed at 0 °C for lh and a solution of 4-bromo-2-fluoro benzyl cyanide (214mg, l.Ommol) in THF (2mL) was added, along with PdO (a fresh suspension prepared as follows: 200 μL 7ϊ-Butyllithium, 2.5M in hexanes added to 144mg PdCl2(PPh3)2 in 5mL of THF). The mixture was refluxed overnight and quenched with sat. NaHCO3
(50mL). After extraction with EtOAc (3x75mL), the organic layers were combined, washed with brine (50mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexanes :EtO Ac (5:1) to afford the desired [2-fluoro-4-(5-methyl-l,3- benzoxazol-2-yl)phenyl] acetonitrile as yellow solid. lH NMR (CD3OD, 300MHz), δ 8.07 (d, IH), 7.95 (d, IH), 7.64 (m,
2H), 7.40 (s, IH), 7.20 (d, IH), 3.90 (s, IH). MS (ESI) 267 (M + H)+.
Example Fll r4-(5-Chloro-l,3- benzoxazol-2-yl)-2-fluorophenyn acetonitrile
Figure imgf000349_0001
To a stirred solution of 4-bromo-2-fluoro benzyl bromide (1.5g, 5.6mmol) in DMF (50mL) was added sodium cyanide (0.8g, 16.8mmol). The reaction was stirred at 90°C for lh, and cooled at rt. After quenching with brine (50mL) and diluted with EtOAc (lOOmL), the EtOAc layer was washed with brine (50mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexanes:EtOAc 5:1) to afford 4-bromo-2-fluoro benzyl cyanide as yellow solid. MS (ESI) 307 (M + H)+.
To a stirred solution of 5-chlorobenzoxazole (200mg, 1.3mmol) in 5mL THF at -78 °C, was added n-Butyllithium (640μL, 2.5M in hexane, 1.6mmol). The reaction was stirred for 15min at -78 °C followed by the addition of ZnCl2 (3.9mL, IM in Et2θ, 3.9mmol) via a syringe. The reaction was then warmed at 0°C for lh. A solution of 4-bromo-2-fluoro benzyl cyanide (214mg, l.Ommol) in THF (2mL) was added, along with PdO (a fresh suspension prepared as follows: 200μL, n- Butyllithium, 2.5M in hexanes added to 144mg of PdCl2(PPh3)2 in 5mL of THF). The reaction was then stirred at reflux overnight and quenched with sat. NaHCO3
(50mL). After diluting the mixture with EtOAc (300mL), the organic extract was washed with H2O (50mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexanes:EtOAc 5:1) to afford the desired [4-(5-chloro-l,3- benzoxazol-2-yl)-2-fluorophenyl] acetonitrile as yellow solid. iH NMR (CD3OD, 300Hz),δ8.10(d, IH), 7.99 (d, IH), 7.79 (d,lH),
7.68 (t, IH), 7.52 (d, IH), 7.39 (q, IH), 3.90 (s, IH). MS (ESI) 287 (M + Hf.
Example F12 ["4-(l,3- Benzoxazol-2-yl)-2-hvdroxyphenvπ acetonitrile
Figure imgf000349_0002
To a lOOmL round-bottom flask with 3-hydroxy-4-methylbenzoic acid (2.5g, 16.4mmol), was added dropwise SOCI2 (15mL). The reaction was refluxed for 30min and cooled to rt. The excess of SOCI2 was removed in vacuo and the oily acid chloride was dissolved in THF (15mL). This resulting solution was added dropwise to a mixture of 2-aminophenol (1.8g, 16.4mmol), triethylamine (1.7g, 16.4mmol) and THF (30mL) at 0°C. The resulting reaction mixture was then brought to rt for 30min and the resulting precipitate was removed by filtration. The filtrate was concentrated and dried under vacuum. The resulting dark brown solid residue was dissolved in toluene (20mL) and p-toluenesulfonic acid (15.6g, 82mmol) was added. The reaction was refluxed overnight, cooled at rt and EtOAc (500mL) was added. The EtOAc solution was washed with brine (3 x 50mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized in EtOAc to afford 5-(l,3-benzoxazol-2-yl)- 2-methylphenol as a light yellow solid. MS (ESI) 226 (M + H)+.
The solution of 5-(l,3-benzoxazol-2-yl)-2-methylphenol (0.8g, 3.5mmol) and triethylamine (0.6mL, 4.3mmol) in CH2CI2 (20mL) was cooled at 0 °C and tert-butyl (900mL, 3.9mmol) was added. The reaction was then warmed to rt for 30min. The mixture was diluted with EtOAc (200mL), washed with H2O (3X50mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 2-(3-{[tert-butyl- (dimethyl)silyl]oxy}-4-methylphenyl )-l,3-benzoxazole as light yellow oil.
To 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-methylphenyl )-l,3- benzoxazole (1.46g, 4.3mmol) dissolved in CCI4 (50mL) was added NBS (770mg, 4.3mmol) and benzoyl peroxide (50mg). The reaction mixture was refluxed for 6h and then cooled to rt. The solvent was removed in vacuo and the residue was diluted with EtOAc (50mL), washed with brine (50mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 2-(3-{[tert-butyl-(dimethysilyl]oxy}-4- bromomethylphenyl )-l,3-benzoxazole as light yellow solid. The mixture of 2-(3-{ [tert-butyl-(dimethyl)silyl]oxy}-4- bromomethylphenyl )-l,3-benzoxazole (1.6g, 3.8mmol) and sodium cyanide (560mg, 11.4mmol) in DMF (lOmL) was stirred at 90°C overnight. After cooling to rt, the mixture was diluted with EtOAc (lOOmL), washed with H2O (2X50mL), dried (MgSO4), filtered, and concentrated in vacuo to afford the desired [4-(l,3- benzoxazol-2-yl)-2-hydroxyphenyl] acetonitrile as yellow solid. iH NMR( CD3OD, 300MHz), δl0.6(s,lH), 7.8(m, 2H), 7.7(m, 2H), 7.5(d, IH), 7.4(m,2H). MS (ESI) 251 (M + H)+.
Example F13 (4-(l,3- BenzoxazoI-2-yl)-2-r2-(4-fluorophenyl) ethoxylphenyl|acetonitriIe
Figure imgf000351_0001
To a lOOmL round-bottom flask with 3-hydroxy-4-methylbenzoic acid ( 2.5g, 16.4mmol), was added SOCI2 (15mL) dropwise. The reaction was refluxed for 30min, cooled to rt and the excess of SOCI2 was removed in vacuo. The oily acid chloride was dissolved in THF (15mL) and the solution was added dropwise to a mixture of 2-aminophenol (1.8g, 16.4mmol), triethylamine (1.7g, 16.4mmol) and THF (30mL) at 0°C. The reaction was then warmed to rt for lh and the precipitate was removed by filtration. The filtrate was concentrated and dried in vacuo and the dark brown solid residue was dissolved in toluene (20mL) and p-toluenesulfonic acid (15.6g, 82mmol) was added. The reaction was refluxed overnight, cooled to rt and dissolved in EtOAc (500mL). The organic solution was washed with brine (3 x 50mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized in EtOAc to afford 5-(l,3-benzoxazol-2-yl)-2-methylphenol as a light yellow solid. MS (ESI) 226 (M + H)+.
A solution of 5-(l,3-benzoxazol-2-yl)-2-methylphenol (0.8g, 3.5mmol) and triethylamine (0.6mL, 4.3mmol) in CH2CI2 (20mL) was cooled to 0°C and
TBDMS-OTf (900mL, 3.9mmol) was added. The reaction was slowly warmed to rt and EtOAc(200mL) was added. The mixture was washed with H2O (3 x 50mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 2-(3-{[tert-butyl- (dimethyl)silyl]oxy}-4-methylphenyl )-l,3-benzoxazole as light yellow oil.
To 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-methylphenyl )-l,3- benzoxazole (1.46g, 4.3mmol) in CCI4 (50mL) was added NBS (770mg, 4.3mmol) and benzoyl peroxide (50mg). The reaction mixture was refluxed for 6h, cooled to rt, and CCI4 was removed in vacuo. The residue was dissolved in EtOAc (50mL), washed with H2O (50mL), dried (MgSO4), filtered and concentrated in vacuo to afford 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-bromomethylphenyl )-l,3-benzoxazole as light yellow solid. A mixture of 2-(3-{[tert-butyl-(dimethyl)silyljoxy}-4- bromomethylphenyl )-l,3-benzoxazole (1.6g, 3.8mmol) and sodium cyanide (560mg, 11.4mmol) in DMF (lOmL) was stirred at 90°C overnight. The reaction was cooled to rt and dissolved in EtOAc (200mL), washed with H2O (2X50mL), dried (MgSO4), filtered, and concentrated in vacuo to afford [4-(l,3- benzoxazol-2-yl)-2- hydroxyphenyl] acetonitrile as yellow solid. MS (ESI) 251 (M + H)+.
A solution of triphenylphosphine (126mg, 0.48mmol), DEAD (84mg, 0.48mmol) and THF (2mL) was stirred 2h and a solution of [4-(l,3- benzoxazol-2-yl)- 2-hydroxyphenyl], acetonitrile (lOOmg, 0.4mmol) and 4-fluorophenethylalcohol (56mg, 0.4mmol) in THF (2mL) was added. The resulting reaction mixture was stirred overnight and the THF was removed in vacuo. The resulting residue was purified on Prep TLC (lOOOμm) to afford {4-(l,3- benzoxazol-2-yl)-2-[2-(4- fluorophenyl)ethoxy]phenyl}acetonitrile. lH NMR (CD3OD, 300MHz), δ 7.88 (d
IH), 7.78 (m, 2H), 7.60 (m, IH), 7.52 (d, IH), 7.40 (d, 2H), 7.30 (m, 2H), 7.05 (m, IH), 4.40 (m, 2H), 3.70 (s,2H), 3.20 (m, 2H). MS (ESI) 373(M + H)+ .
Example F14 T4-(l,3- BenzoxazoI-2-yl)-2-ethoxyphenyll acetonitrile
Figure imgf000352_0001
Example F15
T4-(l,3- BenzoxazoI-2-yI)-2-(methoxymethoxy)phenvn acetonitrile
Figure imgf000352_0002
To a lOOmL round-bottom flask with 3-hydroxy-4-methylbenzoic acid ( 2.5g, 16.4mmol), was added SOCI2 (15mL) dropwise. The reaction was refluxed for 30min, cooled to rt. The excess of SOCI2 was removed in vacuo and the oily acid chloride was dissolved in THF (15mL). The resulting solution was added dropwise to a mixture of 2-aminophenol (1.8g, 16.4mmol), triethylamine (1.7g, 16.4mmol) and THF (30mL) at 0°C. The reaction mixture was brought to rt for 30min, after which time, the precipitate was filtered. The filtrate was concentrated and dried in vacuo. The dark brown solid residue was dissolved in toluene (20mL) and p-toluenesulfonic acid (15.6g, 82mmol) was added. The mixture was refluxed overnight, cooled to rt and EtOAc (500mL) was added. The EtOAc solution was washed with brine (3 x 50mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized in EtOAc to afford 5-(l,3-benzoxazol-2-yl)-2-methylphenol as a light yellow solid. MS (ESI) 226(M + H)+.
A solution of 5-(l,3-benzoxazol-2-yl)-2-methylphenol (200mg,0.89mmol) in THF (6mL) was cooled to -78°C under Argon and sodium hydride (24mg, l.Ommol) was added. After 30min at this temperature, bromomethyl ether (225mg,1.8mmol) was added via syringe. The reaction was warmed to rt for lh. The reaction mixture was concentrated and the residue was purified by flash column (silica gel, hexanes:EtOAc 4:1) to afford 2-[3-(methoxymethoxy)-4-methylphenyl]- 1 ,3-benzoxazole. MS (ESI) 270 (M + H)+.
A solution of 2-[3-(methoxymethoxy)-4-methylphenyl]-l,3- benzoxazole (200mg, 0.74mmol, 84%), NBS (179mg, 0.8 Immol), and benzoyl peroxide (50mg) in CCI4 (lOmL), was refluxed for 12h. After cooling to rt, CCI4 was removed in vacuo and residue was purified by flash column (silica gel, hexanes:EtOAc 5: 1) to afford 2-[4-(bromomethyl)-3-(methoxymethoxy) phenyl]-l ,3- benzoxazole. MS (ESI) 349 (M + H)+.
2-[4-(Bromomethyl)-3-(methoxymethoxy) phenyl]-l,3- benzoxazole (250mg, 0.72mmol) was treated with sodium cyanide (150mg, 2.2mmol) in DMF/H2O (15mL/1.5mL) at 90°C for 3h and EtOAc (150mL) was added. The EtOAc solution was washed with H2O (2 x 20mL), brine (2 x 20mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was eluted with flash column (silica gel, hexanes:EtOAc 4:1) to afford the desired [4-(l,3- benzoxazol-2-yl)-2- (methoxymethoxy)phenyl] acetonitrile as a yellow solid. iH NMR (CD3OD,
300MHz), δ 8.02 (d, 2H), 7.95 (m, IH), 7.80 (m,l H), 7.63 (m, IH), 7.57 (d, 2H), 7.40 (m, 2H). MS (ESI) 295 (M + H)+. Example F16 T4-(l,3- Benzoxazol-2-yl)-2-(hvdroxyethoxy)phenyn acetonitrile
Figure imgf000354_0001
To a lOOmL round-bottom flask with 3-hydroxy-4-methylbenzoic acid (2.5g, 16.4mmol) was added SOCI2 (15mL) dropwise. This reaction was refluxed for 30min, cooled to rt and the excess SOCI2 removed in vacuo. The oily acid chloride was dissolved in THF (15mL) and the solution was added dropwise to a mixture of 2- aminophenol (1.8g, 16.4mmol), triethylamine(1.7g, 16.4mmol) in THF (30mL) at 0°C. The reaction was then brought to rt for 0.5h and the precipitate was removed by filtration. The filtrate was concentrated and dried in vacuo. To the dark brown solid residue was added toluene (20mL) and p-toluenesulfonic acid (15.6g, 82mmol). The reaction was refluxed overnight, cooled to rt and dissolved in EtOAc (500mL). The EtOAc solution was washed with H2O (3x 50mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized in EtOAc to afford 5-(l,3- benzoxazol-2-yl)-2-methylphenol as a light yellow solid. MS (ESI) 226 (M + H)+.
A solution of 5-(l,3-benzoxazol-2-yl)-2-methylphenol (355mg, l.δmmol) in DMF(lOmL) was cooled to 0°C and NaH (70mg, 1.7mmol) was added slowly. After 15min, (2-bromoethoxy)(tert-butyl)dimethylsilane (370μL, 1.7mmol) was added. The reaction was then elevated to 90°C for lh and EtOAc (lOOmL) was added. The EtOAc solution was washed with brine (3x 20mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column (silica gel, hexanes:EtOAc 1:5) to afford 2-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethoxy)-4- methylphenyl]-l ,3-benzoxazole. 2-[3-(2-{[rert-butyl(dimethyl)silyl]oxy}ethoxy)-4-methylρhenyl)]-l,3- benzoxazole (550mg, 1.4mmol) was combined with NBS (255mg, 1.4mmol), benzoyl peroxide (50mg, catalyst) and CCI4 (30mL). The mixture was refluxed overnight, cooled to rt and EtOAc (200mL) was added. The EtOAc solution was washed with brine (3 x 20mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column (silica gel, hexanes:EtOAc 5:1) to afford 2-[4- bromomethylphenyl-3-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethoxy)]-l,3-benzoxazole.
The mixture of 2-[4-bromomethylphenyl-3-(2-{[tert- butyl(dimethyl)silyl]oxy}-ethoxy)]-l,3-benzoxazole(515mg, 1. Immol) and sodium cyanide (I64mg, 3.3mmol) in DMF/H2θ(10mL, 10/1) was stirred at 90°C for 4h, cooled to rt and EtOAc (200mL) was added. The EtOAc solution was washed with brine (3 x 20mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column (silica gel, hexanes :EtO Ac 1:1) to afford the desired [4- (1,3- benzoxazol-2-yl)-2-(hydroxyethoxy)phenyl] acetonitrile. iH NMR (CD3OD, 300MHz) δ 7.90 (m 1H), 7.80 (m, 2H), 7.62 (m, 1H), 7.49 (d, IH), 7.40 (m, 2H),4.3 6(m,2H), 4.10 (m, 2H), 3.78 (s, 2H). MS (ESI) 295 (M + H)+.
Example F17 r4-(l,3-Benzoxazol-2-yl)-2-chlorophenyllacetonitrile
Figure imgf000355_0001
A solution of 2-(3-chloro-4-methylphenyl)-l,3-benzoxazole (780mg, 3.2mmol), N- bromosuccinimide (590mg, 3.3mmol) and CCI4 (30mL) was mixed with a catalytic quantity of benzoyl peroxide. The mixture was heated at reflux for 12h. The reaction mixture was concentrated, and partitioned between saturated aqueous Νa2Cθ3 (20mL) and CH2CI2 (20mL). The aqueous layer was extracted with CH2CI2 (2 x 20mL). The combined organic extracts were dried (MgSO4), and concentrated under reduced pressure to afford, after chromatography on silica gel (EtOAc:hexanes 1:9), 2-[4-(bromomethyl)-3-chlorophenyl]-l,3-benzoxazole as a colorless solid. A slurry of NaCN (435mg, 8.9mmol), 2-[4-(bromomethyl)-3- chlorophenylj-1 ,3-benzoxazole (940mg, 2.9mmol), DMF (30mL) and H2O (30mL) was stirred at rt for 12h. The reaction mixture was poured into brine (250mL) and filtered. The resultant colorless solid was purified by flash chromatography on silica gel (EtOAc: hexanes 1:9) to afford the desired [4-(l,3-benzoxazol-2-yl)-2- chlorophenyl] acetonitrile as a colorless solid: iH NMR (CDCI3, 300MHz) δ 8.32 (s, IH), 8.19 (dd, IH), 7.77-7.80 (m, IH), 7.70 (d, IH), 7.59-7.61 (m, IH), 7.38-7.41 (m, 2H), 3.92 (s, 2H). MS (ESI) 269 (M + H)+.
Example F18
Figure imgf000356_0001
A solution of 2-[4-(bromomethyl)-3-chlorophenyl]-l,3-benzoxazole (150mg, 0.46mmol), KCN (36mg, 0.55mmol), and 18-crown-6 (145mg, 0.55mmol) is refluxed in MeCN (5 mL) for 10 minutes. The reaction is poured into H2O (100 mL) and extracted with CH2CI2 (2 x 30 mL). The organic extracts are dried (MgSO4), concentrated under reduced pressure, and purified by flash chromatography (EtOAc: hexanes 1:10) to afford the desired 2,3-bis[4-(l,3-benzoxazol-2-yl)-2- chlorophenyljpropanenitrile as a colorless solid: iHNMR (CDCI3, 300MHz) δ 8.32
(dd, 2H), 8.20 (d, IH), 8.11 (d, IH), 7.80-7.83 (m, 2H), 7.71 (d, IH), 7.61-7.63 (m, 2H), 7.39-7.45 (m, 5), 4.85 (t, IH), 3.40-3.50 (m, 2H). MS (ESI) 511 (M + H)+.
Example F19 l-r4-(l,3-Benzoxazol-2-yl)-2-chlorophenvπcyclopentanecarbonitrile
Figure imgf000356_0002
A solution of [4-(l,3-benzoxazol-2-yl)-2-chlorophenyl]acetonitrile (270mg, l.Ommol) and THF (20mL) was cooled to -78°C. A solution of NaHMDS (3.7mL, 2.2mmol, 0.6M solution in PhMe) was added dropwise via syringe to the reaction. After 15min at -78°C, 1,4-dibromobutane (143μL, 1.2mmol) was added dropwise via syringe. The cooling bath was removed, and the reaction was allowed to warm to rt. The reaction was quenched by the addition of silica gel (600mg) and concentrated to dryness. The residue was purified by flash chromatography on silica gel (EtOAc:hexanes 1:5) to afford the desired l-[4-(l,3-benzoxazol-2-yl)-2- chlorophenyl]cyclopentanecarbonitrile as a colorless solid: iH NMR (CDCI3,
300MHz) δ 8.34 (s, IH), 8.12 (dd, IH), 7.77-7.80 ( , IH), 7.56-7.62 (m, 2H), 7.35- 7.42 (m, 2H), 2.71-2.78 (m, 2H), 2.14-2.26 (m, 2H), 1.89-2.01 (m, 4H). MS (ESI) 323 (M + H)+.
Example F20 l-14-(l.,3-Benzoxazol-2-yl)-2chlorophenvπ cyclohexanecarbonitrile
Figure imgf000357_0001
Utilizing the general procedure outlined for l-[4-(l,3-benzoxazol-2-yl)-2- chlorophenyljcyclopentanecarbonitrile, [4-(l,3-benzoxazol-2-yl)-2- chlorophenyl] acetonitrile (400mg, 1.5mmol) and 1,5-dibromopentane (250μL, 1.8mmol) reacted to afford the desired l-[4-(l,3-benzoxazol-2-yl)-2- chlorophenyljcyclohexanecarbonitrile as a colorless solid: iHNMR (CDCI3,
300MHz) δ 8.22 (d, IH), 8.06 (d, IH), 7.68-7.73 (m, IH), 7.51-7.55 (m, 2H), 7.28- 7.35 (m, 2H), 2.49 (d, 2H), 1.73-2.00 (m, 8H). MS (ESI) 337 (M+H)+.
Example F21 r4-(l,3-Benzoxazol-2-yl)-2-chlorophenvπ(fluoro)acetonitrile
Figure imgf000357_0002
A solution of [4-(l,3-benzoxazol-2-yl)-2-chlorophenyl]acetonitrile (98mg, 0.36mmol) and dry THF (5mL) was cooled to -78 °C. A solution of tert-butyllithium (500μL,
0.80mmol, 1.7M solution in pentane) was added dropwise via syringe at -78°C. After lh, a solution of N-fluorobenzenesulfonimide (113mg, 0.36mmol) and dry THF (1.5mL) was added dropwise via syringe at -78°C. The cooling bath was removed, and the reaction mixture was gradually allowed to warm to rt, and was maintained at rt for 8h. The reaction was quenched with silica gel (300mg) and concentrated to dryness. The residue was purified by flash chromatography on silica gel (EtOAc :hexanes, 1:3) to afford the desired [4-(l,3-benzoxazol-2-yl)-2- chlorophenyl](fluoro)acetonitrile as a colorless solid: lHΝMR (CDCI3, 300MHz) δ
8.32 (s, IH), 8.24 (2, IH), 7.74-7.84 (m, 2H), 7.56-7.60 (m IH), 7.35-7.43 (m, 2H), 6.45 (d, IH). MS (ESI) 287 (M+H)+.
Example F22 2-r4-(l,3-Benzoxazol-2-yl)-2-methoxyphenynacetonitrile
Figure imgf000358_0001
3-Methoxy-4-methyl benzoic acid (1.2g, 7.2mmol) and thionyl chloride (lOmL) was heated to reflux conditions under argon until no starting material was observed by TLC. After cooling mixture to rt and concentration in vacuo, the resulting brown oil was dissolved in THF (15mL) and slowly added to a cooled mixture of 2- aminophenol (780mg, 7. Immol), diisopropylethyl amine (1.5mL, 8.6mmol) and THF (20mL) at 0°C. Reaction mixture was allowed to warm to rt. After one hour, no starting material acid was observed by TLC. After concentrating reaction mixture in vacuo, the resulting brown oil was purified by flash chromatography on silica gel, using 1:4 EtOAc:hexanes. This afforded the desired intermediate, N-(2- hydroxyphenyl)-3-methoxy-4-methylbenzamide, as a yellow solid. A mixture of N-(2-hydroxyphenyl)-3-methoxy-4-methylbenzamide (1.5g, 5.8mmol), toluene (30mL), p-toluenesulfonic acid monohydrate (7.6g, 40mmol) and molecular sieves was refluxed overnight. After cooling reaction to rt, filtered washing with warm chloroform and concentrated filtrate in vacuo. The resulting brown oil was purified by flash chromatography on silica gel using 1:4 EtOAc:hexanes to give the desired intermediate, 2-(3-methoxy-4-methylphenyl)-l,3-benzoxazole, as a colorless solid. 2-(3-Methoxy-4-methylphenyl)-l,3-benzoxazole (l.Og, 4. Immol), carbon tetrachloride (18mL), benzoyl peroxide (66mg, 0.3mmol) and N- bromosuccinimide (970mg, 5.4mmol) was heated to reflux conditions under argon and placed under a UV light. After one hour, no starting material was observed by TLC. After cooling mixture to rt, filtered, washing with dichoromethane. After concentrating filtrate in vacuo, the resulting colorless solid was purified by flash chromatography, using a gradient elution of 1:4 EtOAc: hexanes to EtOAc. This afforded the desired intermediate, 2-[4-(bromomethyl)-3-methoxyphenyι]-l,3- benzoxazole, as a colorless solid. A mixture of 2-[4-(bromomethyl)-3-methoxyphenyl]-l,3 - benzoxazole (318mg, Immol), dimethylformamide (7.5mL) and deionzed water (2.5mL) was stirred at rt. Sodium cyanide (150mg, 3.0mmol) was added to reaction. After 3h, dimethylformamide (lOmL) was added to help dissolve solids in reaction mixture. Let reaction mixture stir overnight at rt. Workup was done by washing reaction with brine (3 x 30mL), extraction with EtOAc, combined organic extracts, dried (Na2SO4), filtered and removed solvent in vacuo. Flash chromatography of resulting orange solid on silica gel using a gradient elution of 1:9 EtOAc:hexanes to 1:3 EtOAc:hexanes afforded the desired intermediate, [4-(l,3-benzoxazol-2-yl)-2- methoxyphenyl] acetonitrile as a yellow solid. iH NMR(CDCl3, 300MHz) δ 7.86- 7.36 (m, 7H), 3.99 (s, 3H), 3.74 (s, 2H), 2.59 - 1.91 (m, 8H). MS (ESI) 265 (M + H)+.
Example F23 2-r4-(l,3-Benzoxazol-2-yl)-2-methoxyphenvnpropanenitrile
Figure imgf000359_0001
4-(l,3-benzoxazol-2-yl)-2-methoxybenzonitrile (22mg, 0.82mmol) was dissolved and cooled to -78°C in THF (8mL) in an oven dried flask flushed with argon. NaHMDS (1.5mL, 0.90mmol) was added and the mixture was stirred at -78°C for 30min. Iodomethane (84μL, 0.90mmol) was added and the mixture was brought to rt and stirred for an additional 45min. The crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 2-[4-(l,3-benzoxazol-2-yl)-2-methoxyphenyl]propanenitrile as a pale yellow oil: iH NMR (CDCI3, 300MHz) δ 7.89-7.86 (d, IH), 7.79-7.76 (m, 2H),
7.61-7.56 (m, 2H), 7.40-7.36 (m, 2H), 4.32-4.30 (q, IH), 4.00 (s, 3H), 1.63-1.61 (d, IH) MS (ESI) 279 (M+H)+.
Example F24 2-r4-(l,3-Benzoxazol-2-yl)-2-methoxyphenvnbutanenitrile
Figure imgf000360_0001
Utilizing the general procedure outlined in the synthesis of 2-[4-(l,3-benzoxazol-2- yl)-2-methoxyphenyl]propanenitrile, 4-(l,3-benzoxazol-2-yl)-2-methoxybenzonitrile (300mg, 1. Immol) was reacted with iodoethane (90μL, 1. Immol) to afford the desired 2-[4-(l,3-benzoxazol-2-yl)-2-methoxyphenyl]butanenitrile as a yellow solid: iH NMR (CDCI3, 300MHz) δ 7.87-7.84 (d, IH), 7.79-7.74 (m, 2H), 7.59-7.53 (m, 2H), 7.37-7.34 (m, 2H), 4.22-4.17 (t, IH), 3.97 (s, 3H), 1.95-1.89 (m, 2H), 1.13-1.08 (t, 3H). MS (ESI) 293 (M+H)+.
Example F25 2-r4-(l,3-Benzoxazol-2-yl)-2-methoxyphenvnpentanenitrile
Figure imgf000360_0002
Utilizing the general procedure outlined in the synthesis of 2-[4-(l,3-benzoxazol-2- yl)-2-methoxyphenyl]propanenitrile, 4-( 1 ,3-benzoxazol-2-yl)-2-methoxybenzonitrile (200mg, 0.75mmol) was reacted with 1-iodopropane (73μL, 0.75mmol) to afford the desired 2-[4-(l,3-benzoxazol-2-yl)-2-methoxyphenyl]pentanenitrile as a yellow solid: IH NMR (CDCI3, 300MHz) δ 7.87-7.84 (d, IH), 7.79-7.75 (m, 2H), 7.60-7.54 (m, 2H), 7.38-7.35 (m, 2H), 4.27-4.23 (t, 1H), 3.98 (s, 3H), 1.89-1.82 (M, 2H), 1.57-1.53 (m, 2H), 1.00-0.95 (t, 3H). MS (ESI) 307 (M+H)+.
Example F26 l-r4-(l,3-Benzoxazol-2-yl)-2-methoxyphenyIlcyclobutanecarbonitrile
Figure imgf000361_0001
Utilizing the general procedure outlined in the synthesis of 2-[4-(l,3-benzoxazol-2- yl)-2-methoxyphenyl]propanenitrile, 4-( 1 ,3-benzoxazol-2-yl)-2-methoxybenzonitrile (250mg, 0.95mmol) was reacted with 1, 3-Dibromopropane (120μL, 1. Immol) to afford the desired l-[4-(l,3-benzoxazol-2-yl)-2- methoxyphenyljcyclobutanecarbonitrile as a colorless solid: iH NMR (CDCI3,
300MHz) δ 7.89-7.87 (m, 3H), 7.62-7.55 (m, IH) 7.39-7.36 (m, 2H), 7.32-7.26 (m, IH), 4.05 (s, 3H), 2.90-2.83 (m, 2H), 2.67-2.47 (m, 4H). MS (ESI) 305 (M+H)+.
Example F27 l-r4-(l,3-Benzoxazol-2-yI)-2-methoxyphenyncyclohexanecarbonitrile
Figure imgf000361_0002
Utilizing the general procedure outlined for the synthesis of l-[4-(l,3-benzoxazol-2- yl)-2-methoxyphenyl]cyclobutanecarbonitrile, 4-(l,3-benzoxazol-2-yl)-2- methoxybenzonitrile (250mg, 0.95mmol) was reacted with 1, 5-dibromopentane (160μL, 1. Immol) to afford the desired l-[4-(l,3-benzoxazol-2-yl)-2- methoxyphenyl]cyclohexanecarbonitrile as a colorless solid: iH NMR (CDCI3,
300MHz) δ 7.83-7.75 (m, 3H), 7.59-7.56 (m, 1H) 7.45-7.43 (d, IH), 7.38-7.34 (m, 2H), 4.04 (s, 3H), 2.41-2.38 (d, 2H), 1.92-1.15 (m, 8H). MS (ESI) 333 (M+H)+. Example F28 l-r4-(l,3-Benzoxazol-2-yl)-2-methoχyphenyncyclopropanecarbonitrile
Figure imgf000362_0001
4-(l,3-benzoxazol-2-yl)-2-methoxybenzonitrile (250mg, 0.95mmol) was dissolved in CH2CI2 (5mL). Benzyltrimethylammonium hydroxide (200μL, 0.095mmol) in 50% aqueous NaOH (5mL) was added and the mixture was stirred overnight at rt and then diluted with H2O. The aqueous mixture was extracted with CH2CI2 (2 x 25mL). The combined organic layers are dried over MgSO4, filtered and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired l-[4-(l,3- benzoxazol-2-yl)-2-methoxyphenyl]cyclopropanecarbonitrile as a yellow solid: iH NMR (CDCI3, 300MHz) δ 7.80-7.78 (m, 3H), 7.60-7.57 (m, IH), 7.39-7.33 (m, 3H),
4.07 (s, 3H), 1.70-1.66 (t, 2H), 1.34-1.30 (t, 2H). MS (ESI) 291 (M+H)+.
Example F29 l-r4-(l,3-Benzoxazol-2-vI)-2-methoxyphenvπcvclopentanecarbonitrile
Figure imgf000362_0002
3-Methoxy-4-methyl benzoic acid (1.2g, 7.2mmol) and thionyl chloride (lOmL) was heated to reflux conditions under argon until no starting material was observed by TLC. After cooling mixture to rt and concentration in vacuo, the resulting brown oil was dissolved in THF (15mL) and slowly added to a cooled mixture of 2- aminophenol (780mg, 7. Immol), diisopropylethyl amine (1.5mL, 8.6mmol) and THF (20mL) at 0°C. Reaction mixture was allowed to warm to rt. After one hour, no starting material acid was observed by TLC. After concentrating reaction mixture in vacuo, the resulting brown oil was purified by flash chromatography on silica gel, using 1:4 EtOAc:hexanes. This afforded the desired intermediate, N-(2- hydroxyphenyl)-3-methoxy-4-methylbenzamide, as a yellow solid.
A mixture of N-(2-hydroxyphenyl)-3-methoxy-4-methylbenzamide (1.5g, 5.8mmol), toluene (30mL), p-toluenesulfonic acid monohydrate (7.6g, 40mmol) and molecular sieves was refluxed overnight. After cooling reaction to rt, filtered washing with warm chloroform and concentrated filtrate in vacuo. The resulting brown oil was purified by flash chromatography on silica gel using 1 :4 EtOAc:hexanes to give the desired intermediate, 2-(3-methoxy-4-methylphenyl)-l,3- benzoxazole, as a colorless solid. 2-(3-Methoxy-4-methylphenyl)-l,3-benzoxazole (l.Og, 4.1mmol), carbon tetrachloride (18mL), benzoyl peroxide (66mg, 0.3mmol) and Ν- bromosuccinimide (970mg, 5.4mmol) was heated to reflux conditions under argon and placed under a UV light. After lh, no starting material was observed by TLC. After cooling mixture to rt, filtered, washing with dichoromethane. After concentrating filtrate in vacuo, the resulting colorless solid was purified by flash chromatography, using a gradient elution of 1:4 EtOAc: hexanes to EtOAc. This afforded the desired intermediate, 2-[4-(bromomethyl)-3-methoxyphenyl]-l,3- benzoxazole, as a colorless solid.
A mixture of, 2-[4-(bromomethyl)-3-methoxyphenyl]-l,3 - benzoxazole (318mg, Immol), dimethylformamide ( 7.5mL) and deionzed water
(2.5mL) was stirred at rt. Sodium cyanide (150mg, 3.0mmol) was added to reaction. After 3h, dimethylformamide (lOmL) was added to help dissolve solids in reaction mixture. Let reaction mixture stir overnight at rt. Workup was done by washing reaction with brine (3x30mL), extraction with EtOAc, combined organic extracts, dried (Νa2S04), filtered and removed solvent in vacuo. Flash chromatography of resulting orange solid on silica gel using a gradient elution of 1:9 EtOAc:hexanes to 1:3 EtOAc:hexanes afforded the desired intermediate, [4-(l,3-benzoxazol-2-yl)-2- methoxyphenyl] acetonitrile, as a light yellow solid.
