WO2010075273A1 - Bicyclic heterocycle derivatives and methods of use thereof - Google Patents

Bicyclic heterocycle derivatives and methods of use thereof Download PDF

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Publication number
WO2010075273A1
WO2010075273A1 PCT/US2009/068972 US2009068972W WO2010075273A1 WO 2010075273 A1 WO2010075273 A1 WO 2010075273A1 US 2009068972 W US2009068972 W US 2009068972W WO 2010075273 A1 WO2010075273 A1 WO 2010075273A1
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alkyl
compound
alkylene
aryl
group
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PCT/US2009/068972
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French (fr)
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Unmesh G. Shah
Craig D. Boyle
Samuel Chackalamannil
Bernard R. Neustadt
Joel M. Harris
Andrew Stamford
William J. Greenlee
Santhosh Francis Neelamkavil
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Schering Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • GPCR BACKGROUND OF THE INVENTION
  • GPCRs Receptors, including GPCRs, for which the endogenous ligand has been identified are referred to as "known" receptors, while receptors for which the endogenous ligand has not been identified are referred to as "orphan" receptors.
  • GPCRs represent an important area for the development of pharmaceutical products, as evidenced by the fact that pharmaceutical products have been developed from approximately 20 of the 100 known GPCRs. This distinction is not merely semantic, particularly in the case of GPCRs.
  • GPCRs share a common structural motif. All these receptors have seven sequences of between 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane (each span is identified by number, i.e., transrnembrane-1 (TMM ), transmembrane-2 (TM-2), etc.).
  • TMM transrnembrane-1
  • TM-2 transmembrane-2
  • transmembrane helices are also joined by strands of amino acids between transmembrane-1 and transmembrane-2, transmembrane-3 and transmembrane-4, and transmembrane-5 and transmembrane-6 on the interior, or "intracellular” side, of the cell membrane (these are referred to as "intracellular” regions 1 , 2 and 3 (IC-1 , IC-2 and IC-3), respectively).
  • the "carboxy" (“C”) terminus of the receptor lies in the intracellular space within the cell, and the "amino" ( 11 N”) terminus of the receptor lies in the extracellular space outside of the cell.
  • GPCRs are "promiscuous" with respect to G proteins, i.e., that a GPCR can interact with more than one G protein, See, Kenakin, T., Life Sciences 43, 1095 (1988). Although other G proteins exist, currently, Gq 1 Gs, Gi, and Go are G proteins that have been identified.
  • Endogenous ligand-activated GPCR coupling with the G-protein begins a signaling cascade process (referred to as "signal transduction"). Under normal conditions, signal transduction ultimately results in cellular activation or cellular inhibition. It is thought that the IC-3 loop as well as the carboxy terminus of the receptor interact with the G protein.
  • G-protein coupled receptors Modulation of G-protein coupled receptors has been well-studied for controlling various metabofic disorders.
  • Small molecule modulators of the receptor GPR119 a G-protein coupled-receptor described in, for example, GenBank (see, e.g., accession numbers XM.sub.--066873 and AY288416), have been shown to be useful for treating or preventing certain metabolic disorders.
  • GPR119 is a G protein-coupled receptor that is selectively expressed on pancreatic beta cells. GPR119 activation leads to elevation of a level of intracellular cAMP, consistent with GPR119 being coupied to Gs. Agonists to GPR119 stimulate glucose-dependent insulin secretion in vitro and lower an elevated blood glucose level in vivo. See, e.g., International Publication Nos. WO 04/065380 and WO 04/076413, and EP 1338651 , the disclosure of each of which is herein incorporated by reference in its entirety.
  • U.S. Patent No. 7,136,426 discloses pyrazoto[3,4-d]pyrimidine ethers and related compounds as modulators of the GPR119 receptor that are useful for the treatment of various metabolic-related disorders such as type i diabetes, type Il diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperfipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X, The compounds are also reported as being useful for controlling weight gain, controlling food intake, and inducing satiety in mammals.
  • the promising nature of these GPCR modulators indicates a need in the art for additional small molecule GPCR modulators with improved efficacy and safety profiles. This invention addresses that need.
  • the present invention provides Compounds of Formula (I):
  • A is aryl or heteroaryl, each of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cydoalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, halo, -OH, -O-haloalkyl, -O-alkyl, -O- alkyl-OH, -O-alkyl-O-alkyl, -O-aryl, -alkylene-O-alkyl, -CN, -N(R 4 ) 2 , -C(O)H, -C(O)R 4 , - C(O)OR 4 , -C(O)N(R 4 ) 2 , -NHC(O)R 4 , -NHS(O) m R 4 , -S(O) n R 4 and -S(O) m N(R
  • aryl or heteroaryl each of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycioalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, -OH, -O-haloalkyl, - O-alkyI, -O-aryl, -alkylene-O-alkyl, -alkylene-S(O) 2 -alkyl, -SF 5 , -CN, -N(R 4 ) 2 , -C(O)H, - C(O)R 4 , -C(O)OR 4 , -C(O)N(R 4 ) 2 , -NHC(O)R 4 , -NHS(O) m R 4 , -S(O) n R 4 and - S(O) m
  • G is -C(R 1 )- or -N-;
  • W is a bond, -O-, -C(O)O-, -C(R 12 )-, -alkylene-O-, alkylene, -C(O)- -S(O)-, ⁇ S(O) 2 - -S(O) 2 -N(R 10 )-, -N(R 12 )-, -NHC(O)- or -C(O)-N(R 10 K such that W is other than -O- when G is -N-, and such that when G is -C(R 1 )- and W is -C(R 12 )-, these R 1 and R 12 groups can combine to form a C 1 -C 3 alkylene bridge between G and W and form a spirocycle;
  • X is a bond, -C(R 1 ) 2 -, -O-, -N(R 10 )- or -S-;
  • each occurrence of R 1 is independently H 1 alkyl, cycloalkyl, halo or -OR 7 ; wherein an alkyl group can be unsubstituted or optionally substituted with one or more of the following groups: -O-alkyl, -OH or -N(R 4 ) 2 ; and wherein any two geminal R 1 groups, together with the common carbon atom to which they are attached, can join to form a spirocyclic 3- to 6-membered cycioalkyl group, a spirocyclic 3- to 6-membered heterocycloalkyl group or a spirocyclic 3- to 6-membered heterocycloalkenyl group; and wherein any two R 1 groups present on separate ring carbon atoms can join to form an alkylene or heteroalkylene bridge between the
  • R 3 is alkyt, -(alkylene) t -alkenyl, -(alkylene) t -alkynyl, -(alkylene) r C(O)R 4 , - (alkylene)t-haloalkyl, -alkylene-O-alkyl, -alkylene-O-(alkylene) r aryl, -alkylene-S-aryl, - alkylene-N(R 4 )C(O)O-alkyl, -CH(cycloalkyl) 2 , -CH(heterocycloalkyl) 2 , -(alkylene) r aryl, - (alkylene)t-cycloalkyl, -(alkylene) t -cycfoalkenyl, -(alkylene)rheterocycloalkyl, - (alkylene)t-heterocydoalkenyl or -
  • R 9 represents from 1 to 4 optional substituents, which can be the same or different, and which are selected from alkyl, hydroxyalkyl, -(alkylene) t -O-R 13 , alkenyl, alkynyl, halo, haloalkyl, -CN, -NO 2 , -O-(alkylene) r R 13 , -S-(alkylene) t -R 13 , -N(R 13 )- (alkylene)t-R 13 , -(alkylene) r R 13 , -(alkylene) r N(R 7 ) 2 , -C(O)-(alkylene ⁇ R 13 , -C(O)O- (alkylene)rR 13 , -N(R 7 )C(OMalkylene) r R 13 , -C(O)N(R 7 )-(alkylene) t -R 13 , -OC(O)
  • R 10 is H, alkyl, aryl, Or -C(O)OR 4 , wherein an alkyl group is unsubstituted or optionally substituted with -OH or -O-alkyl;
  • R 12 is H, alkyl or aryl; each occurrence of R 13 is independently H, haloalkyl, aryl, cycloalkyl, cycloalkanoyl, cycioalkenyl, heterocycioalkyl, heterocycloalkenyl or heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyj, heterocycloalkenyl or heteroaryl group can be optionally substituted with up to 3 groups, which can be the same or different, and which are selected from alkyl, alkenyl, halo, haloalkyl, -CN, - N(R 7 ) 2 , -OH, -O-alkyl or-O-haloalkyl; each occurrence of R 14 is independently H, alkyl or aryl, or both R 14 groups, and the carbon atom to which they are attached, combine to form a cycloalkyl or heteroc
  • A is aryl or heteroary ⁇ , any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, haio, -OH, -O-haloalkyl, -O-alkyl, -O- alkyl-OH, -O-alkyl-O-alkyl, -O-aryl, -alkylene-O-alkyl, -CN, -N(R 4 ) 2 , -C(O)H, -C(O)R 4 , - C(O)OR 4 , -C(O)N(R 4 ) 2 , -NHC(O)R 4 , -NHS(O) m R 4 , -S(O) n R 4 and -S(O) m N(R 4
  • B is aryl or heteroaryl, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, -OH, -O-haloalkyl, - O-alkyl, -O-aryl, -alkylene-O-alkyl, -alkylene-S(O) 2 -alkyl, -SF 5 , -CN, -N(R 4 ) 2 , -C(O)H, - C(O)R 4 , -C(O)OR 4 , -C(O)N(R 4 ) 2) -NHC(O)R 4 , -NHS(O) m R 4 , -S(O) n R 4 and - S(O) m N(R 4
  • X is "C(R 1 ) 2 -, -O-, -N(R 10 )- or -S-; each occurrence of R 1 is independently H, alkyl, cycloalkyl, halo or -OR 7 ; R 3 is alkyl, -(alkytene) t -alkenyl, -(alkylene) r alkynyl, -(alkylene) r C(O)R 4 , -
  • (alkylene)rhaloalkyl -alkylene-O-alkyl, -alkylene-O-(alkyIene) t -aryl, -alkylene-S-aryl, - alkylene-N(R 4 )C(O)O-alkyl, -CH(cycloalkyl) 2 , -CH(heterocycIoalkyl) 2 , -(alkylene ) r aryl, - (alkylene)t-cycloalkyl, -(alkylene)rcycloalkenyl, -(alkylene) t -heterocycloalkyl, - (alkylene) t -heterocycloalkenyl or -(alkylene) t -heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can
  • R 10 is H, alkyl, aryl, or -C(O)OR 4 , wherein an alkyl group is unsubstituted or optionally substituted with -OH or -O-alkyl; each occurrence of R 13 is independently H, haloalkyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl, wherein an aryl, cycloalkyl, cycioalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be optionally substituted with up to 3 groups, which can be the same or different, and which are selected from alkyl, halo, haloalkyl, -CN, -N(R 7 ) 2 , -OH, -O-alkyl or -O- haloalkyl; each occurrence of m is independently 1 or 2; each occurrence of n is independently O
  • the Compounds of Formulas (i) and (II) and pharmaceutically acceptable salts, solvates, esters or prodrugs thereof can be useful for treating or preventing obesity, diabetes, a diabetic complication, metabolic syndrome, a cardiovascular disease or a disorder related to the activity of a GPCR (each being a "Condition") in a patient. Also to provide by the invention are methods for treating or preventing a GPCR (each being a "Condition") in a patient. Also to provide by the invention are methods for treating or preventing a
  • the present invention provides Bicyclic Heterocycle Derivatives of Formulas (I) and (II), compositions comprising one or more Bicyclic Heterocycle Derivatives, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing a Condition in a patient.
  • a "patient” is a human or non-human mammal.
  • a patient is a human.
  • a patient is a non-human mammal, including, but not limited to, a monkey, dog, baboon, rhesus, mouse, rat, horse, cat or rabbit.
  • a patient is a companion animal, including but not limited to a dog, cat, rabbit, horse or ferret.
  • a patient is a dog. in another embodiment, a patient is a cat.
  • an obese patient refers to a patient being overweight and having a body mass index (BMI) of 25 or greater.
  • BMI body mass index
  • an obese patient has a BMI of 25 or greater
  • an obese patient has a BMI from 25 to 30.
  • an obese patient has a BMI greater than 30. in stil! another embodiment, an obese patient has a BMI greater than 40,
  • obesity-related disorder refers to: (i) disorders which result from a patient having a BMI of 25 or greater; and (ii) eating disorders and other disorders associated with excessive food intake.
  • Non-limiting examples of an obesity- related disorder include edema, shortness of breath, sleep apnea, skin disorders and high blood pressure.
  • metabolic syndrome refers to a set of risk factors that make a patient more succeptible to cardiovascular disease and/or type 2 diabetes. A patient is said to have metabolic syndrome if the patient simultaneously has three or more of the following five risk factors:
  • central/abdominal obesity as measured by a waist circumference of greater than 40 inches in a male and greater than 35 inches in a female; 2 ⁇ a fasting triglyceride level of greater than or equal to 150 mg/dL;
  • an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount
  • alkyl refers to an aliphatic hydrocarbon group which may be straight or branched and which contains from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms.
  • an alkyl group contains from about 1 to about 6 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • An a ⁇ kyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , - NH(alkyl), -N(alkyl) 2) -NH(cycloalkyl), -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(O)OH and -C(O)O-alkyl.
  • an alkyl group is unsubstituted.
  • an alkyl group is linear.
  • an alkyl group is branched.
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and contains from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms.
  • Non- limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyf.
  • An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , -NH(alkyl), -N ⁇ alkyl) 2 , -NH(cycloalkyl), -O-C(O)-alkyl, -O-C(O)-aryl, -0-C(O)- cycloalkyl, -C(O)OH and -C(O)O-alkyl.
  • an alkenyl group is unsubstituted.
  • alkynyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and contains from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon atoms.
  • Non- limiting examples of alkynyl groups include ethynyl, propynyl, 2 ⁇ butynyl and 3- methylbutynyl.
  • alkynyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , -
  • alkynyl group is unsubstituted.
  • alkylene refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond.
  • Non-timiting examples of alkylene groups include -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH(CH 3 )- and - CH 2 CH(CH 3 )CH 2 -.
  • an alkylene group has from 1 to about 6 carbon atoms.
  • an alkylene group is branched.
  • an alkylene group is linear.
  • aryl refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms. An aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of aryl groups include phenyl and naphthyl. in one embodiment, an aryl group is unsubstituted. In another embodiment, an aryl group is phenyl.
  • cycloalkyl refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkyl contains from about 5 to about 7 ring atoms.
  • cycloalkyl also encompasses a cycloalkyl group, as defined above, that is fused to an aryl (e.g., benzene) or heteroaryl ring. A cycloalkyl group can be joined via a ring carbon or ring nitrogen atom.
  • a ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group.
  • An illustrative example of such a cycloalkyl group ⁇ also referred to herein as a "cycloalkanoyl" group) includes, but is not limited to, cyclobutanoyl:
  • cycloalkenyl refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms and containing at least one endocyclic double bond. In one embodiment, a cycloalkenyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms.
  • monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like.
  • a cycloalkenyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • a cydoalkenyl group is unsubstituted.
  • a cycloalkenyl group is a 5-membered cycloalkenyl.
  • heteroalkylene refers to group having the formula - alkylene-X-alkylene- wherein X is -O-, -S- or -NH-.
  • Non-limiting examples of heteroalkylene groups include -CH 2 OCH 2 -, -CH 2 SCH 2 -, -CH 2 N(H)CH 2 -, - CH 2 OCH 2 CH 2 -, -CH 2 SCH 2 CH 2 - and -CH 2 N(H)CH 2 CH 2 -.
  • a heteroalkylene group has from 2 to about 6 carbon atoms.
  • a heteroalkylene group has from 2 to about 3 carbon atoms.
  • heteroaryl refers to an aromatic monocyclic or multicyciic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms.
  • a heteroaryl group has 5 to 10 ring atoms.
  • a heteroaryl group is monocyclic and has 5 or 6 ring atoms.
  • a heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide,
  • heteroaryl also encompasses a heteroaryl group, as defined above, that is fused to a benzene ring.
  • heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazo ⁇ yl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1 ,2, 4-th iadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzim ⁇ dazolyl, benzothienyl, quinolinyl, imidazolyl, thien
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinoSyl, tetrahydroquinolyl and the like.
  • a heteroaryf group is unsubstituted.
  • a heteroaryl group is a 5- membered heteroaryl.
  • a heteroaryl group is a 6-membered heteroaryl.
  • heterocycloalkyl refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 10 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S or N and the remainder of the ring atoms are carbon atoms.
  • a heterocydoalkyl group can be joined via a ring carbon or ring nitrogen atom.
  • a heterocydoalkyl group has from about 5 to about 10 ring atoms.
  • a heterocycloalkyl group has 5 or 6 ring atoms. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • heterocycloalkyl any -NH group in a heterocycloalkyl ring may exist protected such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention.
  • heterocycloalkyl also encompasses a heterocycloalkyl group, as defined above, that is fused to an aryl (e.g., benzene) or heteroaryl ring.
  • a heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • monocyclic heterocycioalkyl rings include oxetanyl, piperidyl, pyrroiidinyl, piperazinyl, morphoiinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiopheny), lactam, lactone and the like, and ail isomers thereof.
  • a ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group.
  • An illustrative example of such a heterocycloalkyl group is pyrrolidonyl:
  • a heterocycloalkyl group is unsubstituted.
  • a heterocycloalkyl group is a 5-membered heterocycloalkyl,
  • a heterocycloalkyl group is a 6-membered heterocycloalkyl.
  • the term "heterocycloalkenyl,” as used herein, refers to a heterocycloalkyl group, as defined above, wherein the heterocycloalkyl group contains from 3 to 10 ring atoms, and at least one endocyclic carbon-carbon or carbon-nitrogen double bond.
  • a heterocycloalkenyl group can be joined via a ring carbon or ring nitrogen atom.
  • a heterocycloalkenyl group has from 5 to 10 ring atoms. In another embodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms.
  • a heterocycloalkenyl group can optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • the nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocycloalkenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2- pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazoSyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluoro- substituted dihydrofuranyl, 7-oxabicycto[2.2.1]heptenyl, dihydrothiophenyf, dihydrothiopyranyl, and the like.
  • a ring carbon atom of a heterocycloalkenyl group may be functionatized as a carbonyl group.
  • a heterocycloalkenyl group is unsubstituted.
  • a heterocycloalkenyl group is a 5- membered heterocycloalkenyl.
  • a heterocycloalkenyl group is a 6-membered heterocycloalkenyl.
  • Ring system substituent refers to a substituent group attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkyl-aryl, -aryl-alkyl, -alkylene-heteroaryl, - alkenylene-heteroaryl, -alkynylene-heteroaryl, hydroxy, hydroxyalkyl, haloalkyl, -O- alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, -C(O)O-alkyl, -C(O)O-ary
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylenedioxy, ethylenedioxy, -C(CH 3 ) 2 ⁇ and the like which form moieties such as, for example:
  • Halo means -F, -Cl, -Br or -I. Sn one embodiment, halo refers to -F, -CI or - Br.
  • haloalkyl refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a halogen.
  • a haloalkyl group has from 1 to 6 carbon atoms, In another embodiment, a haloalkyl group is substituted with from 1 to 3 F atoms.
  • Non- limiting examples of haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CI and -CCI 3 .
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, to provide that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as weli as by reference to standard textbooks such as, for example, T. W. Greene et a/, Protective Groups in Organic Synthesis (1991 ), Wiiey, New York. When any variable (e.g., aryl, heterocycle, R 2 , etc.) occurs more than one time in any constituent or in Formula (I) or (II), its definition on each occurrence is independent of its definition at every other occurrence.
  • any variable e.g., aryl, heterocycle, R 2 , etc.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is to provide in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • the term "prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yleld a Bicyciic Heterocycle Derivative or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
  • the transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • mechanisms e.g., by metabolic or chemical processes
  • prodrugs are to provide by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversibie Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C 1 -C 8 )alkyl, (C 2 - C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1 ⁇
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C 1 - C 10 )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H 1 ( C 1 -C 6 )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is ( C 1 -C 6 )alkyl, carboxy (C 1 -C 6 )alkyl, amino(C 1 -C 4 )alkyI or mono-N — or di
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et a/ J. Pharmaceutical Sci., 93(3), 601-611 (2004) describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et a/, AAPS PharmSciTechours. , 5(1), article 12 (2004); and A. L. Bingham et a/, Chem. Commun., 603-604 (2001 ).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the Bicyc ⁇ ic Heterocycle Derivatives can form salts which are also within the scope of this invention.
  • Reference to a Bicyclic Heterocycle Derivative herein is understood to include reference to salts thereof, unless otherwise indicated.
  • salt(s) denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a Bicyclic Heterocycle Derivative contains both a baste moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxyltc acid, zwitterions ("inner salts”) may be formed and are included within the term “salt(s)" as used herein.
  • the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt.
  • the salt is other than a pharmaceutically acceptable salt.
  • Salts of the Bicyclic Heterocycle Derivatives may be formed, for example, by reacting a Bicyclic Heterocycle Derivative with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by iyophiiization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthatenesuifonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like.
  • alkali metal salts such as sodium, lithium, and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • salts with organic bases for example, organic amines
  • organic bases for example, organic amines
  • amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl, and
  • esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, ethyl, n-propyl, isopropyt, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C 1-4 a[kyl, or -O-C 1-4 alkyl or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesuifonyl)
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • Sterochemicaliy pure compounds may also be prepared by using chiral starting materials or by employlng salt resolution techniques.
  • some of the Bicyclic Heterocycle Derivatives may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral HPLC column
  • Bicyclic Heterocycle Derivatives may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, ail keto-enol and imine-enamtne forms of the compounds are included in the invention.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyridyl and 3-pyridyt).
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelied compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S 1 18 F, and 36 CI, respectively.
  • Certain isotopically-labelied Pyrimidine Derivatives are useful in compound and/or substrate tissue distribution assays.
  • tritiated (i.e., 3 H) and carbon-14 (Le., 14 C) isotopes are employed for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements)
  • one or more hydrogen atoms of a Bicyclic Heterocycie Derivative is replaced with a deuterium atom.
  • lsotoptcally iabelied Bicyclic Heterocycie Derivatives can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • Polymorphic forms of the BicycHc Heterocycle Derivatives, and of the salts, solvates, hydrates, esters and prodrugs of the Bicyctic Heterocycfe Derivatives are intended to be included in the present invention.
  • the present invention provides Bicyclic Heterocycle Derivatives of Formula (I):
  • G is -CH-. in another embodiment, G is -N-. in one embodiment, W is a bond, -O- or TMalkylene-O-. in another embodiment, W is a bond.
  • W is alkylene. In another embodiment, W is -O-.
  • W is -alkylene-O-. In another embodiment, W is -C(O)O-.
  • W is -C(O)-.
  • W is -S(O) 2 -. In another embodiment, W is -S(O) 2 N(R 10 )-.
  • W is -C(O)N(R 10 )-.
  • G is -CH- and W is a bond, -O- or-alkylene-O-.
  • G is -CH- and W is a bond.
  • X is -C(R 1 ) 2 -. In another embodiment, X is -O-,
  • X is -S-
  • X is -N(R 10 )-.
  • X is -NH-.
  • Z is -C(R 1 ) 2 -. In another embodiment, Z is a single bond.
  • Z is a double bond.
  • Z is -O-. in another embodiment, Z is -S-.
  • Z is -N(R 10 )-. In another embodiment, Z is -CHR 1 -.
  • Z is -CH 2 -.