[4-(l ,3-Benzoxazol-2-yl)-2-methoxyphenyl]acetonitrile (130mg, 0.49mmol) in THF (5.0mL) was cooled to -78°C under argon atmosphere. Sodium bis(trimethylsilyl)amide (1.8mL, 1.08mmol) was added slowly and after fifteen minutes, added 1,4- dibromobutane (0.07mL, 0.59mmol) to dark brown reaction mixture. Let mixture warm to rt overnight. After concentrating reaction mixture in vacuo, the resulting pink oil was purified by flash chromatography, using a gradient elution of 1:9 EtOAc:hexanes to 1:4 EtOAc :hexanes. This afforded the desired compound, l-[4-(l,3-benzoxazol-2-yl)-2-methoxyphenyl]cyclopentanecarbonitrile, as a yellow solid. iH NMR(CDCl3, 300MHz) δ 7.86-7.26 (m, 7H), 4.07 (s, 3H), 2.59 -
1.91 (m, 8H). MS (ESI) 319.1 (M+H)+.
Example F30 r4-(l,3-Benzoxazol-2-yl)-2,6-dimethoxyphenyr|acetonitrile
Figure imgf000364_0001
Thionyl chloride (lOmL) and 3,5-dimethoxy-4-methylbenzoic acid (l.Og, 5. Immol) was refluxed under argon until no starting material was observed by TLC. After cooling reaction mixture to rt, concentrated mixture in vacuo. The resulting brown oil was added to a mixture of 2-aminophenol (580mg, 5.3mmol), diisopropylethyl amine (l.lmL, 6.3mmol) and THF ( 40mL) at 0°C and then brought to rt overnight. After concentrating mixture in vacuo, the resulting brown oil was purified by flash chromatography on silica gel, using a gradient elution from 1:9 EtOAc :hexanes to 1:1 EtOAc:hexanes. This afforded the desired intermediate, 3,5-dimethoxy-N-(2- methoxyphenyl)-4-methylbenzamide, as a colorless solid.
A mixture of 3,5-dimethoxy-Ν-(2-methoxyphenyl)-4- methylbenzamide (1.29g, 4.49mmol), toluene (22mL), p-toluenesulfonic acid monohydrate (5.9g, 3 Immol) and molecular sieves was refluxed until no starting material was observed by TLC. Cooled mixture to rt and filtered, washing with warm chloroform. Removal of solvent from filtrate afforded a yellow solid. Purification of crude solid by flash chromatography on silica gel using 1:3 EtOAc :hexanes gave the desired intermediate, 2-(3,5-dimethoxy-4-methylphenyl)-l,3-benzoxazole, as a colorless solid. A mixture of 2-(3,5-dimethoxy-4-methylphenyl)-l ,3-benzoxazole
(260mg, Immol), carbon tetrachloride (4.2mL), benzoyl peroxide (15mg, 0.06mmol) and N-bromosuccinimide (270mg, 1.5mmol) was heated to reflux conditions under argon overnight. Concentration of cooled reaction mixture in vacuo afforded a yellow solid. Flash chromatography on silica gel of crude material using 1:4 EtOAc:hexanes gave the desired intermediate, 2-[4-bromomethyl)-3,5-dimethoxyphenyl]-l,3- benzoxazole, as a colorless solid. 2-[4-bromomethyl)-3,5-dimethoxyphenyl]-l,3-benzoxazole (160mg, 0.46mmol), dimethylformamide (5.0mL), deionized water (1.2mL) and sodium cyanide (77mg, 1.6mmol) was stirred at rt. After no starting material was observed by TLC, washed reaction mixture with brine (3xl5mL) and extracted with EtOAc (3x20mL). Combined organic extracts, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was chromatographed on silica gel, eluting with 1:4 EtOAc:hexanes to give the desired compound, [4-(l,3-benzoxazol-2-yl)-2,6- dimethoxyphenyl] acetonitrile, as a colorless solid. iH NMR (CDCI3, 300MHz) δ 7.62 (m,lH), 7.49 (m, IH), 7.42 (s, 2H), 7.41(m, IH), 7.40 (m,lH), 4.03 (s, 6H), 3.77 (s, 2H). MS (ESI) 295 (M + H)+.
Example F31 (2-Chloro-4-ri,31oxazolor4,5-61pyridin-2-ylphenyI)acetonitrile
Figure imgf000365_0001
A solution of 3-chloro-4-methylbenzoic acid (5.0g, 29mmol), N-bromosuccinimide (5.7g, 32mmol), benzoyl peroxide (710mg, 2.9mmol) in CCI4 (300mL) was heated at reflux for 2.5h. The mixture was concentrated under reduced pressure and dissolved in MTBE. The organic mixture was washed with IN ΝaOH (3 x 25mL). The aqueous mixture was acidified with IN HCI to pH 2 and extracted with CH2CI2 (3 x 25mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford 4-(bromomethyl)-3-chlorobenzoic acid.
A suspension of 4-(bromomethyl)-3-chlorobenzoic acid (4.0g, 16mmol) in DMF (120mL) and H2O (40mL) was treated with ΝaCΝ (2.4g, 49mmol) and heated to 80°C for 2h. The mixture was cooled to rt and acidified with IN HCI. The aqueous mixture was extracted with CH2CI2 (3 x 25mL). The combined organic layers were concentrated under reduced pressure and dissolved in MTBE. The organic mixture was washed with H2O and brine (3 x 25mL), dried over MgSO4, filtered and concentrated to afford 3-chloro-4-(cyanomethyl)benzoyl chloride.
Oxalyl chloride (1.7mL, 19mmol) was added to a suspension of 3- chloro-4-(cyanomethyl)benzoyl chloride (2.5g, 13mmol) in CH2CI2 (120mL). DMF (1 drop) was added to the suspension and the mixture was stirred for 2h at rt. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 3-chloro-4-(cyanomethyl)benzoyl chloride.
The acid chloride was dissolved in CH2CI2 (20mL) and added in solution to a stirring suspension of 2-amino-3-hydroxypyridine (1.4g, 13mmol) and triethylamine (5.4mL, 38mmol) in CH2CI2 (lOOmL). The mixture was stirred overnight. The reaction mixture was partitioned between CH2CI2 and H2O. Aqueous mixture was extracted with CH2CI2 (2 x 25mL). Combined organic layers are washed with sat. NaHCO3, and brine (2 x 25mL) dried over MgSO4, filtered and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford 3-chloro- 4-(cyanomethyl)-N-(3-hydroxypyridin-2-yl)benzamide as a yellow solid. MS (ESI) 288 (M+H).
3-chloro-4-(cyanomethyl)-N-(3-hydroxypyridin-2-yl)benzamide (550mg, 1.9mmol) was refluxed in POCI3 (15mL) for 2.5h. Excess POCI3 was removed by distillation and the mixture was cooled to rt. The crude mixture was diluted with H2O. The aqueous layer was made basic (pH 14) with IN ΝaOH and extracted with CH2CI2 (3 x 20mL). The residue was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexane gradient to afford (2-chloro-4-[l,3]oxazolo[4,5-b]pyridin-2-ylphenyl)acetonitrile as a colorless solid: 1H ΝMR (CDCI3, 300MHz) δ 8.65-8.63 (d, IH), 8.41 (s,lH), 8.30-8.27 (d,
IH), 7.93-7.90 (d, 2H), 7.77-7.74 (d, 2H), 7.38-7.34 (m, 2H)3.95 (s, 2H). MS (ESI) 270 (M+H)+.
Example F32 r4-(5-Chloro-l,3-benzoxazol-2-yl)phenyllacetonitrile
Figure imgf000366_0001
To a solution of 5-chlorobenzoxazole (lOOmg, 0.65mmol) in anhydrous THF at -78°C under Argon was added n-Butyllithium (0.45mL, 1.6M in hexanes). 30min later, zinc chloride (1.95mL, l.OM in ether) was added. The reaction mixture was warmed to 0°C for lh and then to 22°C. Then 4-bromophneylphenylacetonitrile (128mg, 0.65mmol) and Pd(Ph3P)4 (38mg, 0.033mmol) were added. The mixture was heated to reflux for overnight, after which time it was cooled to rt and poured in to a separatory funnel containing EtOAc (50mL), where it was washed with sat. brine (3x20mL). The EtOAc solution was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was chromatographed on silica gel, eluting with 3:1 hexanes:EtOAc to afford a off-colorless solid. iH NMR (CDCI3, 300MHz) δ 8.26 (d,
2H), 7.76 (d, IH), 7.51 (m, 3H), 7.35 (m, IH), 3.87 (s, 3H). MS (ESI) 269(M + H)+.
Example F33 and F34 2-r3-Methoxy-4-(lH-l,2,3-triazol-l-yImethyl)phenvπ-l,3 benzoxazole
Figure imgf000367_0001
2-r3-Methoχy-4-(2H-l,2,3-triazol-2-ylmethyl)phenyn-l,3-benzoxazole
Figure imgf000367_0002
A slurry of 2-[4-(bromomethyl)-3-methoxyphenyl]-l,3-benzoxazole (300mg, l.Ommol) and lH-l,2,3-triazole (70mg, l.Ommol), and CS2CO3 (325mg, l.Ommol) and MeCN (lOmL) was stirred vigorously at rt for 8h. Silica gel (600mg) was added, and the reaction mixture was concentrated to dryness. The residue was purified by flash chromatography on silica gel (linear gradient of EtOAc in hexanes from 0 to 100% over 25min) to afford 2-[3-methoxy-4-(lH-l,2,3-triazol-l-ylmethyl)phenyl]- 1 ,3-benzoxazole and 2-[3-methoxy-4-(2H- 1 ,2,3-triazol-2-ylmethyl)phenyl]- 1 ,3- benzoxazole as colorless solids. 2-[3-methoxy-4-(lH-l,2,3-triazol-l- ylmethyl)phenyl]-l,3-benzoxazole: lΗ NMR (CDCI3, 300MΗz) δ 7.72-7.78 (m, 3H),
7.69 (s, IH), 7.59 (s, IH), 7.53-7.56 (m, IH), 7.31-7.34 (m, 2H), 7.20 (d, IH), 5.59 (s, 2H), 3.96 (s, 3H). MS (ESI) 307 (M+H). 2-[3-methoxy-4-(2H-l,2,3-triazol-2- ylmethyl)phenyl]-l,3-benzoxazole: iH NMR (CDCI3, 300MHz) δ 7.76-7.80 (m, 3H), 7.68 (s, IH), 7.56-7.59 (m, 2H), 7.34-7.38 (m, 2H), 7.04 (d, IH), 5.74 (s, 2H), 3.99 (s, 3H). MS (ESI) 307 (M+H)+.
Example F35
2-r3-Methoxy-4-(lHr-l,2,4-triazol-l-ylmethyl)phenvn-l,3-benzoxazole
Figure imgf000368_0001
Utilizing the general procedure outlined for 2-[3-methoxy-4-(lH-l,2,3-triazol-l- ylmethyl)phenyl]-l,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3- methoxyphenyl]-l,3-benzoxazole (300mg, l.Ommol) and 1,2,4-triazole (70mg, l.Ommol) afforded the desired 2-[3-methoxy-4-(lH-l,2,4-triazol-l-ylmethyl)phenyl]- 1,3-benzoxazole as a colorless solid: lΗ NMR (CDCI3, 300MΗz) δ 8.13 (s, IH), 7.92
(s, IH), 7.71-7.78 (m, 2H), 7.51-7.54 (m, IH), 7.29-7.34 (m, 2H), 7.24 (d, 2H), 5.34 (s, 2H), 3.92 (s, 3H). MS (ESI) 307 (M+H)+.
Example F36 2-r4-(lH-Imidazol-l-yImethyl)-3-methoxyphenyn-l,3-benzoxazole
Figure imgf000368_0002
Utilizing the general procedure outlined for 2-[3-methoxy-4-(lH-l,2,3-triazol-l- ylmethyl)phenyl]-l,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3- methoxyphenyl]-l,3-benzoxazole (300mg, l.Ommol) and imidazole (70mg, l.Ommol) afforded the desired 2-[4-(lH-imidazol-l-ylmethyl)-3-methoxyphenyl]-l,3- benzoxazole as a colorless solid: lΗ NMR (CDCI3, 300MΗz) δ 7.57-7.86 (m, 6H),
7.26-7.40 (m, 4H), 5.53 (s, 2H), 4.02 (s, 3H). MS (ESI) 306 (M+H)+.
Example F37 2-r3-Methoxy-4-(lH-pyrazoI-l-ylmethyl)phenyIl-l,3-benzoxazole
Figure imgf000369_0001
Utilizing the general procedure outlined for 2-[3-methoxy-4-(lH-l,2,3-triazol-l- ylmethyl)phenyl]-l,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3- methoxyphenyl]-l,3-benzoxazole (300mg, l.Ommol) and pyrazole (70mg, l.Ommol) afforded the desired 2-[3-methoxy-4-(lH-pyrazol-l-ylmethyl)phenyl]-l,3- benzoxazole as a colorless solid: lΗ NMR (CDCI3, 300MΗz) δ 7.60-7.91 (m, 7H),
7.38-7.41 (m, 2H), 6.54 (m, IH), 5.81 (s, 2H), 4.11 (s, 3H). MS (ESI) 306 (M+H)+.
Example F38
2-{4-r(4-Bromo-lH-imidazol-l-yl)methyll-3-methoxyphenvI)-l,3-benzoxazole
Figure imgf000369_0002
Utilizing the general procedure outlined for 2-[3-methoxy-4-(lH-l,2,3-triazol-l- ylmethyl)phenyl]-l,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3- methoxyphenyl]-l,3-benzoxazole (300mg, l.Ommol) and 4-bromo-lH-imidazole
(150mg, l.Ommol) afforded the desired 2-{4-[(4-bromo-lH-imidazol-l-yl)methyl]-3- methoxyphenyl}-l,3-benzoxazole as a colorless solid: lΗ NMR (CDCI3, 300MΗz) δ
7.94-7.99 (m, 3H), 7.85-7.87 (m, IH), 7.75-7.78 (m, IH), 7.65-7.68 (m, IH), 7.43- 7.49 (m, 2H), 7.20 (s, IH), 5.55 (s, 2H), 4.09 (s, 3H). MS (ESI) 384 (M+H)+.
Example F39 and F40: 2- f 3-Methoxy-4- (2H-tetrazol-2- ylmethyDphenyll -1 ,3-benzoxazole
Figure imgf000369_0003
2-r3-Methoxy-4-(lH-tetrazol-l-ylmethvI)phenvIl-l,3-benzoxazole
Figure imgf000370_0001
Utilizing the general procedure outlined for 2-[3-methoxy-4-(lH-l,2,3-triazol-l- ylmethyl)phenyl]-l,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3- methoxyphenyl]-l,3-benzoxazole (300mg, l.Ommol) and lH-tetrazole (70mg, l.Ommol) afforded 2-[3-methoxy-4-(2H-tetrazol-2-ylmethyl)phenyl]-l,3-benzoxazole and 2-[3-methoxy-4-(lH-tetrazol-l-ylmethyl)phenyl]-l,3-benzoxazole as colorless solids. 2-[3-methoxy-4-(2H-tetrazol-2-ylmethyl)phenyl]-l,3-benzoxazole: lΗ NMR (CDCI3, 300MΗz) δ 8.52 (s, IH), 7.72-7.79 (m, 3H), 7.52-7.55 (m, IH), 7.31-7.34 (m, 2H), 7.21 (d, IH), 5.86 (s, 2H), 3.93 (s, 3H). MS (ESI) 308 (M+H). 2-[3- methoxy-4-(lH-tetrazol-l-ylmethyl)phenyl]-l,3-benzoxazole: lΗ NMR (CDCI3,
300MΗz) δ 8.66 (s, IH), 7.85 (d, IH), 7.74-7.83 (m, 2), 7.55-7.59 (m, IH), 7.41 (d, IH), 7.34-7.40 (m, 2H), 5.61 (s, 2H), 3.98 (s, 3H). MS (ESI) 308 (M+H)+.
Example F41 and F42:
Methyl l-r4-(l,3-benzoxazol-2-yl)-2-methoxybenzyl1-lH-imidazoIe-5-carboxylate
Figure imgf000370_0002
Methyl l-r4-(l,3-benzoxazoI-2-yl)-2-methoxybenzyl1-lH-imidazoIe-4-carboxylate
Figure imgf000370_0003
Utilizing the general procedure outlined for 2-[3-methoxy-4-(lH-l,2,3-triazol-l- ylmethyl)phenyl]-l,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3- methoxyphenyl]-l,3-benzoxazole (300mg, l.Ommol) and methyl 4-imidazole carboxylate (126mg, l.Ommol) afforded methyl l-[4-(l,3-benzoxazol-2-yl)-2- methoxybenzyl]-lH-imidazole-5-carboxylate and methyl l-[4-(l,3-benzoxazol-2-yl)- 2-methoxybenzyl]-lH-imidazole-4-carboxylate as colorless solids. Methyl l-[4-(l,3- benzoxazol-2-yl)-2-methoxybenzyl]-lH-imidazole-5-carboxylate: lΗ NMR (CDCI3,
300MΗz) δ 7.73-7.80 (m, 4H), 7.57-7.60 (m, IH), 7.34-7.38 (m, 2H), 7.15 (d, IH), 5.58 (s, 2H), 4.00 (s, 3H), 3.83 (s, 3H). MS (ESI) 364 (M+H)+. Methyl l-[4-(l,3- benzoxazol-2-yl)-2-methoxybenzyl]-lH-imidazole-4-carboxylate: lΗ NMR (CDCI3,
300MΗz) δ 7.75-7.84 (m, 3H), 7.57-7.64 (m, 3H), 7.34-7.38 (m, 2H), 7.18 (d, IH), 5.17 (s, 2H), 3.97 (s, 3H), 3.86 (s, 3H). MS (ESI) 364 (M+H)+.
Example F43 2-{3-methoxy-4-r(l-methyI-lHr-tetrazol-5-yl)methynphenyl}-l,3-benzoxazole
Figure imgf000371_0001
Azidotrimethylsilane (251μL, 1.89mmol) was added to a stirring suspension of 4- (l,3-benzoxazol-2-yl)-2-methoxybenzonitrile (250mg, 0.949mmol) and dibutyltin oxide (24mg, 0.09mmol) in toluene (5mL). The mixture was heated at 110°C overnight. The mixture was cooled to rt and the toluene was removed in vacuo. The residue was dissolved in EtOAc and extracted 10% NaHCO3 (3 x 25mL). The combined aqueous extracts were acidified to pH 2 with 3N HCI. The acidic aqueous mixture was extracted with EtOAc (3 x 25mL). The combined organic layers are dried over MgSO4, filtered and concentrated in vacuo to afford 2-[3-methoxy-4-(lH- tetrazol-5-ylmethyl)phenyl]-l,3-benzoxazole: lΗ NMR (DMSO-doM 300MΗz) δ 7.82- 7.78 (m, 3H), 7.75 (s, IH), 7.46-7.42 (m, 3H), 4.30 (s, 2H), 3.90 (s, 3H). MS (ESI) 308 (M+H)+.
Iodomethane (38μL, 0.42mmol) was added to a stirring solution of 2- [3 -methoxy-4-( lH-tetrazol-5 -ylmethyl)phenyl] -1,3 -benzoxazole ( 13 Omg, 0.42mmol) and triethylamine (120μL, 0.83mmol) in CΗ3CN (5mL). The mixture was stirred at rt overnight. The crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 2-[3-methoxy-4-(morpholin-4-ylmethyl)phenyl]-l,3-benzoxazole as a colorless solid: iHNMR (CDCI3, 300MHz) δ 7.84-7.77 (m, 3H), 7.58 (m IH), 7.39-
7.36 (m, 2H), 7.30-7.27 (d, IH), 4.32 (s, 2H), 3.96 (s, 6H). MS (ESI) 322 (M+H)+.
Example F44 2-r3-Methoxy-4-(pyrroIidin-l-ylmethyl)phenvπ-l,3-benzoxazoIe
Figure imgf000372_0001
Pyrrolidine (226μL, 2.83mmol) was added to a stirring solution of 2-[4-
(bromomethyl)-3-methoxyphenyl]-l,3-benzoxazole (300mg, 0.94mmol) and triethylamine (390μL, 2.8mmol) in CH2CI2 (5mL). The mixture was stirred at rt overnight. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 2- [3- methoxy-4-(pyrrolidin-l-ylmethyl)phenyl]-l,3-benzoxazole as a colorless solid: iH NMR (CDCI3, 300MHz) 8 7.82-7.80 (m, IH), 7.77-7.74 (m, IH), 7.71 (s, 1H), 7.56-
7.50 (m, 2H), 7.35-7.30 (m, 2H), 3.94 (s, 3H), 3.71 (s, 2H), 2.59 (s, 4H), 1.81-1.78 (m, 4H). MS (ESI) 309 (M+H)+.
Example F45
2-r3-Methoxy-4-(piperidin-l-ylmethyl)phenvn-l,3-benzoxazole
Figure imgf000372_0002
Utilizing the general procedure outlined for 2-[3-methoxy-4-(pyrrolidin-l- ylmethyl)phenyl]-l,3-benzoxazole, 2-[4-(bromomethyl)-3-methoxyphenyl]-l,3- benzoxazole (300mg, 0.942mmol) was reacted with piperidine (279μL, 2.83mmol) and triethylamine (394μL, 2.83mmol) in CH2CI2 (5mL) to afford the desired 2-[3- methoxy-4-(piperichn-l-ylmethyl)phenylj-l,3-benzoxazole as a colorless solid: iH NMR (CDCl3-d, 300MHz) δ 7.86-7.83 (m, IH), 7.79-7.76 (m, IH), 7.73 (s, IH),
7.61-7.55 (m, 2H), 7.37-7.34 (m, 2H), 3.96 (s, 3H), 3.59 (s, 2H), 2.47 (br, 4H), 1.66- 1.58 (m, 4H), 1.46-1.45 (m, 2H). MS (ESI) 323 (M+H)+.
Example F46 2-r3-Methoxy-4-(pyridin-2-ylmethyl)phenvπ-l,3-benzoxazoIe
Figure imgf000373_0001
A solution of 2-[4-(bromomethyl)-3-methoxyphenyl]-l,3-benzoxazole (320mg, l.Ommol) and THF (lOmL) was treated with Zn powder (activated by grinding with mortar and pestle), a drop of chlorotrimethylsilane, and a drop of 1,2-dibromoethane. The mixture was heated at reflux for lh. The resultant organozinc reagent was filtered through a plug of Celite, and transferred to a flask containing 2- bromopyridine (360mg, 2.0mmol) and Pd(Ph3P)4 (115mg, O.lmmol). The mixture was degassed with bubbling argon for 15min, and heated at reflux for 12h. The reaction was poured into H2O (40mL) and extracted with CH2CI2 (2 x 30mL). The organic extracts were dried (MgSO4) and concentrated to afford a colorless solid. Purification of the solid by flash chromatography on silica gel (EtOAc:hexanes 3:1) afforded the desired 2-[3-methoxy-4-(pyridin-2-ylmethyl)phenyl]-l,3-benzoxazole as a yellow solid: iH NMR (CDCI3, 300MHz) δ 8.55 (d, IH), 7.76-7.82 (m, 3H), 7.56-
7.62 (d, 2H), 7.32-7.36 (m, 3H), 7.11-7.16 (m, 2H), 4.23 (s, 2H), 3.95 (s, 3H). MS (ESI) 317 (M+H)+.
Example F47 2- 13-Methoxy-4- (pyridin-3-ylmethyl)phenyll - 1,3-benzoxazole
Figure imgf000374_0001
A mixture of 2-[4-(bromomethyl)-3-methoxyphenyl]-l,3-benzoxazole (190mg, 0.58mmol), 3-pyridylboronic acid (70mg, 0.58mmol), Pd(Ph3P)4 (70mg, 0.06mmol), K2CO3 (200mg, 1.5mmol), DME (6mL) and H2O (3mL) was degassed with bubbling Ar for 15min. The mixture was heated at 80°C for lh. The reaction was poured into H2O (40mL) and extracted with CH2CI2 (2 x 30mL). The organic extracts were dried (MgSO4) and concentrated to afford a colorless solid. Purification of the solid by flash chromatography on silica gel (EtOAc:hexanes 3:1) afforded the desired 2-[3- methoxy-4-(pyridin-3-ylmethyl)phenyl]-l,3-benzoxazole as a yellow solid: iHNMR (CDCI3, 300MHz) δ 8.56 (br s, IH), 8.45 (br d, IH), 7.74-7.80 (m, 3H), 7.50-7.58 (m,
2H), 7.32-7.37 (m, 2H), 7.17-7.24 (m, 2H), 4.00 (s, 2H), 3.93 (s, 3H). MS (ESI) 317 (M+H)+.
Example F48 2-r3-Methoxy-4-(pyridin-4-ylmethyI)phenyn-l,3-benzoxazole
Figure imgf000374_0002
Utilizing the general procedure outlined for 2-[3-methoxy-4-(pyridin-3- ylmethyl)phenyl]-l,3-benzoxazole, 2-[4-(bromomethyl)-3-methoxyphenyl]-l,3- benzoxazole (270mg, 0.81mmol), 4-pyridylboronic acid (lOOmg, 0.81mmol) reacted to afford the desired 2-[3-methoxy-4-(pyridin-4-ylmethyl)phenyl]-l,3-benzoxazole as a colorless solid: iH NMR (CDCI3, 300MHz) δ 8.46 (br s, 2H), 7.75-7.81 (m, 3H),
7.56-7.59 (m, IH), 7.34-7.36 (m, 2H), 7.22 (d, IH), 7.13 (d, 2H), 4.00 (s, 2H), 3.92 (s, 3H). MS (ESI) 317 (M+H)+. Example F49 r4-(l,3-BenzoxazoI-2-yl)-2-chlorophenvH(pyridin-2-yI)methanol
Figure imgf000375_0001
A solution of benzoxazole (5.4g, 46mmol) and THF (150mL) was cooled to -78°C. A solution of n-butyllithium (29mL, 47mmol, 1.6M solution in hexanes) was added dropwise via syringe over 15min. After lh at -78°C, a solution of ZnCl2 (95mL,
47mmol, 0.5M solution in ether) was added dropwise via syringe over 5min. The reaction mixture was allowed to warm to rt, and maintained for lh. 2-Chloro-4- bromobenzonitrile (3.3g, 15mmol) and Pd(Ph3P)4 (880mg, 0.76mmol) were added to the reaction mixture. The mixture was degassed with bubbling argon for 15min, then heated at reflux for lh. The reaction was quenched by the addition of 1 N HCI (150mL), and extracted with CH2CI2 (3 x 150mL). The organic extracts were combined, dried (MgSO4), and concentrated to afford, after flash chromatography on silica gel (acetone:hexane 1:5), 4-(l,3-benzoxazol-2-yl)-2-chlorobenzonitrile as a yellow solid.
A solution of 4-(l,3-benzoxazol-2-yl)-2-chlorobenzonitrile (510mg, 2.0mmol) and CH2CI2 was cooled to -78°C. Diisobutylaluminum hydride (2mL, l.OM solution in PhMe) was added to the reaction dropwise via syringe over 30min. The cooling bath was removed, and the reaction mixture is allowed to warm to rt. The reaction was quenched by the addition of a saturated solution of sodium potassium tartrate (50mL). The resultant slurry was filtered, and the organic layer was separated, dried (MgSO4), and concentrated under reduced pressure to afford, after flash chromatography (acetone:hexane 1:5), 4-(l,3-benzoxazol-2-yl)-2- chlorobenzaldehyde as a yellow solid. A solution of 2-bromopyridine (1 lOmg, 0.7mmol) and THF (lOmL) was cooled to -78°C. 7i-Butyllithium (0.44mL, 0.7mmol, 1.6M solution in THF) was added dropwise via syringe. After 15min, a solution of 4-(l,3-benzoxazol-2-yl)-2- chlorobenzaldehyde (150mg, 0.6mmol) and THF (2mL) was added via syringe, and the reaction was allowed to warm to rt. The reaction is quenched by the addition of H2O (20mL). The mixture is extracted with EtOAc (3 x 120mL), and the combined organic extracts are dried (MgSO4), and concentrated under reduced pressure to afford, after flash chromatography on silica gel (EtOAc :hexanes 1:1), the desired [4- (l,3-benzoxazol-2-yl)-2-chlorophenyl](pyridin-2-yl)methanol as a colorless solid: iH NMR (CDCI3, 300MHz) δ 8.58 (d, IH), 8.28 (d, IH), 8.10 (dd, 1H), 7.55-7.55 (m,
4H), 7.23-7.37 (m, 4H). MS (ESI) 337 (M+H)+.
Example F50 2-r3-ChIoro-4-(2-morpholin-4-ylethyl)phenyn-l,3-benzoxazole
Figure imgf000376_0001
A solution of [4-(l,3-benzoxazol-2-yl)-2-chlorophenyl] acetonitrile (l.llg, 3.88mmol) in CH2CI2 (40mL) was cooled -78°C. Diisobutylaluminum hydride (4.7mL,
4.7mmol, l.OM solution in PhMe) was added slowly. The mixture was stirred at - 78°C under argon for 3h and allowed to warm slowly to rt overnight. Reaction mixture was cooled to 0°C quenched with acetone and IN HCI. The mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3 x lOOmL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford [4-(l,3-benzoxazol-2-yl)-2-chlorophenyl]acetaldehyde.
The crude aldehyde was treated with NaCNBH3 and morpholine in MeOH CH2Cl2 (2mL). The crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 2-[3-chloro-4-(2-morpholin-4-ylethyl)phenyl]-l,3-benzoxazole: iH NMR (CDCI3, 300MHz) δ 8.26-8.25 (d, IH), 8.09-8.06 (m, IH), 7.79-7.74 (m, IH), 7.43-
7.34 (m, 3H), 3.78-3.75 (m, 4H), 3.05-3.00 (m, 2H), 2.68-2.59 (m, 6H). MS (ESI) 343 (M+H)+.
Example F51 2- (3-Methyl-4-pyridin-2- ylphenyl)- 1 ,3-benzoxazole
Figure imgf000376_0002
Polyphosphoric acid (lOOmL) was added to a beaker containing 2-aminophenol (17.7g, 162mmol) and 4-bromo-3-methylbenzoic acid (13.6g, 64mmol). The mixture was heated at 200°C for lh, then poured into ice water (IL) and allowed to stand overnight. The mixture was filtered and dried to afford 2-(4-bromo-3- methyl(phenyl))-benzoxazole as a colorless solid. A solution of 2-(4-bromo-3- methyl(phenyl))-benzoxazole (670mg, 2.3mmol), 2-(tributylstannyl)pyridine (850mg, 2.3mmol), Pd(Ph3P)4 (270mg, 0.23mmol) and DMF (23mL) was degassed with bubbling argon for 15min. The reaction mixture was heated at 100°C for 8h. The reaction was cooled to rt, and KF (500mg) and H2O (250mL) were added. The mixture was extracted with MTBE (3 x 50mL), and the combined organic extracts were washed with water (2 x 20mL), brine (1 x 20mL), dried (MgSO4), and concentrated to afford an oil. Purification of the oil by flash chromatography on silica gel (EtOAc:hexanes 1:2) afforded the desired 2-(3-methyl-4-pyridin-2-ylphenyl)-l,3- benzoxazole as a colorless solid: iH NMR (CDCI3, 300MHz) δ 8.91 (d, IH), 8.52 (t, IH), 8.19 (s, IH), 8.15 (d, IH), 7.97 (br t, IH), 7.89 (d, IH), 7.70-7.72 (m, IH), 7.61 (d, IH), 7.51-7.54 (m, IH), 7.30-7.33 (m, 2H), 2.45 (s, 3H), MS (ESI) 287 (M+H)+.
Example F52 2-(3-Methyl-4-pyrimidin-2-ylphenyI)-l,3-benzoxazole
Figure imgf000377_0001
A slurry of 2-(4-bromo-3-methyl(phenyl))-benzoxazole (330mg, 1. Immol), KOAc (330mg, 3.4mmol), [l,r-bis(diphenylphosphino)ferrocene]di-chloropalladium(II) (93mg, 0.1 Immol), bis(pinacolato)diboron (360mg, 1.4mmol), and dioxane (30mL) was degassed with Ar for 15min. The reaction was heated at 80°C for 12h, then quenched by the addition of H2O (20mL). The mixture was extracted with MTBE (3 x 50mL), and the combined organic extracts were dried (MgSO4), and concentrated under reduced pressure to afford, after flash chromatography on silica gel (EtOAc:hexanes 1:3), 2-[3-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)phenyl]-l,3-benzoxazole as a colorless solid. A mixture of 2-[3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]-l,3-benzoxazole (190mg, 0.5mmol), Pd(Ph3P)4 (60mg, 0.05mmol), CsF
(300mg, 2.0mmol), and DME (5mL) was degassed with Ar for 15min. The reaction was heated at 80°C for 12h, then quenched by the addition of H2O (20mL). The mixture was extracted with MTBE (3 x 50mL), and the combined organic extracts were dried (MgSO4), and concentrated under reduced pressure to afford, after flash chromatography on silica gel (EtOAc :hexanes 1:1) the desired 2-(3-methyl-4- pyrimidin-2-ylphenyl)-l,3-benzoxazole as a colorless solid: iH NMR (CDCI3,
300MHz), δ 8.82 (d, 2H), 7.99-8.20 (m, 2H), 7.98 (d, 2H), 7.75-7.77 (m, IH), 7.54- 7.57 (m, IH), 7.30-7.35 (m, 2H), 7.20 (t, IH), 2.64 (s, 3H). MS (ESI) 288 (M+H)+.
Example F53 4-(l,3-Benzoxazol-2-yl)-2-methoxyphenol
Figure imgf000378_0001
4-hydroxy-3-methoxybenzoic acid (25g, 149mmol) and 2-amino phenol(16.2g, 149mmol) were combined in a round bottom flask. Trimethylsilyl polyphosphate (80mL) was added neat. The mixture was heated at 180°C for 30min. The mixture is poured over ice and allowed to stir overnight. The suspension was filtered to afford 4-(l,3-benzoxazol-2-yl)-2-methoxyphenol as a pale green solid. MS (ESI) 242 (M + H)+.
Example F54 2-(3-Methoxy-4-pyridin-2-ylphenyI)-l,3-benzoxazole hydrochloride salt
Figure imgf000378_0002
The solution of 4-(l,3-benzoxazol-2-yl)-2-methoxyphenol (7.1g, 29.4mmol) in anhydrous DMF (lOOmL) was treated with CS2CO3 (9.6g, 29.4mmol) and N-phenyl trifluoromethanesulfonimide (10.5g, 29.4mmol) at 22°C for 30min. After which time it was quenched with sat. NaHCO3 (50mL) and diluted with EtOAc (500mL). The EtOAc solution was washed with sat. brine (3 x lOOmL), dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 4:1 hexanes:EtOAc to afford 4-(l,3-benzoxazol-2-yl)-2-methoxyphenyl trifluoromethanesulfonate as a colorless oil. MS (ESI) 374 (M + H)+.
The solution of 4-(l,3-benzoxazol-2-yl)-2-methoxyphenyl trifluoromethanesulfonate (11.7g, 31.3mmol) in anhydrous DMF (150mL) was degassed via Argon for lOmin. Then 2-tri-n-butylstannylpyridine (11.5g, 31.3mmol) and Pd(Ph3P)4 (3.6g, 3. Immol) were added at 22°C. The resulting mixture was then heated at 100°C for lh under Argon. Cooled the reaction mixture to 22°C, then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give after purification by flash chromatography (silica gel, 3:1; hexanes:EtOAc) the desired compound as a off -colorless solid which was then disolved in diethyl ether (200mL) and precipitated as the hydrochloride salt upon treatment with IM HCI in diethyl ether (20mL). The resulting colorless solid was then treated with EtOAc (IL), heated at refiuxing, then cooled to 22°C, collected the solid by filtration to yield a colorless solid as desired compound. (M.p. 215 °C). iH NMR (CD3OD, 300MHz) δ
8.88 (m, 1 H), 8.69 (m, IH), 8.41 (d, IH), 8.09 ( , 3H), 7.91 (d, IH), 7.82 (m, IH), 7.45 (m, IH), 7.48 (m, 2H), 4.10 (s, 3H). MS (ESI) 303 (M+H)+.
Example F55 5-(l,3-Benzoxazol-2-yl)-2-pyridin-2-yl benzonitrile
Figure imgf000379_0001
To a solution of methyl 3-cyano-4-methoxy-benzoate (1.5g, 7.9mmol) in CH3OH/H2O (25mL; 1 : 1), was added LiOH (2.5g, 60.0mmol). The reaction mixture was refluxed for 2h, cooled at rt and 6M HCI was added dropwise until pH 2 was obtained. The precipitate was collected, washed with H2O (3 x 20mL), dried in vacuo to afford 3-cyano-4-methoxy-benzoic acid. MS (ESI) 178 (M + H)+. To a lOOmL round-bottom flask with 3-cyano-4-methoxy-benzoic acid (1.4g, 7.8mmol), was added SOCI2 (15mL) dropwise. The reaction was refluxed for lh and was cooled to rt. The excess of SOC12 was removed in vacuo and the oily acid chloride was dissolved in THF (15mL). The resulting solution was added dropwise to a mixture of 2-aminophenol (1.3g, 11.7mmol), triethylamine (1.3g, 11.7mmol) and THF (30mL) at 0°C. The reaction was warmed up to rt and stirred an additional 3h. The precipitate was removed by filtration and the filtrate was concentrated and dried in vacuo. The dark brown solid residue was dissolved in toluene (20mL) andp- toluenesulfonic acid (6.0g, 46.8mmol) was added. The reaction was refluxed overnight, cooled to rt, and EtOAc (300mL) was added. The EtOAc solution was washed with brine (3 x 20mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chhromatography (silica gel, CHCl3:CH3OH 8:1) to afford 5-(l,3-benzoxazol-2-yl)-2-methoxy benzonitrile. MS (ESI) 251(M + H)+.
To a solution of 5-(l,3-benzoxazol-2-yl)-2-methoxy benzonitrile (270mg, 1. Immol) in CH2CI2 (5mL) at 0°C, was added BBr3 (l.OM solution in CH2CI2, 430μL, 4.4mmol) dropwise. The reaction was stirred at rt for 4h. EtOAc (150mL) was added, as well as H2O (30mL). The organic layer was washed with brine (2 x 20mL), dried (MgSO4),concentrated and the crude product was recrystallized in EtOAc to afford 5-(l,3-benzoxazol-2-yl)-2-hydroxy benzonitrile. MS (ESI) 237 (M + H)+.
To a solution of 5-(l,3-benzoxazol-2-yl)-2-hydroxy benzonitrile (230mg, l.Ommol) and pyridine (154mg, 2mmol) in CH2CI2 (5mL) at 0°C,was added trifluoromethane-sulfonic anhydride (330mg, 1.2mmol) dropwise. The reaction was elevated to rt and stirred for 2h. EtOAc (150mL) was added, as well as H2O (50mL). The organic layer was washed with brine (2 x 20mL), dried (MgSO4) and the crude material was purified by flash column (silica gel, hexanes:EtOAc 4:1) to afford 4- (l,3-benzoxazol-2-yl)-2-cyanophenyltrifIuoromethanesulfonate as yellow oil.
The degassed solution of 4-(l,3-benzoxazol-2-yl)-2-cyanophenyl trifluoromethanesulfonate (300mg, 1.2mmol) in DMF (5mL) was added 2-tri-n- butylstannylpyridine (273mg, 0.74mmol), tetrakis(triphenylphosphine) palladium(O) (150mg, O.lmmol). The reaction was stirred at 90°C overnight and cooled to rt. EtOAc(lOOmL) was added, as well as brine (50mL). The organic layer was washed with brine (2 x 20mL), dried (MgSO4), and the crude material was purified on flash column (silica gel, hexanes.ΕtOAc 3:1) to afford desired 5-(l,3-benzoxazol-2-yl)-2- pyridin-2-yl benzonitrile as pinkish solid. iH NMR (CD3OD, 300MHz), δ 8.85 (d IH), 8.72 (d, IH), 8.59 (m, IH), 8.08 (d, IH), 7.91 (d, 2H), 7.85 (m, IH), 7.65 (m, IH), 7.45 (m, 3H). MS (ESI) 298 (M + H)+.
Example F56 2-(3-Methoxy-4-pyridin-3-ylphenyl)-l,3-benzoxazoIe
Figure imgf000381_0001
The solution of 4-(l,3-benzoxazol-2-yl)-2-methoxyphenyl trifluoromethanesulfonate (148mg, 0.4mmol) in 6mL of 2:1 DMF:H2θ was degassed via Argon for lOmin. Then K2CO3 (137mg, 0.99mmol), Pd(Ph3P)4 (23mg, 0.02mmol), n-Bu4NBr (128mg, 0.40mmol) and 3-Pyridylboronic acid (73mg, 0.60mmol) were added at
22°C. The resulting mixture was then heated at 75°C for lh under Argon. Cooled the reaction mixture to 22°C, then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give after purification by flash chromatography (silica gel, 3:1; hexanes :EtO Ac) the desired compound as a yellow solid. iH NMR (CDCI3, 300MHz) δ 8.83 (d, IH), 8.60 (dd, IH), 7.92 (m, 3H), 7.81
(m, IH), 7.62 (m, IH), 7.48 (d, IH), 7.39 (m, 3H), 3.98 (s, 3H). MS (ESI) 303 (M + H)+.
Example F57 2-(3-Chloro-4-pyridin-3-ylphenyl)-l,3-benzoxazole
Figure imgf000381_0002
A suspension of 3-chloro-4-hydroxybenzoic acid (20.0g, 1 l.δmmol) in anhydrous dichloromethane (lOOmL) was treated with oxalyl chloride(20mL, 23.2mmol) followed by few drops of DMF at 22°C under argon. After 2h stirring, the solution became clear, concentrated to dryness, dissolved in dichloromethane (50mL) and added slowly to a solution of 2-aminophenol (12.6g, 1 l.όmmol) and TEA (9mL, 1 l.δmmol) in anhydrous DMC (50mL). After 20min stirring, filtered off salt, concentrated the mixture to afford 4-chloro-3-hydroxy-N-phenylbenzamide as a brown solid. MS (ESI) 264(M + H)+. 4-Chloro-3-hydroxy-N-phenylbenzamide (4g, 15.2 mmol) was treated with POCI3 (5mL) at reflux for lh. Concentrated and dissolved in dichloromethane (50mL), washed with sat. NaHCO3 (3x25mL) and sat. brine (3x25mL), dried (MgSO4), concentrated in vacuo. The crude residue was chromatographed on silica gel, eluting with 2:1 hexanes:EtOAc to afford 4-(l,3- benzoxazol-2-yl)-2-chlorophenol as a colorless solid. MS (ESI) 246(M + H)+. The solution of 4-(l,3-benzoxazol-2-yl)-2-methoxyphenol (800mg, 3.3mmol) in anhydrous DMF (lOmL) was treated with CS2CO3 (l.lg, 3.2mmol) andN-phenyl trifluoromethanesulfonimide (1.2g, 3.2mmol) at 22°C for 30min. After which time it was quenched with sat. ΝaHCθ3 (20mL) and diluted with EtOAc (50mL). The EtOAc solution was washed with sat. brine (3xl0mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 6:1 hexanes:EtOAc to afford 4-(l,3-benzoxazol-2-yl)-2-chlorophenyl trifluoromethanesulfonate a colorless oil. MS (ESI) 378 (M + H)+. The solution of 4- (l,3-benzoxazol-2-yl)-2-chlorophenyl trifluoromethanesulfonate (150mg, 0.4mmol) in 6mL of 2:1 DMF:H2θ was degassed via Argon for lOmin. Then K2CO3 (137mg, 0.99mmol), Pd(Ph3P)4 (23mg, 0.02mmol), n-Bu4NBr (128mg, 0.40mmol) and 3- Pyridylboronic acid (73mg, O.όOmmol) were added at 22°C. The resulting mixture was then heated at 75°C for lh under Argon. Cooled the reaction mixture to 22°C, then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give after purification by flash chromatography (silica gel, 3:1; hexanes :EtO Ac) the desired compound, as a yellow solid. iH NMR (CDCI3,
300MHz) δ 8.75 (d, IH), 6.68 (dd, IH), 8.42 (d, IH), 8.24 (dd, IH), 7.89 (dt, IH), 7.81 (m, IH), 7.63 (m, IH), 7.52 (d, IH), 7.42 (m, 3H). MS (ESI) 307 (M + H)+.
Example F58 5-Fluoro-2-(3-methoxy-4-pyridin-2-ylphenyl)-l,3-benzoxazole hydrochloride
Figure imgf000382_0001
To 700mL of degassed CH3CN was added methyl vanillate (21. lg, 116mmol), N- phenyltrifluoromethanesulfonimide (41.3g, llόmmol), and cesium carbonate (37.7g, ll6mmol). The mixture was stirred under an argon atmosphere for 48h at which point it was partitioned between EtOAc (750mL) and H2O (750mL). The organic layer was washed with saturated Na2CO3, H2O, and brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by column chromatography (1:9 EtOAc / hexanes) to give methyl 3-methoxy-4- { [(trifluoromethyl)sulfonyl]oxy}benzoate as a colorless oil that became a colorless solid upon standing. iH NMR (DMSO- tf, 300MHz) δ 7.77 (d, IH), 7.68 (dd, IH),
7.59 (d, IH), 4.00 (s, 3H), 3.91 (s, 3H).
To 300mL of degassed THF was added methyl 3-methoxy-4- { [(trifluoromethyl)sulfonyl]oxy }benzoate (20.95g, 66.7mmol), 2-pyridylzinc bromide (200mL of 0.5M solution in THF, lOOmmol), and tetrakis(triphenylphosphine) palladium(O) (5.00g, 4.3mmol). The mixture was degassed with argon for an additional 30 minutes and heated at reflux under an argon atmosphere overnight. The reaction mixture was cooled to rt and concentrated in vacuo. The resultant brown residue was partitioned between EtOAc (1500mL) and 50% saturated NaHCO3 (lOOOmL). The aqueous layer was extracted with EtOAc (500mL), and the combined organic layers washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (0-25% EtOAc/hexanes) to give methyl 3-methoxy-4-pyridin-2-ylbenzoate as a colorless solid. IH NMR (DMSO-Jf5, 300MHz) δ 8.70 (d, IH), 7.92-7.83 (m, 3H), 7.70-7.65 (m, 2H), 7.40-7.36 (m, IH), 3.91 (s, 3H), 3.90 (s, 3H).
To 154mL of a 50/50 solution of MeOH and H2O was added lithium hydroxide monohydrate (13.85g, 330mmol). The solution was stirred until all of the salt dissolved, at which point methyl 3-methoxy-4-pyridin-2-ylbenzoate (8.02g, 32.9mmol) was added. The mixture was heated at reflux and stirred overnight. The reaction mixture was cooled to rt, neutralized with 6N HCI, and acidified to pH 4 with IN HCI. A colorless solid crashed out of solution and was filtered to give 3-methoxy- 4-pyridin-2-ylbenzoic acid as a colorless solid. iH NMR (OMSO-dβ, 300MHz) δ
8.70 (d, IH), 7.92-7.84 (m, 3H), 7.69-7.65 (m, 2H), 7.40-7.36 (m, IH), 3.91 (s, 3H). To a stirred solution of 4-fluoro-2-nitrophenol (4.05g, 25.8mmol) in MeOH (200mL) was added tin(II) chloride dihydrate (17.47g, 77.4mmol). The reaction mixture was heated at reflux and monitored by LC/MS. When significant reduction was complete, the reaction mixture was cooled to rt, poured over ice, and made basic (pH 9) with 50% saturated NaHCO3. The aqueous layer was extracted with EtOAc (2 x 200mL) and the combined extracts washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 2-amino-4-fluorophenol as a grayish green solid. lH NMR (CDCI3, 300MHz) δ 6.64 (dd, IH), 6.47 (dd, IH), 6.33 (dt, IH), 4.48 (br s, IH), 3.78 (br s, 2H).
To 20mL trimethylsilyl polyphosphate was added 2-amino-4- fluorophenol (523mg, 4.1 Immol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (857mg, 3.74mmol). The mixture was heated at 200°C for 2h, quenched over ice, and made basic (pH 14) with IN NaOH. The aqueous phase was extracted with MTBE (300mL), EtOAc (300mL), MTBE (300mL), and CH2CI2 (300mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (0-50% EtOAc/hexanes). The free base was dissolved in ether and HCI (IN in ether) was added. The solution was filtered to give 5-fluoro-2-(3-methoxy-4-pyridin-2-ylphenyl)-l,3-benzoxazole hydrochloride as a purple solid. lH NMR (DMSO- , 300MHz) δ 8.87 (d, IH), 8.34
(t, IH), 8.18 (d, IH), 7.97-7.93 (m, 3H), 7.90 (dd, IH), 7.81-7.75 (m, 2H), 7.37 (dt, IH), 4.02 (s, 3H); MS (ESI) 321 (M + H)+.
Example F59 7-Fluoro-2-(3-methoxy-4-pyridin-2-ylphenyl)-l,3-benzoxazole hydrochloride
Figure imgf000384_0001
To a stirred slurry of 10% palladium on carbon (2.26g, 2.12mmol) in MeOH (lOOmL) was added 4-bromo-2-fluoro-6-nitrophenol (5.00g, 21.2mmol). The reaction mixture was stirred under an H2 atmosphere until significant reduction was seen by TLC. The mixture was filtered through Celite and concentrated in vacuo. The resultant solid was triturated with hexanes and reconcentrated to remove residual MeOH and give 2- amino-6-fluorophenol as a dark gray solid. lH NMR (DMSO-cfo, 300MHz) δ 10.86
(br s, IH), 9.54 (br s, 2H), 7.25-7.19 (m, IH), 7.13 (d, IH), 6.94-6.86 (m, IH).
To 7mL trimethylsilyl polyphosphate was added 2-amino-6- fluorophenol (166mg, 1.31mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (300mg, 1.3 Immol). The mixture was heated at 200°C for 2h, quenched over ice, and made basic (pH 14) with IN NaOH. The aqueous phase was extracted with EtOAc (3 x 150mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resultant oil was taken up in ether and reconcentrated to give a tan solid. The free base was dissolved in ether and HCI (IN in ether) was added. The solution was filtered to give 7-fluoro-2-(3-methoxy-4- pyridin-2-yrphenyl)-l,3-benzoxazole hydrochloride as a yellow solid. lH NMR (DMSO- oM 300MHz) δ 8.71 (d, IH), 8.00 (t, IH), 7.97-7.84 (m, 4H), 7.70 (d, IH),
7.49-7.37 (m, 3H), 4.00 (s, 3H); MS (ESI) 321 (M + H)+.
Example F60 5-Bromo-2-(3-methoxy-4-pyridin-2-ylphenyl)-l,3-benzoxazole
Figure imgf000385_0001
To a stirred solution of 4-bromo-2-nitrophenol (5.00g, 22.9mmol) in MeOH (120mL) was added tin(II) chloride dihydrate (15.53g, 68.8mmol). The reaction mixture was heated at reflux and monitored by LC/MS. When significant reduction was complete, the reaction mixture was cooled to rt, poured over ice, and made basic (pH 9) with 50% saturated NaHCO3. The aqueous layer was extracted with EtOAc (2 x 150mL) and the combined extracts washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 2-amino-4-bromophenol as a dark gray solid. lH NMR (CDCI3, 300MHz) δ 9.29 (br s, IH), 6.71 (d, IH), 6.56 (d, IH), 6.49 (dd, IH), 4.83
(br s, 2H). To 20mL trimethylsilyl polyphosphate was added 2-amino-4- bromophenol (752mg, 4.00mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (916mg, 4.00mmol). The mixture was heated at 200°C for 2h, quenched over ice, and made basic (pH 14) with IN NaOH. The aqueous phase was extracted with MTBE (3 x 300mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (20-50%
EtOAc/hexanes) to give 5-bromo-2-(3-methoxy-4-pyridin-2-ylphenyl)-l,3- benzoxazole as a pink solid. lH NMR (DMSO-J , 300MHz) δ 8.71 (d, IH), 8.10 (d,
IH), 8.00 (t, IH), 7.97-7.86 (m, 4H), 7.84 (d, IH), 7.63 (dd, IH), 7.39 (dt, IH), 4.00 (s, 3H); MS (ESI) 382 (M + H)+.
Example F61 5-Cyano-2-(3-methoxy-4-pyridin-2-ylphenyl)-l,3-benzoxazole
Figure imgf000386_0001
To lmL of degassed DMF was added 5-bromo-2-(3-methoxy-4-pyridin-2-ylphenyl)- 1,3-benzoxazole (622mg, 1.63mmol), zinc cyanide (115mg, O.98mmol), tris(dibenzylideneacetone)-dipalladium (O)-chloroform complex (30mg, 0.029mmol), and l,l'-bisdiphenylphosphinoferrocene (41mg, 0.073mmol). The reaction mixture was degassed with argon for an additional lOmin and heated at 120°C under an argon atmosphere for 20h. The mixture was cooled to 80°C, 4mL of a 4:1:4 saturated NH4Cl:NH4OH:H2O solution was added dropwise, and the mixture cooled to rt and stirred overnight. The mixture was cooled to -9°C and filtered, the solid washed with 5mL of a 4: 1 :5 sat. NB4Cl:NH4θH:H2θ solution followed by 5mL H2O, and dried under vacuum to a dark yellow solid. The crude solid was purified by column chromatography (20-80% EtOAc/hexanes) to give 5-cyano-2-(3-methoxy-4-pyridin- 2-ylphenyl)-l,3-benzoxazole as a tan solid. lH NMR (DMSO-df5, 300MHz) δ 8.72 (d, IH), 8.47 (d, IH), 8.09-7.85 (m, 7H), 7.40 (ddd, IH), 4.01 (s, 3H); MS (ESI ) 328 (M + H)+.
Example F62 5-Chloro-2-(3-methoxy-4-pyridin-2-ylphenyl)-l,3-benzoxazole hydrochloride
Figure imgf000386_0002
To a suspension of 4-amino-3-methoxy benzoic acid (21g, .125 mole) in H2SO4 (2M, lOOmL) was added dropwise aqueous sodium nitrite (9.54g, 0.138mole) at 5°C. The mixture was stirred an additional lOmin at this temperature. Aqueous potassium iodide (22.9g, 0.138 mole) was added dropwise. The solution was warmed at 40°C until end of the gas evolution. The reaction mixture was cooled at rt and EtOAc
(150mL) was added. The aqueous layer was extracted two with EtOAc (2xl50mL). The organic layers were combined and washed with a 5% solution of sodium thiosulfate (200mL), brine (200mL), dried (MgSO4) and concentrated under vacuum to give a yellow solid. The crude material was dissolved in MeOH ((400mL), H2SO4 was added (8mL) and the reaction was heated under reflux overnight. After classical work-up the crude material was purified by flash chromatography using a mixture of hexane and ethyl acetate (80/20) as eluant to give 22.2 g of pure 4-iodo-3-methoxy- methylbenzoate (0.076 mole, 60.8%). A mixture of 4-iodo-3-methoxy- methylbenzoate (7g, 24mmol), 2-pyridyl zinc bromide (0.5M in THF, 62mL, 31.2mmol), and tetrakis(triphenylphosphine) palladium (1.4g, 1.2mmol) in THF (40mL) was refluxed for 5h and then stirred at rt overnight. H2O was added and the solution was filtered through Celite, the pad was washed with EtOAc, and the two layers were separated. The aqueous was washed with EtOAc (2 x 50mL), dried over Na2SO4, and evaporated to dryness. The dark residue was purified by flash chromatography on silica gel eluting with EtOAc:hexane (1:5) to afford the desired intermediate, methyl-3-methoxy-4-pyridin-2-yl benzoate, as a yellow solid. Methyl-3-methoxy-4-pyridin-2-yl benzoate (4.70g, 19.3mmol) and
10% lithium hydroxide in 1:1 water: methanol (14.8mL) was heated to reflux conditions until no starting material was observed by TLC. 6N HCI aqueous solution was added to the cooled mixture until pH 5, A yellow solid precipated was filtered to give the desired intermediate, 3-methoxy-4-pyridin-2-yl benzoic acid, as a grey solid. 3-Methoxy-4-pyridin-2-yl benzoic acid (500mg, 2.2mmol), 2-amino-4- chlorophenol (620mg, 4.3mmol) and trimethyl silylpolyphosphate (2mL) was heated to 180 °C overnight under argon. To the cooled reaction mixture, water (lOOmL) was added and extracted with EtOAc (4 x 20mL). Set aside organic layer. Filtered aqueous layer through Celite pad and basified filtrate to pH 9 (solid NaHCO3). Extracted with EtOAc (2 x 30mL), combined all organic layers and concentrated in vacuo. The resulting orange oil was purified by flash chromatography using a gradient elution of 15:85 ethyl acetate:hexane to 1:1 ethyl acetate:hexane to give the desired intermediate, 5-chloro-2-(3-methoxy-4-pyridin-2-yl phenyl) -1 ,3- benzoxazole as a colorless solid. 5-Chloro-2-(3-methoxy-4-pyridin-2-yl phenyl)-l,3- benzoxazole
(26mg) was stirred in dichloromethane. l.OM HCI in diethyl ether (0.95mL) was added and allowed reaction mixture to stir for 30 minutes. Concentration of reaction mixture in vacuo gave the desired compound, 5-chloro-2-(3-methoxy-4-pyridin-2-yl phenyl)- 1,3- benzoxazole hydrochloride, as a pink solid. lH NMR (CD3OD, 300MHz) δ 8.88-7.46 (m, 10H), 4.11 (s, 3H). MS (ESI) 337 (M + H)+.
Example F63 2-(3-Methoxy-4-pyridin-2-yl henyl)-5-methyI-l,3-benzoxazole
Figure imgf000388_0001
A mixture of A mixture of 4-iodo-3-methoxy-methylbenzoate (see example 62) (7g, 24mmol), 2-pyridyl zinc bromide (0.5M in THF, 62mL, 31.2mmol), and tetrakis(triphenylphosphine)palladium (1.4g, 1.2mmol) in THF (40mL) was refluxed for 5h and then stirred at rt overnight. H2O was added and the solution was filtered through Celite, the pad was washed with EtOAc, and the two layers were separated. The aqueous was washed with EtOAc (2 x 50mL), dried over Na2SO4, and evaporated to dryness. The dark residue was purified by flash chromatography on silica gel eluting with EtOAc:hexane (1:5) to afford the desired intermediate, methyl- 3-methoxy-4-pyridin-2-yl benzoate, as a yellow solid.
Methyl-3-methoxy-4-pyridin-2-yl benzoate (4.70g, 19.3mmol) and 10% lithium hydroxide in 1:1 water:methanol (14.8mL) was heated to reflux conditions until no starting material was observed by TLC. 6N HCI aqueous solution was added to the cooled mixture until pH 5, A yellow solid precipated out of solution and was filtered to give the desired intermediate, 3-methoxy-4-pyridin-2-yl benzoic acid, as a grey solid.
3-Methoxy-4-pyridin-2-yl benzoic acid (490mg, 2. Immol), 2-amino-p- cresol (527mg, 4.28mmol) and trimethylsilyl polyphosphate (2mL) was refluxed overnight under argon. Added water (lOOmL) to the cooled reaction mixture and basified to pH 8 (solid NaHCO3). Extracted with EtOAc (3 x 60mL), dried
(Na2SO4) and concentrated in vacuo. The resulting yellow residue was purified by flash chromatography using a gradient elution of 1:9 EtOAc: hexanes to 1:4 EtOAc: hexanes to give the desired compound, 2-(3-methoxy-4-pyridin-2-yl phenyl)-5- methyl-l,3-benzoxazole, as a yellow solid. lH NMR (CDCI3, 300MHz) δ 8.74 (m, IH), 7.98 - 7.16 (m, 10H), 4.03 (s, 3H), 2.51 (s, 3H). (ESI) 317 (M + H)+. Example F64 2-(3-Methoxy-4-pyridin-2-ylphenyl)ri,31oxazolor4,5-ft1pyridine
Figure imgf000389_0001
To 5mL of trimethylsilyl polyphosphate was added 2-aminopyridin-3-ol (175mg, 1.59mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (344mg, 1.50mmol). The mixture was heated at 200°C for 2h, quenched over ice, and made basic (pH 14) with IN NaOH. The aqueous phase was extracted with MTBE (3 x 200mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 2-(3-methoxy-4-pyridin-2-ylphenyl)[l,3]oxazolo[4,5- /3]pyridine as a light yellow solid. lH NMR (DMSO-JoM 300MHz) δ 8.72 (d, IH),
8.58 (d, IH), 8.30 (d, IH), 8.05-7.91 (m, 4H), 7.88 (t, IH), 7.51 (dd, IH), 7.40 (dd, IH), 4.02 (s, 3H); MS (ESI) 304 (M + H)+.
Example F65 2-(3-Methoxy-4-pyridin-2-ylphenyl)ri,31oxazolor4,5-c1pyridine
Figure imgf000389_0002
To a stirred solution of 3-aminopyridine (9.41g, lOOmmol) and triethylamine (16.7mL, 120mmol) in CH2CI2 (300mL) at 0°C was added trimethylacetyl chloride
(14.8mL, 120mmol) dropwise over 15min. The reaction was warmed to rt and stirred overnight. The mixture was concentrated in vacuo, the residue partitioned between EtOAc and H2O, and the layers separated. The aqueous layer was made basic with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to give N-(pyridin-3-yl)-2,2-dimethylpropanamide as a tan solid. lH ΝMR (CDCI3, 300MHz) δ 8.57 (d, IH), 8.33 (dd, IH), 8.17 (ddd, IH),
7.69 (br s, IH), 7.27 (dd, IH), 1.33 (s, 9H). To a stirred solution of N-(pyridin-3-yl)-2,2-dimethylpropanamide (8.90g, 50.0mmol) in THF (200mL) at -78°C was added n-Butyllithium (50mL, 125mmol) dropwise over 30min. After addition, the reaction mixture was warmed to 0°C and stirred an additional 3h. The reaction was then cooled back to -78°C and trimethyl borate (14.2mL, 125mmol) in THF was added dropwise over 15min. After addition, the reaction mixture was warmed to 0°C and stirred an additional 2h. Glacial AcOH (10.8mL, 188mmol) was added to the reaction, followed by dropwise addition of 30 % H2O2 (14.3mL, 138mmol). The reaction mixture was warmed to rt and stirred overnight. The mixture was diluted with H2O and concentrated in vacuo. The residue was extracted three times with 10% tPrOH / CHCI3, the combined extracts treated with activated charcoal, and the slurry filtered through Celite. The organic layer was washed three times with H2O, once with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (3-10% MeOH/ CHCI3) to giveN-(4-hydroxypyridin-3-yl)-2,2- dimethylpropanamide as a light yellow solid. lH ΝMR (DMSO-< , 300MHz) δ
11.58 (br s, IH), 8.76 (br s, IH), 8.67 (s, IH), 7.68 (d, IH), 6.26 (d, IH), 1.22 (s, 9H).
To a stirring solution of 3Ν HCI (50mL, 150mmol) was added N-(4- hydroxypyridin-3-yl)-2,2-dimethylpropanamide (1.94g, lO.Ommol). The mixture was heated at reflux overnight. After cooling to rt, the mixture was neutralized with 5Ν NaOH and concentrated in vacuo. The residue was taken up in MeOH, the salts filtered out, and the organic layer reconcentrated. The resulting residue was taken up in EtOH, the salts filtered out, and the organic layer reconcentrated to give 3- aminopyridin-4-ol, which was taken into the next step without purification. lH NMR (DMSO-dtf, 300MHz) δ 12.25 (br s, IH), 7.35 (dd, IH), 7.18 (d, IH), 6.00 (d, IH), 4.54 (br s, 2H).
To 7mL trimethylsilyl polyphosphate was added 3-aminopyridin-4-ol (330mg, 3.00mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (460mg, 2.00mmol). The mixture was heated at 200°C for 2h, quenched over ice, and made basic (pH 14) with IN NaOH. The aqueous phase was extracted with MTBE (3 x 200mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (50-100% EtOAc/hexanes followed by 10% MeOH/CHCl3) to give 2-(3-Methoxy-4-pyridin-2- ylphenyl)[l,3]oxazolo[4,5-c]pyridine as a yellow solid. lH NMR (DMSO-<ir5, 300MHz) δ 9.16 (s, IH), 8.71 (d, IH), 8.62 (d, IH), 8.03-7.84 (m, 6H), 7.39 (t, IH), 4.00 (s, 3H); MS (ESI) 304 (M + H)+. Example ¥66 2-(3-Methoχy-4-pyridin-2-ylphenyl)ri,31oxazolor5,4-ft1pyridine
Figure imgf000391_0001
To a stirred slurry of 10% palladium on carbon (1.08g, 1.02mmol) in MeOH (lOOmL) was added 3-nitropyridin-2-ol (1.42g, 10.2mmol). The reaction mixture was stirred under an H2 atmosphere until significant reduction was seen by TLC. The mixture was filtered through Celite and concentrated in vacuo. The resultant semisolid was triturated with hexanes and concentrated to remove residual MeOH and purified by UV Prep to give 3-aminopyridin-2-ol as a dark brown oil.
To 5mL of trimethylsilyl polyphosphate was added 3-aminopyridin-2- ol (150mg, 1.59mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (229mg, l.Ommol). The mixture was heated at 200°C for 2h, quenched over ice, and made basic (pH 14) with IN NaOH. The aqueous phase was extracted with EtOAc (3 x 200mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resultant oil was taken up in a minimum of EtOAc and purified by prep TLC (1:1 EtOAc/hexanes) to give 2-(3-methoxy-4-pyridin-2- ylphenyl)[l,3]oxazolo[5,4-b]pyridine as a light yellow solid. lH NMR (DMSO-d<5,
300MHz) δ 8.73 (dq, IH), 8.43 (dd, IH), 8.32 (dd, IH), 8.02 (d, IH), 7.99-7.93 (m, 2H), 7.92-7.85 (m, 2H), 7.55 (dd, IH), 7.40 (ddd, IH), 4.01 (s, 3H); MS (ESI) 304 (M + H)+.
Example F67 2-f4-(6-Bromopyridin-2-yl)-3-methoxyphenyll-l,3-benzoxazoIe
Figure imgf000391_0002
4-hydroxy-3-methoxybenzoic acid (25g, 150mmol) and 2-amino phenol (16g, 150mmol) were combined in a round bottom flask. Trimethylsilyl polyphosphate (80mL) was added. The mixture was heated at 180°C for 30min. The mixture was poured over ice and allowed to stir overnight. The suspension was filtered to afford 4-(l,3-benzoxazol-2-yl)-2-methoxyphenol as a pale green solid. MS (ESI) 242 (M+H).
A solution of 4-(l,3-benzoxazol-2-yl)-2-methoxyphenol (7.1g, 29mmol) in anhydrous DMF (lOOmL) was treated with CS2CO3 (9.6g, 29mmol) and
N-phenyl trifluoromethanesulfonimide (lOg, 29mmol) at 22°C for 30min. The resulting mixture was quenched with saturated aqueous ΝaHCθ3 (50mL) and diluted with EtOAc (500mL). The EtOAc solution was washed with brine (3 x lOOmL), dried (MgSO4), filtered and concentrated in vacuo. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using and EtOAc/hexanes gradient to afford 4-(l,3-benzoxazol-2-yl)-2-methoxyphenyl trifluoromethanesulfonate as a colorless oil: MS (ESI) 374 (M+H)+.
4-(l ,3-benzoxazol-2-yl)-2-methoxyphenyl trifluoromethanesulfonate (480mg, 1.3mmol), potassium acetate (380mg, 3.8mmol), bis(diphenylphosphino)ferrocene palladium dichloride (lOOmg, 0.13mmol), and bis(pinacolato)diboron (390mg, 1.5mmol) were combined in a 2-neck flask. The flask was evacuated and filled with argon and dioxane (lOmL) was added. The suspension was deoxygenated with a stream of argon for lOmin. The reaction mixture was stirred under argon at 80°C for 24h. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using and EtOAc/hexanes gradient to afford 2-[3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l,3- benzoxazole as an orange solid: lH NMR (CDCI3, 300MHz) δ 7.83-7.83 (m, 3H),
7.74 (s, IH), 7.62-7.55 (m, IH), 7.39-7.36 (m, 2H), 3.98 (s, 3H), 1.39 (s, 12H).
2-[3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]- 1,3-benzoxazole (200mg, 0.57mmol) CsF (350mg, 2.3mmol), Pd(Ph3P)4 (65mg,
0.057mmol), and 2-bromopyridine (140mg, 0.57mmol) were combined in a 2-neck flask. The flask was evacuated and filled with argon and DME (5mL) was added. The suspension was deoxygenated with a stream of argon for lOmin. The reaction mixture was stirred under argon at 80°C for 24h. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using and EtOAc/hexanes gradient to afford the desired 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-l,3- benzoxazole as a colorless solid: lH NMR (CDCI3, 300MHz) δ 8.08-8.05 (d, IH), 7.98-7.95 (m, 2H), 7.89 (s, IH), 7.84-7.79 (m, IH), 7.63-7.60 (m, IH), 7.45-7.38 (m, 3H), 4.02 (s, 3H). MS (ESI) 382 (M + H)+.
Example F68 2-r3-Methoxy-4-(6-methylpyridin-2-yl)phenvπ-l,3-benzoxazoIe
Figure imgf000393_0001
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2- yl)-3-methoxyphenyl]-l,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-l,3-benzoxazole (200mg, 0.57mmol) was reacted with 2- bromo-6-methylpyridine (65μL, 0.57mmol) to afford the desired 2-[3-methoxy-4-(6- methylpyridin-2-yl)phenyl]-l,3-benzoxazole as a colorless solid: lH NMR (CDCI3,
300MHz) δ 7.96-7.95 (m, 2H), 7.89 (s, IH), 7.82-7.79 (m, IH), 7.67-7.60 (m, 3H), 7.39-7.36 (m, 2H), 7.14-7.12 (m, IH), 4.00 (s, 3H), 2.65 (s, 3H). MS (ESI) 317 (M+H)+.
Example F69 2- r3-Methoxy-4- (6-methoxypyridin-2- vDphenyll - 1,3-benzoxazoIe
Figure imgf000393_0002
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2- yl)-3-methoxyphenyl]-l,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-l,3-benzoxazole (200mg, 0.57mmol) was reacted with 2- bromo-6-methoxypyridine (65μL, 0.57mmol) to afford the desired 2-[3-methoxy-4- (6-methoxypyridin-2-yl)phenyl]-l,3-benzoxazole as a colorless solid: lH NMR (CDCI3, 300MHz) δ 7.96-7.95 (m, 2H), 7.89 (s, IH), 7.82-7.79 (m, IH), 7.67-7.60 (m, 3H), 7.39-7.36 (m, 2H), 7.14-7.12 (m, IH), 4.00 (s, 3H), 2.65 (s, 3H). MS (ESI) 333 (M+H)+. Example F70 2-r4-(5-Chloropyridin-2-yl)-3-methoxyphenvπ-l,3-benzoxazole
Figure imgf000394_0001
A solution of 5-chloro-2-pyridinol (3.0g, 23mmol), N-phenyl trifluoromethanesulfonimide (8.3g, 23mmol), and CS2CO3 (7.5g, 23mmol) in CH3CΝ (lOOmL) was stirred at room temp for 24h. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford 4-chlorophenyl-2-trifluoromethanesulfonate as an orange oil: MS (ESI) 262 (M+H)+.