  • Z is -NH-
  • W is -C(O)O- and Z is a single bond
  • W is a bond and Z is a single bond
  • W is -C(O)O-
  • Z is a single bond
  • X is -O- .
  • W is a bond
  • Z is a single bond
  • X is -O-.
  • W is -C(O)O-
  • Z is a single bond
  • X is-NH-.
  • W is a bond
  • Z is a single bond
  • X is-NH-.
  • A is aryl
  • A is 5 or 6-membered heteroaryt.
  • A is phenyl. In still another embodiment, A is pyrimidinyl.
  • -A- is:
  • -A- is:
  • A is:
  • A is pyridyl.
  • X is -O- and A is pyrimidinyl, in another embodiment, X is -NH- and A is pyrimidinyl. In one embodiment, X is -O- and A is:
  • X is -NH- and A is:
  • Q wherein Q is H, F, methyl or -OCH 3 .
  • B is aryl. In another embodiment, B is heteroaryl. In another embodiment, B is 5 or 6-membered heteroaryl. In another embodiment, B is phenyl.
  • B is pyrimidinyl. In another embodiment, B is pyridyl.
  • B is phenyl, which is ⁇ nsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S(O) 2 -alkyl, -S(O) 2 - cycloalkyl, heteroaryl and halo.
  • B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from -CN, -S(O)ralkyl and halo.
  • B is:
  • B is:
  • X is -NH- or -O-
  • B is:
  • X is -O- and B is:
  • X is -NH- and B is:
  • a and B are each independently he In another ambodiment, A and B are each independently a 5 or 6-membered heteroaryl.
  • A is a 5 or 6-membered heteroaryl and B is pyridyl.
  • -A- is:
  • X is -NH- • oorr --O0--, and -A- is:
  • X is -NH- or -O-, and -A- is:
  • A is: , wherein Q is H, halo, alkyl or -O-alkyl; and B is heteroaryl. In another embodiment, A is:
  • A is;
  • O is H, halo, alkyl or -O-alkyl; and B is:
  • A is 5 or 6-membered heteroaryl and B is phenyl.
  • A is pyrimidinyl and B is phenyl.
  • A is pyrimidinyl and B is pyridyl.
  • B is phenyl which is optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S ⁇ O) 2 -alkyl, -S(O) 2 -cycloalkyl, heteroaryl and halo; and A is:
  • B is phenyl which is optionally substituted with up to 3 groups, each independently selected from methyl, triazoiyl, -CN 1 -Cl, -F 1 -S(O) 2 CH 3 and -S(O) 2 -cyclopropyl; and A is:
  • Q wherein Q is H, F, methyl or methoxy.
  • B is pyridyl and A is:
  • Q wherein Q is H 5 halo, alkyl or -O ⁇ alkyl.
  • X is -O 1
  • A is pyrimidinyl and B is pyridyl
  • X is -NH-
  • A is pyrimidinyl
  • B is pyridyl
  • X is -O- , A is pyrimidinyl and B is phenyl. In another embodiment, X is -NH-, A is pyrimidinyl and B is phenyl.
  • X is -0-
  • A is pyrimidinyl and B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S(O) 2 -alkyl, -S(O) 2 -cycloalkyl, heteroaryl and halo.
  • X is -NH-
  • A is pyrimidinyl
  • B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S(O) 2 -alkyl, -S(O) 2 -cycloalkyl, heteroaryl and halo.
  • a and B are each independently a 5 or 6-membered heteroaryf, each of which is unsubstituted or optionally substituted with one substituent, independently selected from alkyl, -CN, -S ⁇ O) 2 -alkyl, -S(O) 2 -cycloalkyl, heteroaryl and halo.
  • a and B are each independently selected from phenyl, pyridyl and pyrimidinyl, each of which is unsubstituted or optionally substituted with one substituent, independently selected from alkyl, -CN, -S(O) 2 -alkyI, -S(O) 2 - cycloalkyl, heteroaryl and halo.
  • a and B are each independently selected from phenyl, pyridyl and pyrimidinyl, each of which is unsubstituted or optionally substituted with one or more substituents, each independently selected from methyl, triazolyl, -CN, - Cl, -F, -S(O) 2 CH 3 or -S(O) 2 -cyclopropyl.
  • X is -O-
  • A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one substituent, independently selected from alkyl, -CN, -S ⁇ O) 2 -alkyl, -S(O) 2 -cycIoalkyl, heteroaryl and halo.
  • X is -O-
  • A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one or more substituents, each independently selected from methyl, triazolyl, -CN, -Cl, -F, -S(O)aCH 3 or -S(O) 2 - cyclopropyl.
  • X is -O-
  • A is pyrirnidinyl and B is pyridyl, wherein A and B are each substituted with at least one alkyl group,
  • X is -O-, A is pyrimidinyl and B is pyridyl, wherein A and B are each substituted with a methyl group.
  • X is -O-, A is pyrimidinyl and B is pyridyl.
  • X is -O-
  • A is pyrimidinyl and B is phenyl.
  • X is -O-, A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one substituent, independently selected from alkyl, -CN, -S(O) 2 -alkyl, -S ⁇ O) 2 -cycloalkyl, heteroaryl and halo,
  • X is -O- , A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one or more substituents, each independently selected from methyl, triazolyl, -CN 1 -C), -F, -S(O) 2 CH 3 Or -S(O) 2 - cyclopropyl.
  • the group B-X-A- is:
  • Q is H, halo, alkyl or -O-alkyl.
  • the group B-X-A- is:
  • the group B-X-A- is:
  • the group B-X-A- is:
  • the group B-X-A- is:
  • the group B-X-A- is:
  • group B-X-A- is: in yet another embodiment, the group B-X-A- is:
  • the group B-X-A- is:
  • group B-X-A- is:
  • the group B-X-A- is:
  • each occurrence of R 1 is selected from H 1 halo or -OH. In another embodiment, each occurrence of R 1 is H.
  • At least one occurrence of R 1 is -OH.
  • At least one occurrence of R 1 is halo.
  • At least one occurrence of R 1 is F.
  • At least one occurrence of R 2 is H, alkyl or -OH. !n another embodiment, at least one occurrence of R 2 is -OH. in still another embodiment, at least one occurrence of R 2 is alkyl.
  • At least one occurrence of R 2 is H.
  • each occurrence of R 2 is H
  • R 3 is alkyl. In another embodiment, R 3 is a linear alkyl group.
  • R 3 is a branched alkyl group.
  • R 3 is methyl. In another embodiment, R 3 is ethyl. In another embodiment, R 3 is isopropyl. In a further embodiment, R 3 is t-butyl.
  • R 3 is alke ⁇ yl
  • R 3 is alkynyl.
  • R 3 is hafoalkyl. In one embodiment, R 3 is cycloalkyl. fn another embodiment, R 3 is cyclopropyl.
  • R 3 is cyclopropyl, substituted with a methyl group.
  • R 3 is cyclobutyl
  • R 3 is cyclopentyl. In another embodiment, R 3 is cyclohexyl.
  • R 3 is aryl. tn another embodiment, R 3 is phenyl.
  • R 3 is phenyl, optionally substituted with halo.
  • R 3 is heteroaryl. In another embodiment, R 3 is 5-membered heteroaryl, in another embodiment, R 3 is 6-membered heteroaryl.
  • R 3 is oxadiazotyl.
  • R 3 is oxadiazolyl, optionally substituted with alkyl, - alkylene-0-alkyl, -alkylene-N(alkyl) 2 , cycloalkyl or alkylene-heterocycloalkyl.
  • R 3 is 4-fluorophenyt, ethyl, t-butyl, isopropyl, -
  • R 3 is:
  • W is a bond and R 3 is heteroaryl or -alkylene-O-alkyl. In another embodiment, W is a bond and R 3 is heteroaryl. In another embodiment, W is a bond and R 3 is oxadiazolyl, optionally substituted with alkyl, -alkylene-O-alkyl, -aIkylene-N(alkyI) 2 , cycioalkyl or alkylene- heterocycloalkyl.
  • W is a bond and R 3 is;
  • R 3 is -alkylene-aryl. In a further embodiment, R 3 is benzyl. In one embodiment, p and u are each 1. In another embodiment, u, p, q, r, and s are each independently O or 1.
  • p and u are each 1 , and r and s are each O.
  • q, p and u are each 1 , r and s are each O and 2 is a bond.
  • q, p and u are each 1 , r and s are each O, Z is a bond, and W is a bond.
  • q, p and u are each 1 , r and s are each O, Z is a bond, W is a bond and X is -O-.
  • q, p and ⁇ are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -O-, A is a 5 or 6-membered heteroaryl, and B is phenyl or a 5 or 6- membered heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is -C(O)O-, X is -O-, A is a 5 or 6-membered heteroaryl, B is phenyl or pyridyl, and R 3 is heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is -C(O)O-, X is -O-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6- membered heteroaryl, each occurrence of R 1 is H, and R 3 is heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -O-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6- membered heteroaryl, each occurrence of R 1 and R 2 is H, and R 3 is heteroaryl,
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond and X is -NH-.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -NH-, A is a 5 or 6-membered heteroaryl, and B is phenyl or a 5 or 6- membered heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond,
  • W is -C(O)O-
  • X is -NH-
  • A is a 5 or 6-membered heteroaryl
  • B is phenyl or pyridyl
  • R 3 is heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is -C(O)O-, X is -NH-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6-membered heteroaryl, each occurrence of R 1 is H, and R 3 is heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -NH-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6- membered heteroaryl, each occurrence of R 1 and R 2 is H, and R 3 is heteroaryl.
  • the group -B-X-A- is:
  • Q is H, halo, alkyl or-O-alkyS, and the group:
  • the group -B-X-A- is:
  • the group -B-X-A- is: wherein Q is H, halo, alkyl or-O-alkyl, and the group:
  • the group -B-X-A- is: wherein Q is H, halo, alkyl or ⁇ O-alkyl, and the group:
  • the group -B-X-A- is: and the group: in still another embodiment, the group -B-X-A- is:
  • Q is H, halo, alkyl or -O-alkyl, and the group:
  • the group -B-X-A- is: and the group:
  • the present invention provides Compounds of Formula (I), wherein A, B 1 G 5 W 1 X, Z 1 R 1 , R 2 , R 3 , p, q, r, s and u are selected independently of each other.
  • a Compound of Formula (I) is in purified form.
  • a Compound of Formula (I) has the formula:
  • A is aryl or -5- or 6-membered heteroaryl, each of which can be optionally substituted with an alkyl, halo or -O-alkyl group;
  • B is aryl or heteroaryl, each of which can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from: alkyl, halo, heteroaryl, -CN or ⁇ S(O) 2 alkyl;
  • W is a bond, -O-, alkylene or -alkylene-O-;
  • X is -O- or -NH-
  • R 3 is alkyl, aryl or heteroaryl, wherein an aryl or heteroaryl group can be unsubstituted or optionally substituted with an alkyl, cycloalkanoyl, cycloalkyl, hydroxyalkyl, -alkylene-N(alkyl) 2 , or -alkylene-O-alkyl group, wherein a cycloalkyl substituent can be further and optionally substituted with up to 3 groups, which can be the same or different, and are selected from alkyl, alkenyl, halo, haioalkyl, -OH or -O- alkyl.
  • A is aryl. In another embodiment, for the Compounds of Formula (Ia), A is 5 or 6- membered heteroaryl,
  • A is phenyl. In still another embodiment, for the Compounds of Formula (Ia), A is pyrimidinyl. In another embodiment, for the Compounds of Formula (Ia), -A- is:
  • B is heteroaryl
  • B is 5 or 6- membered heteroaryl. In still another embodiment, for the Compounds of Formula (Ia), B is phenyl.
  • B is pyrimidinyl
  • B is pyridyl
  • B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN 1 -S(O) 2 -alkyl, -S(O) 2 -cycloalkyl ! heteroaryl and halo.
  • B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from -CN, -S(O) 2 -alkyl and halo.
  • B is:
  • B is:
  • W is a bond.
  • W is alkylene. In another embodiment, for the Compounds of Formula (Ia), W is -O-.
  • W is - alkylene-O-.
  • X is -O- .
  • X is -NH-.
  • X is -O- and B is:
  • a and B are each independently heteroaryl.
  • a and B are each independently a 5 or 6-membered heteroaryl.
  • A is a 5 or 6- membered heteroaryl and B is pyridyl.
  • A is a 5 or 6- membered heteroaryl and B is substituted phenyl.
  • X is -NH- or -O-, and -A- is:
  • X is -NH- or -O-, and -A- is:
  • A is:
  • Q is H, halo, alkyl or -O-alkyl; and B is heteroaryt
  • Q is H 1 halo, alkyl or -O-alkyl; and B is pyridyl.
  • A is:
  • A is 5 or 6-membered heteroaryl and B is phenyl.
  • A is pyrimidinyl and B is phenyl.
  • A is pyrimidinyl and B is pyridyl.
  • R 3 is alkyl
  • R 3 is a linear alkyl group.
  • R 3 is a branched alkyl group. In still another embodiment, for the Compounds of Formula (Ia), R 3 is methyl.
  • R 3 is ethyl. In another embodiment, for the Compounds of Formula (Ia), R 3 is isopropyl, in a further embodiment, for the Compounds of Formula (Ia), R 3 is t-butyl. In yet another embodiment, for the Compounds of Formula (Ia), R 3 is aryl. In another embodiment, for the Compounds of Formula (Ia), R 3 is phenyl.
  • R 3 is phenyl, optionally substituted with halo.
  • R 3 is heteroaryl. In another embodiment, for the Compounds of Formula (Ia), R 3 is 5-membered heteroaryl. In another embodiment, for the Compounds of Formula (Ia), R 3 is 6-membered heteroaryl.
  • R 3 is oxadiazoiyl.
  • R 3 is oxadiazolyl, optionally substituted with alkyl, -alkylene-O-alkyl, -alkylene-N(alkyl) 2 , cycioalkyl or alkylene-heterocycloalkyl.
  • R 3 is 4- fluorophenyl, ethyl, t-butyl, isopropyl,
  • R 3 is: in another embodiment, for the Compounds of Formula (Ia), R 3 is:
  • W is a bond and R 3 is heteroaryi
  • W is a bond and R 3 is oxadiazolyl, optionally substituted with alkyl, -alkylene-O-alkyl» -alky ⁇ ene- N(alkyl) 2 , cycloalkyl or alkylene-heterocycloalkyl.
  • W is a bond and R 3 is:
  • A is 6-membered heteroaryl, which can be optionally substituted with an alkyl group;
  • B is phenyl, which can be optionally substituted with up to 2 substituents, which can be the same or different and are selected from halo and -S(O) 2 -alkyl;
  • W is a bond; and
  • X is -0-.
  • A is 6-membered heteroaryl, which can be optionally substituted with an alkyl group
  • B is phenyl, which can be optionally substituted with up to 2 substituents, which can be the same or different and are selected from halo and -S ⁇ O) 2 -alkyl
  • W is a bond
  • X is -0-
  • R 3 is heteroaryl, which can be optionally substituted with an alkyl group.
  • A is pyrimidinyl, which can be optionally substituted with an alkyl group;
  • B is phenyl, which can be optionally substituted with up to 2 substituents, which can be the same or different and are selected from halo and ⁇ S(O) 2 -alkyl;
  • W is a bond;
  • X is -O-; and
  • R 3 is heteroaryl, which can be optionally substituted with an alkyl group.
  • the present invention provides compounds of Formula (Ia), wherein A, B, W and X are selected independently of each other.
  • a compound of formula (Ia) is in purified form.
  • the present invention further provides Bicyclic Heterocycle Derivatives of Formula (II):
  • G is -CH-. In another embodiment, G is -N-. In one embodiment, W is a bond Or -C(O)O-. In another embodiment, W is a bond. In another embodiment, W is -C(O)O-.
  • W is -C(O)-. In yet another embodiment, W is -S(O) 2 -. In another embodiment, W is -S(O) 2 N(R 10 )-. In a further embodiment, W is -C(O)N(R 10 )-.
  • G is N and W is -C(O)O-.
  • G is --CH- and W is a bond.
  • X is -C(R 1 ) 2 -.
  • X is -O-.
  • X is -S-.
  • X is -N(R 10 )-.
  • X is -NH-.
  • A is aryl
  • A is 5 or 6-membered heteroaryl.
  • A is phenyl
  • A is pyrimidtnyl.
  • A is pyridyl
  • A is 5-methylpyrimidinyl
  • B is aryl
  • B is 5 or 6-membered heteroaryl.
  • B is phenyl
  • B is pyrimidinyl
  • B is pyridyl. in another embodiment, B is 2-methyS pyridyl.
  • B is 2-chloro-4-cyanophenyl.
  • B is:
  • B is:
  • a and B are each independently a 5 or 6-membered heteroaryl.
  • X is -NH- and A is pyrimidinyf. In yet another embodiment, X is -NH- and B is phenyl.
  • X is -NH-
  • A is pyrimidinyl and B is phenyl.
  • a and B are each independently a 5 or 6-membered heteroaryl, each of which can be optionally substituted with one substituent, independently selected from alkyl, aryl, -S(O) 2 -alkyl and halo.
  • a and B are each independently selected from phenyl, pyridyl and pyrimidinyl, each of which can be optionally substituted with one substituent, independently selected from alkyl, aryl, -S(O) 2 -alkyl and halo.
  • a and B are each independently selected from phenyl, pyridyl and pyrirnidinyl, each of which can be optionally substituted with one or more substituents, each independently selected from methyl, phenyl, F 5 Cl and -S(O) 2 CH 3 .
  • X is -NH-
  • A is pyrimidinyl and B is phenyl, wherein each of A and B can be optionally substituted with one substituent, independently selected from alkyl, -CN, halo and -S(O) 2 -alkyl.
  • X is -NH-
  • A is pyrimidinyl and B is phenyl, wherein each of A and B can be optionally substituted with one or more substituents, each independently selected from methyl, -CN, F, -S(O ⁇ CH 3 and Cl.
  • the group B-X-A- is:
  • each occurrence of R is selected from H, alkyl, halo or -
  • each occurrence of R 1 is H.
  • R 3 is alkyl. in another embodiment, R 3 is a linear alkyl group.
  • R 3 is a branched alkyl group.
  • R 3 is methyl
  • R 3 is ethyl. in another embodiment, R 3 is isopropyl. In a further embodiment, R 3 is t-butyl. In one embodiment, R 3 is cycloalkyl. In yet another embodiment, R 3 is aryl. In another embodiment, R 3 is phenyl. In another embodiment, R 3 is -alkylene-aryl. In another embodiment, R 3 is benzyl. In another embodiment, R 3 is heteroaryl. In another embodiment, R 3 is:
  • R 3 is alkyl or heteroaryl, wherein a heteroaryl group can be optionally substituted with an alkyl or cycloalkyl group,
  • R 3 is isopropyl or t-butyl.
  • W is -C(O)O- and R 3 is alkyl.
  • W is a bond and R 3 is heteroaryl.
  • W is -C(O)O- and R 3 is isopropyl or t-butyl.
  • W is a bond and R 3 is:
  • p and q are each 1.
  • r and s are each 1.
  • p, q, r and s are each 1.
  • the sum of p and q is 1.
  • the sum of p and q is 2. in another embodiment, the sum of p and q is 3.
  • the sum of p and q is 4. In another embodiment, the sum of p and q is 5.
  • the sum of p and q is 6.
  • the sum of r and s is 1.
  • the sum of r and s is 2.
  • the sum of r and s is 3.
  • the sum of r and s is 4.
  • the sum of r and s is 5.
  • G is N; p is 1 ; and q, r and s are each 2.
  • G is N; p is 0; q is 3; and r and s are each 2.
  • G is N; p is 0; q is 2; and r and s are each 2.
  • G is N; p and q are each 2; and r and s are each 1.
  • G is N; p and q are each 2; r is 1 ; and s is 2.
  • G is -CH-; p and q are each 2; and the sum of r and s is 1.
  • G is N; W is -C(O)O-; R 3 is alkyl; and the group B-X-A- is:
  • G is -CH-; W is a bond; R 3 is heteroaryl; and the group B-X-A- is:
  • G is N; W is -C(O)O-; R 3 is isopropyl or t-butyl; and the group B-X-A- is: tn stilf
  • G is -CH-; W is a bond; R 3 is:
  • the present invention provides compounds of Formula (Ii), wherein A 1 B 1 G, W, X 1 R 1 , p, q, r and s are selected independently of each other.
  • a compound of formula (II) is in purified form.
  • Non-t ⁇ miting examples of the Bicyclic Heterocycle Derivatives include compounds 1-100, depicted below:
  • Scheme 1 illustrates a method useful for making the compounds of formula ill, which are useful intermediates for making the Bicyclic Heterocycle Derivatives of Formula (I).
  • a and B are defined above for the compounds of formulas (I) and (II); G is ⁇ OH, -SH 1 -NHR 10 or a carbon nucleophile; and X is -S-, -O-, -C(R V or -NR 10 .
  • a dichloro aryl or heteroaryl compound of formula i can be reacted with a compound of formula ii in the presence of a base, such as potassium carbonate or sodium hydride, to provide the intermediate compounds of formula Ui.
  • a base such as potassium carbonate or sodium hydride
  • Scheme 2 illustrates a general method useful for making the Compounds of Formula (I).
  • a compound of formula iv can be coupled with a compound of formula iii in the presence of diisopropylethylamine (DIPEA) in dioxane to provide the Compounds of Formula (I).
  • DIPEA diisopropylethylamine
  • Scheme 3 illustrates an alternative method useful for making the Compounds of Formula (i).
  • R 1 , R 2 , R 3 , A, B, G, W, X, Y, Z, p, q, r, s and u are defined above for the Compounds of Formula (I).
  • a compound of formula iv can be coupled with a compound of formula i in the presence of diisopropylethylamine (DIPEA) to provide the intermediate compounds of formula v, A compound of formula v can then be reacted with a compound of formula it using the method described in Scheme 1 for coupling i and H, This provides the Compounds of Formula (i) via a two step process.
  • DIPEA diisopropylethylamine
  • Scheme 4 illustrates a method useful for making the compounds of formula (II).
  • R 1 , R 3 , A, B, G, W, X, Y 1 p, q, r and s are defined above for the compounds of formula (II).
  • a compound of formula vi can be coupled with a compound of formula i in the presence of diisopropylethylamine (DiPEA) to provide the intermediate compounds of formula vii.
  • DiPEA diisopropylethylamine
  • a compound of formula vii can then be reacted with a compound of formula ii using a Buchwald N-arylation process or the method described in Scheme 1 for coupling i and ii. This provides the compounds of formula (H).
  • Derivatives may require the need for the protection of certain functional groups (i.e., derivatization for the purpose of chemical compatibility with a particular reaction condition).
  • Suitable protecting groups for the various functional groups of the Bicyclic Heterocycle Derivatives and methods for their installation and removal may be found in Greene et ah, Protective Groups in Organic Synthesis, Wiley-lntersctence, New York, (1999).
  • Step D Synthesis of Compound 1 To a solution of Compound 1D (-0.23 mmol) in DMF (1 mL) was added
  • Step C Synthesis of Compound 2C
  • a solution of Compound 2B (2.0 g, 8.3 mmol) in a mixture of acetonitrile (8 mL), ethyl acetate (8 mL), and water (12 mL) was added sodium periodate (8.17 g, 38.17 mmol) followed by ruthenium chloride (0.1 g, 0.48 mmoi).
  • the resulting reaction was allowed to stir at room temperature for 20 hours, after which time it was diluted with dichloromethane and washed with brine solution.
  • Step D Synthesis of Compound 2D
  • 4-methylmorpholine (0.71 mL, 6.47 mmoi) followed by isopropyl chloroformate (1M in toluene, 6.5 mL, 6.5 mmol).