Utilizing the general procedure outlined in the synthesis of 2-[4-(6- bromopyridin-2-yl)-3-methoxyphenyl]-l,3-benzoxazole, 2-[3-methoxy-4-(4 ,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l,3-benzoxazole (lOOmg, 0.28mmol) was reacted with 4-chlorophenyl trifluoromethanesulfonate (74mg, 0.28mmol) to afford the desired 2-[4-(5-chloropyridin-2-yl)-3-methoxyphenyl]-l,3-benzoxazole as a colorless solid: lH NMR (CDCI3, 300MHz) δ 8.69-8.68 (d, IH), 7.98 (s, 2H), 7.94-
7.90 (m, 2H), 7.86-7.78 (m, IH), 7.74-7.73 (m, IH), 7.65-7.58 (m, IH), 7.40-7.37 ( , 2H), 4.03 (s, 3H). MS (ESI) 337 (M+H)+.
Example F71
2- r3-Methoxy-4- (3-methylp yridin-2- vDphenyll ■ 1,3-benzoxazole
Figure imgf000394_0002
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2- yl)-3-methoxyphenyl]- 1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]- 1,3-benzoxazole (150mg, 0.43mmol) was reacted with 2- bromo-5-methylpyridine (73mg, 0.43mmol) to afford the desired 2-[3-methoxy-4-(3- methylpyridin-2-yl)phenylj-l,3-benzoxazole as a colorless solid: lH NMR (CDCI3, 300MHz) δ 8.60-8.58 (d, IH), 7.96-7.90 (m, 3H), 7.80-7.79 (m, IH), 7.70 (s, IH), 7.62-7.60 (m, IH), 7.39-7.36 (m, 2H), 7.10-7.08 (m, IH), 4.01(s, 3H), 2.43 (s, 3H). MS (ESI) 317 (M+H)+.
Example F72 2-r3-Methoxy-4-(4-methyIpyridin-2-yl)phenyl1-l,3-benzoxazole
Figure imgf000395_0001
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2- yl)-3-methoxyphenyl]-l,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-l,3-benzoxazole (150mg, 0.43mmol) was reacted with 2- bromo-4-methylpyridine (47μL, 0.43mmol) to afford the desired 2-[3-methoxy-4-(4- methylpyridin-2-yl)phenyl]-l,3-benzoxazole as a colorless solid: iH NMR (CDCI3,
300MHz) δ 8.57 (s, IH), 7.97-7.96 (m, 2H), 7.89 (s, IH), 7.82-7.79 (m, 2H), 7.63- 7.54 (m, 2H), 7.39-7.36 (m, 2H), 4.01 (s, 3H), 2.39 (s, 3H). MS (ESI) 317 (M+H)+.
Example F73 2 3-Methoxy-4-(5-methyIpyridin-2-yl)phenyl1-l,3-benzoxazole
Figure imgf000395_0002
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2- yl)-3-methoxyphenyl]-l,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-l,3-benzoxazole (200mg, 0.57mmol) was reacted with 2- bromo-3-methylpyridine (63 μL, 0.57mmol) to afford the desired 2-[3-methoxy-4-(5- methylpyridin-2-yl)phenyl]- 1,3 -benzoxazole as a colorless solid: iHNMR (CDCI3, 300MHz) δ 8.55-8.53 (d, 1H), 7.98-7.95 (m, 1H), 7.88 (s, IH), 7.81-7.78 (m, IH), 7.61-7.56 (m, 2H), 7.46-7.44 (d, IH), 7.39-7.35 (m, 2H), 7.23-7.19 (m, IH), 3.91 (s, 3H), 2.19 (s, 3H). MS (ESI) 317 (M+H)+.
Example F74 2-r4-(6-Fluoropyridin-3-yl)-3-methoxyphenvH-l,3-benzoxazole
Figure imgf000396_0001
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2- yl)-3-methoxyphenyl]-l,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-l,3-benzoxazole (200mg, 0.57mmol) was reacted with 5- bromo-2-fluoropyridine (59μL, 0.57mmol) to afford the desired 2-[4-(6- fluoropyridin-3-yl)-3-methoxyphenyl]-l,3-benzoxazole as a colorless solid: iH NMR (CDCI3, 300MHz) δ 8.42 (s, IH), 8.07-8.00 (m, IH), 7.97-7.94 (m, IH), 7.89 (s, IH),
7.82-7.79 (m, IH), 7.64-7.59(m, IH), 7.48-7.45 (d, IH), 7.41-7.38 (m, IH), 7.03-6.99 (m, IH), 3.98 (s, 3H). MS (ESI) 321 (M+H)+.
Example F75 2-r4-(6-Chloropyridin-3-yl)-3-methoxyphenvπ-l,3-benzoxazole
Figure imgf000396_0002
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2- yl)-3-methoxyphenyTJ-l,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-l,3-benzoxazole (lOOmg, 0.29mmol) was reacted with 5- bromo-2-chloropyridine (55mg, 0.29mmol) andNa2CO3 (90mg, 0.86mmol) in DME (2mL), and H2O (2mL) to afford the desired 2-[4-(6-chloropyridin-3-yl)-3- methoxyphenyl]-l,3-benzoxazole as a colorless solid: iH NMR (CDCI3, 300MHz) δ 8.59 (d, IH), 7.85-7.66 (m, 3H), 7.44-7.78 (m, IH), 7.56-7.60 (m, IH), 7.48-7.45 (d, IH), 7.42-7.38 (m, 3H), 3.98 (s, 3H). MS (ESI) 337 (M + H)+. Example F76 2-r3-Methoχy-4-(6-morpholin-4-ylpyridin-2-yl)phenyn-l,3-benzoxazole
Figure imgf000397_0001
2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-l ,3-benzoxazole (150mg, 0.39mmol), morpholine (41 μL, 0.47mmol), Pd2(dba)3 (8.2mg, 0.0078mmol), BINAP (9.8mg,
0.016mmol), and NaOtBu (53mg, 0.55mmol) were combined in a sealable tube evacuated and backfilled with argon. Toluene (4mL) was added and the mixture was degassed with a stream of argon for 5min. The tube was sealed and the mixture was heated to 70°C for 18h. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 2-[3-methoxy-4-(6-morpholin-4-ylpyridin-2-yl)phenyl]-l,3-benzoxazole as an orange solid: lH NMR (CDCI3, 300MHz) δ 8.07-8.05 (d, IH), 7.96-7.95 (m, IH),
7.88 (s, IH), 7.83-7.78 (m, IH), 7.65-7.58 ( m, 2H), 7.42-7.36 (m, 3H), 6.65-6.62 (d, IH), 4.02 (s, 3H), 3.88-3.85 (t, 4H), 3.61-3.58 (t, 4H). MS (ESI) 388 (M + H)+.
Example F77 2-r3-Methoxy-4-(5-morpholin-4-ylpyridin-2-yl)phenyn-l,3-benzoxazoIe
Figure imgf000397_0002
2-[4-(5-chloropyridin-2-yl)-3-methoxyphenyl]-l ,3-benzoxazole (58mg, 0.17mmol), morpholine (18μL, 0.21mmol), Pd(OAc)2 (0.38mg, 0.0017mmol), 1,1 -biphenyl-2- yl[di(tert-butyl)]phosphine ( Omg, 0.0034mmol), and NaOtBu (23mg, 0.24mmol) were combined in a sealable tube evacuated and backfilled with argon. Toluene (800μL) was added and the mixture was degassed with a stream of argon for 5min. The tube was sealed and the mixture was heated to 110°C for 18h. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford 2-[3-methoxy-4-(5-morpholin-4-ylpyridin-2- yl)phenyl]-l,3-benzoxazole as a yellow solid. The freebase was dissolved in Et2O/CH2Cl2 and treated with IN HCI in Et2θ. Resulting yellow solid was filtered and dried under high vacuum to afford the desired 2-[3-methoxy-4-(5-morpholin-4- ylpyridin-2-yl)phenyl]-l,3-benzoxazole hydrochloride as a yellow solid: lH NMR (CD3OD, 300MHz) δ 8.33-8.30 (d, IH), 8.20-8.09 (m, 2H), 8.08-8.02 (m, 2H), 7.87-
7.77 (m, 2H), 7.75-7.71 (m, IH), 7.53-7.42 (m, 2H), 4.10 (s, 3H), 3.89 (t, 4H), 3.49- 3.47 (t, 4H). MS (ESI) 388 (M + H)+.
Example F78
6-r4-(l,3-Benzoxazol-2-yl)-2-methoxyphenynpyridin-3-amine
Figure imgf000398_0001
2-[4-(5-chloropyridin-2-yl)-3-methoxyphenyl]-l ,3-benzoxazole (lOOmg, 0.30mmol), benzophenone imine (60μL, 0.36mmol), Pd2(dba)3 (15mg, 0.015mmol), 1,1 - biphenyl-2-yl(dicyclohexyl)phosphine (lOmg, 0.015mmol), NaOtBu (40mg,
0.42mmol) were combined in a sealable tube evacuated and backfilled with argon. Toluene (600μL) was added and the mixture was degassed with a stream of argon for 5min. The tube was sealed and the mixture was heated to 80°C for 24h. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford 6-[4-(l,3-benzoxazol-2-yl)-2- methoxyphenyl]-N-(diphenylmethylene)pyridin-3-amine as a yellow solid.
6- [4-( 1 ,3-benzoxazol-2-yl)-2-methoxyphenyl] -N- (diphenylmethylene)pyridin-3-amine (61mg, 0.13mmol) was dissolved in MeOH (2mL) and ΝaOAc (25mg, 0.3 Immol) and hydroxylamine hydrochloride (16mg, 0.23mmol) were added. The resulting suspension was stirred at rt for lh. The mixture was partitioned between CH2CI2 and 0.1Ν aqueous ΝaOH. Aqueous layer was extracted with CH2CI2 (3 x 15mL). The combined organic layers were dried over MgSO4, filtered and concentrated. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 6-[4-(l,3-benzoxazol-2-yl)-2-methoxyphenyl]pyridin-3-amine: lH NMR (CDCI3, 300MHz) δ 8.25-8.24 (d, IH), 7.95 (s, 2H), 7.86 (s, IH), 7.80-7.76 (m, 2H), 7.62-7.59 (m, IH), 7.38-7.35 (m, 2H), 7.07-7.04 (m, IH), 4.01 (s, 3H). MS (ESI) 318 (M+H)+.
Example F79
6-r4-(l,3-BenzoxazoI-2-yl)-2-methoxyphenyn-N V-dimethylpyridin-3-amine
Figure imgf000399_0001
6-[4-(l ,3-benzoxazol-2-yl)-2-methoxyphenyl]pyridin-3-amine (22mg, 0.070mmol) was dissolved in MeOH (2mL), and AcOH (2 drops). ΝaCΝBH3 (44mg, 0.70mmol) and formaldehyde (50μL, 0.70mmol) were added and the mixture was stirred overnight. The mixture was partitioned between CH2CI2 and dilute brine. The aqueous layer was extracted with CH2CI2 (3 x 15mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 6-[4-(l,3-benzoxazol-2-yl)-2- methoxyphenyl]-N,N-dimethylpyridin-3-amine: lH ΝMR (CDCI3, 300MHz) δ 8.24-
8.23 (d, IH), 7.94 (s, 2H), 7.87 (s, IH), 7.84-7.79 (m, 2H), 7.59 (m, IH), 7.38-7.35 (m, 2H), 7.07-7.06 (m, IH), 4.01 (s, 3H), 3.04 (s, 6H). MS (ESI) 346 (M + H)+.
EXAMPLE F80 r2-methoxy-4-(4,5,6,7-tetrahydro-l,3-benzoxazoI-2-yl)phenynacetonitrile
Figure imgf000399_0002
To a solution of methyl 4-(bromoethyl)-3-methoxy benzoate (25g, 96.5mmol) in acetonitrile (200mL) was added TMSCΝ (19mL, 144.7mmol) and TBAF (144mL, l.OM in THF) at 22°C. 20min later, the resulting reaction mixture was concentrated under reduced pressure to give after purification by flash chromatography (silica gel, 4:1; hexanes:EtOAc) the to give methyl 4-(cyanomethyl)-3-ethoxybenzoate as a white solid. MS (ESI) 206 (M + H)+.
A solution of methyl 4-(cyanomethyl)-3-ethoxybenzoate (18g, 88mmol) in 150mL of MeOH:THF:H2O (3:3:1) was treated with lithium hydroxide monohydrate (1 lg, 263mmol) at 22°C for overnight. Then 10% aqueous HCI
(lOOmL) was added to quench the reaction, the mixture was extracted with EtOAc (3 x 200mL), the combined organic extracts were washed with brine (lOOmL) and dried (MgSO4), filtered and concentrated in vacuo to afford 4-(cyanomethyl)-3- methoxybenzoic acid as a white solid. MS (ESI) 192 (M + H)+. The 4-(cyanomethyl)-3-methoxybenzoic acid (0.33g, 1.7mmol) was suspended in anhydrous dichloromethane (5mL) and treated with oxalyl chloride(0.3mL, 3.5mmol) followed by few drops of DMF at 22°C under argon. After 2h stirring, the resulting solution was concentrated to dryness, dissolved in dichloromethane (5mL), and added slowly to a solution of trans-2-aminocyclohexanol hydrochloride (0.26g, 1.7mmol) and TEA (0.5mL, 3.5mmol) in anhydrous dichloromethane (lOmL). After 20min stirring, filtered off salt, and concentrated to afford 4-(cyanomethyl)-N-[(2R)-2-hydroxycyclohexyl]-3-methoxybenzamide as a yellow solid. MS (ESI) 289 (M + H) +.
To a solution of oxalyl chloride (0.2mL, 2.2mmol) in anhydrous dichloromethane (2mL) at -78°C was added DMSO (0.32mL, 4.5mmol) under Argon. The solution was maintained for lOmin where upon a solution of 4-(cyanomethyl)-N- [(2R)-2-hydroxycyclohexyl]-3-methoxybenzamide (430mg, 1.5mmol) in anhydrous dichloromethane (13mL) was added dropwide. The reaction was stirred at -78°C for 30min, whereupon TEA (lmL, 7.5mmol) was added. The reaction was warmed to 22°C for 2h. Then, 50mL dichloromethane was added to the mixture, washed with sat ΝaHCθ3 (3 x 15mL) and sat. brine (3 x 15mL), dried (MgSO4), and concentrated to afford a yellow solid of 4-(cyanomethyl)-3-methoxy-N-(2-oxocyclohexyl)benzamide. MS (ESI) 287 (M + H) +.
4-(cyanomethyl)-3-methoxy-N-(2-oxocyclohexyl)benzamide (0.8g, 2.8mmol) was treated with POCI3 (5mL) at reflux for lh. The resulting mixture was concentrated and dissolved in dichloromethane (50mL), washed with sat. ΝaHC03 (3 x 15mL) and sat. brine (3xl5mL), dried (MgSO4), and concentrated in vacuo. The crude residue was chromatographed on silica gel, eluting with 2:1 hexanes:EtOAc to afford the desired compound, [2-methoxy-4-(4,5,6,7-tetrahydro-l,3-benzoxazol-2- yl)phenyl] acetonitrile, the desired compound, as white solid. lH NMR (CDCI3, 300MHz) δ 7.58 (dd, IH), 7.53 (m, IH), 7.42 (d, IH), 3.95 (s, 3H), 3.72 (s, 2H), 2.71 (m, 2H), 2.62 (m, 2H), 1.87 (m, 4H). MS (ESI) 269 (M + H)+.
ASSAYS DEMONSTRATING BIOLOGICAL ACTIVITY The compounds of this invention were tested against the hmGluR5a receptor stably expressed in mouse fibroblast Ltk- cells (the hmGluR5a/L38-20 cell line) and activity was detected by changes in [Ca++]i, measured using the fluorescent Ca++-sensitive dye, fura-2. InsP assays were performed in mouse fibroblast Ltk" cells (LM5a cell line) stably expressing hmGluR5a. The assays described in International Patent Publication WO 0116121 may be employed.
Calcium Flux Assay
The activity of compounds was examined against the hmGluR5a receptor stably expressed in mouse fibroblast Ltk- cells (the hmGluR5a/L38 cell line). See generally Daggett et al., Neuropharmacology 34:871-886 (1995). Receptor activity was detected by changes in intracellular calcium ([Ca2+]j) measured using the fluorescent calcium-sensitive dye, fura-2. The hmGluR5a/L38-20 cells were plated onto 96-well plates, and loaded with 3 μM fura-2 for lh. Unincorporated dye was washed from the cells, and the cell plate was transferred to a 96-channel fluorimeter (SIBIA-SAIC, La Jolla, CA) which is integrated into a fully automated plate handling and liquid delivery system. Cells were excited at 350 and 385nm with a xenon source combined with optical filters. Emitted light was collected from the sample through a dichroic mirror and a 510nm interference filter and directed into a cooled CCD camera (Princeton Instruments). Image pairs were captured approximately every Is, and ratio images were generated after background subtraction. After a basal reading of 20s, an ECso concentration of glutamate (lOμM) was added to the well, and the response evaluated for another 60s. The glutamate- evoked increase in [Ca^ in the presence of the screening compound was compared to the response of glutamate alone (the positive control).
Phosphatidylinositol hydrolysis (PI) assays
Inositolphosphate assays were performed as described by Berridge et al. [Berridge et al, Biochem. J. 206: 587-5950 (1982); and Nakajima et al., J. Biol. Chem. 267:2437-2442 (1992)] with slight modifications. Mouse fibroblast Ltk cells expressing hn GluR5 (hmGluR5/L38- 20 cells) were seeded in 24-well plates at a density of 8xl05cells/well. One μCi of [3H]-inositol (Amersham PT6-271; Arlington Heights, 111.; specific activity = 17.7 Ci/mmol) was added to each well and incubated for 16h at 37°C. Cells were washed twice and incubated for 45min in 0.5mL of standard Hepes buffered saline buffer (HBS ; 125mM NaCl, 5mM KCI, 0.62mM MgS04, 1.8mM CaCl2, 20mM HEPES, 6mM glucose, pH to 7.4). The cells were washed with HBS containing lOmM LiCl, and 400μL buffer added to each well. Cells were incubated at 37°C for 20min. For testing, 50μL of 10X compounds used in the practice of the invention (made in HBS/LiCl (lOOmM)) was added and incubated for 10 minutes. Cells were activated by the addition of lOμM glutamate, and the plates left for 1 hour at 37°C. The incubations were terminated by the addition of lmL ice-cold methanol to each well. In order to isolate inositol phosphates (IPs), the cells were scraped from wells, and placed in numbered glass test tubes. One mL of chloroform was added to each tube, the tubes were mixed, and the phases separated by centrifugation. IPs were separated on Dowex anion exchange columns (AG 1-X8 100-200 mesh formate form). The upper aqueous layer (750μL) was added to the Dowex columns, and the columns eluted with 3mL of distilled water. The eluents were discarded, and the columns were washed with lOmLs of 60mM ammonium formate/5mM Borax, which was also discarded as waste. Finally, the columns were eluted with 4mL of 800mM ammonium formate/0. IM formic acid, and the samples collected in scintillation vials. Scintillant was added to each vial, and the vials shaken, and counted in a scintillation counter after 2 hours. Phosphatidylinositol hydrolysis in cells treated with certain exemplary compounds was compared to phosphatidylinositol hydrolysis in cells treated with the agonist alone in the absence of compound.
The compounds useful in the methods and compositions of this invention have mGluR5 inhibitory activity as shown by IC50 values of 10 μM or less in the calcium flux assay or inhibition at a concentration of 100 μM in the PI assay. Preferably, the compounds should have IC50 values of 1 μM or less in the calcium flux assay and IC50 values of less than 10 μM in the PI assay. Even more preferably, the compounds should have IC50 values of 500 nM or less in the calcium flux assay and IC50 values of less than 1 μM in the PI assay
The compounds in the preceeding examples have mGluR5 inhibitory activity as shown by inhibition at a concentration 10 μM or lower in the calcium flux assay or inhibition at 100 μM or less in the PI assay. Acute food intake studies in rats or mice: General Procedure
Adult rats or mice are used in these studies. After at least 2 days of acclimation to the vivarium conditions (controlled humidity and temperature, lights on for 12 hours out of 24 hours) food is removed from rodent cages. Experimental compounds or their vehicles are administered orally, intraperitoneally, subcutaneously or intravenously before the return of a known amount of food to cage. The optimal interval between dosing and food presentation is based on the half-life of the compound based on when brain concentrations of the compound is the highest. Food remaining is measured at several intervals. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant effect of the compounds are compared to the effect of vehicle. In these experiments many strains of mouse or rat, and several standard rodent chows can be used.
Chronic weight reduction studies in rats or mice: General Procedure
Adult rats or mice are used in these studies. Upon or soon after weaning, rats or mice are made obese due to exclusive access to diets containing fat and sucrose in higher proportions than in the control diet. The rat strains commonly used include the Sprague Dawley bred through Charles River Laboratories. Although several mouse strains may be used, c57Bl/6 mice are more prone to obesity and hyperinsulinemia than other strains. Common diets used to induce obesity include: Research Diets D12266B (32% fat) or D12451 (45% fat) and BioServ S3282 (60% fat). The rodents ingest chow until they are significantly heavier and have a higher proportion of body fat than control diet rats, often 9 weeks. The rodents receive injections (1 to 4 per day) or continuous infusions of experimental compounds or their vehicles either orally, intraperitoneally, subcutaneously or intravenously. Food intake and body weights are measured daily or more frequently. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant and weight loss effects of the compounds are compared to the effects of vehicle.
IN VIVO EXAMPLE 1 Acute food intake reduction in rats
Sprague-Dawley rats (150-250g) purchased from Harlan, were deprived of food from 8 AM until 5 PM (lights on from 6 AM until 6 PM). Rats received intraperitoneal injections of 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile @ 5 mg / kg or vehicle (50% PEG/saline) at 5 PM and rat chow was immediately returned to the cage. Rat chow intake was measured after 4 hours. 3-(5-Pyridin-2-yl-2H-tetrazol-2- yl)benzonitrile reduced rat chow intake by 50%, as compared to vehicle injection at the end of the 4-hour time period.
IN VΓVΌ EXAMPLE 2
Acute food intake reduction in mice
C57B1/6 mice (20-30g), purchased from Ηarlan, were deprived of food from 5:30 PM until 7:10 AM (lights on from 6 AM until 6 PM). Mice received intraperitoneal injections of mGluR5 antagonist 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2- yl)benzonitrile @ 10 mg / kg or vehicle (50% PEG/Saline) immediately before mouse chow was returned to the cage. Mouse chow intake was measured after 1.5 hours. 3- Fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile reduced mouse chow intake by 70% as compared to vehicle injection at the end of the 1.5-hour time period.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A method of treating or preventing an eating disorder asssociated with excessive food intake comprising administration to a subject in need of such treatment or prophylaxis, of a therapeutically effective or prophylactically effective amount of a compound selected from:
Figure imgf000405_0001
(IA);
(IB):
Figure imgf000405_0003
(IC);
Figure imgf000405_0004
(ID);
Figure imgf000406_0001
(IE); and
Figure imgf000406_0002
(IF)
or pharmaceutically acceptable salts thereof, wherein:
X and Ya each independently is aryl or heteroaryl wherein at least one of Xa and Ya is a heteroaryl with N adjacent to the position of attachment to Aa or Ba respectively;
Xa is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NRlR2, -C(=NRl)NR2R3, _ N(=NRl)NR2R3, -NR1COR2, -NRlC02R2, -NRISO2R4, -NR1CONR2R3 -SR4, -SOR4, -SO2R4, -Sθ2NRlR2, -CORl, -CO2Rl, -CONR1R2, -C(=NR1)R2, or -
C(=NORl)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rl, R2, and R3 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci^alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R4 is -Cι_6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cχ-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Aa is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9cθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9sO2-Co-2alkyl- or -heteroCθ-4alkyl;
Ya is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5, -NR5R6, -C(=NR5)NR6R7, -N(=NR5)NR6R7, -NR5COR6, -NR5CO2R6, -NR5S02R8, -NR5C0NR6R7 -SR8, -SOR8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, -CONR5R6, -C(=NR5)R6, or- C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5, R6; and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
R8 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3. 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Ba is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOCO-Cθ-2alkyl- -Cθ- 2alkyl-NRl°SO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rll, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of
Rll, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Cχ-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Co-6alkyl)(aryl) groups;
Xb and Yb each independently is aryl or heteroaryl wherein at least one of Xb and Yb is a heteroaryl with N adjacent to the position of attachment to Ab or B respectively; Xb is optionally substituted with 1-7 independent halogen, -CN, NO2,
-Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORlb -NRlbR2b -C(=NRlb)NR2bR3b -N(=NRlb)NR2bR3b _NRlbCOR2b, -NRl cθ2R2b, -N lbSO2R4b, - NRlbCONR2bR3b _SR4b; -SOR4b -SO2R4b, -SO2NRlbR2b -CORlb, -CO2Rl , -CONRlbR2b -C(=NRlb)R2b or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rib, R2b and R3b each independently is -Cθ-6alkyl, -C3.
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R4b s -Ci-βalkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(CQ-6alkyl)(aryl) substituents; Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5b -NR5bR6b -C(=NR5b)NR6bR7b -N(=NR5b)NR6bR7b, -NR5bcOR6b -NR5bcθ2R6b, -NR5bsθ2R8b, - NR5bcONR6bR7b _SR8b, -SORδb -SO2R8b, -SO2NR5bR6b -COR5b -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b; or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b; R6b and R7b each independently is -Cθ-6alkyl, -C3.. 7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cl_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Co-6alkyl)(aryl) substituents;
R8b is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bb is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Co_ 2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9b and RlOb each independently is -Cθ-6alkyl, -C3-7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b;
Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rl lb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(C0-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Q)- 6alkyl)(aryl) groups; and wherein optionally Rl lb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond;
Xc and Yc each independently is aryl or heteroaryl wherein at least one of Xc and Yc is a heteroaryl with N adjacent to the position of attachment to Ac or Bc respectively; three of Ale, A C, A3C, A4C, and A5c are N, the remaining are C, and one of Ale and A C musl be N, but not both Ale and A4c are N;
Xc is optionally substituted with 1-7 independent halogen, -CN, NO2,
-Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORl, -NR1CR2C,
Figure imgf000410_0001
_
N(=NR1C)NR2CR3C, -NRlcCOR2c, -NR1CCO2R2C, -NRlcSO2R4c, - NR1CCONR2CR3C _SR4c, -SOR4C, -SO2R4c, -SO2NR1CR2C, -CORlc, -CO2Rlc, -
CONRlcR2c, -C(=NR1C)R2C, or -C(=NOR1C)R2C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xc; wherein the -Cχ-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rlc, R2C; and R c each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-
6alkyl)(aryl) substituents;
R4c is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Ac is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ccθ-Cθ-2alkyl- -Cθ-2alkyl-
NR9csO2-Co-2alkyl- or -heteroCQ-4alkyl; Yc is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5c, -NR5CR6C,
Figure imgf000411_0001
-N(=NR5C)NR6CR7C, -NR5CCOR6C, -NR5ccθ2R6c, -NR5CS02R8C, - NR5CCONR6CR7C _SR8C5 -SOR8c, -SO2R8 , -SO2NR5CR6C, -COR5C, -CO2R5c, - CONR5CR6C; -C(=NR5C)R6C, Dr -C(=NOR5C)R6C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to YC; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5c, R6C, and R7c each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Q)- 6alkyl)(aryl) substituents;
R8c is -Cl_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents; Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOccθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOcsO2-Co-2alkyl-, or -heteroCθ-4alkyl;
R9c and RlOc each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ-
6alkyl)(aryl) substituents;
Rl lc is halogen, -Cθ-6alkyl, -Cθ-6alkoxyl, =O, =N(Cθ-4alkyl),or -
N(Cθ-4alkyl)(Cθ-4alkyl); Xd and Y each independently is aryl or heteroaryl wherein at least one of Xd and Yd is a heteroaryl with N adjacent to the position of attachment to Ad or βd respectively;
Xd is optionally substituted with 1-7 independent halogen, -CN, NO2,
-Ci_6alkyl, -Cl-6alkenyl, -Cι_6alkynyl, -ORl, -NRldRd2; -C(=NRld)NR2dR3d _ N(=NRld)NR2dR3d -NRldcOR2d -NRldCO2R2d, -NRldsθ2R4d, _ NRldC0NR2dR3d _SR4d -SOR4d, -SO2R4d, -SO2N ldR2d, -CORld -CO2Rld, -CONRdlR2d, -C(=NRld)R2d or-C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d and R3d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Cχ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Cθ-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2~Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yd is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι.6alkynyl, -OR5, -NR5dR6d, -C(=NR5d)NR6dR7d -N(=NR5d)NR6dR7d -NR5dcOR6d, -NR5dcθ2R6d, -NR5dsθ2R8d, - NR5dcONR6dR7d _SR8d -SORδd -SO2R8d, -SO2NR5dR6d, -COR5d -CO2R5d, -CONR5dR6d; -C(=NR5d)R6d, 0r -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, - O(C0-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O (heteroaryl), -N(C0-6alkyl)(C0- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, R6d and R7d e ch independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Ci-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl; R d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; Xe and Ye each independently is aryl or heteroaryl wherein at least one of Xe and Ye is a heteroaryl with N adjacent to the position of attachment to Ae or Be respectively;
Xe is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORle, -NRleR2e, -C(=NRle)NR2eR3e -N(=NRle)NR2eR3e -NRleCOR2e, -NRleCO2R2e, -NRleSO2R4e, -
NRleCONR2eR3e _SR4e, -SOR4e, -SO2R4e, -SO2NRleR2e, -CORle, -CO2Rle, - CONRleR2e, -C(=NRle)R2e; Qr -C(=NORle)R2e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xe; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rle, R2e, and R3e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Q)- 6alkyl)(aryl) substituents;
R4e is -Ci-galkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Ae is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ecθ-Cθ-2alkyl-, -Co-2alkyl- NR9esO2-Co-2alkyl- or -heteroCθ-4alkyl;
Ye is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5e, _NR5eR6e, -C(=NR5e)NR6eR7e, -N(=NR5e)NR.6eR7e -NR5ecOR6e, -NR5ecθ2R6e, -NR5esθ2R8e, - NR5ecONR6eR7e _SR8e, -SORδe, -SO2R8e, -SO2NR5eR6e, -COR5e, -CO2R5e, - CONR5eR6e, -C(=NR5e)R6e, or -C(=NOR5e)R6e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5e, R6e5 and R7e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) substituents;
R8e is -Cχ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents; Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOecθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlOesθ2-Cθ-2alkyl-, or -heteroCθ-4alkyl;
R9e and RlOe each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rile and Rl2e is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl); Xf is N, CH, or NH;
Yf is O, or N-R4f; one of Zl, Z , Z3 or Z2 optionally is N, or NH;
Rlf is -OH, halogen, or-CN; or a -Cι_6alkyl, -Cι_4alkoxyl, - cycloC3_6alkyl, -Cθ-4alkyl-phenyl, -Cθ-4alkyl-pyridyl, -Cθ-4alkyl-imidazolyl, - Cθ-4alkyl-pyrazolyl, -Cθ-4alkyl-triazolyl, -Cθ-4alkyl-tetrazolyl, -Cθ-4alkyl- dioxolanyl, -Cθ-4alkyl-thiazolyl, -Cθ-4alkyl-piperidinyl, -Cθ-4alkyl-pyrrolidinyl, - Cθ-4alkyl-morpholinyl, -Cθ-4alkyl-pyrimidinyl, -C2-6alkynyl-thiazolyl, or -N(Cθ- 4alkyl)(-Cθ-4alkyl) group, wherein any of the groups is optionally substituted with 1- 5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Cι_ 6alkyl, -Ci-4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, - Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is hydrogen, halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), - NO2; or -Ci_6alkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or -Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, -CN, or-Cι_4alkoxyl substituents; R3f is hydrogen or -Cι_4alkoxyl; R4 is -Co-4alkyl; R5 is H, halogen, or-Cι_4alkyl; any alkyl optionally substituted with 1-5 independent halogen substitutents, and any N is optionally an N-oxide; and provided that when X = 2-pyridyl, Rl le = Rl2e = H and Ae = Be = Coalkyl, then Ye is not 3-cyanophenyl; and provided that when Ye = 2-pyridyl, Rl le = Rl2e = H and Ae = βe = Coalkyl, then Xe is not 3-cyanophenyl; and provided that when X is 2-pyridyl, Ale and A3c are each C, A2c and A4c and A5c are each N, Ac and βc are each direct bonds, and RHc is OH, then Yc is not unsubstituted phenyl or 4-methoxyphenyl; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b = H and Ab = βb = Coalkyl, then Yb is not 4-methoxyphenyl or 2,5- dimethoxyphenyl .
2. The method according to Claim 1, wherein the subject is human.
3. The method according to Claim 2, which comprises treating an eating disorder associated with excessive food intake by administration of a therapeutically effective amount of a compound of formula IA, IB, IC, ID, IE or IF.
4. The method according to Claim 3, wherein the eating disorder associated with excessive food intake is selected from obesity, obesity related conditions, bulimia nervosa, and compulsive eating disorders.
5. The method according to Claim 4, wherein the eating disorder associated with excessive food intake is obesity.
6. The method according to Claim 4, wherein the eating disorder associated with excessive food intake is an obesity related condition is selected from: diabetes, non-insulin dependent diabetes mellitus-type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver, cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, infertility, hyperlipidemia, and cardiovascular disease.
7. The method according to Claim 2, comprising administration of a compound of structural formula (ID):
Figure imgf000416_0001
(ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORld, _NRldR2d _ C(=NRld)NR2dR3d -N(=NRl )NR2dR3d -NRldcOR2d -NRldCO2R2d -NRldSO2R4d, -NRldCONR2dR3d _SR4d -SOR4d, -SO2R4d, -SO2NRldR2d, -CORld, -CO2Rld, -CONRldR2d, -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yd is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cl-6alkenyl, -Ci_6alkynyl, -OR5d _NR5dR6d, -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dC0R6d -NR5dcθ2R6d, -NR5dsθ2R8d, -NR5dcONR6dR7d _SR8d, -SOR8d, -SO2R8d, -SO2NR5dR6d, -COR5d, -Cθ2R5d, -CONR5dR6d -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Cl-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, R6d and R7d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(CQ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
Rδd is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cl-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(C0-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl; R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N is optionally N-oxide.
8. The method according to Claim 2, comprising administration of a compound selected from:
( I ) 3 -( 1 -pyridin-2-yl- lH-pyrrol-3-yl)benzonitrile; (2) 2-[3-(3-chlorophenyl)-lH-pyrrol-l-yl]pyridine;
(3) 2-[3-(3-methoxyphenyl)-lH-pyrrol-l-yl]pyridine;
(4) 3-(3-pyridin-2-yl-lH-pyrrol-l-yl)benzonitrile;
(5) 2-{ l-[3-(trifluoromethyl)phenyl]-lH-pyrrol-3-yl}pyridine;
(6) 2-[ 1 -(3 ,5-dichlorophenyl)- lH-pyrrol-3-yl]pyridine; (7) 2-[l-(3-methylphenyl)-lH-pyrrol-3-yl]pyridine;
(8) 2-[l-(3-methoxyphenyl)-lH-pyrrol-3-yl]pyridine;
(9) 3-[3-(l,3-thiazol-2-yl)-lH-pyrrol-l-yl]benzonitrile;
(10) 3-fluoro-5-(3-pyridin-2-yl-lH-pyrrol-l-yl)benzonitrile;
(II) 3-(3-bromo-4-pyridin-2-yl-lH-pyrrol-l-yl)-5-fluorobenzonitrile; (12) 3-fluoro-5-(3-methyl-4-pyridin-2-yl-lH-pyrrol-l-yl)benzonitrile;
(13) 3-(3-chloiO-4-pyridin-2-yl-lH-pyrrol-l-yl)-5-fluorobenzonitrile;
(14) 3-fluoro-5-[3-(lH-pyrazol-l-yl)-lH-pyrrol-l-yl]benzonitrile;
(15) 2-chloro-6-(3-pyridin-2-yl-lH-pyrrol-l-yl)pyridine;
(16) 2-(pyridin-3-yloxy)-6-(3-pyridin-2-yl-lH-ρyrrol-l-yl)pyridine; (17) 2-chloro-4-methyl-6-(3-ρyridin-2-yl-lH-pyrrol-l-yl)pyridine;
(18) 3-chloro-5-(3-pyridin-2-yl- lH-pyrrol- 1 -yl)benzonitrile;
(19) 2-{ l-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-pyrrol-3-yl }pyridine;
(20) 3 -bromo-5-(3 -pyridin-2-yl- lH-pyrrol- 1 -yl)benzonitrile ; (21) 3-methyl-5-(3-pyridin-2-yl-lH-pyrrol-l-yl)benzonitrile;
(22) 3-fluoro-5-[3-(l ,3-thiazol-2-yl)-lH-pyrrol-l-yl]benzonitrile;
(23) 3-(4-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(24) 2- [ 1 -(3 -fluorophenyl)- lH-pyrazol-4-yl] pyridine ;
(25) 2-[l-(l-naphthyl)-lH-pyrazol-4-yl]pyridine; (26) 2-(l-pyridin-3-yl-lH-pyrazol-4-yl)pyridine;
(27) 3-(l-pyridin-2-yl-lH-pyrazol-4-yl)benzonitrile;
(28) 2-[4-(3-chlorophenyl)- lH-pyrazol- 1 -yljpyridine;
(29) 2-[4-(3-methoxyphenyl)-lH-pyrazol-l-yl]pyridine;
(30) 3-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile; (31) 2-[l-(3-chlorophenyl)-lH-pyrazol-3-yl]pyridine;
(32) 3-(l-pyridin-2-yl-lH-pyrazol-3-yl)benzonitrile;
(33) 2-bromo-6-(4-pyridin-2-yl-lH-pyrazol-l-yl)pyridine;
(34) 6-(4-pyridin-2-yl-lΗ-pyrazol-l-yl)pyridine-2-carbonitrile;
(35) 2- [ 1 -(3 -bromophenyl)- lH-pyrazol-4-yl]pyridine; (36) 3-(4-pyrazin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(37) 2-methyl-6-(4-pyridin-2-yl- 1 H-pyrazol- 1 -yl)pyridine ;
(38) 5-(4-pyridin-2-yl- lH-pyrazol- 1 -yl)nicotinonitrile;
(39) 2-methoxy-6-(4-pyridin-2-yl-lH-pyrazol-l-yl)pyridine;
(40) 2-[l-(3-bromo-5-chlorophenyl)-lH-pyrazol-4-yl]pyridine; (41) 2-[l-(3,5-dichlorophenyl)-lH-pyrazol-4-yl]pyridine;
(42) 3-[4-(l,3-thiazol-2-yl)-lH-pyrazol-l-yl]benzonitrile;
(43) 3-[4-(l,3-thiazol-4-yl)-lH-pyrazol-l-yl]benzonitrile;
(44) 2-{ l-[3-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl }- 1,3 -benzoxazole;
(45) 2-[l-(5-bromo-2-methylphenyl)-lH-pyrazol-4-yl]-l,3-benzoxazole; (46) 2-[l-(3,5-dichlorophenyl)-lH-pyrazol-3-yl]pyridine;
(47) 3-fluoro-5-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(48) 3-fluoro-5-(5-methyl-3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(49) 2-[l-(2,5-difluorophenyl)-lH-pyrazol-3-yl]pyridine;
(50) 3-(3,5-dimethyl-4-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile; (51) 3-(4-pyrimidin-2-yl-lH-pyrazol-l-yl)benzonitrile; (52) 2-[l-(3-chloro-4-fluoro-phenyl)-lH-pyrazol-3-yl]-pyridine;
(53) 2-(l-pyridin-2-yl-lH-pyrazol-3-yl)pyridine;
(54) 2-[l-(2,3,5,6-Tetrafluoro-phenyl)-lH-pyrazol-3-yl]-pyridine;
(55) 2-[l-(3,5-difluoro-ρhenyl)-lH-ρyrazol-3-yl]-pyridine; (56) 2-(l-pentafluorophenyl-lH-pyrazol-3-yl)-pyridine;
(57) 2-[l-(4-methoxy-phenyl)-lH-pyrazol-3-yl]-pyridine;
(58) 2-[l-(3-chloro-4-methyl-phenyl)-lH-pyrazol-3-yl]-pyridine;
(59) 2- [ l-(2,3 ,5 ,6-tetrafluoro-4-methyl-phenyl)- lH-pyrazol-3-yl] -pyridine;
(60) 2-[l-(3-nitro-phenyl)-lH-pyrazol-3-yl]-pyridine; (61) 3-fluoro-5-(4-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(62) 2-{ l-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-4-yl }pyridine;
(63) 4-(4-pyridin-2-yl- lH-pyrazol- 1 -yl)pyridine-2-carbonitrile;
(64) 2-[l-(4-nitro-phenyl)-lH-pyrazol-3-yl]-pyridine;
(65) 2-[l-(3,4-dichloro-phenyl)-lH-pyrazol-3-yl]-pyridine; (66) 3-(l-pyridin-2-yl-lH-pyrazol-3-yl)benzonitrile;
(67) 2-[4-(2-chlorophenyl)-lH-pyrazol-l-yl]pyridine;
(68) 2- [4-(3 -methylphenyl)- lH-pyrazol- 1 -yl] pyridine ;
(69) 2-[4-(l-naphthyl)-lH-pyrazol-l-yl]pyridine;
(70) 2-[4-(2-naphthyl)-lH-pyrazol-l-yl]pyridine; (71) 5-(l-pyridin-2-yl-lH-pyrazol-4-yl)quinoline;
(72) N- { 4- [4-(4-methyl-quinolin-2-yl)-pyrazol- 1 -yl] -phenyl } -acetamide;
(73) 2-[l-(3-fluoro-phenyl)-lH-pyrazol-4-yl]-pyridine;
(74) 2-(l-phenyl-lH-pyrazol-4-yl)-benzooxazole;
(75) 2-(l-naphthalen-2-yl-lH-pyrazol-4-yl)-pyridine; (76) 2-[l-(5,6,7,8-tetrahydro-naphthalen-l-yl)-lH-pyrazol-4-yl]-benzooxazole;
(77) 2-[l-(3,4-dimethyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(78) 2- [ 1 -(4-phenoxy-phenyl)- 1 H-pyrazol-4-yl] -pyridine ;
(79) 2- [ 1 -(3 -methoxy-phenyl)- 1 H-pyrazol-4-yl] -pyridine ;
(80) 2- [ 1 -(2-benzyl-phenyl)- lH-pyrazol-4-yl] -pyridine; (81) 2-[l-(3-propyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(82) 2-[l-(4-isopropoxy-phenyl)-lH-pyrazol-4-yl]-pyridine;
(83) 2-[l-(3-chloro-2-methyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
(84) 2-[l-(3-ethyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(85) 2- [ 1 -(3 -tert-butyl-phenyl)- 1 H-pyrazol-4-yl] -benzooxazole; (86) 2-[l-(3-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-ρyridine; (87) 2-[l-(2,4-dimethyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(88) 2-[l-(3-bromo-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(89) 4-methyl-2-[l-(2-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-quinoline;
(90) 4-[l-(3,5-dimethyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine; (91) 2-[l-(2-fluoro-5-trifluoromethyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(92) 2-[l-(3-tert-butyl-phenyl)-lH-pyrazol-4-yl]-ρyridine;
(93) 2-[l-(5-bromo-2-methyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(94) 2-[l-(4-chloro-3-methyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(95) 2-[l-(4-chloro-naphthalen-l-yl)-lH-pyrazol-4-yl]-pyridine; (96) 3-fluoro-5-(3-methyl-l 'H-l ,4'-bipyrazol-l -yl)benzonitrile;
(97) 3-(l'H-l,4'-bipyrazol-l -yl)-5-fluorobenzonitrile;
(98) 2-[l-(2,3,5-trifluorophenyl)-lH-pyrazol-3-yl]pyridine;
(99) 2-{ l-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-3-yl }pyridinium;
(100) 2-{ l-[3-cyano-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-3-yl }pyridinium; (101) 3-(3-pyridin-2-yl-lH-pyrazol-l-yl)-5-(trifluoromethyl)benzonitrile;
(102) 2- [ 1 -(3-chloro-5-fluorophenyl)- lH-pyrazol-3-yl]pyridine;
(103) 2-{ l-[3-chloro-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-3-yl }pyridine;
(104) 3-chloro-5-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(105) 3-chloro-5-[3-chloro-5-(3-pyridin-2-yl-lH-pyrazol-l-yl)phenoxy]pyridine; (106) 3-[(5-chloropyridin-3-yl)oxy]-5-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(107) 5-chloro-2-(3-pyridin-2-yl-lH-pyrazol-l-yl)pyridine;
(108) 2-(3-pyridin-2-yl-lH-pyrazol-l-yl)isonicotinonitrile;
(109) 2-[l-(3,5-dibromophenyl)-lH-pyrazol-3-yl]pyridine;
(110) 3-bromo-5-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile; (111) 2-{4-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-l-yl}pyridine;
(112) 2-[l-(5-chloro-2-fluorophenyl)-lH-pyrazol-3-yl]pyridine;
(113) 2-[l-(3-bromo-5-fluorophenyl)-lH-pyrazol-3-yl]pyridine;
(114) 3-[(3-pyridin-2-yl-lH-pyrazol-l-yl)methyl]benzonitrile;
(115) 2-[l-(pyridin-2-ylmethyl)-lH-pyrazol-3-yl]pyridine; (116) 2-[l-(2,4-difluorophenyl)-lH-pyrazol-3-yl]pyridine;
(117) 3-[4-(6-methylpyridin-2-yl)-lΗ-pyrazol-l-yl]benzonitrile;
(118) 4-[(4-pyridin-2-yl-lH-pyrazol-l-yl)methyl]benzonitrile;
(119) 3-[(4-pyridin-2-yl-lH-pyrazol-l-yl)methyl]benzonitrile;
(120) 6-(4-pyridin-2-yl-lH-pyrazol-l-yl)nicotinonitrile; (121) 2-[(4-pyridin-2-yl-lH-pyrazol-l-yl)methyl]benzonitrile; (122) 2-[l-(3,5-Bis-trifluoromethyl-phenyl)-lH-pyrazol-3-yl]-ρyridine;
(123) 2-[4-(4-fluorophenyl)-lH-pyrazol-l-yl]pyridine;
(124) 4-(l-pyridin-2-yl-lH-pyrazol-4-yl)benzonitrile;
(125) 2-{4-[3-(trifluoromethyl)ρhenyl]-lH-ρyrazol-l-yl }pyridine; (126) 2-{4-[4-(trifluoromethyl)phenyl]-lH-pyrazol-l-yl}pyridine;
( 127) 3-( 1 -pyridin-2-yl- lH-pyrazol-4-yl)quinoline ;
(128) 2-[4-(3-fluorophenyl)-lH-ρyrazol-l-yl]pyridine;
(129) 2-[4-(3,5-dichlorophenyl)-lH-pyrazol-l-yl]pyridine;
(130) 2- [4-(3 ,5 -difluorophenyl)- 1 H-pyrazol- 1 -yljpyridine ; (131) 2-[l-(3,5-dimethyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(132) l-methyl-3-[4-(4-pyrimidin-4-yl-pyrazol-l-yl)-phenyl]-imidazolidin-2-one;
(133) 2-[l-(3-bromo-4-methyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(134) 2- [ 1 -(3-trifluoromethoxy-phenyl)- 1 H-pyrazol-4-yl] -quinoxaline ;
(135) 2- [ 1 -(4-cyclohexyl-phenyl)- lH-pyrazol-4-yl] -quinoline; (136) 2-[ 1 -(2,6-dimethyl-phenyl)- lH-pyrazol-4-yl] -4-methyl -quinoline;
(137) 2-(l-p-tolyl-lH-pyrazol-4-yl)-quinoxaline;
(138) 2-[ 1 -(2-bromo-phenyl)- lH-pyrazol-4-yl] -quinoxaline;
(139) 2- [ 1 -(3-bromo-4-methylphenyl)- lH-pyrazol-4-yl]pyridine;
(140) 2-[l-(2-trifluoromethyl-phenyl)-lΗ-pyrazol-4-yl]-quinoxaline; (141) 4-[l-(4-isopropyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
( 142) 2- [ 1 -(4-cyclohexyl-phenyl)- 1 H-pyrazol-4-yl] -quinoxaline;
(143) 2-[l-(2,6-dimethyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
( 144) 2- [ 1 -(3 ,5 -dimethyl-phenyl)- lH-pyrazol-4-yl] -4-methyl-quinoline ;
(145) 4-[l-(3-tert-butyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine; (146) 2-[l-(3 -trifluoromethoxy-phenyl)- 1 H-pyrazol-4-yl] -benzooxazole ;
(147) 2-(4-pyrimidin-4-yl-pyrazol-l-yl)-quinoline;
(148) 2-(l-indan-5-yl-lH-pyrazol-4-yl)-quinoxaline;
(149) 2-[l-(2-fluoro-4-methyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(150) 2-[l-(3-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-quinoline; (151) 2-(4-pyridin-2-yl-pyrazol-l-yl)-benzooxazole;
(152) dimethyl-carbamic acid 4-(4-quinoxalin-2-yl-pyrazol-l-yl)-phenyl ester;
(153) 2-[l -(2,3-dimethyl-phenyl)- 1 H-pyrazol-4-yl] -quinoxaline ;
(154) 4- [ 1 -(3-bromo-2-methyl-phenyl)- 1 H-pyrazol-4-yl] -pyrimidine ;
(155) 2-[l-(2-isopropyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole; (156) 4- [ 1 -(5 ,6,7,8-tetrahydro-naphthalen- 1 -yl)- lH-pyrazol-4-yl] -pyrimidine; (157) 2-[ 1 -(3-chloro-phenyl)- lH-pyrazol-4-yl] -quinoxaline;
(158) 2-[l-(2-chloro-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(159) 2-[l-(2-isopropyl-phenyl)-lH-pyrazol-4-yl]-quinoline;
(160) 2-[l-(4-chloro-naphthalen-l-yl)-lH-pyrazol-4-yl]-quinoxaline; (161) 2-[l-(2-fluoro-4-methyl-phenyl)-lH-pyrazol-4-yl]-quinoline;
(162) l-methyl-3-{4-[4-(4-methyl-quinolin-2-yl)-pyrazol-l-yl]-phenyl}- imidazolidin-2-one ;
(163) 4- [ 1 -(4-cyclohexyl-phenyl)- lH-pyrazol-4-yl] -pyrimidine ;
( 164) 2- [ 1 -(2-fluoro-5 -trifluoromethyl-phenyl)- lH-pyrazol-4-yl] -4-methyl- quinoline;
(165) 2,2-dimethyl-propionic acid 4-(4-benzooxazol-2-yl-pyrazol-l-yl)-phenyl ester;
(166) 2,2-dimethyl-propionic acid 4-(4-quinoxalin-2-yl-pyrazol-l-yl)-phenyl ester;
(167) 2-[l-(3-nitro-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(168) 4-methyl-2-(l-naphthalen-2-yl-lH-pyrazol-4-yl)-quinoline; (169) 2-[l-(4-bromo-3-methyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(170) 4- [ 1 -(4-phenoxy-phenyl)- 1 H-pyrazol-4-yl] -pyrimidine ;
(171) 2- [ 1 -(2-fluoro-phenyl)- 1 H-pyrazol-4-yl] -quinoxaline;
(172) 2-[l-(4-propyl-phenyl)-lH-pyrazol-4-yl]-benzoxazole;
(173) 2-[l-(4-sec-butyl-phenyl)-lH-pyrazol-4-yl]-pyridine; (174) 2-[l-(2-fluoro-4-methyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(175) 2- [ 1 -(2-fluoro-4-methyl-phenyl)- 1 H-pyrazol-4-yl] -4-methyl-quinoline ;
(176) 2-[l-(3 -tert-butyl-phenyl)- lH-pyrazol-4-yl] -4-methyl-quinoline;
(177) 2-[l-(2-benzyloxy-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(178) 3-(4-quinoxalin-2-yl-pyrazol-l-yl)-benzoic acid ethyl ester; (179) 4-[l-(2-isopropyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(180) 4-[l-(3-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(181) 2-[l-(4-fluoro-3-trifluoiOmethyl-phenyl)-lH-pyrazol-4-yl]-4-methyl- quinoline;
(182) 2,2-dimethyl-propionic acid 4-(4-quinolin-2-yl-pyrazol-l-yl)-phenyl ester; (183) 3-(4-benzooxazol-2-yl-pyrazol-l-yl)-4-methyl-benzoic acid ethyl ester;
( 184) 2-[ 1 -(3 ,5-dimethyl-phenyl)- lH-pyrazol-4-yl] -quinoxaline;
(185) 2- [ 1 -(2-propyl-phenyl)- 1 H-pyrazol-4-yl] -quinoline ;
(186) 2-[l-(4-propyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(187) 4-methyl-2- [ 1 -(2-propyl-phenyl)- lH-pyrazol-4-yl] -quinoline ; (188) 2-[l-(2-sec-butyl-phenyl)-lH-pyrazol-4-ylj-quinoline; (189) 2-[ 1 -(4-sec-butyl-phenyl)- lH-pyrazol-4-yl] -4-methyl-quinoline;
(190) 2-[l-(4-cyclohexyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(191) 2- [ 1 -(2-trifluoromethoxy-phenyl)- lH-pyrazol-4-yl] -benzooxazole ;
(192) 2-[l-(2-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-quinoline; (193) 4-methyl-2-[l-(5,6,7,8-tetrahydro-naphthalen-l-yl)-lH-pyrazol-4-yl]- quinoline;
( 194) 2- [ 1 -(4-chloro-3 -methyl -phenyl)- 1 H-pyrazol-4-yl] -quinoxaline;
(195) 2- [ 1 -(4-sec-butyl-phenyl)- lH-pyrazol-4-yl] -quinoxaline ;
(196) 2-[l-(5,6,7,8-tetrahydro-naphthalen-l-yl)-lH-pyrazol-4-yl]-pyridine; (197) 2-[l-(5,6,7,8-tetrahydro-naphthalen-l-yl)-lH-pyrazol-4-yl]-quinoxaline;
(198) 4- [ 1 -(4-chloro-3 -methyl-phenyl)- 1 H-pyrazol-4-yl] -pyrimidine;
(199) 2- [ 1 -(4-chloro-naphthalen- 1 -yl)- lH-pyrazol-4-yl] -4-methyl-quinoline ;
(200) 2-[l-(3-tert-butyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(201 ) 2- [ 1 -(2-fluoro-5-trifluoromethyl-phenyl)- 1 H-pyrazol-4-yl] -benzooxazole ; (202) 2-[l-(2,5-dichloro-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(203) 2-[l-(3-benzyloxy-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
(204) 4-(l-naphthalen-2-yl-lH-pyrazol-4-yl)-pyrimidine;
(205) 4-[l-(3-bromo-4-methyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(206) 4- [ 1 -(2-propyl-phenyl)- 1 H-pyrazol-4-yl] -pyrimidine ; (207) 2-[l-(3-chloro-2-methyl-phenyl)-lH-ρyrazol-4-yl]-quinoxaline;
(208) 2-[l-(4-chloro-naphthalen-l-yl)-lH-pyrazol-4-yl]-benzooxazole;
(209) 1 - { 4- [4-(4-methyl-quinolin-2-yl)-pyrazol- 1 -yl] -phenyl } -imidazolidin-2-one ;
(210) 2,2-dimethyl-propionic acid 4-(4-pyridin-2-yl-pyrazol-l-yl)-phenyl ester;
(211) 2,2-dimethyl-propionic acid 4-(4-pyrimidin-4-yl-pyrazol-l-yl)-phenyl ester; (212) 2-[l-(2,6-dimethyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(213) 2-[l-(3,4-dimethyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(214) 4-[l-(5-bromo-2-methyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(215) 2-[l-(2-sec-butyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(216) 4- [ l-(2-fluoro-5-trifluoromethyl-phenyl)- lH-pyrazol-4-yl] -pyrimidine; (217) 2-(4-benzooxazol-2-yl-pyrazol-l-yl)benzooxazole;
(218) 2-( 1 -benzooxazol-2-yl- lH-pyrazol-4-yl)-4-methyl-quinoline;
(219) 2-[l-(3 -benzyloxy-phenyl)- 1 H-pyrazol-4-yl] -quinoxaline ;
(220) 2-(l-quinolin-6-yl-lH-pyrazol-4-yl)-quinoxaline;
(221 ) 2- [ 1 -(5-isopropyl-2-methyl-phenyl)- lH-pyrazol-4-yl] -quinoxaline; (222) 2-[l-(2,5-dimethyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline; (223) 2-[l-(3-bromo-4-methyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
(224) 2-[l-(2-propyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(225) 2-[l-(3-tert-butyl-phenyl)-lH-pyrazol-4-yl]-quinoline;
(226) 2-[l-(5,6,7,8-tetrahydro-naphthalen-l-yl)-lH-pyrazol-4-yl]-quinoline; (227) dimethyl-carbamic acid 4-(4-pyridin-2-yl-pyrazol-l-yl)-phenyl ester;
(228) 2-[l-(5-bromo-2-methyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(229) 2-[l-(2H-indazol-5-yl)-lH-pyrazol-4-yl]-quinoxaline;
(230) 2-(l-naphthalen-2-yl-lH-pyrazol-4-yl)-benzooxazole;
(231) 4-[l-(4-bromo-3-methyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine; (232) 2-[l-(3-ethyl-phenyl)-lH-ρyrazol-4-yl]-4-methyl-quinoline;
(233) 2- [ 1 -(4-cyclohexyl-phenyl)- lH-pyrazol-4-yl] -4-methyl-quinoline ;
(234) 2-[l-(2-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(235) 4-methyl-2-[l-(4-phenoxy-phenyl)-lH-pyrazol-4-yl]-quinoline;
(236) 2-(4-pyrimidin-4-yl-pyrazol-l-yl)-benzooxazole; (237) 2- [l-(2-benzyl-phenyl)-lH-pyrazol-4-yl] -quinoxaline;
(238) 2-(l-o-tolyl-lH-pyrazol-4-yl)-quinoxaline;
(239) 3-(4-pyrimidin-4-yl-pyrazol-l-yl)-benzoic acid ethyl ester;
(240) 2-{ l-[2-(3H-imidazol-4-yl)-ethyl]-lH-pyrazol-4-yl }-pyridine;
(241) dimethyl-carbamic acid 4-(4-quinolin-2-yl-pyrazol-l-yl)-phenyl ester; (242) 2-[l-(4-methoxy-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(243) 2- [ 1 -(2-nitro-phenyl)- 1 H-pyrazol-4-yl] -quinoxaline ;
(244) 4-methyl-3-(4-quinolin-2-yl-pyrazol-l-yl)-benzoic acid ethyl ester;
(245) 2-[l-(3-chloro-2-methyl-phenyl)-lH-pyrazol-4-yl]-quinoline;
(246) 4-[l-(2-fluoro-4-methyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine; (247) 2-[ 1 -(3 ,5-bis-trifluoromethyl-phenyl)- lH-pyrazol-4-yl] -quinoxaline;
(248) 2-( 1 -phenyl- 1 H-pyrazol-4-yl)-quinoxaline ;
(249) 2-[l-(3-benzyloxy-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(250) 2-[ 1 -(2-propyl-phenyl)- lH-pyrazol-4-yl] -quinoxaline;
(251) 4-[l-(2-sec-butyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine; (252) 4-[l-(4-sec-butyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(253) 2- [ 1 -(4-sec-butyl-phenyl)- lH-pyrazol-4-yl] -quinoline ;
(254) 2-[l-(2-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-pyridine;
(255) 2-[l-(4-phenoxy-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(256) 2-[l-(3-methoxy-phenyl)-lH-pyrazol-4-yl]-quinoxaline; (257) 4-[l-(2-trifluoromethyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine; (258) 3-(4-benzooxazol-2-yl-pyrazol-l-yl)-benzoic acid ethyl ester;
259) 2-[l-(4-sec-butyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
260) 4-[l-(4-chloro-naphthalen-l-yl)-lH-pyrazol-4-yl]-pyrimidine;
261) 2,2-dimethyl-propionic acid 4-[4-(4-methyl-quinolin-2-yl)-pyrazol-l-yl]- phenyl ester;
262) 2-[l-(2,6-dimethyl-phenyl)-lH-ρyrazol-4-yl]-pyridine;
263) 2-[l-(2,4-dimethyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
264) 2- [ 1 -( lH-indazol-6-yl)- lH-pyrazol-4-yl] -quinoxaline ;
265) 2-[l-(2-isopropyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
266) 2-[l-(2-methoxy-5-methyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
267) N-[4-(4-quinoxalin-2-yl-pyrazol-l-yl)-phenyl]-acetamide;
268) 2-[l-(3-bromo-2-methyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
269) 2-[l-(4-propyl-phenyl)-lH-pyrazol-4-yl]-quinoline;
270) 4- [ 1 -(2,6-dimethyl-phenyl)- lH-pyrazol-4-yl] -pyrimidine ;
271) 2-[l-(2,6-dimethyl-phenyl)-lH-pyrazol-4-yl]-quinoline;
272) N- [3 -(4-quinoxalin-2-yl-pyrazol- 1 -yl)-phenyl] -acetamide;
273) 4-methyl-3-(4-quinoxalin-2-yl-pyrazol-l-yl)-benzoic acid ethyl ester;
274) 6-(4-pyridin-2-yl-pyrazol-l-yl)-quinoline;
275) 2-[ 1 -(3 ,5-dimethyl-phenyl)- lH-pyrazol-4-yl] -quinoline;
276) 2-[l-(2-fluoro-4-methyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
277) 2- [1 -(3-bromo-2-methyl-phenyl)- lH-pyrazol-4-yl] -pyridine;
278) 4-[l-(2-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
279) dimethyl-carbamic acid 4-(4-benzooxazol-2-yl-pyrazol-l-yl)-phenyl ester;
280) 2-[l-(3-phenoxy-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
281) 2- [ 1 -(4-phenoxy-phenyl)- 1 H-pyrazol-4-yl] -benzooxazole ;
282) 4-methyl-2-[l-(3-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-quinoline;
283) 2-[l-(4-chloro-3-methyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
284) 2-[l-(4-benzyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
285) l-methyl-3-[4-(4-quinolin-2-yl-pyrazol-l-yl)-phenyl]-imidazolidin-2-one;
286) 1 -methyl-3 - [4-(4-quinoxalin-2-yl-pyrazol- 1 -yl)-phenyl] -imidazolidin-2-one ;
287) 2-[l-(4-tert-butyl-benzyl)-lH-pyrazol-4-yl]-benzooxazole;
288) 2-[l-(3-trifluoromethyl-benzyl)-lH-pyrazol-4-yl]-benzooxazole;
289) 2- [ 1 -(2,4-dichloro-benzyl)- 1 H-pyrazol-4-yl] -benzooxazole ;
290) 2-[l-(4-methanesulfonyl-benzyl)-lH-pyrazol-4-yl]-benzooxazole;
291) 2-[l-(2,4-dichloro-phenyl)-lH-pyrazol-4-yl]-benzooxazole; (292) dimethyl-carbamic acid 4-[4-(4-methyl-quinolin-2-yl)-pyrazol-l-yl]-phenyl ester;
(293) 2-(l-pyridin-2-yl-lH-pyrazol-4-yl)-benzooxazole;
(294) 2- [ l-(4-bromo-3-chlorophenyl)- lH-pyrazol-3-yl]pyridine; (295) 4-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzoic acid;
(296) 2-{ l-[3-(pyridin-4-yloxy)phenyl]-lH-pyrazol-3-yl }pyridine;
(297) 2-[l-(3-chloro-2-fluorophenyl)-lH-pyrazol-3-yl]pyridine;
(298) 2-(3-pyridin-2-yl-lH-pyrazol-l-yl)-5-(trifluoromethyl)pyridine;
(299) 2-(l -phenyl- lH-pyrazol-3-yl)pyridine; (300) 3-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzoic acid;
(301) 2-{ l-[3-fluoro-5-(pyridin-4-ylthio)phenyl]-lH-pyrazol-3-yl }pyridine;
(302) 2-{ l-[(4-methylphenyl)sulfonyl]-lH-pyrazol-3-yl}pyridine;
(303) 2-[l-(3-chlorophenyl)-lH-l,2,4-triazol-3-yl]pyridine;
(304) 3-(3-ρyridin-2-yl-lH-l,2,4-triazol-l-yl)benzonitιile; (305) 3-(l-pyridin-2-yl-lH-l,2,4-triazol-3-yl)benzonitrile;
(306) 2-[3-(3-chlorophenyl)-lH-l,2,4-triazol-l-yl]pyridine;
(307) 3-(2-pyridin-2-yl-2H-l ,2,3-triazol-4-yl)benzonitrile;
(308) 3-(l-pyridin-2-yl-lH-l,2,3-triazol-4-yl)benzonitrile;
(309) 3-(4-pyridin-2-yl-2H-l ,2,3-triazol-2-yl)benzonitrile; (310) 3-(4-pyridin-2-yl-lH-l,2,3-triazol-l-yl)benzonitrile;
(311) 2-[2-(3-chlorophenyl)-2H-l ,2,3-triazol-4-yl]pyridine;
(312) 2-[l-(3-chlorophenyl)-lH-l,2,3-triazol-4-yl]pyridine;
(313) 2-[2-(3,5-difluorophenyl)-2H-l ,2,3-triazol-4-yl]pyridine;
(314) 2-[l-(3,5-difluorophenyl)-lH-l,2,3-triazol-4-yl]pyridine; (315) 2-{2-[3-fluoro-5-(pyridin-2-yloxy)phenyl]-2H-l,2,3-triazol-4-yl}pyridine;
(316) 2-{ l-[3-fluoro-5-(pyridin-2-yloxy)phenyl]-lH-l,2,3-triazol-4-yl}pyridine;
(317) 2-{4-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-2H-l,2,3-triazol-2-yl}pyridine;
(318) 2-{4-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-l,2,3-triazol-l-yl}pyridine;
(319) 2-[4-(3-cyanophenyl)-2H-l,2,3-triazol-2-yl] nicotinotrile; (320) 3-[2-(5-nitropyridin-2-yl)-2H-l ,2,3-triazol-4-yl]benzonitrile;
(321) 3-[l-(5-nitropyridin-2-yl)-lH-l,2,3-triazol-4-yl]benzonitrile;
(322) 3-[l-(3-nitropyridin-2-yl)-lH-l,2,3-triazol-4-yl]benzonitrile;
(323) 3-[2-(3-nitropyridin-2-yl)-2H-l,2,3-triazol-4-yl]benzonitrile;
(324) 3-[l-(5-aminopyridin-2-yl)-lH-l,2,3-triazol-4-yl]benzonitrile hydrochloride; (325) N-[3-(l-pyridin-2-yl-lH-l,2,3-triazol-4-yl)phenyl]pyridin-3-amine; (326) N-[3-(2-pyridin-2-yl-2H-l,2,3-triazol-4-yl)phenyl]pyridin-3-amine;
(327) 3-(2-pyridin-2-yl-lH-l ,2,3-triazol-4-yl)phenol;
(328) 3-(2-pyridin-2-yl-2H-l ,2,3-triazol-4-yl)phenol;
(329) 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine; (330) 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile;
(331) 2-(2-pyridin-3-yl-2H-tetrazol-5-yl)ρyridine;
(332) 2-(3-chlorophenyl)-5-(2-methyl- 1 ,3-thiazol-4-yl)-2H-tetrazole;
(333) 3-[5-(2-methyl-l,3-thiazol-4-yl)-2H-tetrazol-2-yl]benzonitrile;
(334) 2-[5-(3-bromophenyl)-2H-tetrazol-2-yl]pyridine; (335) 2-[5-(3-chloroρhenyl)-2H-tetrazol-2-yl]ρyridine;
(336) 3-(2-pyridin-2-yl-2H-tetrazol-5-yl)benzonitrile;
(337) 2-[2-(3,5-difluorophenyl)-2H-tetrazol-5-yl]pyridine;
(338) 2-[2-(3-methoxyphenyl)-2H-tetrazol-5-yl]pyridine;
(339) 2-[2-(3-trifluoromethylphenyl)-2H-tetrazol-5-yl]pyridine; (340) 2-[2-(3-iodophenyl)-2H-tetrazol-5-yl]pyridine;
(341) 2-[2-(3-bromophenyl)-2H-tetrazol-5-yl]pyridine;
(342) 2-[2-(3-Methylmercaptophenyl)-2H-tetrazol-5-yl]pyridine;
(343) 2-[2-(4-fluorophenyl)-2H-tetrazol-5-yl]pyridine;
(344) 2-[2-(3-fluorophenyl)-2H-tetrazol-5-yl]ρyridine; (345) 2-[2-(2-methoxyphenyl)-2H-tetrazol-5-yl]pyridine;
(346) 2-[2-(3-ethylphenyl)-2H-tetrazol-5-yl]pyridine;
(347) 2-[2-(3-methylphenyl)-2H-tetrazol-5-yl]pyridine;
(348) 2-[2-(2-chloro-3-pyridyl)-2H-tetrazol-5-yl]pyridine;
(349) 2-[2-(3,5-dichlorophenyl)-2H-tetrazol-5-yl]pyridine; (350) 2-[2-(2-chlorophenyl)-2H-tetrazol-5-yl]pyridine;
(351) 2-[2-(4-methoxyphenyl)-2H-tetrazol-5-yl]pyridine;
(352) 2-[2-(4-pyridyl)-2H-tetrazol-5-yl]pyridine;
(353) 2-[2-(3,5-dimethylρhenyl)-2H-tetrazol-5-yl]pyridine;
(354) 3-[5-(6-methylpyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile; (355) 3-[5-(4-methylpyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile;
(356) 3-[5-(4-methylpyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile;
(357) 2-[2-(3-isopropylphenyl)-2H-tetrazol-5-yl]pyridine;
(358) 2-{2-[3-(trifluoromethoxy)phenyl]-2H-tetrazol-5-yl}pyridine;
(359) 2-[2-(3-ethoxyphenyl)-2H-tetrazol-5-yl]pyridine; (360) 2-{2-[3-methoxy-5-(trifluoromethyl)phenyl]-2H-tetrazol-5-yl }pyridine; (361) 3-[5-(l,3-thiazol-2-yl)-2H-tetrazol-2-yl]benzonitrile;
(362) 3-[5-(5-methylpyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile;
(363) 3-[5-(3-methylρyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile;
(364) 3-[5-(l-methyl-lH-imidazol-2-yl)-2H-tetrazol-2-yl]benzonitrile; (365) 2-[2-(3,4-dimethylphenyl)-2H-tetrazol-5-yl]pyridine;
(366) 2-[2-(3,4,5-trichlorophenyl)-2H-tetrazol-5-yl]pyridine;
(367) 3-[5-(l ,3-thiazol-4-yl)-2H-tetrazol-2-yl]benzonitrile;
(368) 2-[2-(2,5-dichlorophenyl)-2H-tetrazol-5-yl]pyridine;
(369) 2-[2-(3,4-difluorophenyl)-2H-tetrazol-5-yl]pyridine; (370) 2-[2-(3-chloro-4-methylphenyl)-2H-tetrazol-5-yl]pyridine;
(371) 2- [2-(2,3-dichlorophenyl)-2H-tetrazol-5-yl]pyridine;
(372) 2-{ 2-[3-methyl-5-(trifluoromethyl)phenyl]-2H-tetrazol-5-yl Ipyridine;
(373) 2-[2-(3-bromo-4-methylphenyl)-2H-tetrazol-5-yl]pyridine;
(374) 2-[2-(3-chloro-4-iodophenyl)-2H-tetrazol-5-yl]pyridine; (375) 2-{2-[3-fluoro-5-(trifluoromethyl)phenyl]-2H-tetrazol-5-yl}pyridine;
(376) 3-(5-pyrazin-2-yl-2H-tetrazol-2-yl)benzonitrile;
(377) 2-[2-(2,3-dihydro-lH-inden-5-yl)-2H-tetrazol-5-yl]pyridine;
(378) 2-[2-(l,3-dihydro-2-benzofuran-5-yl)-2H-tetrazol-5-yl]pyridine;
(379) 2-[2-(4-methoxy-2-naphthyl)-2H-tetrazol-5-yl]pyridine; (380) 2-[2-(l-naphthyl)-2H-tetrazol-5-yl]pyridine;
(381) 2-[2-(3,5-dimethoxyphenyl)-2H-tetrazol-5-yl]pyridine;
(382) 2-[2-(4-phenoxyphenyl)-2H-tetrazol-5-yl]pyridine;
(383) 3-[5-(3-fluoro-pyridin-2-yl)-tetrazol-2-yl]-benzonitrile;
(384) 3-(5-isoxazol-3-yl-tetrazol-2-yl)-benzonitrile; (385) 3-[5-(l-methyl-lΗ-pyrazol-3-yl)-tetrazol-2-yl]-benzonitrile;
(386) 3-(5-oxazol-4-yl-tetrazol-2-yl)-benzonitrile;
(387) 3-[5-(2H-pyrazol-3-yl)-tetrazol-2-yl]-benzonitrile;
(388) 3-[5-(lH-imidazol-2-yl)-tetrazol-2-yl]-benzonitrile;
(389) 3-[5-(5 -hydroxy-pyridin-2-yl)-tetrazol-2-yl] -benzonitrile ; (390) 3-[5-(5-bromo-pyridin-2-yl)-tetrazol-2-yl]-5-fluoro-benzonitrile;
(391) 3-fluoro-5-[5-(3-fluoro-pyridin-2-yl)-tetrazol-2-yl]-benzonitrile;
(392) 3-fluoro-5-(5-oxazol-2-yl-tetrazol-2-yl)-benzonitrile;
(393) 3 - { 3-fluoro-5 - [5 -( 1 H-imidazol-2-yl)-tetrazol-2-yl] -phenoxy } -pyridine ;