  • the resulting reaction was allowed to stir at room temperature for 2 hours, after which time it was washed with water and brine.
  • the combined organic extracts were dried (Na 2 SO 4 ), filtered, and concentrated in vacuo and the resulting oily residue was taken up in 30 mL DMF.
  • Compound 2E was prepared from Compound 2D using the method described in Example 1 , Step C.
  • Step G Synthesis of Compounds 2 and 3
  • a solution of Compounds 2E (0.45 g, 2.05 mmoi) and 2F (0.65 g, 2.05 mmol) and N,N-diisopropylethylamine (0.75 ml_, 4.3 mmol) in 3.5 mL dioxane and 1.0 ml_ 1- methyl-2-pyrrolidinone was heated to 170 °C and allowed to stir at this temperature for 16 hours. The reaction was cooled to room temperature, water was added and the resulting solution was extracted with ethyl acetate.
  • Compound 8 was prepared by reacting Compound 2F with Compound 6D using the method described in Example 2, Step G; LCMS: 479 (M+H) + .
  • Step B Synthesis of Compound IB To a solution of Compound 7A (150 mg, 0.5 mmol) in 2 mi_ EtOH and 2 mL
  • Step C - Synthesis of Compound 9 Compound 9 was synthesized from compound 7B using the method described in Example 2, LCMS: 480 (IvHH) + .
  • Step D was replaced with N-hydroxy-2-methoxy- acetamidine (as synthesized in EP 1479674 A1 , 2004); LCMS: 503 (M+H) + ,
  • Step A - Synthesis of Compound 19A Compound 28 (0.015 g, 0.031 mmol) was diluted with 4.0M HCl/dioxane (2.0 mL) and the resulting solution was allowed to stir for 2 hours. The reaction mixture was then concentrated in vacuo to provide Compound 19A as its hydrochloride salt, which was used without further purification.
  • Step A (heating in a microwave apparatus for 2 hours at 14O°C)
  • Compound 21 C was converted to Compound 21 D, as a yellow solid.
  • Compound 22D was prepared from Compound 22C using the method described in Example 18, Step A.
  • Step E Synthesis of Compound 25F
  • Compound 25E and 5-methyl-4,6-dichloropyrimidine were reacted using the method described in Example 18, Step A, heating by microwave at 140 °C for 1.5 hours.
  • the resulting mixture of the exo- and encfo-isomers were separated by chromatography on silica ⁇ 0-20% EtOAc/hexane), with the e ⁇ cfo-isomer (Compound 25F) eluting first.
  • Step D Compound 27D was converted to Compound 27E, which was used without further purification.
  • Step F- Synthesis of Compound 27 F Compound 27E and 5-methyl-4,6-dichloropyrimidine were reacted according to the method described in Example 18, Step A, heating by microwave at 140 °C for 1 hour. Purification using preparative TLC provided Compound 27F as a yellow oil. Step G - Synthesis of Compound 38
  • Step B Synthesis of Compound 42
  • a solution of Compound 31 A (15 mg) in 0.5 mL THF was added dimethylamine (2M in THF, 1 mL) and the resulting reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was purified using preparative TLC (3% MeOH in CH 2 CI 2 ) to provide Compound 42.
  • LCMS 516 (M+H) + .
  • Step A Synthesis of compound 35A To a solution of 4,6-dichloro-5-methylprylmidine (0.28 g, 1.7 mmol) in 15 ml
  • Compound 46 was synthesized by reacting 35A with 2E according to the method described in Example 2, step G without using 1-methyl-2-pyrro!idine; LCMS: 465, 467 (M+Hf .
  • Compound 47 was synthesized by reacting 1E and 2E according to the method described in Example 2, step G without using i-methyl-2-pyrrolidine; LCMS: 421 (M+H) + .
  • Compound 50 was prepared from Compound 49 using the method described in Example 37; LCMS: 531 (M+H) + ,
  • Compound 51 was prepared using the method described in Example 35 and replacing 3-Chioro-4-hydroxybenzonitrile with 2-fluoro-4-methylsulfonylphenol in step A.
  • Compound 46C was synthesized from 46B using the method described in Example 2 for the synthesis of Compound 2E.
  • step A 1 Compound 2E was replaced with Compound 46C.
  • step B 1 4-(methylsulfonyl)- aniline was replaced with 2-fluoro-4-(methylsulfonyl)aniline and the reaction was conducted in dioxane using Cs 2 CO 3 and ( ⁇ )-BINAP instead of K 3 PO 4 and (o ⁇ biphenyl)PCy 2 respectively.
  • Compounds 65 and 66 were prepared using the method described in Example 35 and replacing 3 ⁇ Chloro- 4-hydroxybenzonitrile with 2-fluoro-4-methylsulfonylphenoi in step A.
  • Compound 65 LCMS: 506 (M-I-H) +
  • Compound 66 LCMS: 506 (M+H) + .
  • Compound 48A was synthesized using the method described above for the synthesis of Compound 2F.
  • Compound 49D was prepared from Compound 49C using the method described in Example 35.
  • Step D Synthesis of Compound 68
  • Compound 68 was prepared from Compound 49E using the method described in Example 2, Step D. LCMS; 518 (M+H) + .
  • Step A Synthesis of Compound 5OA
  • a solution of triethylphosphonoacetate (1.78 mL, 8.88 mmol) in 40 mL THF was added 60% NaH (0.36 g, 8.88 mmol).
  • the resulting reaction was allowed to stir for 30 minutes at 0 °C, after which time a solution of Compound 1 A (1.0 g, 4.44 mmol) in 4 mL THF was added.
  • the reaction was allowed to stir for 16 hours, during which time it was allowed to warm to room temperature on its own.
  • the reaction was then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2 x 40 mL).
  • the combined organic extracts were dried (Na 2 SO 4 ) t filtered and concentrated in vacuo to provide Compound 5OA which was used without further purification.
  • Compound 5OB was converted to Compound 5OC using the method described in Example 2, Steps E and G.
  • Step D Synthesis of Compound 69
  • Trifluoroacetic acid (0.32 mL, 4.2 mmol, 4 eq) was added to a solution of Compound 51 B (0.330 g, 1.05 mmol, 1 eq) in dichloromethane 10 mL at room temperature and the resulting reaction was allowed to stir at room temperature for 4 hours then was concentrated in vacuo. The resulting residue was taken up in 1 ,4- dioxane (10 mL) and to the resulting solution was added DIPEA (0.73 mL, 4.2 mmol, 4 eq) » followed by Compound 51 C (0.297 mg, 1.05 mmol, 1 eq). The resulting reaction was heated to 110 °C and allowed to stir at this temperature for 4 hours.
  • Step C Synthesis of Compound 52D
  • a solution of Compound 52C (0.78 g, 3.0 mmol), 4,6-dichloro-5- methylpyrimidine (0.51 g, 3.1 mmof) and DiPEA (1.06 mL, 6.1 mmol) in 1 ,4-dioxane (6 mL) was sealed and heated in a microwave apparatus at 155 °C for 1 hour.
  • the reaction mixture was then cooled to room temperature and concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica (0-40% EtOAc/hexanes) to provide Compound 52D.
  • Step D Synthesis of Compound 71
  • HEK293 cells expressing human GPR119 were maintained in culture flasks at 37 °C/5% CO 2 in DMEM containing 10% fetal bovine serum, 100 U/ml Pen/Strep, and 0.5 mg/ml geneticin. The media was changed to Opttmem and cells were incubated overnight at 37 °C /5% CO2. The Optimem was then aspirated and the cells were removed from the flasks using room temperature Hank's balanced saline solution (HBSS).
  • HBSS Hank's balanced saline solution
  • the cells were pelleted using centrifugation (1300 rpm, 7 minutes, room temperature), then resuspended in stimulation buffer (HBSS, 0.1 % BSA, 5 mM HEPES, 15 ⁇ M RO-20) at 2.5 x 10 6 ceils/mL. Alexa Fluor 647-anti cAMP antibody (1 :100) was then added to the cell suspension and incubated for 30 minutes.
  • a representative Bicyclic Heterocycle Derivative (6 ⁇ l at 2X concentration) in stimulation buffer containing 2% DMSO were then added to white 384 well Matrix plates. Cell suspension mix (6 ⁇ l) was added to each well and incubated with the Bicyclic Heterocycle Derivative for 30 minutes.
  • a cAMP standard curve was also created in each assay according to the kit protocol. Standard concentrations of cAMP in stimulation buffer (6 ⁇ l) were added to white 384 well plates. Subsequently, 6 ⁇ l of 1 :100 anti-cAMP antibody was added to each well. Following the 30 minute incubation period, 12 ⁇ l of detection mix (included in kit) was added to all wells and incubated for 2-3 hours at room temperature. Fluorescence was detected on the plates using an Envision instrument. The level of cAMP in each well is determined by extrapolation from the cAMP standard curve.
  • EC 50 values for various illustrative Bicyclic Heterocycle Derivatives pf the present invention were calculated and range from about 1 nM to about 20 ⁇ M.
  • Glucose was administered to the animals 30 minutes post-dosing (3 g/kg p.o.). Blood glucose was measured prior to administration of test compound and glucose, and at 20 minutes after glucose administration using a hand-held glucometer (Ascensia Elite, Bayer).
  • Derivatives of the present invention are effective in lowering blood glucose levels after glucose challenge. Uses of the Bicyclic Heterocycle Derivatives
  • the Bicyclic Heterocycle Derivatives are useful in human and veterinary medicine for treating or preventing a Condition in a patient.
  • the Bicyciic Heterocycle Derivatives can be administered to a patient in need of treatment or prevention of a Condition.
  • Bicyclic Heterocycle Derivatives are useful for treating obesity or an obesity-related disorder.
  • the invention provides methods for treating obesity or an obesity-related disorder in a patient, wherein the method comprises administering to the patient an effective amount of one or more Bicycfic Heterocycle Derivatives, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
  • the Bicyclic Heterocycle Derivatives are useful for treating diabetes in a patient. Accordingly, in one embodiment, the present invention provides a method for treating diabetes in a patient, comprising administering to the patient an effective amount of one or more Bicyclic Heterocycle Derivatives.
  • Non-limiting examples of diabetes treatable or preventable using the Bicyclic Heterocycle Derivatives include, type I diabetes (insulin-dependent diabetes mellitus), type II diabetes (non-insulin dependent diabetes mellitus), gestational diabetes, autoimmune diabetes, insulinopathies, idiopathic type I diabetes (Type 1 b), latent autoimmurnne diabetes in adults, early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition- related diabetes, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), type A insulin resistance syndrome, type B insulin resistance syndrome, lipatrophic diabetes, diabetes induced by ⁇ -cell toxins, and diabetes induced by drug therapy (such as diabetes induced by antipsychotic agents).
  • type I diabetes
  • the diabetes is type I diabetes. In another embodiment, the diabetes is type Il diabetes,
  • the Bicyclic Heterocycle Derivatives are useful for treating a diabetic complication in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a diabetic complication in a patient, comprising administering to the patient an effective amount of one or more Bicyciic Heterocycle Derivatives.
  • Non-limiting examples of diabetic complications treatable or preventable using the Bicyclic Heterocycle Derivatives include diabetic cataract, glaucoma, retinopathy, aneuropathy (such as diabetic neuropathy, polyneuropathy, mononeuropathy, autonomic neuropathy, microaluminuria and progressive diabetic neuropathyl), nephropathy, gangrene of the feet, immune-complex vasculitis, systemic lupsus erythematosus (SLE), atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorumobesity), hyperlipidemia, cataract, hypertension, syndrome of insulin resistance, coronary artery disease, a fungal infection, a bacterial infection, and cardiomyopathy.
  • the Bicyclic Heterocycle Derivatives are useful for treating a metabolic disorder. Accordingly, in one embodiment, the invention provides methods for treating a metabolic disorder in a patient, wherein the method comprises administering to the patient an effective amount of one or more Bicyclic Heterocycle Derivatives, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
  • Non-limiting examples of metabolic disorders treatable include metabolic syndrome (also known as "Syndrome X”), impaired glucose tolerance, impaired fasting glucose, hypercholesterolemia, hyperiipidemia, hypertriglyceridemia, low HDL levels, hypertension, phenylketonuria, post-prandial lipidemia, a glyc ⁇ gen-storage disease, Gaucher's Disease, Tay-Sachs Disease, Niernann-Pick Disease, ketosis and acidosis.
  • the metabolic disorder is hypercholesterolemia.
  • the metabolic disorder is hyperlipidemia.
  • the metabolic disorder is hypertriglyceridemia.
  • the metabolic disorder is metabolic syndrome.
  • the metabolic disorder is low HDL levels.
  • the Bicyclic Heterocycle Derivatives are useful for treating or preventing a cardiovascular disease in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a cardiovascular disease in a patient, comprising administering to the patient an effective amount of one or more Bicyclic Heterocycle Derivatives.
  • Non-iimitng examples of cardiovascular diseases treatable or preventable using the present methods include atherosclerosis, congestive heart failure, cardiac arrhythmia, myocardial infarction, atrial fibrillation, atrial flutter, circulatory shock, left ventricular hypertrophy, ventricular tachycardia, supraventricular tachycardia, coronary artery disease, angina, infective endocarditis, non-infective endocarditis, cardiomyopathy, peripheral artery disease, Reynaud's phenomenon, deep venous thrombosis, aortic stenosis, mitral stenosis, pulmonic stenosis and tricuspid stenosis.
  • the cardiovascular disease is atherosclerosis.
  • the cardiovascular disease is congestive heart failure. In another embodiment, the cardiovascular disease is coronary artery disease.
  • the present invention provides methods for treating a Condition in a patient, the method comprising administering to the patient one or more Bicyclic Heterocycle Derivatives, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof and at least one additional therapeutic agent that is not a Bicyclic Heterocycle Derivative, wherein the amounts administered are together effective to treat or prevent a Condition.
  • Non-iirniting examples of additional therapeutic agents useful in the present methods for treating or preventing a Condition include, anti-obesity agents, antidiabetic agents, any agent useful for treating metabolic syndrome, any agent useful for treating a cardiovascular disease, cholesterol biosynthesis inhibitors, cholesterol absorption inhibitors, bile acid sequestrants, probucol derivatives, IBAT inhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors, choiesteryl ester transfer proten (CETP) inhibitors, low-denisity lipoprotein (LDL) activators, fish oil, water-soluble fibers, plant sterols, plant stands, fatty acid esters of plant stanols, or any combination of two or more of these additional therapeutic agents.
  • anti-obesity agents any agent useful for treating metabolic syndrome
  • any agent useful for treating a cardiovascular disease cholesterol biosynthesis inhibitors, cholesterol absorption inhibitors, bile acid sequestrants, probucol derivatives, IBAT inhibitors, nico
  • Non-limiting examples of anti-obesity agents useful in the present methods for treating a Condition include CB 1 antagonists or inverse agonists such as rimonabant, neuropeptide Y antagonists, MCR4 agonists, MCH receptor antagonists, histamine H 3 receptor antagonists or inverse agonists, metaboiic rate enhancers, nutrient absorption inhibitors, leptin, appetite suppressants and lipase inhibitors.
  • CB 1 antagonists or inverse agonists such as rimonabant, neuropeptide Y antagonists, MCR4 agonists, MCH receptor antagonists, histamine H 3 receptor antagonists or inverse agonists, metaboiic rate enhancers, nutrient absorption inhibitors, leptin, appetite suppressants and lipase inhibitors.
  • Non-limiting examples of appetite suppressant agents useful in the present methods for treating or preventing a Condition include cannabinoid receptor 1 (CBi) antagonists or inverse agonists (e.g., rimonabant); Neuropeptide Y (NPY1 , NPY2, NPY4 and NPY5) antagonists; metabotropic glutamate subtype 5 receptor (mGluR5) antagonists (e.g., 2-methyl-6-(phenyIethynyl)-pyridine and 3[(2-methyl-1 ,4-thiazol-4- yl)ethynyl]pyridine); melanin-concentrating hormone receptor (MCH1 R and MCH2R) antagonists; melanocortin receptor agonists (e.g., Melanotan-ll and Mc4r agonists); serotonin uptake inhibitors (e.g., dexfenfluramine and fluoxetine); serotonin (5HT) transport inhibitors (e.g., paroxetine, fluoxetine
  • Non-timiting examples of metabolic rate enhancers useful in the present methods for treating or preventing a Condition include acetyl-CoA carboxylase-2 (ACC2) inhibitors; beta adrenergic receptor 3 ( ⁇ 3) agonists; diacylglyceroi acyltransferase inhibitors (DGAT1 and DGAT2); fatty acid synthase (FAS) inhibitors (e.g., Cerulenin); phosphodiesterase (PDE) inhibitors (e.g., theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram and cilom ⁇ ast); thyroid hormone ⁇ agonists; uncoupling protein activators (UCP-1 ,2 or 3) (e.g., phytanic acid, 4-[(E ⁇ -2-(5,6,7,84etramethyl-2-naphthalenyl)-1-propeny
  • Non-limiting examples of nutrient absorption inhibitors useful in the present methods for treating or preventing a Condition include lipase inhibitors (e.g., oriistat, lipstatin, tetrahydrolipstatin, teasaponin and diethylumbell ⁇ feryl phosphate); fatty acid transporter inhibitors; dicarboxylate transporter inhibitors; glucose transporter inhibitors; and phosphate transporter inhibitors.
  • lipase inhibitors e.g., oriistat, lipstatin, tetrahydrolipstatin, teasaponin and diethylumbell ⁇ feryl phosphate
  • fatty acid transporter inhibitors e.g., oriistat, lipstatin, tetrahydrolipstatin, teasaponin and diethylumbell ⁇ feryl phosphate
  • dicarboxylate transporter inhibitors e.g., dicarboxylate transporter inhibitors
  • glucose transporter inhibitors e.
  • Non-limiting examples of cholesterol biosynthesis inhibitors useful in the present methods for treating or preventing a Condition include HMG-CoA reductase inhibitors, squalene synthase inhibitors, squalene epoxidase inhibitors, and mixtures thereof.
  • Non-limiting examples of cholesterol absorption inhibitors useful in the present methods for treating or preventing a Condition include ezetimibe.
  • the cholesterol absorption inhibitor is ezetimibe.
  • HMG-CoA reductase inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, statins such as iovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, cerivastatin, CI-981 , resuvastatin, rivastatin, pravastatin, rosuvastatin or L-659,699 ((E,E)-11-[3'R-(hydroxy-methyl)-4'- oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoic acid).
  • Squalene synthesis inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, squalene synthetase inhibitors; squalestatin 1 ; and squalene epoxidase inhibitors, such as NB-598 ((E)-N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yf)methoxy]benzene- methanamine hydrochloride).
  • squalene synthetase inhibitors such as NB-598 ((E)-N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yf)methoxy]benzene- methanamine hydrochloride).
  • BtIe acid sequestrants useful in the present methods for treating or preventing a Condition include, but are not limited to, cholestyramine (a styrene-d ⁇ vinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available from Bristol-Myers Squibb), colestipol (a copolymer of diethy ⁇ enetriamine and 1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are available from Pharmacia), coiesevelam hydrochloride (such as WelChol® Tablets (poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1- bromodecane and ⁇ 6-bromohexyl)-trimethylammonium bromide) which are available from Sankyo), water soluble derivatives such as 3,3-
  • Suitable inorganic cholesterol sequestrants include bismuth salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids.
  • Probucol derivatives useful in the present methods for treating or preventing a Condition include, but are not limited to, AG 1-1067 and others disclosed in U.S. Patent Nos. 6,121 ,319 and 6,147,250.
  • IBAT inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, benzothiepines such as therapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1 ,1-dioxide structure such as are disclosed in International Publication No. WO 00/38727.
  • Nicotinic acid receptor agonists useful in the present methods for treating or preventing a Condition include, but are not limited to, those having a pyridine-3- carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers, where available.
  • nicotinic acid receptor agonists useful in the present methods include nicotinic acid, niceritrol, nicofuranose and acipimox.
  • An example of a suitable nicotinic acid product is NIASPAN® (niacin extended-release tablets) which are available from Kos Pharmaceuticals, Inc. (Cranbury, NJ).
  • nicotinic acid receptor agonists useful in the present methods for treating or preventing a Condition include, but are not limited to, the compounds disclosed in U.S. Patent Publication Nos, 2006/0264489 and 2007/0066630, and U.S. Patent Application No. 11/771538, each of which is incorporated herein by reference.
  • ACAT inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, avasimibe, HL-004, lecimibide and CL- 277082 (N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyI)phenyl]-methyl]-N- heptylurea). See P. Chang er al., "Current, New and Future Treatments in Dysiipidaemia and Atherosclerosis", Drugs 2000 Jul;60(1); 55-93, which is incorporated by reference herein.
  • CETP inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, those disclosed in International Publication No. WO 00/38721 and U.S. Patent No. 6,147,090, each of which are incorporated herein by reference.
  • LDL-receptor activators useful in the present methods for treating or preventing a Condition include, but are not limited to, include HOE-402, an imidazolidinyl- pyrimidine derivative that directly stimulates LDL receptor activity. See M. Huettinger et ai, "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb. 1993; 13:1005-12.
  • Natural water-soluble fibers useful in the present methods for treating or preventing a Condition include, but are not limited to, psyllium, guar, oat and pectin.
  • Fatty acid esters of plant stands useful in the present methods for treating or preventing a Condition include, but are not limited to, the sitostanol ester used in BENECOL® margarine.
  • Non-limiting examples of antidiabetic agents useful in the present methods for treating a Condition include insulin sensitizers, ⁇ -glucostdase inhibitors, DPP-IV inhibitors, insulin secretogogues, hepatic glucose output lowering compounds, antihypertensive agents, sodium glucose uptake transporter 2 fSGLT-2) inhibitors, insulin and insulin-containing compositions, and anti-obesity agents as set forth above.
  • the antidiabetic agent is an insulin secretagogue.
  • the insulin secretagogue is a sulfonylurea.
  • sulfonylureas useful in the present methods include glipizide, tolbutamide, glyburide, glimeptrtde, chlorpropamide, acetohexamide, gliamilide, gliclazide, giiquidone, glibenclamide and tolazamide.
  • the insulin secretagogue is a meglitinide.
  • meglitinides useful in the present methods for treating a Condition include repaglinide, mitiglinide, and nateglinide.
  • the insulin secretagogue is GLP- 1 or a GLP- 1 mimetic.
  • GLP-1 mimetics useful in the present methods include Byetta-Exanatide, Liraglutinide, CJC-1131 (ConjuChem, Exanatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and compounds disclosed in International Publication No. WO 00/07617.
  • insulin secretagogues useful in the present methods include exendin, GIP and secretin.
  • the antidiabetic agent is an insulin sensitizer.
  • Non-limiting examples of insulin sensitizers useful in the present methods include PPAR activators or agonists, such as troglitazone, rosiglitazone, pioglitazone and englitazone; biguanidines such as metformin and phenformin; PTP- 1 B inhibitors; and glucokinase activators.
  • the antidiabetic agent is a ⁇ -Glucosidase inhibitor.
  • Non-limiting examples of ⁇ -Glucosidase inhibitors useful the present methods include miglitol, acarbose, and voglibose.
  • the antidiabetic agent is an hepatic glucose output lowering agent.
  • hepatic glucose output lowering agents useful in the present methods include Glucophage and Glucophage XR.
  • the antidiabetic agent is insulin, including all formualtions of insulin, such as long acting and short acting forms of insulin.