(394) 3-fluoro-5-[5-(4-methyl-lH-imidazol-2-yl)-tetrazol-2-yl]-benzonitrile; (395) 3-{3-fluoro-5-[5-(lH-[l,2,3]triazol-4-yl)-tetrazol-2-yl]-phenoxy}-pyridine; (396) 2-{2-[3-fluoro-5-(ρyridin-3-yloxy)-phenyl]-2H-tetrazol-5-yl}-pyrimidine;
(397) 3-{3-fluoro-5-[5-(lH-ρyrazol-3-yl)-tetrazol-2-yl]-phenoxy}-pyridine;
(398) 3-{3-fluoro-5-[5-(l-methyl-lH-pyrazol-3-yl)-tetrazol-2-yl]-phenoxy}pyridine;
(399) 3-fluoro-5-[5-(l-methyl-lH-pyrazol-3-yl)-tetrazol-2-yl]-benzonitrile; (400) N-[4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-3-amine;
(401) 2-{ 2-[4-(pyridin-3-ylmethyl)phenyl]-2H-tetraazol-5-yl }pyridine;
(402) N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-3-amine;
(403) N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-2-amine;
(404) 2-{2-[3-(pyridin-2-yloxy)phenyl]-2H-tetraazol-5-yl}pyridine; (405) 2-[2-(3-ethynylphenyl)-2H-tetraazol-5-yl]pyridine;
(406) 2-{ 2-[4-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5-yl }pyridine;
(407) 2-{2-[3-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5-yl}ρyridine;
(408) 2-[2-(3-nitrophenyl)-2H-tetraazol-5-yl]pyridine;
(409) 2-methyl-3-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenoxy]pyridine; (410) 2-methyl-N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-3-amine;
(411) N-methyl-N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-3-amine;
(412) N-[3-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]-N-methylpyridin-3- amine;
(413) 2-{2-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5-yl}pyridine; (414) N-[3-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-3-amine;
(415) N- { 3 - [5 -(5-bromopyridin-2-yl)-2H-tetraazol-2-yl] -5 -fluorophenyl } pyridin-3 - amine;
(416) 2- { 2- [3-fluoro-5-(pyridin-3-ylmethyl)phenyl]-2H-tetraazol-5-yl } pyridine;
(417) 5-[3-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzyl]-2-methylpyridine; (418) 3-{ 3-fluoro-5-[5-(l ,3-thiazol-2-yl)-2H-tetraazol-2-yl]phenoxy }pyridine;
(419) 2-{2-[3-fluoro-5-(pyridin-3-ylthio)phenyl]-2H-tetraazol-5-yl}ρyridine;
(420) 2-(2-{ 3-fluoro-5-[(pyridin-3-yloxy)methyl]phenyl }-2H-tetraazol-5- yl)pyridine;
(421) 3-fluoro-2-{2-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5- yl}pyridine;
(422) 2-{2-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5-yl}-6- methylpyridine;
(423) 2-{2-[3-methoxy-4-(3H-l,2λ5,3,4-tetraazol-2-ylmethyl)phenyl]-2H-tetraazol- 5-yl Ipyridine; (424) 3-bromo-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine; (425) 2-{ 2-[4-(allyloxy)-3-methoxyρhenyl]-2H-tetraazol-5-yl }pyridine;
(426) 2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenol;
(427) 2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl ethylcarbamate;
(428) 2-[2-(4-bromo-3-methoxyphenyl)-2H-tetraazol-5-yl]pyridine; (429) 2-{2-[3-methoxy-4-(pyridin-2-yloxy)phenyl]-2H-tetraazol-5-yl}pyridine;
(430) 5-(5-pyridin-2-yl-2H-tetraazol-2-yl)nicotinonitrile;
(431) [3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenoxy]acetonitrile;
(432) N-pyridin-3-yl-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-3-amine;
(433) 3-(pyridin-3-yloxy)-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine; (434) 3-bromo-5-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]pyridine;
(435) 3-bromo-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine;
(436) 2-(pyridin-3-yloxy)-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine;
(437) 2-[(5-chloropyridin-3-yl)oxy]-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine;
(438) 2-methyl-5-{[5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-yl]oxy}pyridine; (439) 2-methyl-3-{ [5-(5-ρyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-yl]oxy}pyridine;
(440) 2-[(4-methylpyridin-3-yl)oxy]-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine;
(441) 2-(pyridin-4-yloxy)-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine;
(442) 2-bromo-5 -(5 -pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile ;
(443) 3-(5-pyridin-2-yl-2H-tetraazol-2-yl)aniline; (444) 3-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(445) 2-{2-[3-bromo-5-(trifluoromethyl)phenyl]-2H-tetraazol-5-yl}pyridine;
(446) 3-(5-pyridin-2-yl-2H-tetraazol-2-yl)-5-(trifluoromethyl)benzonitrile;
(447) 3-nitro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(448) 3-amino-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile; (449) 3-chloro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(450) 2-[2-(3-cyano-5-fluorophenyl)-2H-tetraazol-5-yl]-l-hydroxypyridinium;
(451) 5-(5-pyridin-2-yl-2Η-tetrazol-2-yl)isophthalonitrile;
(452) 2-{ 5-[3-chloro-5-(pyridin-3-yloxy)phenyl]-2H-tetraazol-2-yl Ipyridine;
(453) 2-[5-(3-bromo-5-chlorophenyl)-2H-tetraazol-2-yl]pyridine; (454) 3-chloro-5-(2-pyridin-2-yl-2H-tetraazol-5-yl)benzonitrile;
(455) 3-methyl-5-(2-pyridin-2-yl-2H-tetraazol-5-yl)benzonitrile;
(456) [3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]methanol;
(457) [3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]acetonitrile;
(458) N-methyl-3-(5-pyridin-2-yl-2H-tetraazol-2-yl)aniline; (459) 2-{2-[3-(lH-imidazol-l-ylmethyl)phenyl]-2H-tetraazol-5-yl|pyridine; (460) 2-methoxy-N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]aniline;
(461) 2-[2-(3-fluoro-5-iodophenyl)-2H-tetraazol-5-yl]pyridine;
(462) 3-fluoro-5-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(463) 3-[5-(4,5-dibromo-lH-imidazol-2-yl)-2H-tetraazol-2-yl]-5-fluorobenzonitrile; (464) 2-{2-[3-fluoro-5-(pyridin-3-ylmethoxy)phenyl]-2H-tetraazol-5-yl Ipyridine;
(465) 2-{ [3-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenoxy]methyl } benzonitrile;
(466) N-{3-fluoro-5-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]phenyl|-N- methylpyridin-3 -amine ; (467) 3-chloro-5-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(468) 3-{3-fluoro-5-[5-(l-methyl-lH-imidazol-2-yl)-2H-tetraazol-2- yl]phenoxy } pyridine ;
(469) 4-chloro-2-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(470) 2-[2-(2,4-dichlorophenyl)-2H-tetraazol-5-yl]pyridine; (471) 2-[2-(5-chloro-2-methoxyphenyl)-2H-tetraazol-5-yl]pyridine;
(472) 3-[5-(2-methyl-2Η-pyrazol-3-yl)-tetrazol-2-yl]-benzonitrile;
(473) 3-[5-(lH-imidazol-4-yl)-tetrazol-2-yl]-benzonitrile;
(474) 3-[5-(5-methoxy-pyridin-2-yl)-tetrazol-2-yl]-benzonitrile;
(475) 3 - [5 -( 1 H-benzoimidazol-2-yl)-tetrazol-2-yl] -benzonitrile; (476) 4-bromo-3-fluoro-5- [5 -(3 -fluoro-pyridin-2-yl)-tetrazol-2-yl] -benzonitrile ;
(477) 3-{3-[5-(4,5-dibromo-lH-imidazol-2-yl)-tetrazol-2-yl]-5-fluoro-phenoxy|- pyridine;
(478) 7-{2-[3-fluoro-5-(pyridin-3-yloxy)-phenyl]-2H-tetrazol-5-yl}-pyrazolo[l,5- a]pyridine; (479) 2-[2-(5-methylisoxazol-3-yl)-2H-tetraazol-5-yl]ρyridine;
(480) N-phenyl-N-[4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]amine;
(481) N-[4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-2-amine;
(482) N-phenyl-N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]amine;
(483) 2-{2-[4-(pyridin-2-yloxy)phenyl]-2H-tetraazol-5-yl|pyridine; (484) 2-{2-[3-(3-methoxyphenoxy)phenyl]-2H-tetraazol-5-yl|pyridine;
(485) 2-bromo-6-{2-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5- yl Ipyridine;
(486) 2-{2-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5-yl}-6- methoxypyridine; (487) 2-{2-[3-methoxy-4-(3H-lλ5,2,3,4-tetraazol-l-ylmethyl)phenyl]-2H-tetraazol- 5-yl Ipyridine;
(488) 2-(2-pyridin-3-yl-2H-tetraazol-5-yl)pyridine;
(489) 2-chloro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine; (490) 3-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]pyridine;
(491) 2-(2-pyridin-2-yl-2H-tetraazol-5-yl)pyridine;
(492) N,N-dimethyl-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-amine;
(493) N-pyridin-2-yl-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-amine;
(494) N-pyridin-3-yl-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-amine; (495) 3-chloro-N-[5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-yl]-5-
(trifluoromethyl)pyridin-2-amine ;
(496) 3-(5-quinolin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(497) 3-(5-isoquinolin-3-yl-2H-tetraazol-2-yl)benzonitrile;
(498) 2-[2-(4-bromo-3-fluorophenyl)-2H-tetraazol-5-yl]pyridine; (499) 2-{ 2-[3,5-bis(trifluoromethyl)phenyl]-2H-tetraazol-5-yl Ipyridine;
(500) 2-{2-[4-bromo-3-(trifluoromethyl)phenyl]-2H-tetraazol-5-yl}pyridine;
(501) imethyl 5-(5-pyridin-2-yl-2Η-tetrazol-2-yl)isophthalate;
(502) 2- [3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenoxy] ethylamine;
(503) 2-{2-[3-fluoro-5-(pyridin-2-ylmethoxy)phenyl]-2H-tetraazol-5-yl|pyridine; (504) 2-[2-(2,6-dichlorophenyl)-2H-tetraazol-5-yl]pyridine;
(505) [3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl] acetic acid;
(506) 2-[2-(3-iodo-4-methylphenyl)-2H-tetraazol-5-yl]pyridine;
(507) 2-[2-(4-chloro-3-methylphenyl)-2H-tetraazol-5-yl]pyridine;
(508) 2-[2-(l ,3-benzodioxol-5-yl)-2H-tetraazol-5-yl]pyridine; (509) 2-{ 2-[2-chloro-5-(trifluoromethyl)phenyl]-2H-tetraazol-5-yl Ipyridine;
(510) 2-chloro-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(511) 2-[2-(4-bromo-3-methylphenyl)-2H-tetraazol-5-yl]pyridine;
(512) 2-[2-(3,4-dichlorophenyl)-2H-tetraazol-5-yl]pyridine;
(513) 2-[2-(3-chloro-4-fluorophenyl)-2H-tetraazol-5-yl]pyridine; (514) 2-[2-(3-fluoro-4-methylphenyl)-2H-tetraazol-5-yl]pyridine;
(515) l-[3-(5-ρyridin-2-yl-2H-tetraazol-2-yl)phenyl]ethanol;
(516) l-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]ethanone;
(517) [3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]methanol;
(518) 2-[2-(3-phenoxyphenyl)-2H-tetraazol-5-yl]pyridine; (519) 2- { 2- [3-(benzyloxy)phenyl] -2H-tetraazol-5-yl } pyridine ;
(520) 2- { 2-[3-(methylsulfonyl)phenyl]-2H-tetraazol-5-yl Ipyridine;
(521) N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]acetamide;
(522) 2-[2-(3-isopropylphenyl)-2H-tetrazol-5-yl]pyridine; (523) 2-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(524) 2-(2-phenyl-2H-tetraazol-5-yl)pyridine;
(525) [2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]acetonitrile;
(526) 2-[2-(3-methoxy-4-methylphenyl)-2H-tetraazol-5-yl]pyridine;
(527) 2-[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl]-2-methylpropanenitrile; (528) 2-{cyano[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]methyl| nicotinonitrile;
(529) 2- [2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl] succinonitrile;
(530) 2- [2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]propane- 1 ,2,3- tricarbonitrile; (531) 2-[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]propanenitrile;
(532) 2-{cyano[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)methyl|benzonitrile;
(533) (6-fluoropyridin-2-yl)[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2- yl)phenyl] acetonitrile;
(534) [2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl](pyridin-2- yl)acetonitrile;
(535) 2-(2-pyridin-3-yl-2H-tetraazol-5-yl)pyridine;
(536) 2-{ 2-[4-(methylthio)phenyl]-2H-tetraazol-5-yl Ipyridine;
(537) 2{ 2-[4-(trifluoromethoxy)phenyl]-2H-tetraazol-5-yl Ipyridine;
(538) 4-((5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile; (539) 2-[2-(4-chlorophenyl)-2H-tetraazol-5-yl]pyridine;
(540) 2-[2-(2-naρhthyl)-2H-tetraazol-5-yl]pyridine;
(541) 2-[2-(3,5-ditert-butylphenyl)-2H-tetraazol-5-yl]ρyridine;
(542) 2-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(543) 2- { 2-[4-(bromomethyl)-3-methoxyphenyl]-2H-tetraazol-5-yl Ipyridine; (544) 2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzoic acid;
(545) 2-[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]ethanamine;
(546) l-nitroso-6-(5-pyridin-2-yl-2H-tetraazol-2-yl)indoline;
(547) 2-[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]propan-2-ol;
(548) 2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzamide; (549) 2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile; (550) 3-bromo-6-(5-ρyridin-2-yl-2H-tetraazol-2-yl)-lH-indole;
(551) 6-(5-pyridin-2-yl-2H-tetraazol-2-yl)-lH-indole;
(552) 6-(5-pyridin-2-yl-2H-tetraazol-2-yl)-lH-indole-l-carbonitrile;
(553) 6-(5-pyridin-2-yl-2H-tetraazol-2-yl)-lH-indole-3-carbonitrile;
(554) 3-methoxy-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(555) 3-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]-5-methylbenzonitrile;
(556) 3-{3-fluoro-5-[5-(4-methyl-lH-imidazol-2-yl)-2H-tetraazol-2- yl]phenoxy|pyridine;
(557) 3-chloro-5-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(558) 3-methyl-5-[5-(5-methyl-lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(559) 3-chloro-5-[5-(5-methyl-lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(560) 3-fluoro-5-[5-(l,3-thiazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(561) 3-fluoro-5-[5-(l,3-thiazol-4-yl)-2H-tetraazol-2-yl]benzonitrile;
(562) 3-{3-fluoro-5-[5-(l,3-thiazol-4-yl)-2H-tetraazol-2-yl]phenoxy}pyridine;
(563) 3-fluoro-5-{ 5-[4-(trifluoromethyl)-lH-imidazol-2-yl]-2H-tetraazol-2-yl } benzonitrile;
(564) 3-[5-(4-methyl-lH-imidazol-2-yl)-2H-tetraazol-2-yl]-5-(pyridin-3-yloxy) benzonitrile;
(565) 3-methoxy-5-[5-(4-methyl-lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(566) 2-[4-(3-chlorophenyl)-lH-imidazol-l-yl]pyridine;
(567) 2-(4-pyridin-3-yl-lH-imidazol-l-yl)pyridine;
(568) 2-[l-(3-chlorophenyl)-lH-imidazol-4-yl]pyridine;
(569) 2-{ l-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-imidazol-4-yl Ipyridine; or a pharmaceutically acceptable salt thereof.
9. The method according to Claim 2, comprising administration of a compound selected from:
Figure imgf000435_0001
or a pharmaceutically acceptable salt thereof.
10. The method according to Claim 2, which comprises preventing an eating disorder associated with excessive food intake by administration of a prophylactically effective amount of a compound of formula IA, IB, IC, ID, IE or IF.
11. The method according to Claim 10, wherein the eating disorder associated with excessive food intake is selected from obesity, obesity related conditions, bulimia nervosa, and compulsive eating disorders.
12. The method according to Claim 11, wherein the eating disorder associated with excessive food intake is obesity.
13. The method according to Claim 12, wherein the human in need of such prophylaxis is a person at risk for obesity and the prophylactically effective amount of the the compound is about about 0.01 mg to about 1000 mg.
14. The method according to Claim 11, wherein the eating disorder associated with excessive food intake is an obesity related condition is selected from: diabetes, non-insulin dependent diabetes mellitus-type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver, cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, infertility, hyperlipidemia, and cardiovascular disease.
15. A composition comprising:
(A) a pharmaceutically acceptable carrier,
(B) an antiobesity agent selected from: an anorectic agent, a growth hormone secretagogue, a growth hormone secretagogue receptor agonist/antagonist, a melanocortin agonist, a melanocortin 4 receptor agonist, a β-3 agonist, a 5HT-2 agonist, an orexin antagonist , a melanin concentrating hormone antagonist, a melanin-concentrating hormone 1 receptor antagonist, a melanin-concentrating hormone 2 receptor agonist/antagonist, a galanin antagonist; a CCK agonist; a CCK-A agonist, a GLP-1 agonist, a corticotropin-releasing hormone agonist a NPY 5 antagonist, a NPY 1 antagonist, a histamine receptor-3 (H3) modulator, a histamine receptor-3 (H3) antagonist/inverse agonist, a β-hydroxy steroid dehydrogenase- 1 inhibitor, a phosphodiesterase inhibitor, a phosphodiesterase-3B inhibitor, a norepinephrine transport inhibitor, a non-selective serotonin/norepinephrine transport inhibitor, a ghrelin antagonist, leptin, a bombesin receptor subtype 3 agonists, a ciliary neurotrophic factor or derivative thereof, a monoamine reuptake inhibitor, an uncoupling protein- 1, 2, or 3 activator, a thyroid hormone β agonist, a fatty acid synthase inhibitor, a diacylglycerol acyltransferase 2 inhibitor, an acetyl-CoA carboxylase-2 inhibitor, a glucocorticoid antagonist, an acyl-estrogen, a fatty acid transporter inhibitor, a dicarboxylate transporter inhibitor, a glucose transporter inhibitor, a phosphate transporter inhibitor, metformin, topiramate, an a cannabinoid receptor 1 antagonist inverse agonist; and (C) a compound compound selected from:
Figure imgf000437_0001
(IA);
Figure imgf000437_0002
(IB):
Figure imgf000437_0003
(IC);
Figure imgf000438_0001
(IE); and
Figure imgf000438_0002
(IF)
or pharmaceutically acceptable salts thereof, wherein:
X and Ya each independently is aryl or heteroaryl wherein at least one of Xa and Ya is a heteroaryl with N adjacent to the position of attachment to Aa or βa respectively;
X is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -ORl, -NRlR2, -C(=NR1)NR2R3, _
N(=NR1)NR2R3, -NR1COR2, -NRlCθ2R2, -NRISO2R4, -NR1CONR2R3 -SR4, -SOR4, -SO2R4 -Sθ2NRlR2, -CORl, -CO2Rl, -CONR1R2, -C(=NR1)R2, or -
C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups; Rl, R2, and R each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6 alkyl) (aryl) substituents;
Aa is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9cθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9sO2-Co-2alkyl- or -heteroCθ-4alkyl;
Y is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5, -NR5R6, -C(=NR5)NR6R7, -N(=NR5)NR6R7, -NR5COR6, -NR5C02R6, -N 5S02R8, -NR5CON 6R7 -BRS, -SOR8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, -CONR5R6, -C(=NR5)R6, 0r -
C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5, R6, and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Q)-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(C0- 6alkyl)(aryl) substituents;
R8 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3- 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3. 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; B is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOCO-Cθ-2alkyl-, -Cθ- 2alkyl-NRl sθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rll, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ- βalkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of
Rll, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
Xb and Yb each independently is aryl or heteroaryl wherein at least one of Xb and Yb is a heteroaryl with N adjacent to the position of attachment to Ab or Bb respectively; Xb is optionally substituted with 1-7 independent halogen, -CN, NO2,
-Ci-6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -ORl -NRlbR2b, -C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b -NRlbC0R2b, -NRlbC02R2 -NRlbSO2R4b, - N lbCONR2bR3b ,_SR4b, -SOR4b _SO2R4b, -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b -C(=NRlb)R2b, or-C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci-galkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rib, R2b, and R3b each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-/7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R4b is -Cχ_6alkyl, -C3-7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Co-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Crj- 2alkyl-NR9bsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
Yb is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -OR5b, -NR5bR6b -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b, -NR5bcOR6b, -NR5bcθ2R6b, -NR5bSO2R8b, -
NR5bGONR6bR7b _SR8b, -SORδb, -SO2R8b, -SO2NR5bR6b, -COR5b -CO2R5b, -CONR5bR6b, -C(=NR5b)R6b, or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to
Yb; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -
O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-
6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b, R6b, and R7b each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R8b is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl-, -Cθ-
2alkyl-NRlObsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- βalkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or-N(Q)- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond;
Xc and Yc each independently is aryl or heteroaryl wherein at least one of Xc and Yc is a heteroaryl with N adjacent to the position of attachment to Ac or βc respectively; three of Ale, A2c, A3C, A4C, and A5c are N, the remaining are C, and one of Ale and A4c must be N, but not both Ale and A4c are N;
Xc is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORl, -NR1CR2C, -C(=NR1C)NR2CR3C, _ N(=NR1C)NR2CR3C, -NR1CCOR2C, -NRlcC02R2c, -NRlcSθ2R4c, - NR1CCONR2CR3C _SR4c, -SOR4C, -Sθ2R4c, -SO2NR1CR2C, -CORlc, -CO2Rlc, - CONRlcR2c, -C(=NR1C)R2C, 0r -C(=NORlc)R2c substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xc; wherein the -Cχ-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rlc, R2c, and R3c each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N( )- 6alkyl)(aryl) substituents;
R4c is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C _ 7cycloalkyl), or -N(CQ-6alkyl)(aryl) substituents; Ac is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ccθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9csO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yc is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5c, -NR5CR6C, -C(=NR5C)NR6CR7C,
Figure imgf000443_0001
-NR5CCOR6C, -NR5CCO2R6 , -NR5CS02R8C, - NR5CCONR6CR7C _SR8c, -SOR8C, -SO2R8c, -SO2NR5CR6C, -COR5C, -CO2R5c, - CONR5CR6C, -C(=NR5C)R6C, or -C(=NOR5C)R6C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yc; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cχ_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5c, R6C, and R7c each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) substituents;
R8c is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOccθ-Cθ-2alkyl- -Cθ- 2alkyl-NRlOcsO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9c and RlOc each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O( )-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C -7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rile is halogen, -Cθ-6alkyl, -Cθ-6alkoxyl, =O, =N(Cθ-4alkyl),or - N(C0-4alkyl)(Co-4alkyl); Xd and Yd each independently is aryl or heteroaryl wherein at least one of Xd and Y is a heteroaryl with N adjacent to the position of attachment to Ad or βd respectively;
Xd is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -ORl, -NRldRd2, -C(=NRld)NR2dR3d _ N(=NRld)NR2dR3d -NRldCOR2d, -NRldcθ2R2d, -N l SO2R d, - NRldC0NR2dR3d _SR4d -SOR4d -SO2R4d, -SO2NRldR2d -CORld -CO2Rld, -CONRdlR2d -C(=NRld)R2d, or-C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d and R3d each independently is -Cθ-6alkyl, -C3-. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yd is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci_6alkyl, -Ci_6alkenyl, -Cι_6alkynyl, -OR5, -NR5dR6d -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d -NR5dC0R6d, -NR5dcθ2R6d, -NR5dS02R8d, - NR5dC0NR6dR7d _SR8d -SOR8d, -SO2R8d, -SO2NR5dR6d, -COR5d, -CO2R5d, -CONR5dR6d -C(=NR5d)R6d, Dr -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, Rod, and R7d each independently is -Cθ-6alkyl, -C3. 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Bd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldsθ2-Cθ-2alkyl- or -heteroCθ-4alkyl; R9d and RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cj._6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; Xe and Ye each independently is aryl or heteroaryl wherein at least one of Xe and Ye is a heteroaryl with N adjacent to the position of attachment to Ae or Be respectively;
Xe is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORle, -NRleR2e, -C(=NRle)NR2eR3e, -N(=NRle)NR2eR3e -NRleCOR2e, -NRleCO2R2e, -NRleSO2R4e, -
NRleCONR2eR3e _SR4e, -SOR4e, -SO2R4e, -SO2NRleR2e, -CORle, -CO2Rle, - CONRleR2e, -C(=NRle)R2e, or -C(=NORle)R2e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xe; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rle, R2e, and R3e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or-N(Q)- 6alkyl)(aryl) substituents;
R4e is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(C0-6alkyl)(C3- 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Ae is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ecθ-Cθ-2alkyl- -Cθ-2alkyl- NR9esO2-Co-2alkyl- or -heteroCθ-4alkyl;
Ye is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5e, _NR5eR6e, -C(=NR5e)NR6eR7e, -N(=NR5e)NR6eR7e, -NR5eC0R6e, -NR5ecθ2R6e, -NR.5esθ2R8e, - NR5ecONR6eR7e _SR8e, -SOR8e, -SO2R8e, -SO2NR5eR6e, -COR5e, -CO2R5e, - CONR5eR6e, -C(=NR5e)R6e, 0r -C(=NOR5e)R6e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5e, R6e, and R7e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Cθ- 6alkyl)(aryl) substituents;
Rδe is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents; Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOeGO-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOesO2-Co-2alkyl-, or -heteroCθ-4alkyl;
R9e and RlOe each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Co-6alkyl)(Co-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rile and Rl2e is each independently halogen, -Cθ-6alkyl, -Cø- βal oxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl);
Xf is N, CH, orNH;
Yf is O, or N-R4f; one of Zl, Z , Z or Z2 optionally is N, or NH;
Rlf is -OH, halogen, or-CN; or a -Ci-galkyl, -Cι_4alkoxyl, - cycloC3_6alkyl, -Cθ-4alkyl-phenyl, -Cθ-4alkyl-pyridyl, -Cθ-4alkyl-imidazolyl, - Cθ-4alkyl-pyrazolyl, -Cθ-4alkyl-triazolyl, -Cθ-4alkyl-tetrazolyl, -Cθ-4alkyl- dioxolanyl, -Cθ-4alkyl-thiazolyl, -Cθ-4alkyl-piperidinyl, -Cθ-4alkyl-pyrrolidinyl, - Cθ-4alkyl-morpholinyl, -Cθ-4alkyl-pyrimidinyl, -C2-6alkynyl-thiazolyl, or -N(Cθ- 4alkyl)(-Cθ-4alkyl) group, wherein any of the groups is optionally substituted with 1- 5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Cχ_ 6alkyl, -Cι_4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, - Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is hydrogen, halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), - NO2; or -Ci-βalkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or -Ci_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, -CN, or -Ci-4alkoxyl substituents; R3f is hydrogen or -Cχ-4alkoxyl; R4f is -Co-4alkyl; R5f is H, halogen, or -Ci-4alkyl; any alkyl optionally substituted with 1-5 independent halogen substitutents, and any N is optionally an N-oxide; and provided that when X = 2-pyridyl, Rile = Rl2e = H and Ae = βe = Coalkyl, then Ye is not 3-cyanophenyl; and provided that when Ye = 2-pyridyl, Rl le = Rl2e = H and Ae = βe = Coalkyl, then Xe is not 3-cyanophenyl; and provided that when X is 2-pyridyl, Ale and A3c are each C, A2c and A4c and A5c are each N, Ac and βc are each direct bonds, and Rile is OH, then Yc is not unsubstituted phenyl or 4-methoxyphenyl; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rllb = Rl2b = H and Ab = βb = Coalkyl, then Yb is not 4-methoxyphenyl or 2,5- dimethoxyphenyl, and pharmaceutically acceptable salts thereof.
16. The use of compound for the manufacture of a medicament useful for treating or preventing an eating disorder asssociated with excessive food intake in a subject in need of such treatment or prophylaxis, wherein the compound is selected from:
Figure imgf000448_0001
(IA);
Figure imgf000448_0002
(IB):
Figure imgf000448_0003
(IC);
Figure imgf000449_0001
(ID);
Figure imgf000449_0002
(IE); and
Figure imgf000449_0003
(IF)
or pharmaceutically acceptable salts thereof, wherein: Xa and Ya each independently is aryl or heteroaryl wherein at least one of Xa and Ya is a heteroaryl with N adjacent to the position of attachment to Aa or Ba respectively;
Xa is optionally substituted with 1-7 independent halogen, -CN, NO2,
-Ci-6alkyl, -Ci_6alkenyl, -Cι_6alkynyl, -ORl, -NRlR2, -C(=NR1)NR2R3, _ N(=NRl)NR2R3, -NR1COR2, -NRICO2R2 -NRISO2R4 -NR1CONR2R3 _SR4,
-SOR4 -SO2R4, -Sθ2NRlR2, -CORl, -CO2Rl, -CONR1R2, -C(=NRl)R2, or-
C(=N0R1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xa; wherein the -Cχ-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Co-6alkyl)(aryl) groups;
Rl, R2, and R3 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ-
6alkyl)(aryl) substituents;
R4 is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Aa is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9cθ-Cθ-2alkyl-, -Cθ-2alkyl-
NR9sO2-Co-2alkyl- or -heteroCθ-4alkyl; Ya is optionally substituted with 1-7 independent halogen, -CN, NO2,
-Cι_6alkyl, -Ci-6alkenyl, -Cι_6alkynyl, -OR5, -NR5R6, -C(=NR5)NR6R7,
-N(=NR5)NR6R7, _NR5C0R6, -NR5CO2R6, -NR5SO2R8, -NR5CONR6R7 _SR8,
-SOR8, -SO2R8, -SO2NR5R6, -COR5, -CO2R5, -CONR5R6, -C(=NR5)R6, 0r -
C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Ya; wherein the -Cχ_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5, R6, and R7 each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cχ-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; R8 is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(CQ-6alkyl)(aryl) substituents; βa is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl- -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOcθ-Cθ-2alkyl-, -Co- 2alkyl-NRlOSθ2-Cθ-2alkyl- or -heteroCθ-4alkyl;
R9 and RlO each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C0-6alkyl)(C0-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(C"θ- 6alkyl)(aryl) substituents;
Rll, Rl2 and Rl3 is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally two of
Rll, Rl2 and Rl3 are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Xb and Yb each independently is aryl or heteroaryl wherein at least one of Xb and Yb is a heteroaryl with N adjacent to the position of attachment to Ab or βb respectively; Xb is optionally substituted with 1-7 independent halogen, -CN, NO2,
-Cι_6alkyl, -Cι_6alkenyl, -Cχ_6alkynyl, -ORlb, -NRlbR2b -C(=NRlb)NR2bR3b, -N(=NRlb)NR2bR3b -NRlbCOR2b -NRlbCO2R2b, -NRlbSO2R4b, - NRlbCONR2bR3b _SR4b, -SOR4b, -SO2R4b, -SO2NRlbR2b, -CORlb, -CO2Rlb, -CONRlbR2b, -C(=NRlb)R2b, or -C(=NORlb)R2b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xb; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; Rib, R2b and R3b each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents; R4b is -Cι_6alkyl, -C3-7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3-
7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; Ab is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NR9bcθ-Cθ-2alkyl-, -Cθ-
2alkyl-NR9bsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yb is optionally substituted with 1-7 independent halogen, -CN, NO2,
-Cι_6alkyl, -Cι.6alkenyl, -Cι_6alkynyl, -OR5b, -NR5bR6b -C(=NR5b)NR6bR7b, -N(=NR5b)NR6bR7b, -NR5bcOR6b, -NR5bCO2R6b, -NR5bS02R8b, -
NR5bcONR6bR7b _SR8b, -SOR8b, -SO2R8b, -SO2NR5bR6b, -COR5b, -CO2R5b,
-CONR5bR6b, -C(=NR5b)R6b or -C(=NOR5b)R6b substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to
Yb; wherein the -Cχ-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -
O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-
6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5b R6b, and R7b each independently is -Cθ-6alkyl, -C3-
7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
Rδb is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βb is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlObcθ-Cθ-2alkyl- -Cθ-
2alkyl-NRlObsO2-Co-2alkyl- or -heteroCθ-4alkyl; R9b and RlOb each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(C0- 6alkyl)(aryl) substituents; one of Alb and A2b is N, the other is CRl2b; Rllb and Rl2b is each independently halogen, -Cθ-6alkyl, -Cθ- βalkoxyl, or -N(Cθ-4alkyl)(Cθ-4alkyl), wherein optionally Rllb and Rl2b are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the -Cχ-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cχ_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Q)- 6alkyl)(aryl) groups; and wherein optionally Rllb and Rl2b each independently forms =O, =N(Cθ-4alkyl) using a bond from the adjoining double bond;
Xc and Yc each independently is aryl or heteroaryl wherein at least one of Xc and Yc is a heteroaryl with N adjacent to the position of attachment to Ac or βc respectively; three of Ale, A c, A3C, A4C, and A5c are N, the remaining are C, and one of Ale and A4c must be N, but not both Ale and A4e are N;
Xc is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORl, -NRlcR2c, -C(=NR1C)NR2CR3C, _ N(=NR1C)NR2CR3C -NR1CCOR2C, -N lcCθ2R2c, -NRlcSO2R4c, - NR1CC0NR2CR3C _SR4c, -SOR4C, -SO2R4C, -SO2NR1CR2C, -CORlc, -CO2Rlc, - CONRlcR2c, -C(=NR1C)R2C, OΓ -C(=NOR1C)R2C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xc; wherein the -Cχ-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rlc, R2C, and R3c each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) substituents;
R4c is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci-galkyl, -O(Co-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(C0-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3. 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents; Ac is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ccθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9csO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yc is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5c, -NR5CR6C, -C(=NR5C)NR6CR7C,
Figure imgf000454_0001
-NR5CCOR6C, -NR5CCO2R6C, -NR5CSO2R8C, - NR5CCONR6CR7C _SR8c, -SORδc, -SO2R8c, -SO2NR5CR6C, -COR5C, -CO2R5C, - CONR5CR6C, -C(=NR5C)R6C, or -C(=NOR5C)R6C substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yc; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, - O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5C, R6C, and R7c each independently is -Cθ-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ- 6alkyl)(aryl) substituents;
R8c is -Ci-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NRlOccθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOcsO2-Co-2alkyl-, or -heteroCθ-4alkyl;
R9c and RlOc each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(C0-6alkyl)(C0-6alkyl), -N(C0-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rile is halogen, -Cθ-6alkyl, -Cθ-6alkoxyl, =O, =N(Cθ-4alkyl),or - N(Cθ-4alkyl)(C0-4alkyl); Xd and Yd each independently is aryl or heteroaryl wherein at least one of Xd and Yd is a heteroaryl with N adjacent to the position of attachment to Ad or βd respectively;
Xd is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -ORl, -NRldRd2, -C(=NRld)NR2dR3d _ N(=NRld)NR2dR3d -NRldcOR2d -NRldcθ2R2d, -NRldSO2R d, - NRldC0NR2dR3d _SR4d -SOR4d -Sθ2R4d, -SO2NRldR2d -CORld, -CO2 ld, -CONRdlR2d -C(=NRld)R2d, or -C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xd; wherein the -Ci_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cχ-6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl- -Cθ- 2alkyl-NRldsO2-Co-2alkyl- or -heteroCθ-4alkyl;
Yd is optionally substituted with 1-7 independent halogen, -CN, NO2, -Ci-6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5, -NR5dR6d -C(=NR5d)NR6dR7d -N(=NR5d)NR6dR7d -NR5dC0R6d, -N 5dcθ2R6d, -N 5dsθ2R8d, - NR5dC0NR6dR7d _SR8d, -SORδd, -SO2R8d, -SO2NR5dR6d -COR5d, -CO2R5d, -CONR5dR6d, -C(=NR5d)R6d 0r -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-6alkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5d, R6d, and R7d each independently is -Cθ-6alkyl, -C3- 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
R8d is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2~Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl; R9d nd RlOd each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cχ_6alkyl, -O(Cθ-6alkyl), -O(C3-7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; Xe and Ye each independently is aryl or heteroaryl wherein at least one of Xe and Ye is a heteroaryl with N adjacent to the position of attachment to Ae or Be respectively;
Xe is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -ORle, -NRleR2e, -C(=NRle)NR2eR3e, -N(=NRle)NR2eR3e -NRleCOR2e, -N leCO2R2e, -NRleS02R4e, -
NRleCONR2eR3e _SR4e, -SOR4e, -SO2R4e, -SO2NRleR2e, -CORle, -CO2Rle, - CONRleR2e, -C(=NRle)R2e, or -C(=NORle)R2e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Xe; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Ci-βalkyl, - O(Co-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rle, R2e, and R3e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Q)- 6alkyl)(aryl) substituents;
R4e is -Ci_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents;
Ae is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ- 2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9ecθ-Cθ-2alkyl-, -Cθ-2alkyl- NR9esO2-Co-2alkyl- or -heteroCθ-4alkyl;
Ye is optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OR5e, -NR5eR6e, -C(=NR5e)NR.6eR7e, -N(=NR5e)NR6eR7e, -NR5ecOR6e, -NR5eC02R6e, -NR5esθ2R8e, - NR5ecONR6eR7e ,_SR8e, -SORδe, -SO2R e, -SO2NR5eR6e, -COR5e, -CO2R5e, - CONR5eR6e, -C(=NR5e)R6e, or -C(=NOR5e)R6e substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the -Cι_6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, - O(Co-6alkyl), -O(C3-7cyeloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ- 6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
R5e, R6e, and R7e each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), or-N(Cθ- 6alkyl)(aryl) substituents;
R8e is -Ci-galkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Ci_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_ 7cycloalkyl), or -N(Cθ-6alkyl)(aryl) substituents; Be is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOecθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRlOesO2-Co-2alkyl-, or -heteroCθ-4alkyl;
R9e and RlOe each independently is -Cθ-6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Ci-6al yl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), - O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents;
Rile and Rl2e is each independently halogen, -Cθ-6alkyl, -Cθ- 6alkoxyl, =O, =N(Cθ-4alkyl),or -N(Cθ-4alkyl)(Cθ-4alkyl);
Xf is N, CH, or NH;
Yf is O, or N-R4f; one of Zl, Z2 , z3 or Z optionally is N, or NH;
Rlf is -OH, halogen, or -CN; or a -Cι_6alkyl, -Cι_4alkoxyl, - cycloC3_6alkyl, -Cθ-4alkyl-phenyl, -Cθ-4alkyl-pyridyl, -Cθ-4alkyl-imidazolyl, - Cθ-4alkyl-pyrazolyl, -Cθ-4alkyl-triazolyl, -Cθ-4alkyl-tetrazolyl, -Cθ-4alkyl- dioxolanyl, -Cθ-4alkyl-thiazolyl, -Cθ-4alkyl-piperidinyl, -Cθ-4alkyl-pyrrolidinyl, - Cθ-4alkyl-morpholinyl, -Cθ-4alkyl-pyrimidinyl, -C2-6alkynyl-thiazolyl, or -N(Cθ- 4alkyl)(-Cθ-4alkyl) group, wherein any of the groups is optionally substituted with 1- 5 substituents; wherein each substituent is independently halogen, -OH, -CN, -Cι_ 6alkyl, -Cι_4alkoxyl, -N(Cθ-4alkyl)(Cθ-4alkyl), -Cθ-4alkyl-C(O)-O-Cθ-4alkyl, - Cθ-4alkyl-morpholinyl, or -Cθ-4alkyl-benzoxazolyl;
R2f is hydrogen, halogen, -OH, -CN, -N(Cθ-4alkyl)(Cθ-4alkyl), - NO2; or -Cι_6alkyl, -Cι_4alkoxyl, -Cθ-4alkyl-phenyl, or-Cι_4alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, -OH, -CN, or -Cι_4alkoxyl substituents; R3f is hydrogen or -Cχ_4alkoxyl; R4f is -Co-4alkyl; R5f is H, halogen, or -Cχ-4alkyl; any alkyl optionally substituted with 1-5 independent halogen substitutents, and any N is optionally an N-oxide; and provided that when X = 2-pyridyl, Rl le = Rl2e = H and Ae = βe = Coalkyl, then Ye is not 3-cyanophenyl; and provided that when Ye = 2-pyridyl, Rile = Rl2e = H and Ae = βe = Coalkyl, then Xe is not 3-cyanophenyl; and provided that when X is 2-pyridyl, Al and A3c are each C, A c and A4c and A5c are each N, Ac and βc are each direct bonds, and Rile is OH, then Yc is not unsubstituted phenyl or 4-methoxyphenyl; and provided that when Xb = 2-pyridyl, Alb = N, A2b = CH, Rl lb = Rl2b = H and Ab = βb = Coalkyl, then Y° is not 4-methoxyphenyl or 2,5- dimethoxyphenyl.
17. The use according to Claim 16, wherein the subject is human.
18. The use according to Claim 17 for treating an eating disorder asssociated with excessive food intake in a human in need of such treatment.
19. The use according to Claim 18, wherein the eating disorder associated with excessive food intake is selected from obesity, obesity related conditions, bulimia nervosa, and compulsive eating disorders.
20. The use according to Claim 19, wherein the eating disorder associated with excessive food intake is obesity.
21. The use according to Claim 19, wherein the eating disorder associated with excessive food intake is an obesity related condition is selected from: diabetes, non-insulin dependent diabetes mellitus-type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver, cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, infertility, hyperlipidemia, and cardiovascular disease.
22. The use according to Claim 17, wherein the compound is of structural formula (ID):
Figure imgf000459_0001
(ID) or a pharmaceutically acceptable salt thereof, wherein:
Xd is 2-pyridyl optionally substituted with 1-4 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Ci-6alkynyl, -ORld, _NRldR2d _ C(=NRld)NR2dR3d -N(=NRld)NR2dR3d -NRldCOR2d, -NRldCO2R2d -NRldS02R4d, -NRldCONR2dR3d _SR4d, -SOR4d, -SO2R4d, -SO2NRldR2d, -CORld -CO2Rld, -CONRldR2d, -C(=NRld)R2d or-C(=NORld)R2d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X ; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl),
-O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups;
Rid, R2d, and R3d each independently is -Cθ-6alkyl, -C3.
7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -
O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -
N(Cθ-6alkyl)(aryl) substituents;
R4d is -Cι_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O (heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_
7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents;
Ad is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl-, -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl-, -Cθ-2alkyl-NR9dcθ-Cθ-2alkyl-, -Cθ-
2alkyl-NRldsO2-Co-2alkyl- or -heteroCθ-4alkyl; Yd is aryl or heteroaryl optionally substituted with 1-7 independent halogen, -CN, NO2, -Cι_6alkyl, -Cι_6alkenyl, -Cι_6alkynyl, -OR5d -NR5dR6d -C(=NR5d)NR6dR7d, -N(=NR5d)NR6dR7d _NR5dcOR6d, -NR5dcθ2R6d, -NR5dsθ2R8d, -NR5dC0NR6dR7d ,_SR8d -SOR8d, -SO2R8d, -SO2NR5dR6d -COR5d, -Cθ2R5d, -CONR5dR6d, -C(=NR5d)R6d, or -C(=NOR5d)R6d substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Yd; wherein the -Ci-βalkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), or -N(Cθ-6alkyl)(aryl) groups; R5d R6d5 and R7d each independently is -Cθ-6alkyl, -C3_ 7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), - O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3_7cycloalkyl), - N(Cθ-6alkyl)(aryl) substituents;
Rδd is -Cχ_6alkyl, -C3_7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, -CN, -Cι_6alkyl, -O(Cθ-6alkyl), -O(C3_ 7cycloalkyl), -O(aryl), -O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3- 7cycloalkyl), -N(Cθ-6alkyl)(aryl) substituents; βd is -Co-4alkyl, -Cθ-2alkyl-SO-Cθ-2alkyl- -Cθ-2alkyl-Sθ2-Cθ-
2alkyl-, -Cθ-2alkyl-CO-Cθ-2alkyl- -Cθ-2alkyl-NRlOdcθ-Cθ-2alkyl-, -Cθ- 2alkyl-NRldSO2-Co-2alkyl- or -heteroCθ-4alkyl;
R9d and RlOd each independently is -Cθ-6alkyl, -C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, -Cχ-6alkyl, -O(Cθ-6alkyl), -O(C3_7cycloalkyl), -O(aryl), -
O(heteroaryl), -N(Cθ-6alkyl)(Cθ-6alkyl), -N(Cθ-6alkyl)(C3-7cycloalkyl), -N(Cθ- 6alkyl)(aryl) substituents; and any N is optionally N-oxide.
23. The use according to Claim 17, wherein the compound is selected from:
(1) 3-( 1 -pyridin-2-yl- lH-pyrrol-3-yl)benzonitrile;
(2) 2- [3 -(3 -chlorophenyl)- lH-pyrrol- 1 -yl]pyridine ;
(3) 2-[3-(3-methoxyphenyl)-lH-pyrrol-l-yl]pyridine; (4) 3-(3-pyridin-2-yl-lH-pyrrol-l-yl)benzonitrile;
(5) 2-{ l-[3-(trifluoromethyl)phenyl]-lH-pyrrol-3-yl|pyridine;
(6) 2-[l-(3,5-dichlorophenyl)-lH-pyrrol-3-yl]pyridine;
(7) 2-[l-(3-methylphenyl)-lH-ρyrrol-3-yl]pyridine;
(8) 2-[l-(3-methoxyphenyl)-lH-pyrrol-3-yl]pyridine; (9) 3-[3-(l,3-thiazol-2-yl)-lH-pyrrol-l-yl]benzonitrile;
(10) 3-fluoro-5-(3-pyridin-2-yl-lH-pyrrol-l-yl)benzonitrile;
(11) 3-(3-bromo-4-pyridin-2-yl-lH-pyrrol-l-yl)-5-fluorobenzonitrile;
(12) 3 -fluoro-5 - (3 -methyl-4-pyridin-2-yl- lH-pyrrol- 1 -yl)benzonitrile;
(13) 3-(3-chloro-4-pyridin-2-yl-lH-pyrrol-l-yl)-5-fluorobenzonitrile; (14) 3-fluoro-5-[3-(lH-pyrazol-l-yl)-lH-pyrrol-l-yl]benzonitrile;
(15) 2-chloro-6-(3-pyridin-2-yl- lH-pyrrol- 1 -yl)pyridine;
(16) 2-(pyridin-3-yloxy)-6-(3-pyridin-2-yl-lH-pyrrol-l-yl)pyridine;
(17) 2-chloro-4-methyl-6-(3 -pyridin-2-yl- lH-pyrrol- 1 -yl)pyridine ; (18) 3-chloro-5-(3-pyridin-2-yl-lH-pyrrol-l-yl)benzonitrile;
(19) 2-{ l-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-pyrrol-3-yl Ipyridine;
(20) 3-bromo-5-(3-pyridin-2-yl-lH-pyrrol-l-yl)benzonitrile;
(21) 3-methyl-5-(3-pyridin-2-yl-lH-pyrrol-l-yl)benzonitrile;
(22) 3-fluoro-5-[3-(l,3-thiazol-2-yl)-lH-ρyrrol-l-yl]benzonitrile; (23) 3-(4-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(24) 2- [ 1 -(3-fluorophenyl)- lH-pyrazol-4-yl]pyridine;
(25) 2- [ 1 -( 1 -naphthyl)- lH-pyrazol-4-yl]pyridine;
(26) 2-(l-pyridin-3-yl-lH-pyrazol-4-yl)pyridine;
(27) 3-( 1 -pyridin-2-yl- lH-pyrazol-4-yl)benzonitrile; (28) 2-[4-(3-chlorophenyl)-lH-pyrazol-l-yl]pyridine;
(29) 2-[4-(3-methoxyphenyl)-lH-pyrazol-l-yl]pyridine;
(30) 3-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(31) 2-[l-(3-chlorophenyl)-lH-pyrazol-3-yl]pyridine;
(32) 3-(l-pyridin-2-yl- lH-pyrazol-3-yl)benzonitrile; (33) 2-bromo-6-(4-pyridin-2-yl-lH-pyrazol-l-yl)pyridine;
(34) 6-(4-pyridin-2-yl-lΗ-pyrazol-l-yl)pyridine-2-carbonitrile;
(35) 2-[l-(3-bromophenyl)-lH-pyrazol-4-yl]pyridine;
(36) 3 -(4-pyrazin-2-yl- 1 H-pyrazol- 1 -yl)benzonitrile ;
(37) 2-methyl-6-(4-pyridin-2-yl- lH-pyrazol- 1 -yl)pyridine; (38) 5-(4-pyridin-2-yl-lH-pyrazol-l-yl)nicotinonitrile;
(39) 2-methoxy-6-(4-pyridin-2-yl-lH-pyrazol-l-yl)pyridine;
(40) 2-[l-(3-bromo-5-chlorophenyl)-lH-pyrazol-4-yl]pyridine;
(41) 2-[l-(3,5-dichlorophenyl)-lH-pyrazol-4-yl]pyridine;
(42) 3-[4-(l ,3-thiazol-2-yl)-lH-pyrazol-l-yl]benzonitrile; (43) 3-[4-(l,3-thiazol-4-yl)-lH-pyrazol-l-yl]benzonitrile;
(44) 2-{ l-[3-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl }-l,3-benzoxazole;
(45) 2-[l-(5-bromo-2-methylphenyl)-lH-pyrazol-4-yl]-l,3-benzoxazole;
(46) 2-[l-(3,5-dichlorophenyl)-lH-pyrazol-3-yl]pyridine;
(47) 3 -fluoro-5 -(3 -pyridin-2-yl- 1 H-pyrazol- 1 -yl)benzonitrile ; (48) 3-fluoro-5-(5-methyl-3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile; (49) 2-[l-(2,5-difluorophenyl)-lH-pyrazol-3-yl]ρyridine;
(50) 3-(3,5-dimethyl-4-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(51) 3-(4-pyrimidin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(52) 2-[l-(3-chloro-4-fluoro-phenyl)-lH-pyrazol-3-yl]-pyridine; (53) 2-(l-pyridin-2-yl-lH-pyrazol-3-yl)pyridine;
(54) 2- [ 1 -(2 ,3 ,5 ,6-Tetrafluoro-phenyl)- 1 H-pyrazol-3-yl] -pyridine ;
(55) 2-[l-(3,5-difluoro-phenyl)-lH-pyrazol-3-yl]-pyridine;
(56) 2-( 1 -pentafluorophenyl- lH-pyrazol-3-yl)-pyridine;
(57) 2- [ 1 -(4-methoxy-phenyl)- 1 H-pyrazol-3-yl] -pyridine ; (58) 2-[l-(3-chloro-4-methyl-phenyl)-lH-pyrazol-3-yl]-pyridine;
(59) 2-[ 1 -(2,3 ,5 ,6-tetrafluoro-4-methyl-phenyl)- lH-pyrazol-3-yl] -pyridine;
(60) 2-[l-(3-nitro-phenyl)-lH-pyrazol-3-yl]-pyridine;
(61) 3-fluoro-5-(4-pyridin-2-yl- lH-pyrazol- 1 -yl)benzonitrile;
(62) 2-{ l-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-4-yl Ipyridine; (63) 4-(4-pyridin-2-yl-lH-pyrazol-l-yl)pyridine-2-carbonitrile;
(64) 2-[l-(4-nitro-phenyl)-lH-pyrazol-3-yl]-pyridine;
(65) 2-[l-(3,4-dichloro-phenyl)-lH-pyrazol-3-yl]-pyridine;
(66) 3-( 1 -pyridin-2-yl- 1 H-pyrazol-3 -yl)benzonitrile ;
(67) 2-[4-(2-chlorophenyl)-lH-pyrazol-l-yl]pyridine; (68) 2-[4-(3-methylρhenyl)-lH-pyrazol-l-yl]pyridine;
(69) 2-[4-(l-naphthyl)-lH-pyrazol-l-yl]pyridine;
(70) 2-[4-(2-naphthyl)-lH-pyrazol-l-yl]pyridine;
(71) 5-(l-pyridin-2-yl-lH-pyrazol-4-yl)quinoline;
(72) N-{4-[4-(4-methyl-quinolin-2-yl)-pyrazol-l-yl]-phenyl|-acetamide; (73) 2-[l-(3-fluoro-phenyl)-lH-pyrazol-4-yl]-pyridine;
(74) 2-(l-phenyl-lH-pyrazol-4-yl)-benzooxazole;
(75) 2-(l-naphthalen-2-yl- lH-pyrazol-4-yl)-pyridine;
(76) 2-[l-(5,6,7,8-tetrahydro-naphthalen-l-yl)-lH-pyrazol-4-yl]-benzooxazole;
(77) 2-[ 1 -(3 ,4-dimethyl-phenyl)- lH-pyrazol-4-yl] -pyridine; (78) 2-[l-(4-phenoxy-phenyl)-lH-pyrazol-4-yl]-pyridine;
(79) 2- [ 1 -(3 -methoxy-phenyl)- 1 H-pyrazol-4-yl] -pyridine ;
(80) 2-[l-(2-benzyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(81) 2-[l-(3-propyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(82) 2-[l-(4-isopropoxy-phenyl)-lH-pyrazol-4-yl]-pyridine; (83) 2-[l-(3-chloro-2-methyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline; (84) 2-[l-(3-ethyl-ρhenyl)- lH-ρyrazol-4-yl]-pyridine;
(85) 2-[l-(3-tert-butyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(86) 2-[l-(3-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-pyridine;
(87) 2-[l-(2,4-dimethyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole; (88) 2-[l-(3-bromo-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(89) 4-methyl-2-[l-(2-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-quinoline;
(90) 4- [ 1 -(3 ,5-dimethyl-phenyl)- lH-pyrazol-4-yl] -pyrimidine ;
(91) 2-[l-(2-fluoro-5-trifluoromethyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(92) 2-[l-(3-tert-butyl-phenyl)-lH-pyrazol-4-yl]-pyridine; (93) 2-[l-(5-bromo-2-methyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(94) 2- [ 1 -(4-chloro-3 -methyl-phenyl)- 1 H-pyrazol-4-yl] -benzooxazole;
(95) 2-[l-(4-chloro-naphthalen-l-yl)-lH-pyrazol-4-yl]-pyridine;
(96) 3-fluoro-5-(3-methyl-l 'H-l ,4 -biρyrazol-1 -yl)benzonitrile;
(97) 3-(l 'H-1,4 -bipyrazol-1 -yl)-5-fluorobenzonitrile; (98) 2-[l-(2,3,5-trifluorophenyl)-lH-pyrazol-3-yl]ρyridine;
(99) 2-{ l-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-3-yl Ipyridinium;
(100) 2-{ l-[3-cyano-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-3-yl Ipyridinium;
(101) 3-(3-pyridin-2-yl-lH-pyrazol-l-yl)-5-(trifluoromethyl)benzonitrile;
(102) 2-[l-(3 -chloro-5 -fluorophenyl)- lH-pyrazol-3-yl]pyridine ; (103) 2-{ l-[3-chloro-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-3-yl Ipyridine;
( 104) 3 -chloro-5 - (3-pyridin-2-yl- lH-pyrazol- 1 -yl)benzonitrile ;
(105) 3-chloro-5-[3-chloro-5-(3-pyridin-2-yl-lH-pyrazol-l-yl)phenoxy]pyridine;
(106) 3-[(5-chloropyridin-3-yl)oxy]-5-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(107) 5-chloro-2-(3-pyridin-2-yl-lH-pyrazol-l-yl)pyridine; (108) 2-(3-pyridin-2-yl-lH-pyrazol-l-yl)isonicotinonitrile;
(109) 2-[l-(3,5-dibromophenyl)-lH-pyrazol-3-yl]pyridine;
(110) 3-bromo-5-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile;
(111) 2-{4-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-l-yl Ipyridine;
(112) 2-[l-(5-chloro-2-fluorophenyl)-lH-pyrazol-3-yl]pyridine; (113) 2-[l-(3-bromo-5-fluorophenyl)-lH-pyrazol-3-yl]pyridine;
(114) 3-[(3-pyridin-2-yl-lH-pyrazol-l-yl)methyl]benzonitrile;
(115) 2-[l-(pyridin-2-ylmethyl)-lH-pyrazol-3-yl]pyridine;
(116) 2-[l-(2,4-difluorophenyl)-lH-pyrazol-3-yl]pyridine;
(117) 3-[4-(6-methylpyridin-2-yl)-lΗ-pyrazol-l-yl]benzonitιile; (118) 4-[(4-pyridin-2-yl-lH-pyrazol-l-yl)methyl]benzonitrile; (119) 3-[(4-pyridin-2-yl-lH-pyrazol-l-yl)methyl]benzonitrile;
(120) 6-(4-pyridin-2-yl-lH-pyrazol-l-yl)nicotinonitrile;
(121) 2-[(4-ρyridin-2-yl- lH-pyrazol- 1 -yl)methyl]benzonitrile;
(122) 2-[l-(3,5-Bis-trifluoromethyl-phenyl)-lH-pyrazol-3-yl]-pyridine; (123) 2-[4-(4-fluorophenyl)-lH-pyrazol-l-yl]pyridine;
(124) 4-(l-pyridin-2-yl-lH-pyrazol-4-yl)benzonitrile;
(125) 2-{4-[3-(trifluoromethyl)phenyl]-lH-pyrazol-l-yl Ipyridine;
(126) 2-{4-[4-(trifluoromethyl)phenyl]-lH-pyrazol-l-yl Ipyridine;
(127) 3-(l-pyridin-2-yl-lH-pyrazol-4-yl)quinoline; (128) 2-[4-(3-fluorophenyl)-lH-pyrazol-l-yl]pyridine;
(129) 2-[4-(3,5-dichlorophenyl)-lH-pyrazol-l-yl]pyridine;
(130) 2-[4-(3,5-difluorophenyl)-lH-pyrazol-l-yl]pyridine;
(131) 2-[l-(3,5-dimethyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(132) l-methyl-3-[4-(4-pyrimidin-4-yl-pyrazol-l-yl)-phenyl]-imidazolidin-2-one; (133) 2-[l-(3-bromo-4-methyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(134) 2-[l-(3-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(135) 2- [ 1 -(4-cyclohexyl-phenyl)- 1 H-pyrazol-4-yl] -quinoline ;
(136) 2- [ 1 -(2,6-dimethyl-phenyl)- lH-pyrazol-4-yl] -4-methyl-quinoline ;
(137) 2-(l-p-tolyl-lH-pyrazol-4-yl)-quinoxaline; (138) 2-[l-(2-bromo-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(139) 2-[l-(3 -bromo-4-methylphenyl)- lH-pyrazol-4-yl]pyridine ;
(140) 2-[l-(2-trifluoromethyl-phenyl)-lΗ-pyrazol-4-yl]-quinoxaline;
(141) 4-[l-(4-isopropyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(142) 2- [ 1 -(4-cyclohexyl-phenyl)- 1 H-pyrazol-4-yl] -quinoxaline ; (143) 2-[l-(2,6-dimethyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(144) 2-[l-(3,5-dimethyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
(145) 4-[l-(3-tert-butyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(146) 2-[l-(3 -trifluoromethoxy-phenyl)- 1 H-pyrazol-4-yl] -benzooxazole ;
(147) 2-(4-pyrimidin-4-yl-pyrazol- 1 -yl)-quinoline; (148) 2-(l-indan-5-yl-lH-pyrazol-4-yl)-quinoxaline;
(149) 2-[l-(2-fluoro-4-methyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(150) 2-[l-(3 -trifluoromethoxy-phenyl)- 1 H-pyrazol-4-yl] -quinoline ;
(151) 2-(4-pyridin-2-yl-pyrazol-l-yl)-benzooxazole;
(152) dimethyl-carbamic acid 4-(4-quinoxalin-2-yl-pyrazol-l-yl)-phenyl ester; (153) 2-[l-(2,3-dimethyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline; (154) 4-[l-(3-bromo-2-methyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(155) 2- [ 1 -(2-isopropyl-phenyl)- 1 H-pyrazol-4-yl] -benzooxazole ;
(156) 4-[l-(5,6,7,8-tetrahydro-naphthalen-l-yl)-lH-pyrazol-4-yl]-pyrimidine;
(157) 2- [ 1 -(3-chloro-phenyl)- lH-pyrazol-4-yl] -quinoxaline; (158) 2-[l-(2-chloro-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(159) 2-[l-(2-isopropyl-phenyl)-lH-pyrazol-4-yl]-quinoline;
(160) 2- [ 1 -(4-chloro-naphthalen- 1 -yl)- lH-pyrazol-4-yl]-quinoxaline ;
(161) 2- [ 1 -(2-fluoro-4-methyl-phenyl)- 1 H-pyrazol-4-yl] -quinoline ;
(162) l-methyl-3-{4-[4-(4-methyl-quinolin-2-yl)-pyrazol-l-yl]-phenyl|- imidazolidin-2-one;
(163) 4-[ 1 -(4-cyclohexyl-phenyl)- 1 H-pyrazol-4-yl] -pyrimidine ;
(164) 2-[l-(2-fluoro-5-trifluoromethyl-phenyl)-lH-ρyrazol-4-yl]-4-methyl- quinoline;
(165) 2,2-dimethyl-propionic acid 4-(4-benzooxazol-2-yl-pyrazol-l-yl)-phenyl ester; (166) 2,2-dimethyl-propionic acid 4-(4-quinoxalin-2-yl-pyrazol-l-yl)-phenyl ester;
(167) 2-[l-(3-nitro-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(168) 4-methyl-2-( 1 -naphthalen-2-yl- lH-pyrazol-4-yl)-quinoline ;
(169) 2-[l-(4-bromo-3-methyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(170) 4- [ 1 -(4-phenoxy-phenyl)- 1 H-pyrazol-4-yl] -pyrimidine ; (171) 2-[l-(2-fluoro-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(172) 2- [ 1 -(4-propyl-phenyl)- 1 H-pyrazol-4-yl] -benzoxazole ;
(173) 2-[l-(4-sec-butyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(174) 2-[l-(2-fluoro-4-methyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(175) 2-[l-(2-fluoro-4-methyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline; (176) 2-[l-(3-tert-butyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
(177) 2- [ 1 -(2-benzyloxy-phenyl)- lH-pyrazol-4-yl] -quinoxaline ;
(178) 3-(4-quinoxalin-2-yl-pyrazol-l-yl)-benzoic acid ethyl ester;
(179) 4-[l-(2-isopropyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(180) 4-[l-(3-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-pyrimidine; (181) 2-[l-(4-fluoro-3-trifluoromethyl-phenyl)-lH-pyrazol-4-yl]-4-methyl- quinoline;
(182) 2,2-dimethyl-propionic acid 4-(4-quinolin-2-yl-pyrazol-l-yl)-phenyl ester;
(183) 3-(4-benzooxazol-2-yl-pyrazol-l-yl)-4-methyl-benzoic acid ethyl ester;