  • orally administrable insulin and insulin containing compositions include AL-401 from Autoimmune, and the compositions disclosed in U.S. Patent Nos. 4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632; 6,191 ,105; and International Publication No. WO 85/05029, each of which is incorporated herein by reference.
  • the antidiabetic agent is a DPP-(V inhibitor.
  • Non-limiting examples of DPP-IV inhibitors useful in the present methods include sitag ⁇ ptin, saxagliptin (JanuviaTM, Merck), denagliptin, vildagliptin (GalvusTM, Novartis), alogiiptin, alogliptin benzoate, ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph), Bl-A and Bl-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513 (Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) or a combination of sitagliptin/metformin HCl (JanumetTM, Merck), in a further embodiment, the antidiabetic agent is a SGLT-2 inhibitor.
  • Non-limiting examples of SGLT-2 inhibitors useful in the present methods include dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) and T-1095 (Tanabe Seiyaku),
  • Non-limiting examples of antihypertensive agents useful in the present methods for treating a Condition include ⁇ -biockers and calcium channel blockers (for example diltiazern, verapamil, nifedipine, amlopidine, and mybefradil), ACE inhibitors (for example captopril, lisinopril, enalapril, spiraprii, ceranopril, zefenopril, fosinopril, cilazoprii, and quinapril), AT-1 receptor antagonists (for example losartan, irbesartan, and valsartan), renin inhibitors and endotheiin receptor antagonists (for example sitaxsentan).
  • ⁇ -biockers and calcium channel blockers for example diltiazern, verapamil, nifedipine, amlopidine, and mybefradil
  • ACE inhibitors for example captopril, lisinopril, en
  • the antidiabetic agent is an agent that slows or blocks the breakdown of starches and certain sugars.
  • Non-limiting examples of antidiabetic agents that slow or block the breakdown of starches and certain sugars and are suitable for use in the compositions and methods of the present invention include alpha-glucosidase inhibitors and certain peptides for increasing insulin production. Atpha-glucosidase inhibitors help the body to lower blood sugar by delaylng the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals.
  • suitable alpha-giucosidase inhibitors include acarbose; migiitol; camiglibose; certain polyamines as disclosed in WO 01/47528 (incorporated herein by reference); voglibose.
  • Non-limiting examples of suitable peptides for increasing insulin production including amlintide (CAS Reg. No. 122384-88-7 from Amylin; pramlintide, exendin, certain compounds having Glucagon-like peptide-1 (GLP- 1 ) agonistic activity as disclosed in Internationa! Publication No. WO 00/07617.
  • Additional therapeutic agents useful in the present methods for treating or preventing a Condition include, but are not limited to, rimonabant, 2-methyl- 6- ⁇ phenylethynyl)-pyridine, 3[(2-methyl-1 ,4-thiazol-4-yl)ethynyl]pyridine, Melanotan-SI, dexfenfiuramine, fluoxetine, paroxetine, fenfluramine, fluvoxamine, sertaline, imipramine, desipramine, talsupram, nomifensine, leptin, naimefene, 3- methoxynaltrexone, naloxone, nalterxone, butabindide, axokine, sibutramine, topiramate, phytopharm compound 57, Cerulenin, theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, roli
  • the present combination therapies for treating or preventing diabetes comprise administering a Bicyclic Heterocycle Derivative, an antidiabetic agent and/or an antiobesity agent.
  • the present combination therapies for treating or preventing diabetes comprise administering a Bicyclic Heterocycle Derivative and an antidiabetic agent. In another embodiment, the present combination therapies for treating or preventing diabetes comprise administering a Bicyclic Heterocycle Derivative and an anti-obesity agent.
  • the present combination therapies for treating or preventing obesity comprise administering a Bicycfic Heterocycle Derivative, an antidiabetic agent and/or an antiobesity agent.
  • the present combination therapies for treating or preventing obesity comprise administering a Bicyclic Heterocycle Derivative and an antidiabetic agent,
  • the present combination therapies for treating or preventing obesity comprise administering a Bicyclic Heterocycle Derivative and an anti-obesity agent.
  • the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative and one or more additional therapeutic agents selected from: anti-obesity agents, antidiabetic agents, any agent useful for treating metabolic syndrome, any agent useful for treating a cardiovascular disease, cholesterol biosynthesis inhibitors, sterol absorption inhibitors, bile acid sequestrants, probucol derivatives, !BAT inhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors, cholesteryl ester transfer proten (CETP) inhibitors, low-denisity lipoprotein (LDL) activators, fish oil, water-soluble fibers, plant sterols, plant stanols and fatty acid esters of plant stanols.
  • additional therapeutic agents selected from: anti-obesity agents, antidiabetic agents, any agent
  • the additional therapeutic agent is a cholesterol biosynthesis inhibitor.
  • the cholesterol biosynthesis inhibitor is a squalene synthetase inhibitor, In another embodiment, the cholesterol biosynthesis inhibitor is a squalene epoxidase inhibitor, In still another embodiment, the cholesterol biosynthesis inhibitor is an HMG-CoA reductase inhibitor, In another embodiment, the HMG-CoA reductase inhibitor is a statin. In yet another embodiment, the statin is lovastatin, pravastatin, simvastatin or atorvastatin. in one embodiment, the additional therapeutic agent is a cholesterol absorption inhibitor, In another embodiment, the cholesterol absorption inhibitor is ezetimibe.
  • the additional therapeutic agent comprises a cholesterol absorption inhibitor and a cholesterol biosynthesis inhibitor. In another embodiment, the additional therapeutic agent comprises a cholesterol absorption inhibitor and a statin. In another embodiment, the additional therapeutic agent comprises ezetimibe and a statin. In another embodiment, the additionai therapeutic agent comprises ezetimibe and simvastatin. In one embodiment, the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative, an antidiabetic agent and/or an antiobesity agent.
  • the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative and an antidiabetic agent. In another embodiment, the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative and an anti-obesity agent.
  • the present combination therapies for treating or preventing a cardiovascular disease comprise administering one or more Bicyclic Heterocycle Derivatives, and an additional agent useful for treating or preventing a cardiovascular disease.
  • the therapeutic agents in the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • the one or more Bicyclic Heterocycle Derivatives are administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
  • the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • the one or more Bicyc ⁇ c Heterocycie Derivatives and the additional therapeutic agent(s) act synergistica ⁇ y and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration.
  • the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
  • the administration of one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) may inhibit the resistance of a Condition to these agents.
  • the additional therapeutic agent when the patient is treated for diabetes or a diabetic complication, is an antidiabetic agent which is not a Bicyclic Heterocycle Derivative.
  • the additional therapeutic agent is an agent useful for reducing any potential side effect of a Bicyclic Heterocycle Derivative. Such potential side effects include, but are not limited to, nausea, vomiting, headache, fever, lethargy, muscle aches, diarrhea, general pain, and pain at an injection site.
  • the additional therapeutic agent is used at its known therapeutically effective dose. In another embodiment, the additional therapeutic agent is used at its normally prescribed dosage. In another embodiment, the additional therapeutic agent is used at less than its normally prescribed dosage or its known therapeutically effective dose.
  • the doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a Condition can be determined by the attending clinician, taking into consideration the the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder.
  • the Bicyclic Heterocycle Derivative(s) and the other agent(s) for treating diseases or conditions listed above can be administered simultaneously or sequentially. This particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another every six hours, or when the preferred pharmaceutical compositions are different, e.g. one is a tablet and one is a capsule.
  • a total daily dosage of the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s)can when administered as combination therapy range from about 0.1 to about 2000 mg per day, although variations will necessarily occur depending on the target of the therapy, the patient and the route of administration.
  • the dosage is from about 0.2 to about 100 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses, (n still another embodiment, the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses, in a further embodiment, the dosage is from about 1 to about 20 mg/day, administered in a single dose or in 2-4 divided doses.
  • the invention provides compositions comprising an effective amount of one or more Bicyclic Heterocycle Derivatives or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • compositions comprising one or more Btcyclic Heterocycle Derivatives, inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g., nitrogen.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • a Bicyclic Heterocycle Derivative is administered orally.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation is from about 0.1 to about 2000 mg. Variations will necessarily occur depending on the target of the therapy, the patient and the route of administration, in one embodiment, the unit dose dosage is from about 0.2 to about 1000 mg. In another embodiment, the unit dose dosage is from about 1 to about 500 mg. In another embodiment, the unit dose dosage is from about 1 to about 100 mg/day. In still another embodiment, the unit dose dosage is from about 1 to about 50 mg. In yet another embodiment, the unit dose dosage is from about 1 to about 10 mg.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 1000 mg/day, 1 mg/day to about 500 mg/day, 1 mg/day to about 300 mg/day, 1 mg/day to about 75 mg/day, 1 mg/day to about 50 mg/day, or 1 mg/day to about 20 mg/day, in one dose or in two to four divided doses.
  • the two active components may be co-administered simultaneously or sequentially, or a single composition comprising one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) in a pharmaceutically acceptable carrier can be administered.
  • the components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc.
  • the dosage of the additional therapeutic agent can be determined from published material, and may range from about 1 to about 1000 mg per dose. In one embodiment, when used in combination, the dosage levels of the individual components are lower than the recommended individual dosages because of an advantageous effect of the combination.
  • the components of a combination therapy regimen are to be administered simultaneously, they can be administered in a single composition with a pharmaceutically acceptable carrier.
  • ком ⁇ онентs of a combination therapy regimen when the components of a combination therapy regimen are to be administered separately or sequentially, they can be administered in separate compositions, each containing a pharmaceutically acceptable carrier.
  • the present invention provides a kit comprising an effective amount of one or more Bicyclic Heterocycle Derivatives, or a pharmaceutically acceptable salt or solvate of the compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • the present invention provides a kit comprising an amount of one or more Bicycitc Heterocycle Derivatives, and an amount of one or more additional therapeutic agents, wherein the combined amounts are effective for enhancing the memory of a patient or effective for treating or preventing a cognitive disorder in a patient.
  • kits comprising comprising: (a) one or more Bicyclic Heterocycle Derivatives together in a pharmaceutically acceptable carrier in a single container, or (b) one or more Bicyclic

Abstract

The present invention relates to Bicyclic Heterocycle Derivatives, compositions comprising a Bicyclic Heterocycle Derivative, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of a GPCR in a patient.

Description

BtCYCLIC HETEROCYCLE DERIVATIVES AND METHODS QF USE THEREOF
FIELD OF THE INVENTION
The present invention relates to Bicyciic Heterocycie Derivatives, compositions comprising a Bicyciic Heterocycie Derivative, and methods of using the Bicyciic Heterocycie Derivatives for treating or preventing obesity, diabetes, a diabetic complication, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of a G-Protein Coupled Receptor ("GPCR") in a patient.
BACKGROUND OF THE INVENTION Although a number of receptor classes exist in humans, by far the most abundant and therapeutically relevant is represented by the GPCR class. It is estimated that there are some 100,000 genes within the human genome, and of these, approximately 2% or 2,000 genes, are estimated to code for GPCRs. Receptors, including GPCRs, for which the endogenous ligand has been identified are referred to as "known" receptors, while receptors for which the endogenous ligand has not been identified are referred to as "orphan" receptors. GPCRs represent an important area for the development of pharmaceutical products, as evidenced by the fact that pharmaceutical products have been developed from approximately 20 of the 100 known GPCRs. This distinction is not merely semantic, particularly in the case of GPCRs.
GPCRs share a common structural motif. All these receptors have seven sequences of between 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane (each span is identified by number, i.e., transrnembrane-1 (TMM ), transmembrane-2 (TM-2), etc.). The transmembrane helices are joined by strands of amino acids between transmembrane-2 and transmembrane-3, transmembrane-4 and transmembrane-5, and transmembrane-6 and transmembrane-7 on the exterior, or "extracellular" side, of the cell membrane (these are referred to as "extracellular" regions 1 , 2 and 3 (EC- 1 , EC-2 and EC-3), respectively). The transmembrane helices are also joined by strands of amino acids between transmembrane-1 and transmembrane-2, transmembrane-3 and transmembrane-4, and transmembrane-5 and transmembrane-6 on the interior, or "intracellular" side, of the cell membrane (these are referred to as "intracellular" regions 1 , 2 and 3 (IC-1 , IC-2 and IC-3), respectively). The "carboxy" ("C") terminus of the receptor lies in the intracellular space within the cell, and the "amino" (11N") terminus of the receptor lies in the extracellular space outside of the cell. Generally, when an endogenous li'gand binds with the receptor (often referred to as "activation" of the receptor), there is a change in the conformation of the intracellular region that allows for coupling between the intracellular region and an intracellular "G-protein." It has been reported that GPCRs are "promiscuous" with respect to G proteins, i.e., that a GPCR can interact with more than one G protein, See, Kenakin, T., Life Sciences 43, 1095 (1988). Although other G proteins exist, currently, Gq1 Gs, Gi, and Go are G proteins that have been identified. Endogenous ligand-activated GPCR coupling with the G-protein begins a signaling cascade process (referred to as "signal transduction"). Under normal conditions, signal transduction ultimately results in cellular activation or cellular inhibition. It is thought that the IC-3 loop as well as the carboxy terminus of the receptor interact with the G protein.
Under physiological conditions, GPCRs exist in the ceil membrane in equilibrium between two different conformations: an "inactive" state and an "active" state. A receptor in an inactive state is unable to link to the intracellular signaling transduction pathway to produce a biological response. Changing the receptor conformation to the active state allows linkage to the transduction pathway (via the G- protein) and produces a biological response. A receptor can be stabilized in an active state by an endogenous ligand or a compound such as a drug.
Modulation of G-protein coupled receptors has been well-studied for controlling various metabofic disorders. Small molecule modulators of the receptor GPR119, a G-protein coupled-receptor described in, for example, GenBank (see, e.g., accession numbers XM.sub.--066873 and AY288416), have been shown to be useful for treating or preventing certain metabolic disorders. GPR119 is a G protein-coupled receptor that is selectively expressed on pancreatic beta cells. GPR119 activation leads to elevation of a level of intracellular cAMP, consistent with GPR119 being coupied to Gs. Agonists to GPR119 stimulate glucose-dependent insulin secretion in vitro and lower an elevated blood glucose level in vivo. See, e.g., International Publication Nos. WO 04/065380 and WO 04/076413, and EP 1338651 , the disclosure of each of which is herein incorporated by reference in its entirety.
U.S. Patent No. 7,136,426 discloses pyrazoto[3,4-d]pyrimidine ethers and related compounds as modulators of the GPR119 receptor that are useful for the treatment of various metabolic-related disorders such as type i diabetes, type Il diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperfipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X, The compounds are also reported as being useful for controlling weight gain, controlling food intake, and inducing satiety in mammals. The promising nature of these GPCR modulators indicates a need in the art for additional small molecule GPCR modulators with improved efficacy and safety profiles. This invention addresses that need.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides Compounds of Formula (I):
Figure imgf000004_0001
(I) and pharmaceutically acceptable salts, solvates, esters, prodrugs and stereoisomers thereof, wherein:
A is aryl or heteroaryl, each of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cydoalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, halo, -OH, -O-haloalkyl, -O-alkyl, -O- alkyl-OH, -O-alkyl-O-alkyl, -O-aryl, -alkylene-O-alkyl, -CN, -N(R4)2, -C(O)H, -C(O)R4, - C(O)OR4, -C(O)N(R4)2, -NHC(O)R4, -NHS(O)mR4, -S(O)nR4 and -S(O)mN(R4)2;
8 is aryl or heteroaryl, each of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycioalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, -OH, -O-haloalkyl, - O-alkyI, -O-aryl, -alkylene-O-alkyl, -alkylene-S(O)2-alkyl, -SF5, -CN, -N(R4)2, -C(O)H, - C(O)R4, -C(O)OR4, -C(O)N(R4)2, -NHC(O)R4, -NHS(O)mR4, -S(O)nR4 and - S(O)mN(R4)2, wherein a cycloalkyl, aryl or heteroaryl substituent group can be uπsubstituted or optionally substituted with R9, and wherein when B is aryl, the aryl group can be optionally fused to a 4 to 7-membered cycloalkyl group or cycloalkanoyl group;
G is -C(R1)- or -N-;
W is a bond, -O-, -C(O)O-, -C(R12)-, -alkylene-O-, alkylene, -C(O)- -S(O)-, ~ S(O)2- -S(O)2-N(R10)-, -N(R12)-, -NHC(O)- or -C(O)-N(R10K such that W is other than -O- when G is -N-, and such that when G is -C(R1)- and W is -C(R12)-, these R1 and R12 groups can combine to form a C1-C3 alkylene bridge between G and W and form a spirocycle;
X is a bond, -C(R1)2-, -O-, -N(R10)- or -S-; Z is a single bond, a double bond, -C(O)-, -C(=NOR12)-, -C=C(R14)2, -C(R1)2-, -
O-, -N(R10)- or -S(O)n-, such that when q is O, Z is other than a double bond; each occurrence of R1 is independently H1 alkyl, cycloalkyl, halo or -OR7; wherein an alkyl group can be unsubstituted or optionally substituted with one or more of the following groups: -O-alkyl, -OH or -N(R4)2; and wherein any two geminal R1 groups, together with the common carbon atom to which they are attached, can join to form a spirocyclic 3- to 6-membered cycioalkyl group, a spirocyclic 3- to 6-membered heterocycloalkyl group or a spirocyclic 3- to 6-membered heterocycloalkenyl group; and wherein any two R1 groups present on separate ring carbon atoms can join to form an alkylene or heteroalkylene bridge between the ring carbon atoms to which they are attached; and wherein when any R1 group is -OR7, then the carbon atom to which the R1 group is attached is not also attached to another oxygen atom or to a nitrogen or halogen atom; each occurrence of R2 is independently H or alkyl;
R3 is alkyt, -(alkylene)t-alkenyl, -(alkylene)t-alkynyl, -(alkylene)rC(O)R4, - (alkylene)t-haloalkyl, -alkylene-O-alkyl, -alkylene-O-(alkylene)raryl, -alkylene-S-aryl, - alkylene-N(R4)C(O)O-alkyl, -CH(cycloalkyl)2, -CH(heterocycloalkyl)2, -(alkylene)raryl, - (alkylene)t-cycloalkyl, -(alkylene)t-cycfoalkenyl, -(alkylene)rheterocycloalkyl, - (alkylene)t-heterocydoalkenyl or -(alkylene)rheteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycioalkyl, heterocycloalkenyl or heteroaryl group can be unsubstituted or optionally substituted with R9; each occurrence of R4 is H1 alkyl, haloalkyl, cycloalkyl, heteroaryl, aryl or alkenyl, any of which is unsubstituted or optionally substituted with one or more groups, which can be the same or different and are selected from haϊo, alkyl, -OH and -O-alkyl; each occurrence of R7 is independently H or alkyl;
R9 represents from 1 to 4 optional substituents, which can be the same or different, and which are selected from alkyl, hydroxyalkyl, -(alkylene)t-O-R13, alkenyl, alkynyl, halo, haloalkyl, -CN, -NO2, -O-(alkylene)rR13, -S-(alkylene)t-R13, -N(R13)- (alkylene)t-R13, -(alkylene)rR13, -(alkylene)rN(R7)2, -C(O)-(alkylene^R13, -C(O)O- (alkylene)rR13, -N(R7)C(OMalkylene)rR13, -C(O)N(R7)-(alkylene)t-R13, -OC(O)- (alkylene)rR13, -N(R7)C(O)N(R7Halkylene)rR13, -N(R7)C(O)O-(alkylene)rR13, -SF5, - S(O)-(alkylene)rR13 or -S(O)2(alkylene)rR13;
R10 is H, alkyl, aryl, Or -C(O)OR4, wherein an alkyl group is unsubstituted or optionally substituted with -OH or -O-alkyl;
R12 is H, alkyl or aryl; each occurrence of R13 is independently H, haloalkyl, aryl, cycloalkyl, cycloalkanoyl, cycioalkenyl, heterocycioalkyl, heterocycloalkenyl or heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyj, heterocycloalkenyl or heteroaryl group can be optionally substituted with up to 3 groups, which can be the same or different, and which are selected from alkyl, alkenyl, halo, haloalkyl, -CN, - N(R7)2, -OH, -O-alkyl or-O-haloalkyl; each occurrence of R14 is independently H, alkyl or aryl, or both R14 groups, and the carbon atom to which they are attached, combine to form a cycloalkyl or heterocycioalkyl group; each occurrence of m is independently 1 or 2; each occurrence of n is independently O, 1 or 2; p is O, 1 or 2; q is O, 1 or 2, such that when Z is -O- or -N(R10)-, then at least one of p and q is other than O; r is 0, 1 or 2, such that when G is -N-, then at least one of p and r is other than 0; s is 0, 1 or 2; each occurrence of t is independently 0 or 1 ; and u is 0, 1 or 2, such that when G is -N-, then at least one of s and u is other than
0.
In another aspect, the present invention provides compounds of Formula (II):
Figure imgf000007_0001
(II) and pharmaceutically acceptable salts, solvates, esters, prodrugs and stereoisomers thereof, wherein:
A is aryl or heteroaryϊ, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, haio, -OH, -O-haloalkyl, -O-alkyl, -O- alkyl-OH, -O-alkyl-O-alkyl, -O-aryl, -alkylene-O-alkyl, -CN, -N(R4)2, -C(O)H, -C(O)R4, - C(O)OR4, -C(O)N(R4)2, -NHC(O)R4, -NHS(O)mR4, -S(O)nR4 and -S(O)mN(R4)2;
B is aryl or heteroaryl, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, -OH, -O-haloalkyl, - O-alkyl, -O-aryl, -alkylene-O-alkyl, -alkylene-S(O)2-alkyl, -SF5, -CN, -N(R4)2, -C(O)H, - C(O)R4, -C(O)OR4, -C(O)N(R4)2) -NHC(O)R4, -NHS(O)mR4, -S(O)nR4 and - S(O)mN(R4)2, wherein a cycloalkyl or heteroaryl substituent group can be unsubstituted or optionally substituted with R9, and wherein when B is aryl, the aryl group can be optionally fused to a 4 to 7-membered cycloalkyl group or cycloalkanoyl group;
G is -CH- or -N-; W is a bond, -O-, -C(O)O-, -alkylene-O-, alkylene, -C(O)-,-S(O)-, -S(O)2-, - S(O)2-N(R1V or -C(O>~N(R10)-, such that when G is -N-, then W is other than -O-;
X is "C(R1)2-, -O-, -N(R10)- or -S-; each occurrence of R1 is independently H, alkyl, cycloalkyl, halo or -OR7; R3 is alkyl, -(alkytene)t-alkenyl, -(alkylene)ralkynyl, -(alkylene)rC(O)R4, -
(alkylene)rhaloalkyl, -alkylene-O-alkyl, -alkylene-O-(alkyIene)t-aryl, -alkylene-S-aryl, - alkylene-N(R4)C(O)O-alkyl, -CH(cycloalkyl)2, -CH(heterocycIoalkyl)2, -(alkylene )raryl, - (alkylene)t-cycloalkyl, -(alkylene)rcycloalkenyl, -(alkylene)t-heterocycloalkyl, - (alkylene)t-heterocycloalkenyl or -(alkylene)t-heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be unsubstituted or optionally substituted with R9; each occurrence of R4 is H1 alkyl, haloalkyl, hydroxyalkyl, -alkylene-O-alkyl, cycloalkyl, heteroaryl or alkenyl; each occurrence of R7 is independently H or alkyl; R9 represents from 1 to 4 optional substituents, which can be the same or different, and which are selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, -CN, - NO2, -O-(alkylene)rR13, -S-(alkylene)rR13, -N(R13)-(alkylene)rR13, -(alkylene)rR13, - C(O)-(aIkylene)t-R13, -C(O)O-(alkylene)rR13, -N(R7)C(O)-(alkylene)rR13, -C(O)N(R7)- (alkylene)t-R13, -OC(OMalkylene}t-R13, -N(R7)C(O)N(R7Halkylene)t-R13, -N(R7)C(O)O- (alkylene)t-R13, -S(O)-(aIkylene)t-R13 or -S(O)2(alkylene)rR13;
R10 is H, alkyl, aryl, or -C(O)OR4, wherein an alkyl group is unsubstituted or optionally substituted with -OH or -O-alkyl; each occurrence of R13 is independently H, haloalkyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl, wherein an aryl, cycloalkyl, cycioalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be optionally substituted with up to 3 groups, which can be the same or different, and which are selected from alkyl, halo, haloalkyl, -CN, -N(R7)2, -OH, -O-alkyl or -O- haloalkyl; each occurrence of m is independently 1 or 2; each occurrence of n is independently O, 1 or 2; p is an integer ranging from O to 3, such that the sum of p and q is at least 1 ; q is an integer ranging from O to 3; r is is an integer ranging from 0 to 3, such that the sum of r and s is at least 1 ; s is an integer ranging from 0 to 3; and each occurrence of t is independently 0 or 1.
The Compounds of Formulas (i) and (II) and pharmaceutically acceptable salts, solvates, esters or prodrugs thereof (referred to collectively herein as the "Bicyclic Heterocycle Derivatives") can be useful for treating or preventing obesity, diabetes, a diabetic complication, metabolic syndrome, a cardiovascular disease or a disorder related to the activity of a GPCR (each being a "Condition") in a patient. Also to provide by the invention are methods for treating or preventing a
Condition in a patient, comprising administering to the patient an effective amount of one or more Bicyclic Heterocycle Derivatives.
The present invention further provides compositions comprising an effective amount of one or more Bicyclic Heterocycle Derivatives or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier. The compositions can be useful for treating or preventing a Condition in a patient.
The details of the invention are set forth in the accompanylng detailed description below. Although any methods and materials similar to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and the claims. Ail patents and publications cited in this specification are incorporated herein by reference.
DETAILED DESCRIPTION OF THE INVENTION In an embodiment, the present invention provides Bicyclic Heterocycle Derivatives of Formulas (I) and (II), compositions comprising one or more Bicyclic Heterocycle Derivatives, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing a Condition in a patient.
Definitions and Abbreviations As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
A "patient" is a human or non-human mammal. In one embodiment, a patient is a human. In another embodiment, a patient is a non-human mammal, including, but not limited to, a monkey, dog, baboon, rhesus, mouse, rat, horse, cat or rabbit. In another embodiment, a patient is a companion animal, including but not limited to a dog, cat, rabbit, horse or ferret. In one embodiment, a patient is a dog. in another embodiment, a patient is a cat.
The term "obesity" as used herein, refers to a patient being overweight and having a body mass index (BMI) of 25 or greater. In one embodiment, an obese patient has a BMI of 25 or greater, in another embodiment, an obese patient has a BMI from 25 to 30. In another embodiment, an obese patient has a BMI greater than 30. in stil! another embodiment, an obese patient has a BMI greater than 40,
The term "obesity-related disorder" as used herein refers to: (i) disorders which result from a patient having a BMI of 25 or greater; and (ii) eating disorders and other disorders associated with excessive food intake. Non-limiting examples of an obesity- related disorder include edema, shortness of breath, sleep apnea, skin disorders and high blood pressure.
The term "metabolic syndrome" as used herein, refers to a set of risk factors that make a patient more succeptible to cardiovascular disease and/or type 2 diabetes. A patient is said to have metabolic syndrome if the patient simultaneously has three or more of the following five risk factors:
1 ) central/abdominal obesity as measured by a waist circumference of greater than 40 inches in a male and greater than 35 inches in a female; 2} a fasting triglyceride level of greater than or equal to 150 mg/dL;
3) an HDL cholesterol level in a mafe of less than 40 mg/dL or in a female of less than 50 mg/dL;
4) blood pressure greater than or equal to 130/85 mm Hg; and
5) a fasting glucose level of greater than or equal to 110 mg/dL. The term "effective amount" as used herein, refers to an amount of Bicyclic
Heterocycle Derivative and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from a Condition. In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount The term "alkyl," as used herein, refers to an aliphatic hydrocarbon group which may be straight or branched and which contains from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In another embodiment, an alkyl group contains from about 1 to about 6 carbon atoms. Non-iimiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. An aϊkyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH2, - NH(alkyl), -N(alkyl)2) -NH(cycloalkyl), -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(O)OH and -C(O)O-alkyl. in one embodiment, an alkyl group is unsubstituted. In another embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched.
The term "alkenyl," as used herein, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and contains from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms. Non- limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyf. An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -NH(alkyl), -N{alkyl)2, -NH(cycloalkyl), -O-C(O)-alkyl, -O-C(O)-aryl, -0-C(O)- cycloalkyl, -C(O)OH and -C(O)O-alkyl. In one embodiment, an alkenyl group is unsubstituted. The term "alkynyl," as used herein, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and contains from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon atoms. Non- limiting examples of alkynyl groups include ethynyl, propynyl, 2~butynyl and 3- methylbutynyl. An alkynyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -
NH(alkyl), -N(alkyl)2l -NH(cycJoalkyl), -O-C(O)~alkyl, -O-C(O)-aryl, -O-C^-cycloalkyl, -C(O)OH and -C(O)O-alkyl. In one embodiment, an alkynyl group is unsubstituted.
The term "alkylene," as used herein, refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond. Non-timiting examples of alkylene groups include -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH(CH3)- and - CH2CH(CH3)CH2-. In one embodiment, an alkylene group has from 1 to about 6 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. The term "aryl," as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms. An aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of aryl groups include phenyl and naphthyl. in one embodiment, an aryl group is unsubstituted. In another embodiment, an aryl group is phenyl.
The term "cydoalkyl," as used herein, refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkyl contains from about 5 to about 7 ring atoms. The term "cycloalkyl" also encompasses a cycloalkyl group, as defined above, that is fused to an aryl (e.g., benzene) or heteroaryl ring. A cycloalkyl group can be joined via a ring carbon or ring nitrogen atom. Non-limiting exampies of monocyctic cycloalkyls include cyclopropyS, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Non-iimiting examples of multicycϋc cycloalkyls include 1-decalinyl, norbornyl and adarnantyl. A cycloalkyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein beiow. In one embodiment, a cycloalkyl group is unsubstituted. A ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group. An illustrative example of such a cycloalkyl group {also referred to herein as a "cycloalkanoyl" group) includes, but is not limited to, cyclobutanoyl:
Figure imgf000013_0001
The term "cycloalkenyl," as used herein, refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms and containing at least one endocyclic double bond. In one embodiment, a cycloalkenyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms. Non-limiting examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like. A cycloalkenyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, a cydoalkenyl group is unsubstituted. In another embodiment, a cycloalkenyl group is a 5-membered cycloalkenyl.
The term "heteroalkylene," as used herein, refers to group having the formula - alkylene-X-alkylene- wherein X is -O-, -S- or -NH-. Non-limiting examples of heteroalkylene groups include -CH2OCH2-, -CH2SCH2-, -CH2N(H)CH2-, - CH2OCH2CH2-, -CH2SCH2CH2- and -CH2N(H)CH2CH2-. In one embodiment, a heteroalkylene group has from 2 to about 6 carbon atoms. In another embodiment, a heteroalkylene group has from 2 to about 3 carbon atoms.
The term "heteroaryl," as used herein, refers to an aromatic monocyclic or multicyciic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. A heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. A heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide, The term "heteroaryl" also encompasses a heteroaryl group, as defined above, that is fused to a benzene ring. Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazoϊyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1 ,2, 4-th iadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimϊdazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyrtdyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4- triazinyl, benzothiazolyl and the like, and all isomeric forms thereof. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinoSyl, tetrahydroquinolyl and the like. In one embodiment, a heteroaryf group is unsubstituted. In another embodiment, a heteroaryl group is a 5- membered heteroaryl. In another embodiment, a heteroaryl group is a 6-membered heteroaryl.
The term "heterocycloalkyl," as used herein, refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 10 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S or N and the remainder of the ring atoms are carbon atoms. A heterocydoalkyl group can be joined via a ring carbon or ring nitrogen atom. In one embodiment, a heterocydoalkyl group has from about 5 to about 10 ring atoms. In another embodiment, a heterocycloalkyl group has 5 or 6 ring atoms. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Any -NH group in a heterocycloalkyl ring may exist protected such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention. The term "heterocycloalkyl" also encompasses a heterocycloalkyl group, as defined above, that is fused to an aryl (e.g., benzene) or heteroaryl ring. A heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclic heterocycioalkyl rings include oxetanyl, piperidyl, pyrroiidinyl, piperazinyl, morphoiinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiopheny), lactam, lactone and the like, and ail isomers thereof. A ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group. An illustrative example of such a heterocycloalkyl group is pyrrolidonyl:
Figure imgf000015_0001
In one embodiment, a heterocycloalkyl group is unsubstituted. In another embodiment, a heterocycloalkyl group is a 5-membered heterocycloalkyl, In another embodiment, a heterocycloalkyl group is a 6-membered heterocycloalkyl. The term "heterocycloalkenyl," as used herein, refers to a heterocycloalkyl group, as defined above, wherein the heterocycloalkyl group contains from 3 to 10 ring atoms, and at least one endocyclic carbon-carbon or carbon-nitrogen double bond. A heterocycloalkenyl group can be joined via a ring carbon or ring nitrogen atom. In one embodiment, a heterocycloalkenyl group has from 5 to 10 ring atoms. In another embodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms. A heterocycloalkenyl group can optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of heterocycloalkenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2- pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazoSyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluoro- substituted dihydrofuranyl, 7-oxabicycto[2.2.1]heptenyl, dihydrothiophenyf, dihydrothiopyranyl, and the like. A ring carbon atom of a heterocycloalkenyl group may be functionatized as a carbonyl group. In one embodiment, a heterocycloalkenyl group is unsubstituted. In another embodiment, a heterocycloalkenyl group is a 5- membered heterocycloalkenyl. In another embodiment, a heterocycloalkenyl group is a 6-membered heterocycloalkenyl.
It should also be noted that tautomeric forms such as, for example, the moieties:
Figure imgf000016_0001
are considered equivalent in certain embodiments of this invention.
The term "ring system substituent," as used herein, refers to a substituent group attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkyl-aryl, -aryl-alkyl, -alkylene-heteroaryl, - alkenylene-heteroaryl, -alkynylene-heteroaryl, hydroxy, hydroxyalkyl, haloalkyl, -O- alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, -C(O)O-alkyl, -C(O)O-aryI, -C(O)O-alkelene-aryl, -S(O)-alkyl, -S(O)2-alkyl, ~ S(O)-aryl, -S(O)2^rYi1 -S(O)-heteroaryl,-S(O)2-heteroaryl, -S-alkyl, -S-aryl, -S- heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, -O- C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyI, -C(=N-CN)-NH2, -Cf=NH)-NH2, -C(-NH)- NH(alkyl), YiY2N-, Y^N-alkyl-, Y1Y2NC(O)-, Y1Y2NS(O)2- and -S(O)2NY1Y2, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylenedioxy, ethylenedioxy, -C(CH3)2~ and the like which form moieties such as, for example:
Figure imgf000016_0003
and
Figure imgf000016_0002
"Halo" means -F, -Cl, -Br or -I. Sn one embodiment, halo refers to -F, -CI or - Br.
The term "haloalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 6 carbon atoms, In another embodiment, a haloalkyl group is substituted with from 1 to 3 F atoms. Non- limiting examples of haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CI and -CCI3.
The term "hydroxyalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with an -OH group, in one embodiment, a hydroxyalkyl group has from 1 to 6 carbon atoms. Non-limiting examples of hydroxyalkyl groups include -CH2OH, -CH2CH2OH, - CH2CH2CH2OH and -CH2CH(OH)CH3.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, to provide that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of the compound after being isolated from a synthetic process (e.g., from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of the compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystalϋzation and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan. It should aiso be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as weli as by reference to standard textbooks such as, for example, T. W. Greene et a/, Protective Groups in Organic Synthesis (1991 ), Wiiey, New York. When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula (I) or (II), its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is to provide in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yleld a Bicyciic Heterocycle Derivative or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is to provide by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversibie Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. For example, if a Bicyciic Heterocycle Derivative or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-C8)alkyl, (C2- C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1~(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4~ crotonolactonyl, gamma-butyrolacton-4-yl, dt-N,N-(C1-C2)alkylamino(C2-C3)alkyI (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di (C1-C2)alkylcarbamoyl-(C1- C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a Bicyclic Heterocycle Derivative contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, ( C1-C6)alkanoyloxymethyl, 1-((C1- C6)alkanoyloxyjethyl, 1-methyl-1-(( C1-C6)alkanoyloxy)ethyl, (C1- C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1- C6)alkanoyl, α-amino(C1-C4)alkyl, α-amino(C1-C4)alkylene-aryl, arylacyl and α- aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, - P(0X0(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a Bicyclic Heterocycle Derivative incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C1- C10)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl, -C(OH)C(O)OY1 wherein Y1 is H1 ( C1-C6)alkyl or benzyl, — C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is ( C1-C6)alkyl, carboxy (C1-C6)alkyl, amino(C1-C4)alkyI or mono-N — or di-N,N-(C1-C6)alkylaminoalkyl, — C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N — or di-N,N-(C1-C6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like. One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varylng degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate wherein the solvent molecule is H2O.
One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et a/, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et a/, AAPS PharmSciTechours. , 5(1), article 12 (2004); and A. L. Bingham et a/, Chem. Commun., 603-604 (2001 ). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate). The Bicycϊic Heterocycle Derivatives can form salts which are also within the scope of this invention. Reference to a Bicyclic Heterocycle Derivative herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a Bicyclic Heterocycle Derivative contains both a baste moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxyltc acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the Bicyclic Heterocycle Derivatives may be formed, for example, by reacting a Bicyclic Heterocycle Derivative with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by iyophiiization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthatenesuifonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1 ) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry ( 1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Pharmaceutically acceptable esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, ethyl, n-propyl, isopropyt, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C1-4a[kyl, or -O-C1-4alkyl or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesuifonyl); (3) amino acid esters (for example, L- valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Sterochemicaliy pure compounds may also be prepared by using chiral starting materials or by employlng salt resolution techniques. Also, some of the Bicyclic Heterocycle Derivatives may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.
It is also possible that the Bicyclic Heterocycle Derivatives may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, ail keto-enol and imine-enamtne forms of the compounds are included in the invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyridyl and 3-pyridyt). For example, if a Bicyclic Heterocycie Derivative incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-eno! and imine-enamine forms of the compounds are included in the invention.
Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
The present invention also embraces isotopically-labelied compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 17O, 31P, 32P, 35S1 18F, and 36CI, respectively.
Certain isotopically-labelied Pyrimidine Derivatives (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. In one embodiment, tritiated (i.e., 3H) and carbon-14 (Le., 14C) isotopes are employed for their ease of preparation and detectability. In another embodiment, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), in one embodiment, one or more hydrogen atoms of a Bicyclic Heterocycie Derivative is replaced with a deuterium atom. lsotoptcally iabelied Bicyclic Heterocycie Derivatives can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent. Polymorphic forms of the BicycHc Heterocycle Derivatives, and of the salts, solvates, hydrates, esters and prodrugs of the Bicyctic Heterocycfe Derivatives, are intended to be included in the present invention.
The following abbreviations are used below and have the folfowing meanings: AcOH is acetic acid, Boc or BOC is -C(O)O~(if-butyl), n-BuLi is n-butyllithium, f-butyl is tertiary butyl, DAST is diethylaminosulfur trichloride, dba is dibenzylidene acetone, DCE is dichloroethane, DCM is dichloromethane, DIAD is diisopropylazodicarboxylate, DlEA is diisopropylethylamine, DMEM is Dulbecco's modified eagle medium, DMF is N,N-dimethylformamide, DMSO is dimethylsulfoxide, dppf is 1 ,1 '-bis(diphenylphosphino)ferrocene, EDC is 1-(dimethylaminopropyl)-3- ethylcarbodiimide, EtOAc is ethyl acetate, EtOH is ethanol, Et3N is trtetbylamine, EtNH2 is ethylamine, HOBt is 1-hydroxy-benzotriazole, LCMS is liquid chromatography mass spectrometry, LDA is ϋthium diisopropylamide, mCPBA is meta-chloroperoxybenzoic acid, MeOH is methanol, NaOEt is sodium ethoxide, NaOtBu is sodium t-butoxide, NMM is n-methylmorphoiine, NMR is nuclear magnetic resonance, Ph is phenyl, PhMe is toluene, PLC is preparative thin-layer chromatography, PS-EDC is polystyrene functionalized with EDC - available from Polymer Laboratories, PS-DIEA is polystyrene functionaiized with disopropylethylamine, TBAF is tetra-n-butyl-ammonium fluoride, THF is tetrahydrofuran, and TLC is thin-layer chromatography.
The BicvcMc Heterocvcle Derivatives of Formula (P
The present invention provides Bicyclic Heterocycle Derivatives of Formula (I):
Figure imgf000024_0001
and pharmaceutically acceptable salts, solvates, esters, prodrugs and stereoisomers thereof, wherein A1 B, G, W, X, Z, R1, R2, R3, p, q, r, s and u are defined above for the Compounds of Formula (I).
In one embodiment, G is -CH-. in another embodiment, G is -N-. in one embodiment, W is a bond, -O- or ™alkylene-O-. in another embodiment, W is a bond.
In another embodiment, W is alkylene. In another embodiment, W is -O-.
In still another embodiment, W is -alkylene-O-. in another embodiment, W is -C(O)O-.
In another embodiment, W is -C(O)-.
In yet another embodiment, W is -S(O)2-. In another embodiment, W is -S(O)2N(R10)-.
In a further embodiment, W is -C(O)N(R10)-. in another embodiment, G is -CH- and W is a bond, -O- or-alkylene-O-. in still another embodiment, G is -CH- and W is a bond.
In one embodiment, X is -C(R1)2-. In another embodiment, X is -O-,
In another embodiment, X is -S-,
In yet another embodiment, X is -N(R10)-.
In another embodiment, X is -NH-.
In one embodiment, Z is -C(R1)2-. In another embodiment, Z is a single bond.
In another embodiment, Z is a double bond.
In another embodiment, Z is -O-. in another embodiment, Z is -S-.
In yet another embodiment, Z is -N(R10)-. In another embodiment, Z is -CHR1-.
In another embodiment, Z is -CH2-.
In still another embodiment, Z is -NH-, In one embodiment, W is -C(O)O- and Z is a single bond,
In another embodiment, W is a bond and Z is a single bond,
In one embodiment, W is -C(O)O-, Z is a single bond and X is -O- .
In another embodiment, W is a bond, Z is a single bond, X is -O-. In another embodiment, W is -C(O)O-, Z is a single bond, and X is-NH-.
In another embodiment, W is a bond, Z is a single bond, and X is-NH-.
In one embodiment, A is aryl.
In another embodiment, A is 5 or 6-membered heteroaryt.
In another embodiment, A is phenyl. In still another embodiment, A is pyrimidinyl.
In one embodiment, -A- is:
Figure imgf000026_0001
, wherein Q is H, halo, alkyl or -O-alkyl. In another embodiment, -A- is:
Figure imgf000026_0002
, wherein Q is H, F, methyl or -OCH3. In another embodiment, A is:
Figure imgf000026_0003
In another embodiment, A is pyridyl. In a further embodiment, X is -O- and A is pyrimidinyl, in another embodiment, X is -NH- and A is pyrimidinyl. In one embodiment, X is -O- and A is:
Figure imgf000026_0004
, wherein Q is H, F, methyl Or -OCH3.
In a further embodiment, X is -NH- and A is:
Figure imgf000027_0001
Q , wherein Q is H, F, methyl or -OCH3.
In one embodiment, B is aryl. In another embodiment, B is heteroaryl. In another embodiment, B is 5 or 6-membered heteroaryl. In another embodiment, B is phenyl.
In still another embodiment, B is pyrimidinyl. In another embodiment, B is pyridyl.
In one embodiment, B is phenyl, which is υnsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S(O)2-alkyl, -S(O)2- cycloalkyl, heteroaryl and halo.
In another embodiment, B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from -CN, -S(O)ralkyl and halo.
In one embodiment, B is:
Figure imgf000027_0002
In another embodiment, B is:
Figure imgf000027_0003
In another embodiment, X is -NH- or -O- , and B is:
Figure imgf000027_0004
In another embodiment, X is -O- and B is:
Figure imgf000027_0005
In still another embodiment, X is -NH- and B is:
Figure imgf000028_0001
In one embodiment, A and B are each independently he In another ambodiment, A and B are each independently a 5 or 6-membered heteroaryl.
In another embodiment, A is a 5 or 6-membered heteroaryl and B is pyridyl. In one embodiment, -A- is:
Figure imgf000028_0002
, wherein Q is H, halo, alkyl or -O-alkyl; and B is:
Figure imgf000028_0003
in another embodiment, X is -NH- • oorr --O0--, and -A- is:
Figure imgf000028_0004
, wherein Q is H, halo, alkyl or -O-alkyl; and B is:
Figure imgf000028_0005
In another embodiment, X is -NH- or -O-, and -A- is:
Figure imgf000028_0006
wherein Q is H, F, methyl Or-OCH3; and B is
Figure imgf000028_0007
In one embodiment, A is:
Figure imgf000029_0001
, wherein Q is H, halo, alkyl or -O-alkyl; and B is heteroaryl. In another embodiment, A is:
Figure imgf000029_0002
, wherein Q is H, hafo, alkyl or -O-alkyl; and B is pyridyl. in another embodiment, A is;
Figure imgf000029_0003
, wherein O is H, halo, alkyl or -O-alkyl; and B is:
Figure imgf000029_0004
In one embodiment, A is 5 or 6-membered heteroaryl and B is phenyl.
In another embodiment, A is pyrimidinyl and B is phenyl. in another embodiment, A is pyrimidinyl and B is pyridyl. in one embodiment, B is phenyl which is optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S{O)2-alkyl, -S(O)2-cycloalkyl, heteroaryl and halo; and A is:
Figure imgf000029_0005
, wherein Q is H, halo, alkyl or -O-alkyl.
In another embodiment, B is phenyl which is optionally substituted with up to 3 groups, each independently selected from methyl, triazoiyl, -CN1 -Cl, -F1 -S(O)2CH3 and -S(O)2-cyclopropyl; and A is:
Figure imgf000029_0006
Q , wherein Q is H, F, methyl or methoxy. In another embodiment, B is pyridyl and A is:
Figure imgf000030_0001
Q , wherein Q is H5 halo, alkyl or -O~alkyl.
In one embodiment, X is -O1 A is pyrimidinyl and B is pyridyl,
In another embodiment, X is -NH-, A is pyrimidinyl and B is pyridyl.
In one embodiment, X is -O- , A is pyrimidinyl and B is phenyl. In another embodiment, X is -NH-, A is pyrimidinyl and B is phenyl.
In one embodiment, X is -0-, A is pyrimidinyl and B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S(O)2-alkyl, -S(O)2-cycloalkyl, heteroaryl and halo.
In another embodiment, X is -NH-, A is pyrimidinyl and B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S(O)2-alkyl, -S(O)2-cycloalkyl, heteroaryl and halo.