(184) 2- [ 1 -(3 ,5 -dimethyl-phenyl)- lH-pyrazol-4-yl] -quinoxaline ; (185) 2-[l-(2-propyl-phenyl)-lH-pyrazol-4-yl]-quinoline; (186) 2-[l-(4-propyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(187) 4-methyl-2- [ 1 -(2-propyl-phenyl)- lH-pyrazol-4-yl] -quinoline ;
(188) 2-[l-(2-sec-butyl-phenyl)-lH-pyrazol-4-yl]-quinoline;
(189) 2-[l-(4-sec-butyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline; (190) 2- [1 -(4-cyclohexyl-phenyl)- lH-pyrazol-4-yl] -pyridine;
(191) 2-[l -(2-trifluoromethoxy-phenyl)- lH-pyrazol-4-yl] -benzooxazole;
( 192) 2- [ 1 -(2-trifluoromethoxy-phenyl)- lH-pyrazol-4-yl] -quinoline;
(193) 4-methyl-2-[ 1 -(5 ,6,7,8-tetrahydro-naphthalen- 1 -yl)- lH-pyrazol-4-yl] - quinoline; (194) 2-[l-(4-chloro-3-methyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(195) 2-[l -(4-sec-butyl-phenyl)- 1 H-pyrazol-4-yl] -quinoxaline;
(196) 2-[l-(5,6,7,8-tetrahydro-naphthalen-l-yl)-lH-pyrazol-4-yl]-pyridine;
(197) 2-[l-(5,6,7,8-tetrahydro-naphthalen-l-yl)-lH-pyrazol-4-yl]-quinoxaline;
(198) 4-[l-(4-chloro-3-methyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine; (199) 2-[l-(4-chloro-naphthalen-l-yl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
(200) 2-[l-(3-tert-butyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(201 ) 2- [ 1 -(2-fluoro-5 -trifluoromethyl-phenyl)- lH-pyrazol-4-yl] -benzooxazole ;
(202) 2- [ 1 -(2 ,5 -dichloro-phenyl)- lH-pyrazol-4-yl] -quinoxaline ;
(203) 2-[l-(3-benzyloxy-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline; (204) 4-(l-naphthalen-2-yl-lH-pyrazol-4-yl)-pyrimidine;
(205) 4- [ 1 -(3 -bromo-4-methyl-phenyl)- lH-pyrazol-4-yl] -pyrimidine ;
(206) 4- [ 1 -(2-propyl-phenyl)- 1 H-pyrazol-4-yl] -pyrimidine ;
(207) 2- [ 1 -(3-chloro-2-methyl-phenyl)- 1 H-pyrazol-4-yl] -quinoxaline ;
(208) 2-[l-(4-chloro-naphthalen-l-yl)-lH-pyrazol-4-yl]-benzooxazole; (209) l-{4-[4-(4-methyl-quinolin-2-yl)-pyrazol-l-yl] -phenyl }-imidazolidin-2-one;
(210) 2,2-dimethyl-propionic acid 4-(4-pyridin-2-yl-pyrazol-l-yl)-phenyl ester;
(211) 2,2-dimethyl-propionic acid 4-(4-pyrimidin-4-yl-pyrazol-l-yl)-phenyl ester;
(212) 2- [ 1 -(2,6-dimethyl-phenyl)- lH-pyrazol-4-yl]-benzooxazole;
(213) 2-[l -(3 ,4-dimethyl-phenyl)- lH-pyrazol-4-yl] -quinoxaline; (214) 4-[l-(5-bromo-2-methyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(215) 2- [ 1 -(2-sec-butyl-phenyl)- 1 H-pyrazol-4-yl] -benzooxazole ;
(216) 4-[ 1 -(2-fluoro-5-trifluoromethyl-phenyl)- lH-pyrazol-4-yl] -pyrimidine;
(217) 2-(4-benzooxazol-2-yl-pyrazol-l-yl)benzooxazole;
(218) 2-(l-benzooxazol-2-yl-lH-pyrazol-4-yl)-4-methyl-quinoline; (219) 2-[l-(3-benzyloxy-phenyl)-lH-pyrazol-4-yl]-quinoxaline; (220) 2-(l-quinolin-6-yl-lH-pyrazol-4-yl)-quinoxaline;
(221) 2-[l-(5-isopropyl-2-methyl-ρhenyl)-lH-pyrazol-4-yl]-quinoxaline;
(222) 2-[ 1 -(2,5-dimethyl-phenyl)- lH-ρyrazol-4-yl] -quinoxaline;
(223) 2- [ 1 -(3 -bromo-4-methyl-phenyl)- 1 H-pyrazol-4-yl] -4-methyl-quinoline;
(224) 2-[l-(2-propyl-phenyl)-lH-pyrazol-4-yl]-pyridine;
(225) 2-[l-(3-tert-butyl-phenyl)-lH-pyrazol-4-yl]-quinoline;
(226) 2-[ 1 -(5 ,6,7,8-tetrahydro-naphthalen- 1 -yl)-lH-pyrazol-4-yl] -quinoline;
(227) dimethyl-carbamic acid 4-(4-pyridin-2-yl-pyrazol-l-yl)-phenyl ester;
(228) 2-[l-(5-bromo-2-methyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(229) 2-[l-(2H-indazol-5-yl)-lH-pyrazol-4-yl]-quinoxaline;
(230) 2-(l-naphthalen-2-yl-lH-pyrazol-4-yl)-benzooxazole;
(231) 4-[l-(4-bromo-3-methyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(232) 2-[l-(3-ethyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
(233) 2-[l-(4-cyclohexyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
(234) 2- [ 1 -(2-trifluoromethoxy-phenyl)- lH-pyrazol-4-yl] -quinoxaline ;
(235) 4-methyl-2- [ 1 -(4-phenoxy-phenyl)- lH-pyrazol-4-yl] -quinoline ;
(236) 2-(4-pyrimidin-4-yl-pyrazol-l-yl)-benzooxazole;
(237) 2-[l-(2-benzyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(238) 2-(l-o-tolyl-lH-pyrazol-4-yl)-quinoxaline;
(239) 3-(4-pyrimidin-4-yl-pyrazol-l-yl)-benzoic acid ethyl ester;
(240) 2- { 1 -[2-(3H-imidazol-4-yl)-ethyl] - lH-pyrazol-4-yl } -pyridine;
(241) dimethyl-carbamic acid 4-(4-quinolin-2-yl-pyrazol-l-yl)-phenyl ester;
(242) 2- [ 1 -(4-methoxy-phenyl)- 1 H-pyrazol-4-yl] -quinoxaline ;
(243) 2-[l-(2-nitro-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(244) 4-methyl-3-(4-quinolin-2-yl-pyrazol-l-yl)-benzoic acid ethyl ester;
(245) 2- [ 1 -(3-chloro-2-methyl -phenyl)- 1 H-pyrazol-4-yl] -quinoline ;
(246) 4- [ 1 -(2-fluoro-4-methyl -phenyl)- 1 H-pyrazol-4-yl] -pyrimidine ;
(247) 2-[l-(3,5-bis-trifluoromethyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(248) 2-( 1 -phenyl- 1 H-pyrazol-4-yl)-quinoxaline ;
(249) 2- [ 1 -(3 -benzyloxy-phenyl)- 1 H-pyrazol-4-yl] -benzooxazole;
(250) 2- [ 1 -(2-propyl-phenyl)- 1 H-pyrazol-4-yl] -quinoxaline ;
(251) 4- [ 1 -(2-sec-butyl-phenyl)- 1 H-pyrazol-4-yl] -pyrimidine ;
(252) 4-[l-(4-sec-butyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(253) 2-[ 1 -(4-sec-butyl-phenyl)- lH-pyrazol-4-yl] -quinoline;
(254) 2-[l-(2-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-pyridine; (255) 2-[l-(4-phenoxy-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(256) 2-[l-(3-methoxy-ρhenyl)-lH-pyrazol-4-yl]-quinoxaline;
(257) 4-[l-(2-trifluoromethyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(258) 3-(4-benzooxazol-2-yl-pyrazol-l-yl)-benzoic acid ethyl ester; (259) 2-[l-(4-sec-butyl-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(260) 4- [ 1 -(4-chloro-naphthalen- 1 -yl)- lH-pyrazol-4-yl] -pyrimidine;
(261) 2,2-dimethyl-propionic acid 4-[4-(4-methyl-quinolin-2-yl)-pyrazol-l-yl]- phenyl ester;
(262) 2-[l-(2,6-dimethyl-phenyl)-lH-ρyrazol-4-yl]-pyridine; (263) 2-[l-(2,4-dimethyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(264) 2-[l-(lH-indazol-6-yl)- lH-pyrazol-4-yl]-quinoxaline;
(265) 2- [ 1 -(2-isopropyl-phenyl)- 1 H-pyrazol-4-yl] -4-methyl-quinoline ;
(266) 2-[l-(2-methoxy-5-methyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(267) N-[4-(4-quinoxalin-2-yl-pyrazol-l-yl)-phenyl]-acetamide; (268) 2- [ 1 -(3 -bromo-2-methyl-phenyl)- 1 H-pyrazol-4-yl] -4-methyl-quinoline ;
(269) 2- [ 1 -(4-propyl-phenyl)- 1 H-pyrazol-4-yl] -quinoline ;
(270) 4-[l-(2,6-dimethyl-phenyl)-lH-pyrazol-4-yl]-pyrimidine;
(271) 2-[l-(2,6-dimethyl-ρhenyl)-lH-pyrazol-4-yl]-quinoline;
(272) N-[3-(4-quinoxalin-2-yl-pyrazol-l-yl)-phenyl]-acetamide; (273) 4-methyl-3-(4-quinoxalin-2-yl-pyrazol-l-yl)-benzoic acid ethyl ester;
(274) 6-(4-pyridin-2-yl-pyrazol-l-yl)-quinoline;
(275) 2- [1 -(3 ,5-dimethyl-phenyl)- lH-pyrazol-4-yl]-quinoline;
(276) 2-[l-(2-fluoro-4-methyl-phenyl)-lH-pyrazol-4-yl]-ρyridine;
(277) 2- [ 1 -(3 -bromo-2-methyl-phenyl)- 1 H-pyrazol-4-yl] -pyridine ; (278) 4- [ 1 -(2-trifluoromethoxy-phenyl)- 1 H-pyrazol-4-yl] -pyrimidine ;
(279) dimethyl-carbamic acid 4-(4-benzooxazol-2-yl-pyrazol-l-yl)-phenyl ester;
(280) 2-[l-(3-phenoxy-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(281) 2-[l-(4-phenoxy-phenyl)-lH-pyrazol-4-yl]-benzooxazole;
(282) 4-methyl-2-[l-(3-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-quinoline; (283) 2-[l-(4-chloro-3-methyl-phenyl)-lH-pyrazol-4-yl]-4-methyl-quinoline;
(284) 2-[l-(4-benzyl-phenyl)-lH-pyrazol-4-yl]-quinoxaline;
(285) l-methyl-3-[4-(4-quinolin-2-yl-pyrazol-l-yl)-phenyl]-imidazolidin-2-one;
(286) l-methyl-3-[4-(4-quinoxalin-2-yl-pyrazol-l-yl)-phenyl]-imidazolidin-2-one;
(287) 2-[ 1 -(4-tert-butyl-benzyl)- lH-pyrazol-4-yl] -benzooxazole; (288) 2-[l-(3-trifluoromethyl-benzyl)-lH-pyrazol-4-yl]-benzooxazole; (289) 2-[l-(2,4-dichloro-benzyl)-lH-pyrazol-4-yl]-benzooxazole;
(290) 2-[l-(4-methanesulfonyl-benzyl)-lH-pyrazol-4-yl]-benzooxazole;
(291) 2-[l-(2,4-dichloro-ρhenyl)-lH-pyrazol-4-yl]-benzooxazole;
(292) dimethyl-carbamic acid 4-[4-(4-methyl-quinolin-2-yl)-pyrazol-l-yl]-phenyl ester;
(293) 2-(l-pyridin-2-yl-lH-pyrazol-4-yl)-benzooxazole;
(294) 2-[l-(4-bromo-3-chlorophenyl)-lH-pyrazol-3-yl]pyridine;
(295) 4-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzoic acid;
(296) 2-{ l-[3-(pyridin-4-yloxy)phenyl]-lH-pyrazol-3-yl Ipyridine; (297) 2-[l-(3-chloro-2-fluoroρhenyl)-lH-pyrazol-3-yl]pyridine;
(298) 2-(3-pyridin-2-yl-lH-pyrazol-l-yl)-5-(trifluoromethyl)pyridine;
(299) 2-(l-phenyl-lH-pyrazol-3-yl)pyridine;
(300) 3-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzoic acid;
(301) 2-{ l-[3-fluoro-5-(pyridin-4-ylthio)phenyl]-lH-pyrazol-3-yl Ipyridine; (302) 2-{ l-[(4-methylphenyl)sulfonyl]-lH-pyrazol-3-yl Ipyridine;
(303) 2-[l-(3-chlorophenyl)-lH-l ,2,4-triazol-3-yl]pyridine;
(304) 3-(3-pyridin-2-yl-lH-l ,2,4-triazol-l-yl)benzonitrile;
(305) 3-(l-pyridin-2-yl-lH-l ,2,4-triazol-3-yl)benzonitrile;
(306) 2-[3-(3-chlorophenyl)-lH-l ,2,4-triazol-l-yl]pyridine; (307) 3-(2-pyridin-2-yl-2H-l,2,3-triazol-4-yl)benzonitrile;
(308) 3-(l-pyridin-2-yl-lH-l,2,3-triazol-4-yl)benzonitrile;
(309) 3-(4-pyridin-2-yl-2H- 1 ,2,3-triazol-2-yl)benzonitrile;
(310) 3-(4-pyridin-2-yl-lH-l,2,3-triazol-l-yl)benzonitrile;
(311) 2-[2-(3-chlorophenyl)-2H-l ,2,3-triazol-4-yl]pyridine; (312) 2-[l-(3-chlorophenyl)-lH-l,2,3-triazol-4-yl]pyridine;
(313) 2-[2-(3 ,5-difluorophenyl)-2H-l ,2,3-triazol-4-yl]pyridine;
(314) 2-[l-(3,5-difluorophenyl)-lH-l,2,3-triazol-4-yl]pyridine;
(315) 2-{2-[3-fluoro-5-(pyridin-2-yloxy)phenyl]-2H-l,2,3-triazol-4-yl}pyridine;
(316) 2-{l-[3-fluoro-5-(pyridin-2-yloxy)phenyl]-lH-l,2,3-triazol-4-yl Ipyridine; (317) 2-{4-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-2H-l ,2,3-triazol-2-yl Ipyridine;
(318) 2-{4-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-l,2,3-triazol-l-yl Ipyridine;
(319) 2-[4-(3-cyanoρhenyl)-2H-l,2,3-triazol-2-yl] nicotinotrile;
(320) 3-[2-(5-nitropyridin-2-yl)-2H-l,2,3-triazol-4-yl]benzonitrile;
(321) 3-[l-(5-nitropyridin-2-yl)-lH-l,2,3-triazol-4-yl]benzonitrile; (322) 3-[l-(3-nitropyridin-2-yl)-lH-l ,2,3-triazol-4-yl]benzonitrile; (323) 3-[2- (3-nitropyridin-2-yl)-2H-l,2,3-triazol-4-yl]benzonitrile;
(324) 3-[l- (5-aminopyridin-2-yl)- IH- 1 ,2,3-triazol-4-yl]benzonitrile hydrochloride;
(325) N-[3 -(l-pyridin-2-yl-lH-l,2,3-triazol-4-yl)phenyl]pyridin-3-arnine;
(326) N-[3 -(2-pyridin-2-yl-2H-l,2,3-triazol-4-yl)phenyl]pyridin-3-amine;
(327) 3-(2- pyridin-2-yl-lH-l,2,3-triazol-4-yl)phenol;
(328) 3-(2- pyridin-2-yl-2H-l,2,3-triazol-4-yl)phenol;
(329) 2-[2- (3-chlorophenyl)-2H-tetrazol-5-yl]pyridine;
(330) 3-(5- pyridin-2-yl-2H-tetrazol-2-yl)benzonitιile;
(331) 2-(2- pyridin-3-yl-2H-tetrazol-5-yl)pyridine;
(332) 2-(3- ■chlorophenyl)-5-(2-methyl-l,3-thiazol-4-yl)-2H-tetrazole;
(333) 3-[5- (2-methyl-l,3-thiazol-4-yl)-2H-tetrazol-2-yl]benzonitrile;
(334) 2-[5- (3-bromophenyl)-2H-tetrazol-2-yl]pyridine;
(335) 2-[5- ■(3-chlorophenyl)-2H-tetrazol-2-yl]pyridine;
(336) 3-(2- •pyridin-2-yl-2H-tetrazol-5-yl)benzonitrile;
(337) 2-[2- ■(3,5-difluorophenyl)-2H-tetrazol-5-yl]pyridine;
(338) 2-[2- ■(3-methoxyphenyl)-2H-tetrazol-5-yl]pyridine;
(339) 2-[2- ■(3-trifluoromethylphenyl)-2H-tetrazol-5-yl]pyridine;
(340) 2-[2- ■(3-iodophenyl)-2H-tetrazol-5-yl]pyridine;
(341) 2-[2- •(3-bromophenyl)-2H-tetrazol-5-yl]pyridine;
(342) 2-[2- ■(3-Methylmercaptophenyl)-2H-tetrazol-5-yl]pyridine;
(343) 2-[2- -(4-fluorophenyl)-2H-tetrazol-5-yl]pyridine;
(344) 2-[2 -(3-fluorophenyl)-2H-tetrazol-5-yl]pyridine;
(345) 2-[2 (2-methoxyphenyl)-2H-tetrazol-5-yl]pyridine;
(346) 2-[2 -(3-ethylphenyl)-2H-tetrazol-5-yl]pyridine;
(347) 2-[2 -(3-methylphenyl)-2H-tetrazol-5-yl]pyridine;
(348) 2-[2 -(2-chloro-3-pyridyl)-2H-tetrazol-5-yl]pyridine;
(349) 2-[2 -(3,5-dichlorophenyl)-2H-tetrazol-5-yl]pyridine;
(350) 2-[2 -(2-chlorophenyl)-2H-tetrazol-5-yl]pyridine;
(351) 2-[2 -(4-methoxyphenyl)-2H-tetrazol-5-yl]pyridine;
(352) 2-[2 -(4-pyridyl)-2H-tetrazol-5-yl]pyridine;
(353) 2-[2 -(3,5-dimethylphenyl)-2H-tetrazol-5-yl]pyridine;
(354) 3-[5 -(6-methylpyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile;
(355) 3-[5 -(4-methylpyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile;
(356) 3-[5 -(4-methylpyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile;
(357) 2-[2 -(3-isopropylphenyl)-2H-tetrazol-5-yl]pyridine; (358) 2-{2-[3-(trifluoromethoxy)phenyl]-2H-tetrazol-5-yl Ipyridine;
(359) 2-[2-(3-ethoxyphenyl)-2H-tetrazol-5-yl]pyridine;
(360) 2- { 2- [3 -methoxy-5 -(trifluoromethyl)phenyl] -2H-tetrazol-5-yl } pyridine ;
(361) 3-[5-(l,3-thiazol-2-yl)-2H-tetrazol-2-yl]benzonitrile; (362) 3-[5-(5-methylpyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile;
(363) 3-[5-(3-methylpyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile;
(364) 3-[5-(l-methyl-lH-imidazol-2-yl)-2H-tetrazol-2-yl]benzonitrile;
(365) 2-[2-(3,4-dimethylphenyl)-2H-tetrazol-5-yl]pyridine;
(366) 2-[2-(3,4,5-trichlorophenyl)-2H-tetrazol-5-yl]pyridine; (367) 3-[5-(l,3-thiazol-4-yl)-2H-tetrazol-2-yl]benzonitrile;
(368) 2-[2-(2,5-dichlorophenyl)-2H-tetrazol-5-yl]pyridine;
(369) 2-[2-(3,4-difluorophenyl)-2H-tetrazol-5-yl]pyridine;
(370) 2-[2-(3-chloro-4-methylphenyl)-2H-tetrazol-5-yl]pyridine;
(371) 2-[2-(2,3-dichlorophenyl)-2H-tetrazol-5-yl]pyridine; (372) 2-{2-[3-methyl-5-(trifluoromethyl)phenyl]-2H-tetrazol-5-yl Ipyridine;
(373) 2-[2-(3-bromo-4-methylphenyl)-2H-tetrazol-5-yl]pyridine;
(374) 2-[2-(3-chloro-4-iodoρhenyl)-2H-tetrazol-5-yl]pyridine;
(375) 2-{2-[3-fluoro-5-(trifluoromethyl)phenyl]-2H-tetrazol-5-yl|pyridine;
(376) 3-(5-pyrazin-2-yl-2H-tetrazol-2-yl)benzonitrile; (377) 2-[2-(2,3-dihydro-lH-inden-5-yl)-2H-tetrazol-5-yl]pyridine;
(378) 2-[2-(l,3-dihydro-2-benzofuran-5-yl)-2H-tetrazol-5-yl]pyridine;
(379) 2-[2-(4-methoxy-2-naρhthyl)-2H-tetrazol-5-yl]pyridine;
(380) 2-[2-(l-naphthyl)-2H-tetrazol-5-yl]pyridine;
(381) 2- [2-(3 ,5-dimethoxyphenyl)-2H-tetrazol-5-yl]pyridine; (382) 2-[2-(4-phenoxyphenyl)-2H-tetrazol-5-yl]pyridine;
(383) 3- [5 -(3 -fluoro-pyridin-2-yl)-tetrazol-2-yl] -benzonitrile ;
(384) 3-(5-isoxazol-3-yl-tetrazol-2-yl)-benzonitrile;
(385) 3-[5-(l-methyl-lΗ-pyrazol-3-yl)-tetrazol-2-yl]-benzonitrile;
(386) 3-(5-oxazol-4-yl-tetrazol-2-yl)-benzonitrile; (387) 3-[5-(2H-pyrazol-3-yl)-tetrazol-2-yl]-benzonitrile;
(388) 3-[5-(lH-imidazol-2-yl)-tetrazol-2-yl]-benzonitrile;
(389) 3-[5-(5-hydroxy-pyridin-2-yl)-tetrazol-2-yl]-benzonitrile;
(390) 3-[5-(5-bromo-pyridin-2-yl)-tetrazol-2-yl]-5-fluoro-benzonitrile;
(391) 3-fluoro-5-[5-(3-fluoro-pyridin-2-yl)-tetrazol-2-yl]-benzonitrile; (392) 3-fluoro-5-(5-oxazol-2-yl-tetrazol-2-yl)-benzonitrile; (393) 3-{3-fluoro-5-[5-(lH-imidazol-2-yl)-tetrazol-2-yl]-phenoxy}-pyridine;
(394) 3-fluoro-5-[5-(4-methyl-lH-imidazol-2-yl)-tetrazol-2-yl]-benzonitrile;
(395) 3-{3-fluoro-5-[5-(lH-[l,2,3]triazol-4-yl)-tetrazol-2-yl]-phenoxy}-pyridine;
(396) 2-{2-[3-fluoro-5-(pyridin-3-yloxy)-phenyl]-2H-tetrazol-5-yl}-pyrimidine; (397) 3-{ 3-fluoro-5-[5-(lH-pyrazol-3-yl)-tetrazol-2-yl]-ρhenoxy }-pyridine;
(398) 3-{3-fluoro-5-[5-(l-methyl-lH-pyrazol-3-yl)-tetrazol-2-yl]-phenoxy Ipyridine;
(399) 3-fluoro-5-[5-(l-methyl-lH-pyrazol-3-yl)-tetrazol-2-yl]-benzonitrile;
(400) N-[4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-3-amine;
(401) 2-{ 2-[4-(pyridin-3-ylmethyl)phenyl]-2H-tetraazol-5-yl Ipyridine; (402) N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-3-amine;
(403) N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-2-amine;
(404) 2-{2-[3-(pyridin-2-yloxy)phenyl]-2H-tetraazol-5-yl Ipyridine;
(405) 2-[2-(3-ethynylphenyl)-2H-tetraazol-5-yl]pyridine;
(406) 2-{ 2-[4-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5-yl Ipyridine; (407) 2-{2-[3-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5-yl]pyridine;
(408) 2-[2-(3-nitrophenyl)-2H-tetraazol-5-yl]pyridine;
(409) 2-methyl-3-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenoxy]pyridine;
(410) 2-methyl-N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-3-amine;
(411) N-methyl-N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-3-amine; (412) N-[3-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]-N-methylpyridin-3- amine;
(413) 2-{ 2-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5-yl Ipyridine;
(414) N-[3-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-3-amine;
(415) N-{3-[5-(5-bromopyridin-2-yl)-2H-tetraazol-2-yl]-5-fluorophenyl|pyridin-3- amine;
(416) 2-{2-[3-fluoro-5-(pyridin-3-ylmethyl)phenyl]-2H-tetraazol-5-yl Ipyridine;
(417) 5-[3-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzyl]-2-methylpyridine;
(418) 3-{3-fluoro-5-[5-(l,3-thiazol-2-yl)-2H-tetraazol-2-yl]phenoxy Ipyridine;
(419) 2-{2-[3-fluoro-5-(pyridin-3-ylthio)phenyl]-2H-tetraazol-5-yl|pyridine; (420) 2-(2-{ 3-fluoro-5-[(pyridin-3-yloxy)methyl]phenyl }-2H-tetraazol-5-yl) pyridine;
(421) 3-fluoro-2-{2-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5-yl| pyridine;
(422) 2-{2-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-2H-tetraazol-5-yl}-6- methylpyridine; (423) 2-{2-[3-methoxy-4-(3H-l,2λ5,3,4-tetraazol-2-ylmethyl)phenyl]-2H-tetraazol- 5-yl} pyridine;
(424) 3-bromo-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine;
(425) 2-{2-[4-(allyloxy)-3-methoxyρhenyl]-2H-tetraazol-5-yl|pyridine; (426) 2-methoxy-4-(5-ρyridin-2-yl-2H-tetraazol-2-yl)phenol;
(427) 2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl ethylcarbamate;
(428) 2-[2-(4-bromo-3-methoxyphenyl)-2H-tetraazol-5-yl]pyridine;
(429) 2-{2-[3-methoxy-4-(pyridin-2-yloxy)phenyl]-2H-tetraazol-5-yl|pyridine;
(430) 5-(5-pyridin-2-yl-2H-tetraazol-2-yl)nicotinonitrile; (431) [3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenoxy]acetonitrile;
(432) N-pyridin-3-yl-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-3-amine;
(433) 3-(pyridin-3-yloxy)-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine;
(434) 3-bromo-5-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]pyridine;
(435) 3-bromo-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine; (436) 2-(pyridin-3-yloxy)-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine;
(437) 2-[(5-chloropyridin-3-yl)oxy]-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine;
(438) 2-methyl-5-{[5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-yl]oxy Ipyridine;
(439) 2-methyl-3-{[5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-yl]oxy|pyridine;
(440) 2-[(4-methylpyridin-3-yl)oxy]-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine; (441) 2-(pyridin-4-yloxy)-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine;
(442) 2-bromo-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(443) 3-(5-pyridin-2-yl-2H-tetraazol-2-yl)aniline;
(444) 3-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(445) 2-{2-[3-bromo-5-(trifluoromethyl)phenyl]-2H-tetraazol-5-yl}pyridine; (446) 3-(5-pyridin-2-yl-2H-tetraazol-2-yl)-5-(trifluoromethyl)benzonitrile;
(447) 3-nitro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(448) 3-amino-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(449) 3-chloro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(450) 2-[2-(3-cyano-5-fluorophenyl)-2H-tetraazol-5-yl]-l-hydroxypyridinium; (451) 5-(5-pyridin-2-yl-2Η-tetrazol-2-yl)isophthalonitrile;
(452) 2-{ 5-[3-chloro-5-(pyridin-3-yloxy)phenyl]-2H-tetraazol-2-yl Ipyridine;
(453) 2- [5 -(3 -bromo-5 -chlorophenyl)-2H-tetraazol-2-yl]pyridine ;
(454) 3-chloro-5-(2-pyridin-2-yl-2H-tetraazol-5-yl)benzonitrile;
(455) 3-methyl-5-(2-pyridin-2-yl-2H-tetraazol-5-yl)benzonitrile; (456) [3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]methanol;
(457) [3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]acetonitrile;
(458) N-methyl-3-(5-ρyridin-2-yl-2H-tetraazol-2-yl)aniline;
(459) 2-{ 2-[3-(lH-imidazol-l-ylmethyl)phenyl]-2H-tetraazol-5-yl Ipyridine; (460) 2-methoxy-N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]aniline;
(461) 2-[2-(3-fluoro-5-iodophenyl)-2H-tetraazol-5-yl]pyridine;
(462) 3-fluoro-5-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(463) 3-[5-(4,5-dibromo-lH-imidazol-2-yl)-2H-tetraazol-2-yl]-5-fluorobenzonitrile;
(464) 2- { 2- [3-fluoro-5 -(pyridin-3 -ylmethoxy)phenyl] -2H-tetraazol-5-yl } pyridine ; (465) 2-{ [3-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenoxy]methyl| benzonitrile;
(466) N-{3-fluoro-5-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]phenyl|-N- methylpyridin-3 -amine ;
(467) 3-chloro-5-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile; (468) 3-{3-fluoro-5-[5-(l-methyl-lH-imidazol-2-yl)-2H-tetraazol-2-yl]phenoxy} pyridine;
(469) 4-chloro-2-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(470) 2-[2-(2,4-dichlorophenyl)-2H-tetraazol-5-yl]pyridine;
(471) 2-[2-(5-chloro-2-methoxyphenyl)-2H-tetraazol-5-yl]pyridine; (472) 3-[5-(2-methyl-2Η-pyrazol-3-yl)-tetrazol-2-yl]-benzonitrile;
(473) 3-[5-(lH-imidazol-4-yl)-tetrazol-2-yl]-benzonitrile;
(474) 3-[5-(5-methoxy-pyridin-2-yl)-tetrazol-2-yl]-benzonitrile;
(475) 3 - [5 -( 1 H-benzoimidazol-2-yl)-tetrazol-2-yl] -benzonitrile ;
(476) 4-bromo-3-fluoro-5-[5-(3-fluoro-pyridin-2-yl)-tetrazol-2-yl]-benzonitrile; (477) 3-{3-[5-(4,5-dibromo-lH-imidazol-2-yl)-tetrazol-2-yl]-5-fluoro-phenoxy|- pyridine;
(478) 7-{2-[3-fluoro-5-(pyridin-3-yloxy)-phenyl]-2H-tetrazol-5-yl|-pyrazolo[l,5- a]pyridine;
(479) 2-[2-(5-methylisoxazol-3-yl)-2H-tetraazol-5-yl]pyridine; (480) N-phenyl-N-[4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]amine;
(481) N-[4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]pyridin-2-amine;
(482) N-phenyl-N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]amine;
(483) 2-{ 2-[4-(pyridin-2-yloxy)phenyl]-2H-tetraazol-5-yl Ipyridine;
(484) 2-{2-[3-(3-methoxyphenoxy)phenyl]-2H-tetraazol-5-yl|pyridine; (485) 2-bromo-6-{2-[3-fluoro-5-(ρyridin-3-yloxy)ρhenyl]-2H-tetraazol-5-yl| pyridine;
(486) 2-{2-[3-fluoro-5-(pyridin-3-yloxy)ρhenyl]-2H-tetraazol-5-yl}-6- methoxypyridine ; (487) 2-{2-[3-methoxy-4-(3H-lλ5,2,3,4-tetraazol-l-ylmethyl)phenyl]-2H-tetraazol- 5-yl Ipyridine;
(488) 2-(2-pyridin-3-yl-2H-tetraazol-5-yl)ρyridine;
(489) 2-chloro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridine;
(490) 3-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]pyridine; (491) 2-(2-pyridin-2-yl-2H-tetraazol-5-yl)pyridine;
(492) N,N-dimethyl-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-amine;
(493) N-pyridin-2-yl-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-amine;
(494) N-pyridin-3-yl-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-amine;
(495) 3-chloro-N-[5-(5-pyridin-2-yl-2H-tetraazol-2-yl)pyridin-2-yl]-5- (trifluoromethyl)pyridin-2-amine;
(496) 3-(5-quinolin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(497) 3-(5-isoquinolin-3-yl-2H-tetraazol-2-yl)benzonitrile;
(498) 2-[2-(4-bromo-3-fluorophenyl)-2H-tetraazol-5-yl]pyridine;
(499) 2-{2-[3,5-bis(trifluoromethyl)phenyl]-2H-tetraazol-5-yl}pyridine; (500) 2-{ 2-[4-bromo-3-(trifluoromethyl)phenyl]-2H-tetraazol-5-yl Ipyridine;
(501) imethyl 5-(5-pyridin-2-yl-2Η-tetrazol-2-yl)isophthalate;
(502) 2-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenoxy]ethylamine;
(503) 2-{2-[3-fluoro-5-(pyridin-2-ylmethoxy)phenyl]-2H-tetraazol-5-yl Ipyridine;
(504) 2-[2-(2,6-dichloroρhenyl)-2H-tetraazol-5-yl]pyridine; (505) [3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl] acetic acid;
(506) 2-[2-(3-iodo-4-methylphenyl)-2H-tetraazol-5-yl]pyridine;
(507) 2-[2-(4-chloro-3-methylphenyl)-2H-tetraazol-5-yl]pyridine;
(508) 2-[2-(l ,3-benzodioxol-5-yl)-2H-tetraazol-5-yl]pyridine;
(509) 2-{2-[2-chloro-5-(trifluoromethyl)phenyl]-2H-tetraazol-5-yl Ipyridine; (510) 2-chloro-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(511) 2-[2-(4-bromo-3-methylphenyl)-2H-tetraazol-5-yl]pyridine;
(512) 2-[2-(3,4-dichlorophenyl)-2H-tetraazol-5-yl]pyridine;
(513) 2-[2-(3-chloro-4-fluorophenyl)-2H-tetraazol-5-yl]pyridine;
(514) 2-[2-(3-fluoro-4-methylphenyl)-2H-tetraazol-5-yl]ρyridine; (515) l-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]ethanol; (516) l-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]ethanone;
(517) [3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]methanol;
(518) 2-[2-(3-phenoxyphenyl)-2H-tetraazol-5-yl]pyridine;
(519) 2- { 2- [3 -(benzyloxy)phenyl] -2H-tetraazol-5-yl } pyridine ; (520) 2-{2-[3-(methylsulfonyl)ρhenyl]-2H-tetraazol-5-yl|pyridine;
(521) N-[3-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]acetamide;
(522) 2-[2-(3-isopropylphenyl)-2H-tetrazol-5-yl]pyridine;
(523) 2-(5-ρyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(524) 2-(2-phenyl-2H-tetraazol-5-yl)ρyridine; (525) [2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]acetonitrile;
(526) 2-[2-(3-methoxy-4-methylphenyl)-2H-tetraazol-5-yl]pyridine;
(527) 2-[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl]-2-methylpropanenitrile;
(528) 2-{cyano[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]methyl| nicotinonitrile; (529) 2-[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]succinonitrile;
(530) 2-[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]propane-l,2,3- tricarbonitrile;
(531) 2-[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]propanenitrile;
(532) 2-{cyano[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)methyl|benzonitrile; (533) (6-fluoropyridin-2-yl)[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2- yl)phenyl] acetonitrile ;
(534) [2-methoxy-4-(5-ρyridin-2-yl-2H-tetraazol-2-yl)phenyl](pyridin-2- yl)acetonitrile;
(535) 2-(2-pyridin-3-yl-2H-tetraazol-5-yl)pyridine; (536) 2-{2-[4-(methylthio)phenyl]-2H-tetraazol-5-yl Ipyridine;
(537) 2{ 2-[4-(trifluoromethoxy)phenyl]-2H-tetraazol-5-yl Ipyridine;
(538) 4-((5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(539) 2-[2-(4-chlorophenyl)-2H-tetraazol-5-yl]pyridine;
(540) 2-[2-(2-naphthyl)-2H-tetraazol-5-yl]pyridine; (541) 2-[2-(3,5-ditert-butylphenyl)-2H-tetraazol-5-yl]pyridine;
(542) 2-fluoro-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitιile;
(543) 2-{2-[4-(bromomethyl)-3-methoxyphenyl]-2Η-tetraazol-5-yl|pyridine;
(544) 2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzoic acid;
(545) 2-[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]ethanamine; (546) l-nitroso-6-(5-pyridin-2-yl-2H-tetraazol-2-yl)indoline; (547) 2-[2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)phenyl]propan-2-ol;
(548) 2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzamide;
(549) 2-methoxy-4-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(550) 3-bromo-6-(5-pyridin-2-yl-2H-tetraazol-2-yl)-lH-indole; (551) 6-(5-pyridin-2-yl-2H-tetraazol-2-yl)-lH-indole;
(552) 6-(5-pyridin-2-yl-2H-tetraazol-2-yl)-lH-indole-l-carbonitrile;
(553) 6-(5-pyridin-2-yl-2H-tetraazol-2-yl)-lH-indole-3-carbonitrile;
(554) 3-methoxy-5-(5-pyridin-2-yl-2H-tetraazol-2-yl)benzonitrile;
(555) 3-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]-5-methylbenzonitrile; (556) 3-{ 3-fluoro-5-[5-(4-methyl-lH-imidazol-2-yl)-2H-tetraazol-2- yl] phenoxy } pyridine ;
(557) 3-chloro-5-[5-(lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(558) 3-methyl-5-[5-(5-methyl-lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(559) 3-chloro-5-[5-(5-methyl-lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile; (560) 3-fluoro-5-[5-(l ,3-thiazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(561) 3-fluoro-5-[5-(l,3-thiazol-4-yl)-2H-tetraazol-2-yl]benzonitrile;
(562) 3-{3-fluoro-5-[5-(l,3-thiazol-4-yl)-2H-tetraazol-2-yl]phenoxy}pyridine;
(563) 3-fluoro-5-{5-[4-(trifluoromethyl)-lH-imidazol-2-yl]-2H-tetraazol-2- yl|benzonitrile; (564) 3-[5-(4-methyl-lH-imidazol-2-yl)-2H-tetraazol-2-yl]-5-(pyridin-3- yloxy)benzonitrile;
(565) 3-methoxy-5-[5-(4-methyl-lH-imidazol-2-yl)-2H-tetraazol-2-yl]benzonitrile;
(566) 2-[4-(3-chlorophenyl)-lH-imidazol-l-yl]pyridine;
(567) 2-(4-pyridin-3-yl- lH-imidazol- 1 -yl)pyridine; (568) 2-[l-(3-chlorophenyl)-lH-imidazol-4-yl]pyridine;
(569) 2-{ l-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-imidazol-4-yl Ipyridine; or a pharmaceutically acceptable salt thereof.
24. The use according to Claim 17 for preventing an eating disorder asssociated with excessive food intake in a human in need of such prophylaxis.
25. The use according to Claim 24, wherein the eating disorder associated with excessive food intake is selected from obesity, obesity related conditions, bulimia nervosa, and compulsive eating disorders.
26. The use according to Claim 25, wherein the eating disorder associated with excessive food intake is obesity.
27. The use according to Claim 26, wherein the human is a person at risk for obesity.
28. The method according to Claim 24, wherein the eating disorder associated with excessive food intake is an obesity related condition is selected from: diabetes, non-insulin dependent diabetes mellitus-type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver, cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, infertility, hyperlipidemia, and cardiovascular disease.
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