In another embodiment, A and B are each independently a 5 or 6-membered heteroaryf, each of which is unsubstituted or optionally substituted with one substituent, independently selected from alkyl, -CN, -S{O)2-alkyl, -S(O)2-cycloalkyl, heteroaryl and halo.
In still another embodiment, A and B are each independently selected from phenyl, pyridyl and pyrimidinyl, each of which is unsubstituted or optionally substituted with one substituent, independently selected from alkyl, -CN, -S(O)2-alkyI, -S(O)2- cycloalkyl, heteroaryl and halo. In another embodiment, A and B are each independently selected from phenyl, pyridyl and pyrimidinyl, each of which is unsubstituted or optionally substituted with one or more substituents, each independently selected from methyl, triazolyl, -CN, - Cl, -F, -S(O)2CH3 or -S(O)2-cyclopropyl.
In still another embodiment, X is -O-, A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one substituent, independently selected from alkyl, -CN, -S{O)2-alkyl, -S(O)2-cycIoalkyl, heteroaryl and halo.
In a further embodiment, X is -O-, A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one or more substituents, each independently selected from methyl, triazolyl, -CN, -Cl, -F, -S(O)aCH3 or -S(O)2- cyclopropyl. In one embodiment, X is -O- , A is pyrirnidinyl and B is pyridyl, wherein A and B are each substituted with at least one alkyl group,
In another embodiment, X is -O-, A is pyrimidinyl and B is pyridyl, wherein A and B are each substituted with a methyl group. In one embodiment, X is -O-, A is pyrimidinyl and B is pyridyl.
!n another embodiment, X is -O-, A is pyrimidinyl and B is phenyl.
In still another embodiment, X is -O-, A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one substituent, independently selected from alkyl, -CN, -S(O)2-alkyl, -S{O)2-cycloalkyl, heteroaryl and halo, In a further embodiment, X is -O- , A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one or more substituents, each independently selected from methyl, triazolyl, -CN1 -C), -F, -S(O)2CH3 Or -S(O)2- cyclopropyl.
In one embodiment, the group B-X-A- is:
Figure imgf000032_0001
wherein Q is H, halo, alkyl or -O-alkyl.
In another embodiment, the group B-X-A- is:
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000033_0003
wherein Q is H, F, methyl or -OCH3. in another embodiment, the group B-X-A- is:
Figure imgf000034_0001
!n one embodiment, the group B-X-A- is:
Figure imgf000034_0002
In another embodiment, the group B-X-A- is:
Figure imgf000034_0003
In another embodiment, the group B-X-A- is:
Figure imgf000034_0004
In stili another embodiment, the group B-X-A- is:
Figure imgf000034_0005
In another embodiment, the group B-X-A- is:
Figure imgf000034_0006
in yet another embodiment, the group B-X-A- is:
Figure imgf000035_0001
In another embodiment, the group B-X-A- is:
Figure imgf000035_0002
In a further embodiment, the group B-X-A- is:
Figure imgf000035_0003
In another embodiment, the group B-X-A- is:
Figure imgf000035_0004
In one embodiment, each occurrence of R1 is selected from H1 halo or -OH. In another embodiment, each occurrence of R1 is H.
In still another embodiment, at least one occurrence of R1 is -OH.
In another embodiment, at least one occurrence of R1 is halo.
In another embodiment, at least one occurrence of R1 is F.
In another embodiment, at least one occurrence of R2 is H, alkyl or -OH. !n another embodiment, at least one occurrence of R2 is -OH. in still another embodiment, at least one occurrence of R2 is alkyl.
In another embodiment, at least one occurrence of R2 is H.
In another embodiment, each occurrence of R2 is H,
In one embodiment, R3 is alkyl. In another embodiment, R3 is a linear alkyl group.
In another embodiment, R3 is a branched alkyl group.
In still another embodiment, R3 is methyl. In another embodiment, R3 is ethyl. In another embodiment, R3 is isopropyl. In a further embodiment, R3 is t-butyl.
In another embodiment, R3 is alkeπyl,
In another embodiment, R3 is alkynyl.
In yet another embodiment, R3 is hafoalkyl. In one embodiment, R3 is cycloalkyl. fn another embodiment, R3 is cyclopropyl.
In another embodiment, R3 is cyclopropyl, substituted with a methyl group.
In another embodiment, R3 is cyclobutyl.
In still another embodiment, R3 is cyclopentyl. In another embodiment, R3 is cyclohexyl.
In yet another embodiment, R3 is aryl. tn another embodiment, R3 is phenyl.
In another embodiment, R3 is phenyl, optionally substituted with halo.
In one embodiment, R3 is heteroaryl. In another embodiment, R3 is 5-membered heteroaryl, in another embodiment, R3 is 6-membered heteroaryl.
In another embodiment, R3 is oxadiazotyl.
Jn another embodiment, R3 is oxadiazolyl, optionally substituted with alkyl, - alkylene-0-alkyl, -alkylene-N(alkyl)2, cycloalkyl or alkylene-heterocycloalkyl. In another embodiment, R3 is 4-fluorophenyt, ethyl, t-butyl, isopropyl, -
CH2OCH3, -CH2OCH2CH(CHS)2, -CH2OCH2CH2CH(CH3)2, -CH2O-{4-methyl-2-pyridyl),
Figure imgf000037_0001
In another embodiment, R3 is:
Figure imgf000038_0001
In one embodiment, W is a bond and R3 is heteroaryl or -alkylene-O-alkyl. In another embodiment, W is a bond and R3 is heteroaryl. In another embodiment, W is a bond and R3 is oxadiazolyl, optionally substituted with alkyl, -alkylene-O-alkyl, -aIkylene-N(alkyI)2, cycioalkyl or alkylene- heterocycloalkyl.
In still another embodiment W is a bond and R3 is;
Figure imgf000039_0001
In another embodiment, R3 is -alkylene-aryl. In a further embodiment, R3 is benzyl. In one embodiment, p and u are each 1. In another embodiment, u, p, q, r, and s are each independently O or 1.
In another embodiment, p and u are each 1 , and r and s are each O. In still another embodiment, q, p and u are each 1 , r and s are each O and 2 is a bond. tn another embodiment, q, p and u are each 1 , r and s are each O, Z is a bond, and W is a bond.
In a further embodiment, q, p and u are each 1 , r and s are each O, Z is a bond, W is a bond and X is -O-.
In another embodiment, q, p and υ are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -O-, A is a 5 or 6-membered heteroaryl, and B is phenyl or a 5 or 6- membered heteroaryl. In another embodiment, q, p and u are each 1 , r and s are each 0, Z is a bond, W is -C(O)O-, X is -O-, A is a 5 or 6-membered heteroaryl, B is phenyl or pyridyl, and R3 is heteroaryl.
In another embodiment, q, p and u are each 1 , r and s are each 0, Z is a bond, W is -C(O)O-, X is -O-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6- membered heteroaryl, each occurrence of R1 is H, and R3 is heteroaryl.
In another embodiment, q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -O-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6- membered heteroaryl, each occurrence of R1 and R2 is H, and R3 is heteroaryl, In one embodiment, q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond and X is -NH-.
In another embodiment, q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -NH-, A is a 5 or 6-membered heteroaryl, and B is phenyl or a 5 or 6- membered heteroaryl. In another embodiment, q, p and u are each 1 , r and s are each 0, Z is a bond,
W is -C(O)O-, X is -NH-, A is a 5 or 6-membered heteroaryl, B is phenyl or pyridyl, and R3 is heteroaryl.
In still another embodiment, q, p and u are each 1 , r and s are each 0, Z is a bond, W is -C(O)O-, X is -NH-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6-membered heteroaryl, each occurrence of R1 is H, and R3 is heteroaryl.
In another embodiment, q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -NH-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6- membered heteroaryl, each occurrence of R1 and R2 is H, and R3 is heteroaryl.
In one embodiment, the group:
Figure imgf000040_0001
Figure imgf000041_0001
In one embodiment, the group:
Figure imgf000041_0002
Figure imgf000041_0003
In another embodiment, the group:
Figure imgf000041_0004
Figure imgf000042_0001
Figure imgf000043_0001
In another embodiment, the group:
Figure imgf000044_0001
Figure imgf000044_0002
In one embodiment, the group -B-X-A- is:
Figure imgf000045_0001
wherein Q is H, halo, alkyl or-O-alkyS, and the group:
Figure imgf000045_0002
Figure imgf000046_0001
In another embodiment, the group -B-X-A- is:
Figure imgf000046_0002
and the group:
Figure imgf000046_0003
Figure imgf000046_0004
In one embodiment, the group -B-X-A- is:
Figure imgf000047_0001
wherein Q is H, halo, alkyl or-O-alkyl, and the group:
Figure imgf000047_0002
Figure imgf000048_0001
In another embodiment, the group -B-X-A- is:
Figure imgf000048_0002
wherein Q is H, halo, alkyl or ~O-alkyl, and the group:
Figure imgf000049_0001
Figure imgf000049_0002
Figure imgf000050_0001
Figure imgf000051_0001
in one embodiment, the group -B-X-A- is:
Figure imgf000051_0002
and the group:
Figure imgf000051_0003
Figure imgf000052_0001
Figure imgf000053_0001
in still another embodiment, the group -B-X-A- is:
Figure imgf000054_0001
wherein Q is H, halo, alkyl or -O-alkyl, and the group:
Figure imgf000054_0002
Figure imgf000055_0001
In a further embodiment, the group -B-X-A- is:
Figure imgf000055_0002
and the group:
Figure imgf000055_0003
Figure imgf000056_0001
In one embodiment, the present invention provides Compounds of Formula (I), wherein A, B1 G5 W1 X, Z1 R1, R2, R3, p, q, r, s and u are selected independently of each other.
In another embodiment, a Compound of Formula (I) is in purified form. In one embodiment, a Compound of Formula (I) has the formula:
Figure imgf000056_0002
(Ia) wherein:
A is aryl or -5- or 6-membered heteroaryl, each of which can be optionally substituted with an alkyl, halo or -O-alkyl group;
B is aryl or heteroaryl, each of which can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from: alkyl, halo, heteroaryl, -CN or ~S(O)2alkyl;
W is a bond, -O-, alkylene or -alkylene-O-;
X is -O- or -NH-;
R3 is alkyl, aryl or heteroaryl, wherein an aryl or heteroaryl group can be unsubstituted or optionally substituted with an alkyl, cycloalkanoyl, cycloalkyl, hydroxyalkyl, -alkylene-N(alkyl)2, or -alkylene-O-alkyl group, wherein a cycloalkyl substituent can be further and optionally substituted with up to 3 groups, which can be the same or different, and are selected from alkyl, alkenyl, halo, haioalkyl, -OH or -O- alkyl.
tn one embodiment, for the Compounds of Formula (Ia), A is aryl. In another embodiment, for the Compounds of Formula (Ia), A is 5 or 6- membered heteroaryl,
In another embodiment, for the Compounds of Formula (Ia), A is phenyl. In still another embodiment, for the Compounds of Formula (Ia), A is pyrimidinyl. In another embodiment, for the Compounds of Formula (Ia), -A- is:
Figure imgf000057_0003
, wherein Q is H, halo, alkyl or -O-alkyl. In another embodiment, for the Compounds of Formula (Ia), -A- is:
Figure imgf000057_0001
, wherein Q is H, F1 methyl or -OCH3. In yet another embodiment, for the Compounds of Formula (Ia)1 A is:
Figure imgf000057_0002
In one embodiment, for the Compounds of Formula (Ia)1 B is aryl.
In another embodiment, for the Compounds of Formula (Ia), B is heteroaryl.
In another embodiment, for the Compounds of Formula (Ia), B is 5 or 6- membered heteroaryl. In still another embodiment, for the Compounds of Formula (Ia), B is phenyl.
In another embodiment, for the Compounds of Formula (Ia), B is pyrimidinyl.
In another embodiment, for the Compounds of Formula (Ia), B is pyridyl.
In yet another embodiment, for the Compounds of Formula (Ia), B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN1 -S(O)2-alkyl, -S(O)2-cycloalkyl! heteroaryl and halo. ϊn another embodiment, for the Compounds of Formula (Ia)1 B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from -CN, -S(O)2-alkyl and halo.
In a further embodiment, for the Compounds of Formula (Ia), B is:
Figure imgf000058_0001
In another embodiment, for the Compounds of Formula (Ia), B is:
Figure imgf000058_0002
In one embodiment, for the Compounds of Formuia (Ia), W is a bond.
In another embodiment, for the Compounds of Formula (Ia), W is alkylene. In another embodiment, for the Compounds of Formula (Ia), W is -O-.
In still another embodiment, for the Compounds of Formula (Ia), W is - alkylene-O-.
In one embodiment, for the Compounds of Formula (Ia), X is -O- .
In another embodiment, for the Compounds of Formuia (ia), X is -NH-. In another embodiment, for the Compounds of Formula (Ia), X is -O- and B is:
Figure imgf000058_0003
In still another embodiment, for the Compounds of Formula (Ia), X is -NH- and
B is:
Figure imgf000058_0004
In one embodiment, for the Compounds of Formula (Ia), A and B are each independently heteroaryl.
In another embodiment, for the Compounds of Formula (Ia), A and B are each independently a 5 or 6-membered heteroaryl.
In another embodiment, for the Compounds of Formula (Ia), A is a 5 or 6- membered heteroaryl and B is pyridyl.
In another embodiment, for the Compounds of Formula (fa), A is a 5 or 6- membered heteroaryl and B is substituted phenyl.
In one embodiment, for the Compounds of Formula (Ia), -A- is:
Figure imgf000059_0006
, wherein Q is H, halo, alkyl or -O-alkyl; and B is:
Figure imgf000059_0001
In another embodiment, for the Compounds of Formula (Ia), X is -NH- or -O-, and -A- is:
, wherein Q is H, halo, alkyl or -O-alkyl; and B is:
Figure imgf000059_0002
Figure imgf000059_0003
In another embodiment, for the Compounds of Formula (Ia), X is -NH- or -O-, and -A- is:
Figure imgf000059_0004
wherein Q is H, F, methyl Or -OCH3; and B is:
Figure imgf000059_0005
In one embodiment, for the Compounds of Formula (Ia), A is:
Figure imgf000060_0001
Q , wherein Q is H, halo, alkyl or -O-alkyl; and B is heteroaryt
In another embodiment, for the Compounds of Formula (Ia)1 A is:
Figure imgf000060_0004
wherein Q is H1 halo, alkyl or -O-alkyl; and B is pyridyl.
In another embodiment, for the Compounds of Formula (ta), A is:
, wherein Q is H1 halo, alkyl or -O-alkyl; and B is:
Figure imgf000060_0002
Figure imgf000060_0003
In one embodiment, for the Compounds of Formula (Ia), A is 5 or 6-membered heteroaryl and B is phenyl.
In another embodiment, for the Compounds of Formula (Ia), A is pyrimidinyl and B is phenyl.
In another embodiment, for the Compounds of Formula (Ia), A is pyrimidinyl and B is pyridyl.
In another embodiment, for the Compounds of Formula (Ia), the group B-X-A- is:
Figure imgf000061_0001
in a further embodiment, for the Compounds of Formula (Ia), the group B-X-A- is:
Figure imgf000061_0002
In one embodiment, for the Compounds of Formula (Ia)1 R3 is alkyl.
In another embodiment, for the Compounds of Formula (Ia), R3 is a linear alkyl group.
In another embodiment, for the Compounds of Formula (Ia), R3 is a branched alkyl group. In still another embodiment, for the Compounds of Formula (Ia), R3 is methyl.
In another embodiment, for the Compounds of Formula (Ia), R3 is ethyl. In another embodiment, for the Compounds of Formula (Ia), R3 is isopropyl, in a further embodiment, for the Compounds of Formula (Ia), R3 is t-butyl. In yet another embodiment, for the Compounds of Formula (Ia), R3 is aryl. In another embodiment, for the Compounds of Formula (Ia), R3 is phenyl.
In another embodiment, for the Compounds of Formula (Ia), R3 is phenyl, optionally substituted with halo.
In still another embodiment, for the Compounds of Formula (Ia), R3 is heteroaryl. In another embodiment, for the Compounds of Formula (Ia), R3 is 5-membered heteroaryl. In another embodiment, for the Compounds of Formula (Ia), R3 is 6-membered heteroaryl.
In a further embodiment, for the Compounds of Formula (Ia), R3 is oxadiazoiyl.
In another embodiment, for the Compounds of Formula (Ia), R3 is oxadiazolyl, optionally substituted with alkyl, -alkylene-O-alkyl, -alkylene-N(alkyl)2, cycioalkyl or alkylene-heterocycloalkyl.
In another embodiment, for the Compounds of Formula (Ia)1 R3 is 4- fluorophenyl, ethyl, t-butyl, isopropyl,
Figure imgf000062_0001
In another embodiment, for the Compounds of Formula (Ia), R3 is:
Figure imgf000063_0001
in another embodiment, for the Compounds of Formula (Ia), R3 is:
Figure imgf000063_0002
In one embodiment, for the Compounds of Formula (Ia), W is a bond and R3 is heteroaryi
In another embodiment, for the Compounds of Formula (Ia), W is a bond and R3 is oxadiazolyl, optionally substituted with alkyl, -alkylene-O-alkyl» -alkyϊene- N(alkyl)2, cycloalkyl or alkylene-heterocycloalkyl.
In another embodiment, for the Compounds of Formula (Ia)1 W is a bond and R3 Ss:
Figure imgf000064_0001
In still another embodiment, for the Compounds of Formula (Ia), W is a bond and R3 is:
Figure imgf000064_0002
In one embodiment, for the Compounds of Formula (Ia), A is 6-membered heteroaryl, which can be optionally substituted with an alkyl group; B is phenyl, which can be optionally substituted with up to 2 substituents, which can be the same or different and are selected from halo and -S(O)2-alkyl; W is a bond; and X is -0-. In another embodiment, for the Compounds of Formula (Ia), A is 6-membered heteroaryl, which can be optionally substituted with an alkyl group; B is phenyl, which can be optionally substituted with up to 2 substituents, which can be the same or different and are selected from halo and -S{O)2-alkyl; W is a bond; X is -0-; and R3 is heteroaryl, which can be optionally substituted with an alkyl group. In another embodiment, for the Compounds of Formula (Ia), A is pyrimidinyl, which can be optionally substituted with an alkyl group; B is phenyl, which can be optionally substituted with up to 2 substituents, which can be the same or different and are selected from halo and ~~S(O)2-alkyl; W is a bond; X is -O-; and R3 is heteroaryl, which can be optionally substituted with an alkyl group.
In one embodiment, the present invention provides compounds of Formula (Ia), wherein A, B, W and X are selected independently of each other. in another embodiment, a compound of formula (Ia) is in purified form.
The Bicyclic Heterocycle Derivatives of Formula III)
The present invention further provides Bicyclic Heterocycle Derivatives of Formula (II):
Figure imgf000065_0001
(fl) and pharmaceutically acceptable salts, solvates, esters, prodrugs and stereoisomers thereof, wherein A, B, G, W, X, Z, R1, p, q, r and s are defined above for the compounds of formula (II).
In one embodiment, G is -CH-. In another embodiment, G is -N-. In one embodiment, W is a bond Or -C(O)O-. In another embodiment, W is a bond. In another embodiment, W is -C(O)O-.
In another embodiment, W is -C(O)-. In yet another embodiment, W is -S(O)2-. In another embodiment, W is -S(O)2N(R10)-. In a further embodiment, W is -C(O)N(R10)-.
In one embodiment, G is N and W is -C(O)O-.
In another embodiment, G is --CH- and W is a bond.
In one embodiment, X is -C(R1 )2-.
In another embodiment, X is -O-.
In another embodiment, X is -S-.
In yet another embodiment, X is -N(R10)-.
In another embodiment, X is -NH-.
In one embodiment, A is aryl,
In another embodiment, A is 5 or 6-membered heteroaryl.
In another embodiment, A is phenyl,
In still another embodiment, A is pyrimidtnyl.
In another embodiment, A is pyridyl.
In another embodiment, A is 5-methylpyrimidinyl,
In one embodiment, B is aryl.
In another embodiment, B is 5 or 6-membered heteroaryl.
In another embodiment, B is phenyl.
In stil! another embodiment, B is pyrimidinyl.
In another embodiment, B is pyridyl. in another embodiment, B is 2-methyS pyridyl.
In a further embodiment, B is 2-chloro-4-cyanophenyl.
In one embodiment, B is:
Figure imgf000066_0001
In another embodiment, B is:
Figure imgf000066_0002
In one embodiment, A and B are each independently a 5 or 6-membered heteroaryl.
In yet another embodiment, X is -NH- and A is pyrimidinyf. In yet another embodiment, X is -NH- and B is phenyl.
In a further embodiment, X is -NH-, A is pyrimidinyl and B is phenyl.
In one embodiment, A and B are each independently a 5 or 6-membered heteroaryl, each of which can be optionally substituted with one substituent, independently selected from alkyl, aryl, -S(O)2-alkyl and halo. in another embodiment, A and B are each independently selected from phenyl, pyridyl and pyrimidinyl, each of which can be optionally substituted with one substituent, independently selected from alkyl, aryl, -S(O)2-alkyl and halo.
In another embodiment, A and B are each independently selected from phenyl, pyridyl and pyrirnidinyl, each of which can be optionally substituted with one or more substituents, each independently selected from methyl, phenyl, F5 Cl and -S(O)2CH3.
In still another embodiment, X is -NH-, A is pyrimidinyl and B is phenyl, wherein each of A and B can be optionally substituted with one substituent, independently selected from alkyl, -CN, halo and -S(O)2-alkyl.
In a further embodiment, X is -NH-, A is pyrimidinyl and B is phenyl, wherein each of A and B can be optionally substituted with one or more substituents, each independently selected from methyl, -CN, F, -S(O^CH3 and Cl.
In one embodiment, the group B-X-A- is:
Figure imgf000067_0001
!n one embodiment, each occurrence of R is selected from H, alkyl, halo or -
OH.
In another embodiment, each occurrence of R1 is H.
In one embodiment, R3 is alkyl. in another embodiment, R3 is a linear alkyl group.
In another embodiment, R3 is a branched alkyl group.
In still another embodiment, R3 is methyl.
In another embodiment, R3 is ethyl. in another embodiment, R3 is isopropyl. In a further embodiment, R3 is t-butyl. In one embodiment, R3 is cycloalkyl. In yet another embodiment, R3 is aryl. In another embodiment, R3 is phenyl. In another embodiment, R3 is -alkylene-aryl. In another embodiment, R3 is benzyl. In another embodiment, R3 is heteroaryl. In another embodiment, R3 is:
Figure imgf000068_0001
fn still another embodiment, R3 is alkyl or heteroaryl, wherein a heteroaryl group can be optionally substituted with an alkyl or cycloalkyl group,
In another embodiment, R3 is isopropyl or t-butyl. In one embodiment, W is -C(O)O- and R3 is alkyl. in another embodiment, W is a bond and R3 is heteroaryl.
In another embodiment, W is -C(O)O- and R3 is isopropyl or t-butyl.
In another embodiment, W is a bond and R3 is:
Figure imgf000068_0002
in one embodiment, p and q are each 1.
In another embodiment, r and s are each 1.
In another embodiment, p, q, r and s are each 1.
In one embodiment, the sum of p and q is 1.
In another embodiment, the sum of p and q is 2. in another embodiment, the sum of p and q is 3.
In still another embodiment, the sum of p and q is 4. In another embodiment, the sum of p and q is 5.
In yet another embodiment, the sum of p and q is 6.
In one embodiment, the sum of r and s is 1.
In another embodiment, the sum of r and s is 2.
In another embodiment, the sum of r and s is 3.
In still another embodiment, the sum of r and s is 4.
In another embodiment, the sum of r and s is 5.
Jn yet another embodiment, the sum of r and s is 6.
In another embodiment, G is N; p is 1 ; and q, r and s are each 2.
In another embodiment, G is N; p is 0; q is 3; and r and s are each 2.
In another embodiment, G is N; p is 0; q is 2; and r and s are each 2.
In another embodiment, G is N; p and q are each 2; and r and s are each 1.
In another embodiment, G is N; p and q are each 2; r is 1 ; and s is 2.
In another embodiment, G is -CH-; p and q are each 2; and the sum of r and s is 1.
In one embodiment, G is N; W is -C(O)O-; R3 is alkyl; and the group B-X-A- is:
Figure imgf000069_0001
In another embodiment, G is -CH-; W is a bond; R3 is heteroaryl; and the group B-X-A- is:
Figure imgf000069_0002
In another embodiment, G is N; W is -C(O)O-; R3 is isopropyl or t-butyl; and the group B-X-A- is:
Figure imgf000070_0001
tn stilf another embodiment, G is -CH-; W is a bond; R3 is:
Figure imgf000070_0002
and the group B-X-A- is:
Figure imgf000070_0003
In one embodiment, the present invention provides compounds of Formula (Ii), wherein A1 B1 G, W, X1 R1, p, q, r and s are selected independently of each other. In another embodiment, a compound of formula (II) is in purified form.
Non-tϊmiting examples of the Bicyclic Heterocycle Derivatives include compounds 1-100, depicted below:
Figure imgf000070_0004
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
and pharmaceutically acceptable salts, solvates, esters, prodrugs and stereoisomers thereof.
Methods For Making the BicycHc Heterocycte Derivatives Methods useful for making the Bicyclic Heterocycle Derivatives are set forth in the Examples below and generalized in Schemes 1-4. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis.
Scheme 1 illustrates a method useful for making the compounds of formula ill, which are useful intermediates for making the Bicyclic Heterocycle Derivatives of Formula (I).
Scheme 1
Figure imgf000085_0001
wherein A and B are defined above for the compounds of formulas (I) and (II); G is ■ OH, -SH1 -NHR10 or a carbon nucleophile; and X is -S-, -O-, -C(R V or -NR10.
A dichloro aryl or heteroaryl compound of formula i can be reacted with a compound of formula ii in the presence of a base, such as potassium carbonate or sodium hydride, to provide the intermediate compounds of formula Ui.
Scheme 2 illustrates a general method useful for making the Compounds of Formula (I).
Scheme 2
Figure imgf000085_0002
IV
(I) wherein R1, R2, R3, A, B, G, W, X, Y, Z, p, q, r, s and u are defined above for the Compounds of Formula (I). A compound of formula iv can be coupled with a compound of formula iii in the presence of diisopropylethylamine (DIPEA) in dioxane to provide the Compounds of Formula (I).
Scheme 3 illustrates an alternative method useful for making the Compounds of Formula (i).
Scheme 3
Figure imgf000086_0001
wherein R1, R2, R3, A, B, G, W, X, Y, Z, p, q, r, s and u are defined above for the Compounds of Formula (I).
A compound of formula iv can be coupled with a compound of formula i in the presence of diisopropylethylamine (DIPEA) to provide the intermediate compounds of formula v, A compound of formula v can then be reacted with a compound of formula it using the method described in Scheme 1 for coupling i and H, This provides the Compounds of Formula (i) via a two step process.
Scheme 4 illustrates a method useful for making the compounds of formula (II). Scheme 4
VI ase r wald ation
Figure imgf000087_0001
wherein R1, R3, A, B, G, W, X, Y1 p, q, r and s are defined above for the compounds of formula (II).
A compound of formula vi can be coupled with a compound of formula i in the presence of diisopropylethylamine (DiPEA) to provide the intermediate compounds of formula vii. A compound of formula vii can then be reacted with a compound of formula ii using a Buchwald N-arylation process or the method described in Scheme 1 for coupling i and ii. This provides the compounds of formula (H).
The starting materials and reagents depicted in Schemes 1-4 are either available from commercial suppliers such as Sϊgma-Aidrich (St. Louis, MO) and Acros Organics Co. (Fair Lawn, NJ), or can be prepared using methods well-known to those of skill in the art of organic synthesis. One skilled in the art will recognize that the synthesis of Bicyclic Heterocycle
Derivatives may require the need for the protection of certain functional groups (i.e., derivatization for the purpose of chemical compatibility with a particular reaction condition). Suitable protecting groups for the various functional groups of the Bicyclic Heterocycle Derivatives and methods for their installation and removal may be found in Greene et ah, Protective Groups in Organic Synthesis, Wiley-lntersctence, New York, (1999).
EXAMPLES The following examples exemplify illustrative examples of compounds of the present invention and are not to be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.
General Methods
Solvents, reagents, and intermediates that are commercially available were used as received. Reagents and intermediates that are not commercially available were prepared in the manner described below. 1H NMR spectra were obtained on a Gemini AS-400 (400 MHz) and are reported as ppm down field from Mβ4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron, 33 mm x 7mm ID; gradient flow: 0 min - 10% CH3CN, 5 min - 95% CH3CN1 7 min - 95% CH3CN, 7.5 min - 10% CH3CN, 9 min - stop. The observed parent ions are given.
Example 1 Preparation of Compound 1
Figure imgf000088_0001
Step A - Synthesis of Compound 1B
To a 0 °C solution of Compound 1 A (1.0 g, 4.45 mmol) in 30 mL methanol was added sodium borohydride (0.25 g, 6.67 mmoi) and the resulting reaction was allowed to stir at 0 °C for 2 hours and then quenched with a solution of saturated aqueous ammonium chloride. The resulting solution was extracted with ethyl acetate and the organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting oily residuey residue was purified using flash column chromatography on silica gel (20% acetone in hexanes) to provide Compound 1B.
Step B - Synthesis of Compound 1C
To a solution of Compound 1 B (227 mg, 1.0 mmol) in 6 mL THF was added 4- fluoropheno! (170 mg, 1.5 mmol) and triphenylphosphine (395 mg, 1 ,5 mmol). To the resulting solution was then added dropwise diisopropyl azodicarboxylate (0.32 mL, 1.5 mmol) and the resulting reaction was allowed to stir for 16 hours. The reaction mixture was then concentrated in vacuo and the resulting oily residuey residue was purified using flash column chromatography on silica gel (5% acetone in hexanes) to provide 1C.
Step C - Synthesis of Compound 1D
To a solution of Compound 1C (75 mg, 0.23 mmol) in 10 mL dichloromethane was added trifluoroacetic acid (2.0 mL). The resulting reaction was allowed to stir at room temperature for 2 hours, the solvent was removed under reduced pressure. The resulting oily residue was diluted with dichloromethane and washed with a solution of saturated aqueous sodium bicarbonate. The combined organic extracts were dried (IS^SO-O, filtered, and concentrated in vacuo to provide Compound 1D, which was used without further purification.
Step D - Synthesis of Compound 1 To a solution of Compound 1D (-0.23 mmol) in DMF (1 mL) was added
Compound 1E (66 mg, 0.28 mmol, synthesized as described in International Publication No. WO 07/035355) and N,N-diisopropylethylamine (0.12 mL, 0.69 mmol). The resulting reaction was heated under microwave irradiation at 180 °C for 1 hour after which time it was cooled to room temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic extracts were dried (Na2SCU), filtered, and concentrated in vacuo to provide an oily residue which was purified using preparative TLC (4% MeOH in CH2CI2) to provide Compound 1 (56 mg, 58% yleld); LCMS: 421 (MH-H)+.
Example 2 Preparation of Compounds 2 and 3 0
Figure imgf000090_0001
Figure imgf000090_0002
Step A - Synthesis of Compound 2A
To a O °C suspension of methyltriphenylphosphonium bromide (23.8 g, 66.7 mmol) in 200 mL THF was added n-BuLi (1.6 M in hexanes, 42.0 mL, 66.7 mmol) and the resulting reaction was allowed to stir at room temperature for 30 minutes and then cooled to O °C. To the cooled solution was added a O °C solution of compound 1 A (5.0 g, 22.2 mmol) in 10 mL THF and the cold bath was removed. The reaction was then allowed to stir 16 hours, during which time the reaction mixture came to room temperature on its own. The reaction was quenched by adding a solution of saturated aqueous ammonium chloride and the resulting solution was extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo and the resulting oily residυey residue was purified using flash column chromatography on silica gel (5-20% ethyl acetate in hexanes) to provide Compound 2A (2.9 g, 59% yleld).
Step B - Synthesis of Compound 2B
To a 0 °C solution of Compound 2A (2.4 g, 10.8 mmol) in 100 mL THF was added a solution of borane-THF complex (1 M in THF, 13,0 mL, 13 mmol) and the resulting reaction was allowed to stir at room temperature for 48 hours. The reaction was then cooled to 0 °C and treated with 14,5 mL 2N aq. NaOH solution followed by 5.0 mL of 35% aq. H2O2 solution. The resulting reaction was allowed to stir at room temperature for 3 hours after time which it was quenched with 10% aqueous sodium bisulfite solution and stirred for additional 30 minutes. The solvent was removed in vacuo and the resulting solution was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo and the resulting oily residuey residue was purified using flash column chromatography on silica gel (20% acetone in hexanes) to provide Compound 2B (2.33 g, 90% yleld).
Step C - Synthesis of Compound 2C To a solution of Compound 2B (2.0 g, 8.3 mmol) in a mixture of acetonitrile (8 mL), ethyl acetate (8 mL), and water (12 mL) was added sodium periodate (8.17 g, 38.17 mmol) followed by ruthenium chloride (0.1 g, 0.48 mmoi). The resulting reaction was allowed to stir at room temperature for 20 hours, after which time it was diluted with dichloromethane and washed with brine solution. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica gel (20% acetone in hexanes) to provide Compound 2C (1.5 g, 71% yleld).
Step D - Synthesis of Compound 2D To a solution of Compound 2C (1.5 g, 5.85 mmol) in 35 mL ethyl acetate was added 4-methylmorpholine (0.71 mL, 6.47 mmoi) followed by isopropyl chloroformate (1M in toluene, 6.5 mL, 6.5 mmol). The resulting reaction was allowed to stir at room temperature for 2 hours, after which time it was washed with water and brine. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo and the resulting oily residue was taken up in 30 mL DMF. To the resulting solutionwas added N-hydroxybutyramidine (0.75 g, 0.74 mmol) and the resulting reaction was allowed to stir at room temperature for 30 minutes and then heated to 110 °C and allowed to stir at this temperature for 12 hours. The reaction mixture was cooled to room temperature, water was added and the resulting solution was extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica gel (5% acetone in hexanes as eluent) to provide Compound 2D (1.7 g, 88% yleld).
Step E - Synthesis of Compound 2E
Compound 2E was prepared from Compound 2D using the method described in Example 1 , Step C.
Step F - Synthesis of Compound 2F
Figure imgf000092_0001
2F To a solution of 2-fluoro-4-(methylsulfonyl)aniline (1.5 g, 7.23 mmol) in 70 ml
THF was added NaH (60% in oil, 0.73 g, 18.08 mmol). The resulting suspension was allowed to stir for 30 minutes at room temperature, then a solution of 4,6-dichloro-5- methylpyrimidine (1.3 g, 7.95 mmol) in 5 mL THF was added and the reaction was allowed to stir at room temperature for and additional 16 hours. The reaction was then quenched by addition of water and the resulting solution was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo and the residue obtained was triturated with ether (100 mL) and filtered. The collected solid was washed two times with ether and dried under vacuum to provide Compound 2F (1.95 g, 78% yleld) which was used without further purification.
Step G - Synthesis of Compounds 2 and 3 A solution of Compounds 2E (0.45 g, 2.05 mmoi) and 2F (0.65 g, 2.05 mmol) and N,N-diisopropylethylamine (0.75 ml_, 4.3 mmol) in 3.5 mL dioxane and 1.0 ml_ 1- methyl-2-pyrrolidinone was heated to 170 °C and allowed to stir at this temperature for 16 hours. The reaction was cooled to room temperature, water was added and the resulting solution was extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo and the residue obtained was purified using preparative TLC (2% MeOH in CH2Cb as eluent) to provide a mixture of Compounds 2 and 3. This mixture was further purified using preparative TLC (50% ethyl acetate in hexanes) to provide Compound 2 (380 mg, 38% yleld); LCMS: 501 (M+H)+ and Compound 3 (120 mg, 12% yleld); LCMS: 501 (M+H)+.
Example 3 Preparation of Compounds 4 and 5
Figure imgf000093_0001
Compounds 4 and 5 were prepared by reacting Compound 3A with Compound
2E using the method described in Example 2, step G. Compound 3A was prepared using the method described in Example 2, step F by replacing 2-fluoπ>4- (methylsulfonyl)aniline with 4-amino-3»chlorobenzonitrile. Compound 4: LCMS: 464, 466 (M+H)÷, Compound 5: LCMS: 464, 466 (M+H)+
Example 4 Preparation of Compound 6
Figure imgf000094_0001
Step A - Synthesis of Compound 4A
To a solution of 4,6-dichloro-5-methylpyrimidine (185 mg, 1.13 mrnol) in 5 mL dioxane was added Compound 2E (250 mg, 1.13 mmol) and DIPEA (0.4 mL, 2.23 mmol). The resulting reaction was allowed to stir at 150 °C for 16 hours, after which time it was cooled to room temperature and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel (5-10% acetone in hexanes) to provide Compound 4A (250 mg, 64% yleld).
Step B - Synthesis of compound 6
A mixture of Compound 4A (38 mg, 0.11 mmol), 4-(methylsulfonyl)-anifine (38 mg, 0.22 mmol), K3PO4 (35 mg, 0.17 mmol), (o-biphenyl)PCy2 (16 mg) and Pd2dba3 (8 mg) in 2 mL dioxane was heated to 120 °C and allowed to stir at this temperature for 16 hours. The reaction was then cooled to room temperature and the solvent was removed in vacuo. The residue obtained was purified using preparative TLC (2% MeOH in CH2CI2) then repurified using preparative TLC (50% ethyl acetate in hexanes) to provide Compound 6 (10 mg); LCMS: 483 (JvRH)+.
Example 5
Preparation of Compound 7
Figure imgf000095_0001
To a solution of (methylsulfonyl)aniϋπe (33 mg, 0.16 mmol) in 4 mL THF was added 60% NaH (26 rng, 0.65 mmol) and the resulting suspension was allowed to cool for 30 minutes at room temperature then cooled to 0 °C. A solution of Compound 4A (45 mg, 0.13 mmol} in 1 mL THF was added to the cooled solution and the reaction was allowed to stir at room temperature for 16 hours. The reaction was then quenched by addition of water and the resulting solution was extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo and the residue obtained was purified using preparative TLC (3% MeOH in CH2Ci2 as eluent) to provide Compound 7 (30 mg); LCMS: 483 (M+H)+
Example 6
Preparation of Compound 8
Figure imgf000095_0002
Step A - Synthesis of Compound 6C
Compound 6B was To a solution of Compound 6B (prepared using the method described in J. Med, Chem. 37:2831 (1994)) in 20 ml EtOH was added 10 mL concentrated HCi solution. The reaction was heated to 110 °C and allowed to stir at this temperature for 20 hours. The reaction mixture was then cooled to 0 °C, basified with 1 N NaOH and extracted with ethyl acetate. The combined organic extracts were dried (Na≤SO^, filtered, and concentrated in vacuo to provide Compound 6C which was used without further purification,
Step B - Synthesis of Compound 6D
To a solution of compound 6C from above in 20 mL ivteOH was added ammonium formate (200 mg, 31.4 mmol) followed by Pd(OH)2 (320 mg). The reaction was refluxed for 2h after which time it was concentrated in vacuo. The residue was taken in dichloromethane and washed with 1N NaOH solution. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give compound 6D which was used without further purification.
Step C - Synthesis of Compound 8
Compound 8 was prepared by reacting Compound 2F with Compound 6D using the method described in Example 2, Step G; LCMS: 479 (M+H)+.
Example 7
Preparation of Compound 9
Figure imgf000096_0001
Step A - Synthesis of Compound 7 A
To a solution of Compound 6D (~ 150 mg, 0.63 mmol) in 20 mL dichloromethane was added triethylamine (0.5 mL, 3.5 mmol) followed by di-fe/f-butyl dicarbonate (0.8 g, 3.7 mmol). The resulting reaction was allowed to stir for 5 hours, after which time water was added and the organic layer was separated, dried (Na2SO4), filtered, and concentrated in vacuo. The residue obtained was purified using flash coiumn chromatography on silica gei to provide Compound 7A (150 mg).
Step B - Synthesis of Compound IB To a solution of Compound 7A (150 mg, 0.5 mmol) in 2 mi_ EtOH and 2 mL
H2O was added lithium hydroxide monohydrate (120 mg, 2.85 mmol). The resulting reaction was allowed to stir at room temperature for 16 hours, then additional lithium hydroxide monohydrate (120 mg» 2.85 mmol) and 0.5 mL H2O were added and the reaction was allowed to stir for an additional 16 hours. The reaction was then diluted with dichloromethane and washed with 10% aq. KHSO4 solution. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide Compound 7B which was used without further purification.
Step C - Synthesis of Compound 9 Compound 9 was synthesized from compound 7B using the method described in Example 2, LCMS: 480 (IvHH)+.
Example 8
Preparation of Compounds 10 and 11
Figure imgf000097_0001
Starting from 4,6-dichloro~5-methoxypyrimidine (synthesized as described in EP 464604), Compounds 10 and 11 were prepared using the method described in Example 2; LCMS: 517 (M+H)+.
Example 9
Preparation of Compounds 12 and 13
Figure imgf000098_0001
Compounds 12 and 13 were prepared from 4,6-dichloropyrimidine using the method described in Example 2. LCMS: 487 (M+H)+.
Example 10
Preparation of Compound 14
Figure imgf000098_0002
To a solution of Compound 2B (240 mg, 1.0 mmol) in 7 mL DMF was added sodium hydride (240 mg, 6.0 mmol) and the resulting reaction was allowed to stir at room temperature for 1 hour, lodoethane (0.48 mL, 6.0 mmol) was then added and the reaction was allowed to stir at room temperature for 24 hours, then quenched by addition of water and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo and the residue obtained was purified using flash column chromatography (5% acetone in hexanes) to provide Compound 14A (quant,). Compound 14A was subsequently converted to Compound 14 using the method described in Example 2; LCMS: 449 (M+H)+.
Example 11
Preparation of Compound 15
Figure imgf000099_0001
Compound 15 was prepared using the method described in Example 10 and substituting 1-bromo-2-methylpropane for iodoethane; LCMS: 477 (M+H)*,
Example 12
Preparation of Compounds 16 and 17
Figure imgf000099_0002
To a solution of Compound 2C (150 mg, 0.56 mmoi) in 5 ml_ DMF was added isobutyric acid hydrazide (152 mg, 1.48 mmoi), DIPEA (0.26 mi, 1.48 mmol) then HATU (563 mg, 1.48 mmol). The resulting reaction was allowed to stir at room temperature for 4 hours, after which time it was diluted with ethyl acetate and washed with saturated ammonium chloride solution. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo and the residue obtained was taken up in 5 mL THF and PS-BEMP (2.2 mmo! base/g, 1.3g, 2.8 mmol). To the resulting solution was added p-toluenesulfonyl chloride (130 mg, 0.67 mmol) and the resulting reaction was heated to 120 °C under microwave irradiation for 15 minutes. After cooling to room temperature the reaction mixture was filtered through celite and the collected solid was washed three times with ethyl acetate. The filtrate was concentrated in vacuo and the resulting residue was purified using flash coiumn chromatography (10-20% acetone in hexanes) to provide Compound 16A (120 mg, 63% yleld).
Compound 16A was converted to Compounds 16 and 17 using the method described in Example 2. LCMS: 501 (M+H)*.
Example 13
Preparation of Compounds 18 and 19
Figure imgf000100_0001
Compounds 18 and 19 were prepared using the method described in Example 12, and substituting methoxyacetic acid hydrazide for isobutyric acid hydrazide. LCMS: 503 (M+H)+,
Example 14
Preparation of Compounds 20 and 21
To a 0 °C solution of Compound 18 (60 mg, 0.12 mmol) in 3 mL dichloromethane was added boron tribromide solution (1M in dichloromethane, 0.6 mL, 0.6 mmol) and the resulting reaction was allowed to stir for 2 hours while warming to room temperature. The reaction mixture was then concentrated in vacuo and the residue obtained was purified using preparative TLC (3% MeOH in CH2CI2) to provide Compound 20 (30 mg, 51 % yleld). LCMS: 489 (M*H)+.
Figure imgf000101_0001
Compound 21 was prepared in a similar fashion starting from Compound 19; LCMS: 489 (M+H)+.
Example 15
Preparation of Compounds 22 and 23
Figure imgf000101_0002
Compounds 22 and 23 were prepared using the method described in Example
2. N-hydroxybutyramidine (Step D) was replaced with N-hydroxy-2-methoxy- acetamidine (as synthesized in EP 1479674 A1 , 2004); LCMS: 503 (M+H)+,
Example 16
Preparation of Compounds 24 and 27
Figure imgf000101_0003
Compounds 24 and 27 were prepared using the method described in Example 10 and substituting the appropriate starting materiais and/or reagents. Compound 24; LCMS: 491 (M+H)÷; Compound 27: LCMS: 512 (M+H)+
Example 17
Preparation of Compounds 25 and 26
Figure imgf000102_0001
Compounds 25 and 26 were prepared using the method described in Example
1O1 and substituting Compound 3A for Compounod 2F. Compound 25: LCMS: 454, 456 (M+H)+; Compound 26: LCMS: 475, 477 (M+H)+
Example 18
Preparation of Compound 28
18A
28
Figure imgf000102_0002
Step A - Synthesis of Compound 18B
5-Methyl-4,6-dichloropyrimidine (0.068 g, 0.66 mmol), Compound 18A (0.100 g, 0.42 mmol), and K2CO3 (0.115 g, 0.83 mmol} were combined in dioxane (2.0 mL) and the resulting reaction was heated to 100 °C and allowed to stir at this temperature for 18 hours. The reaction was then cooled to room temperature and concentrated in vacuo and the residue obtained was purified using preparative TLC to provide Compound 18B as a yellow oil. Step B — Synthesis of Compound 28
Compound 18B (0.080 g,.0.22 mmol), 4-amino-3-chlorobenzonitri!e (0.040 g, 0.26 mmol), (±)-BINAP (0.014 g, 0.02 mmol), Pd2dba3 (0.0075 g, 0.013 mrnoi), and NaO-ffiu (0.027 g, 0.28 mmoi) were combined in toluene (4.0 mL) and the resulting reaction was heated in a microwave apparatus at 140 °C for 1 hour. The reaction mixture was cooied to room temperature, concentrated in vacuo, and the residue obtained was purified using preparative TLC to provide Compound 28 as a yellow solid; LCMS: 483, 485 (M+Hf
Example 19 Preparation of Compound 29
Figure imgf000103_0001
28 29
Step A - Synthesis of Compound 19A Compound 28 (0.015 g, 0.031 mmol) was diluted with 4.0M HCl/dioxane (2.0 mL) and the resulting solution was allowed to stir for 2 hours. The reaction mixture was then concentrated in vacuo to provide Compound 19A as its hydrochloride salt, which was used without further purification.
Step B ~ Synthesis of Compound 29
To a solution of Compound 19A in CH2CI2 (2.0 mL) was added Et3N (0.020 mLs 0.14 mmoi) and isopropyl chloroformate (1.0M in toluene, 0.069 mL, 0.069 mmol). The resulting reaction was allowed to stir for 1 hour at room temperature, then was concentrated in vacuo and the residue obtained was purified using preparative TLC to provide Compound 29 as a white solid; LCMS: 469, 471 (M+H)+
Example 20
Preparation of Compound 30 18A 2OA
Figure imgf000104_0001
Using the method described in Example 18, 4,6-dichloropyrimidine was converted to Compound 30 as a yellow solid; LCMS: 469, 471 (M+H)+,
Example 21 Preparation of Compound 31
Figure imgf000104_0002
Step A - Synthesis of Compound 21 B
Compound 21A (0.200 g, 0.72 mmol) and Et3N (0.40 mL, 2.9 mmol) were combined in CH2Cb (5 mL) and to the resulting solution was added isopropyl chloroformate (1 ,0M in toluene, 1.0 mL, 1.0 mmol). The resulting reaction was allowed to stir for 1 hour and the reacton mixture, which contains Compound 21B1 was used directly in the next step.
Step B - Synthesis of Compound 21 C
To the reaction mixture from Step A (containing Compound 21B) was added 4.0IvI HCl/dioxane (4.0 mL, 16 mmol). The resulting reaction was allowed to stir for 18 hours, then the reaction mixture was concentrated in vacuo and the residue obtained was partitioned between EtOAc and 1 N NaOH. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to provide Compound 21 C as a yellow oil, which was used without further purification. Step C - Synthesis of Compound 21 D
Using the method described in Example 18, Step A (heating in a microwave apparatus for 2 hours at 14O°C), Compound 21 C was converted to Compound 21 D, as a yellow solid.
Step D - Synthesis of Compound 31
Using the method described in Example 18, Step B, Compound 21 D was converted to Compound 31, as a yellow solid; LCMS: 455, 457 (M+H)+.
Example 22
Preparation of Compound 32
Figure imgf000105_0001
Figure imgf000105_0002
Step A ~ Synthesis of Compound 22B
A solution of N~Boc-4-methylenepiperidine (2.5 g, 13 mmol) in CH2CI2 (35 mL) was cooled to 0 °C and a solution of chlorosulfonyl isocyanate (1.35 mL, 15.5 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred for 18 hours, then diluted with ether (70 mL) and cooled in ice. To the icy mixture was added a solution of Na2S2O3 (6.0 g) and KOH (1.5 g) in water (40 mL) and the resulting solution was allowed to stir at 0 °C for 3 hours. The organic and aqueous layers were separated, the aqueous layer was washed with EtOAc1 then the combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to provide Compound 228, which was used without further purification. Step B - Synthesis of Compound 22C
To a solution of Compound 22B (0,30 gs 1.2 mmol) in THF (5 ml_) was added borane-dimethyl sulfide complex (0.24 mL, 1.5 mmol). The resulting reaction was heated to reflux and allowed to stir at this temperature for 28 hours. The reaction was then allowed to cool to room temperature, quenched with MeOH and concentrated in vacuo to provide Compound 22C, which was used without further purification.
Step C ~ Synthesis of Compound 22D
Compound 22D was prepared from Compound 22C using the method described in Example 18, Step A.
Step D ~ Synthesis of Compound 32
Compound 22D (0.050 g, 0.15 mmol), 4-amino-3-chlorobenzonitrile (0.030 g, 0.20 mmol) and NaH (60% in oil, 0.0094 g, 0,24 mmol) were combined in THF (3 mL) and the resulting reaction was heated to 65 °C and allowed to stir at this temperature for 20 hours. Additional 4-amino-3~chlorobenzonitrile (0.011 g) and NaH (0.004 g) were then added and the reaction was allowed to stir at reflux for an additional 24 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue obtained was purified using preparative TLC to provide Compound 32 as a brown gum; LCIvIS: 455, 457 (M+H)+.
Example 23
Preparation of Compound 33
Figure imgf000106_0001
Step A - Synthesis of Compound 23B
Compound 23A (0.274 g, 1.04 mmol) was combined with 4,6- dichloropyrimidine (0.196 g, 1.31 mmol) and DIPEA (0.45 mL, 2.6 mmol) in dioxane (6 mL) and the resulting reaction was heated to 110 °C and allowed to stir at this temperature for 20 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the resulting residue was purified using preparative TLC to provide Compound 23B as an off-white solid.
Step B - Synthesis of Compound 33
Using the method described in Example 22, Step B, Compound 23B was converted to Compound 33 as a yellow gum; LCMS: 455, 457 (IVHH)+.
Example 24 Preparation of Compound 34
Figure imgf000107_0001
Using the method described in Example 23, Compound 24A was converted to Compound 34. LCMS: 469, 471 (M+H)*.
Example 25 Preparation of Compounds 35 and 36
Figure imgf000107_0002
Step A - Synthesis of Compound 25B
Compound 25A (5.00 g, 15.1 mmol) was combined with 10% Pd/C (1.00 g) and Et3N (2.52 mLs 18.2 mmol} in MeOH (20 mL) and the resulting solution was hydrogenated at 50 psi for 18 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to provide Compound 25B, which was used without further purification.
Step B - Synthesis of Compound 2SC
Compound 25B (1.00 g, 3.9 mmol) was combined with ION NaOH (7.8 mL, 7.8 mmol) in MeOH (15 mL). The mixture was allowed to stir for18 hours at room temperature, then was acidified with 1.0N HCl (10 mL) and extracted ether. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to provide Compound 25C, which was used further purification.
Step C - Synthesis of Compound 250
Compound 25C (0.96 g, 4.0 mmol) was combined with Et3N (0,5 6mL, 4.0 mmol) in THF (10 mL). The mixture was cooled to 0 °C, isopropyl chloroformate (1.0M in toluene, 4.8 mL, 4.8 mmol) was added, and the resulting reaction was allowed to stir for 2 hours. Ether (20 mL) was added to the reaction mixture and the resulting suspension was filtered. The filtrate was concentrated in vacuo, the residue obtained was taken up in dioxane (10 mL), and to the resulting solution was added isobutyramide oxime (0.45 g, 4,4 mmol), The resulting reaction was allowed to stir for 2 hours, then POCI3 (0.75 mL, 8.1 mmol) was added and the reaction was heated to 100 °C and allowed to stir at this temperature for 2 hours. The reaction mixture was then allowed to coof to room temperature and the cooled reaction mixture, which contains Compound 25D, was used directly in the next step.
Step D - Synthesis of Compound 25E
The solution from Step C (containing Compound 25D) was treated with 4.0M HCl in dioxane (2.0 mL, 8.0 mmol) and the resulting reaction was allowed to stir for 20 minutes, then was concentrated in vacuo. The resulting residue was partitioned between ether and 1.0N NaOH. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to provide Compound 25E, which was used without further purification.
Step E ~~ Synthesis of Compound 25F Compound 25E and 5-methyl-4,6-dichloropyrimidine were reacted using the method described in Example 18, Step A, heating by microwave at 140 °C for 1.5 hours. The resulting mixture of the exo- and encfo-isomers were separated by chromatography on silica {0-20% EtOAc/hexane), with the eπcfo-isomer (Compound 25F) eluting first.
Step F- Synthesis of Compounds 35 and 36
The enc/o-isomer 25F from Step E (0.095 g, 0.29 mmol) was combined with 2- fluoro-4-methylsulfonylaniline (0.108 g, 0.57 mmol), X-Phos (0.027 g, 0.057 mmol), Pd(OAc)2 (0.013 g, 0.058 mmol), and Cs2CO3 (0.184 g, 0.57 mmol) in dioxane (5.0 mL) and the resulting reaction was heated in a microwave apparatus at 140 °C for 2 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the resulting residue was purified using preparative TLC to provide Compounds 35 and 36. LCMS: 487 (M+H)+.
Example 26
Preparation of Compound 37
Figure imgf000109_0001
Figure imgf000109_0002
260 26E 37 Step A - Synthesis of Compound 26B
Compound 26A (0.64 g, 2.8 mmol, prepared as described in US Patent No. 968929) and Et3N (0.47 mL, 3.4 mmol) were combined in CH2CI2 (10 mL). The solution was cooled to 0 °C, and methanesulfonyl chloride (0.26 mL, 3.3 mmol) was added. The reaction was allowed to stir at 0 °C for 1 hour, then was warmed to warm to room temperature, and stirred for an additional 2 hours. The reaction mixture was diluted with ether (20 mL) was added and the resulting solution was filtered. The filtrate was concentrated in vacuo and the resulting residue was taken up in DMF (15 mL). To the resulting solution was added NaN3 (0.37 g, 5.6 mmol) and the mixture was heated to 80 °C and allowed to stir at this temperature for 18 hours, then cooled to room temperature and partitioned between EtOAc and water. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to provide Compound 26B, which was used without further purification.
Step B - Synthesis of Compound 26C
Compound 26B (0.68 g, 2.7 mmol) was combined with condensed 3-methyl-1- butyne (0.73 g, 10.8 mmol), CuI (0.020 g, 0.11 mmol) and DIPEA (0.47 mL, 2.7 mmol) in toluene (5 mL) in a sealed tube. The reaction was heated to 90 °C and allowed to stir at this temperature for 18 hours, then cooled to room temperature. The reaction mixture was then partitioned between ether and water and the organic phase was dried (MgSO4) filtered and concentrated in vacuo to provide Compound 26C, which was used without further purification.
Step C - Synthesis of Compound 26D
Compound 26C (0.80 g, 2.5 mmol) was dissolved in 1:1 CH3CN/CH2CI2 (10 mL) and 4,0!Vl HCl/dioxane (4.0 mL) added. The mixture was heated to 40 °C and allowed to stir at this temperature for 20 minutes, then concentrated in vacuo. The residue obtained was partitioned between EtOAc and 1N NaOH and the organic phase was dried (MgSO4), filtered and concentrated in vacuo to provide Compound 26D, which was used without further purification. Step D ~ Synthesis of Compound 26E
Compound 26D and 5-methyl-4,6-dichloropyrimidine were reacted using the method described in Example 18, Step A, heating by microwave at 140 °C for 2 hours. Purification using preparative TLC provided Compound 26E as an oil.
Step E- Synthesis of Compound 37
Compound 26E was reacted according to the method described in Example 25, Step F1 but using NaO-tBu as the base. Purification using preparative TLC provided Compound 37 as a yellow solid. LCMS: 500 (M+H)+.
Example 27 Preparation of Compound 38
Figure imgf000111_0001
Step A - Synthesis of Compound 27 A
Compound 25B (2.00 g, 7.8 mmol) was combined with LiBH4 (0.44 g, 15 mmol) in THF (20 mL) and the resulting reaction was heated to reflux and allowed to stir at this temperature for 4 hours. After cooling to room temperature, the mixture was partitioned between ether and water. The organic phase was dried (MgSO4) filtered and concentrated in vacuo to provide Compound 27A as a colorless oil, which was used without further purification. Step B - Synthesis of Compound 27B
Compound 27 A (1.70 g, 7.2 mrnol) and Et3N (1 ,25 mL, 9.0 mmol) were combined in CH2CI2 (10 mL). Methanesulfonyl chloride (0.70 mL, 9.0 mrnol) was added and the mixture was allowed to stir for 2 h at room temperature. Ether (20 mL) was added, the resulting solution was filtered, and the filtrate was concentrated under in vacuo. The resulting residue was taken up in DMF (10 mL) and to the resulting solution was added NaCN (0.73 g, 10,6 mmoi) the reaction was heated to 80 °C and allowed to stir at this temperature for 68 hours. After cooling it to room temperature, the reaction was partitioned between ether and water and the organic phase was dried (MgSO4), filtered and concentrated in vacuo to provide Compound 27B, which was used without further purification.
Step O - Synthesis of Compound 27 C
Compound 27B (1.50 g, 6.6 mmol) was taken up in EtOH (5 mL), treated with 1.0N NaOH (20 mL), and the resulting reaction was heated to reflux and allowed to stir at this temperature for 4 hours. After cooling to room temperature, the mixture was acidified with HCl to pH 2, and partitioned between ether and water. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to provide Compound 27C, which was used without further purification.
Step D - Synthesis of Compound 27D
Using the method described in Example 25, Step C, Compound 27C was converted to Compound 27D.
Step E - Synthesis of Compound 27E
Using the method described in Example 25, Step D, Compound 27D was converted to Compound 27E, which was used without further purification.
Step F- Synthesis of Compound 27 F Compound 27E and 5-methyl-4,6-dichloropyrimidine were reacted according to the method described in Example 18, Step A, heating by microwave at 140 °C for 1 hour. Purification using preparative TLC provided Compound 27F as a yellow oil. Step G - Synthesis of Compound 38
Compound 27F was reacted according to the method described in Example 25, Step F1 but using NaO-fBu as the base. Purification using preparative TLC provided Compound 38 as a yellow solid; LCMS: 501 (M+Hf.
Example 28 Preparation of Compound 39
Figure imgf000113_0001
Step A: Synthesis of Compound 2BB
To a solution of compound 28A (0.50Og, 1.96 mmol, prepared as described in International Publication No. WO 06/002133) in EtOAc (10 mL) was added W- methylmorpholine (0.43 mL, 3.92 mmol) and /so-propyl chlroformate (2.3 mL of a 1 IVI solution in toluene, 2.3 mmol}. The resulting reaction was allowed to stir at room temperature for 1 hour, then was quenched with water and extracted with EtOAc. The organic phase was dried (MgSO^1 filtered and concentrated in vacuo to provide a crude residue, which was taken up in DMF (5 mL) and pyridine (0.5 mL). The resulting reaction was heated to 120°C and allowed to stir at this temperature for 16 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo and the resulting residue was purified using preparative TLC (20%EtOAc/hexanes) to provide Compound 28B (0.515g, 82%). Step B: Synthesis of Compound 28C
Trifluoroacetic acid (0.36 mL, 4.8 mmol) was added to a solution of compound 28B (0.515 g, 1.60 mmoi) in dichloromethane (5 mL) at room temperature and the resulting reaction was allowed to stir for 3 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was taken up in dichloromethane, washed with sat. aq. NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to provide Compound 28C (0.35 g, 99%).
Step C: Synthesis of Compound 28D
To a solution of compound 28C (0.35 g, 1.6 mmol) and 4,6-dichloro-5- methylpyrimidine (0.28 g, 1.7 mmol) in dioxane (6 mL) was added DIPEA (0.55 mL, 3.2 mmol) and the resulting reaction was heated to 110°C and allowed to stir at this temperature for 1 hour. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the resulting residue was purified using preparative TLC (30%EtOAc/hexanes) to provide Compound 28D (0.4Og1 73%).
Step D: Synthesis of Compound 39
To a solution of compound 28D (0.14 g, 0.40 mmol) and 2-fluoro-4- (methylsulfonyl)aniline (0.083 g, 0.44 mmol) in DMF (2 mL) was added NaH (60% oil, 0.035 g, 0.88 mmol) and the resulting reaction was heated to 80°C and allowed to stir at this temperature for 16 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the resulting residue was purified using preparative TLC (50%EtOAc/hexanes) to provide Compound 39 (0.116g, 58%); LCMS: 501 (M+H)+.
Example 29
Preparation of Compound 40
Figure imgf000114_0001
Using the method described in Example 28 and substituting 4-amino-3- chlorobenzonitrile for 2-fluoro-4-(methylsulfonyl)aniline, compound 40 was prepared. LCMS: 464, 466 (M+H)+.
Example 30
Preparation of Compound 41
Figure imgf000115_0001
Using the method described in Example 14, Compound 22 was converted to
Compound 41; LCMS: 489 (M+Hf,
Example 31
Preparation of Compound 42
Figure imgf000115_0002
Figure imgf000115_0003
Step A - Synthesis of Compound 31 A
To an ice-cold solution of Compound 41 (30 mg, 0.06 mrnoi) in 3 mL dichlororrtethane was added triethylamine (0.03 mL, 0.18 mmol) followed by methanesulfonyl chloride (6 μL, 0.07 mmol). The reaction was allowed to stir for 1 hour, after which time it was quenched with water and extracted with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide Compound 31 A which was used without further purification.
Step B - Synthesis of Compound 42 To a solution of Compound 31 A (15 mg) in 0.5 mL THF was added dimethylamine (2M in THF, 1 mL) and the resulting reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was purified using preparative TLC (3% MeOH in CH2CI2) to provide Compound 42. LCMS: 516 (M+H)+.
Example 32
Preparation of Compound 43
Figure imgf000116_0001
To a solution of Compound 31 A (15 mg) in 0.5 mL THF was added pyrrolidine (0.05 mL) and potassium carbonate (15 mg) and the resulting reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was purified using preparative TLC (3% MeOH in CH2CI2) to provide Compound 43. LCMS: 542 <M+H)+. W
116
Example 33
Preparation of Compound 44
Figure imgf000117_0001
Compound 44 was prepared using the method described in Example 2 and substituting N-hydroxybutyramidine with N'-hydroxy-3-methylenecyclobutane carboximidamide in step D. LCMS: 525 (M+H)+.
Example 34 Preparation of Compound 45
Figure imgf000117_0002
To a solution of Compound 44 (90 mg, 0.17 mmol) in 3 mL acetone and 2 mL H2O was added K2OsO4 (6 mg, 5 mo!%) foflowed by sodium periodate (150 mg, 0.69 mmol). The reaction was allowed to stir at room temperature and monitored using TLC. When TLC indicated that all starting material was consumed, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The resuling residue was diluted with dichloro methane and washed with 10% aqueous Na2S2O3 solution. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo and the residue obtained was purified using preparative TLC (2% MeOH in CH2CI2) to provide Compound 45 (76 mg) as a white solid. LCMS: 527 (M+H)+.
Example 35 Preparation of Compound 46
D
Figure imgf000118_0001
Step A - Synthesis of compound 35A To a solution of 4,6-dichloro-5-methylprylmidine (0.28 g, 1.7 mmol) in 15 ml
DMF was added potassium carbonate (0.24 g, 1.7 mmoi) and 3-chloro-4- hydroxybenzonitrile (0.26 g, 1.7 mmol). The reaction was heated to 50 °C and allowed to stir at this temperature for 20 hours, then was quenched with water and extracted with ethyl acetate The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica gel (10% acetone in hexane) to provide Compound 35A.
Step B: Synthesis of compound 46
Compound 46 was synthesized by reacting 35A with 2E according to the method described in Example 2, step G without using 1-methyl-2-pyrro!idine; LCMS: 465, 467 (M+Hf .
Example 36
Preparation of Compound 47
Figure imgf000119_0001
Compound 47 was synthesized by reacting 1E and 2E according to the method described in Example 2, step G without using i-methyl-2-pyrrolidine; LCMS: 421 (M+H)+.
Example 37
Preparation of Compound 48
Figure imgf000119_0002
To a solution of Compound 45 (18 mg, 0.03 mmol) in 2 mL dichloromethane at
0 °C was added DAST (0,01 mL, 0.07 mmol). The reaction was and stirred for 16 hours, during which time it was allowed to warm to room temperature on its own. The reaction was then quenched with saturated NaHCθ3 solution and extracted with dichloromethane (2 x 5 mL), The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to provide a residue which was purified using preparative TLC (30% acetone in hexane) to provide Compound 48 (19 mg). LCMS: 549 (M+Hf,
Example 38
Preparation of Compound 49
Figure imgf000120_0001
H
To a solution of Compound 45 (52 mg, 0.1 mmol) in 2 mL THF and 2 mL MeOH at 0 °C was added sodium borohydride (12 mg, 0.3 mmol The reaction was and stirred for 16 hours, during which time it was allowed to warm to room temperature on its own. The reaction was then quenched with saturated NH4Ci solution and extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried (!^2SO4), filtered and concentrated in vacuo to provide a residue which was purified using preparative TLC (3% MeOH in CH2CI2) to provide Compound 49 (42 mg). LCMS: 529 (M+H)+.
Example 39
Preparation of Compound 50
Figure imgf000120_0002
Compound 50 was prepared from Compound 49 using the method described in Example 37; LCMS: 531 (M+H)+,
Example 40
Preparation of Compound 51
Figure imgf000121_0001
Compound 51 was prepared using the method described in Example 35 and replacing 3-Chioro-4-hydroxybenzonitrile with 2-fluoro-4-methylsulfonylphenol in step A. LCMS: 502 (M+H)+.
Example 41
Preparation of Compound 52
Figure imgf000121_0002
Compound 52 was prepared using the method described in Example 2. The corresponding aniline used in step F was synthesized as described in International Publication No. WO 09/055331. LCMS: 487 (M+H)+.
Example 42 Preparation of Compound 53
Figure imgf000121_0003
Compound 53 was prepared using the method described in Example 2. LCMS: 434 (M+H)+.
Example 42
Preparation of Compound 54
Figure imgf000122_0001
Compound 54 was prepared using the method described in Example 2. LCMS: 420 (M+H)+.
Example 43 Preparation of Compounds 55 and 56
Figure imgf000122_0002
Compounds 55 and 56 were prepared using the method described in Example 40 and replacing W-hydroxybutyramidine with N~hydroxy-2-methoxy-acetamidine (prepared as described in European Patent Application No. EP 1479674). Compound 55: LCMS: 504 (M+Hf, Compound 56: LCMS: 504 (M+H)+.
Example 44 Preparation of Compounds 57 and 58
Figure imgf000123_0001
Compounds 57 and 58 were prepared using the method described in Example 2. Compound 57: LCMS: 495 (M-HH)+, Compound 58: LCMS: 495 (M+Hf.
Example 45
Preparation of Compounds 59 and 60
Figure imgf000123_0002
Compounds 59 and 60 were prepared using the method described in Example
3 and replacing 4,6-Dichloro-5-methylpyrimidine with 4,6-dtchloro-5-fluoropyrimidine. Compound 59: LCMS: 468, 470 (M+H)+, Compound 60: LCMS: 468, 470 (M+H)+.
Example 46
Preparation of Compound 61
Figure imgf000124_0001
Step A - Synthesis of Compound 46A
To a O °C solution of Compound 46A (0.22 g, 0.9 mmol) in 7 mL THF was added Tebbe reagent (0.5M in THF, 2.2 mL, 1.1 mmol). The resulting reaction was allowed to stir at room temperature for 16 hours, after which time it was quenched with 1 N NaOH solution and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to provide a residue which was purified using flash column chromatography on silica gel to provide Compound 46B.
Step B: Synthesis of Compound 46C
Compound 46C was synthesized from 46B using the method described in Example 2 for the synthesis of Compound 2E.
Step C; Synthesis of Compound 61
Compound 46C was converted to Compound 61 using the method described in Example 40. LCMS: 518 (M+H)+.
Example 47 Preparation of Compound 62
Figure imgf000125_0001
Compound 62 was prepared using the method described in Example 4. In step A1 Compound 2E was replaced with Compound 46C. in step B1 4-(methylsulfonyl)- aniline was replaced with 2-fluoro-4-(methylsulfonyl)aniline and the reaction was conducted in dioxane using Cs2CO3 and (±)-BINAP instead of K3PO4 and (o~ biphenyl)PCy2 respectively. LCMS: 517 (M+H)+.
Example 47
Preparation of Compounds 63 and 64
Figure imgf000125_0002
Using 4,6-dichloro-5-methoxypyrimidine {synthesized as described in Eur. Pat Appl., 464604, 08 Jan 1992) as a starting material, Compounds 63 and 64 were prepared using the method described in Example 35 and replacing 3-Chloro~4- hydroxybenzo nitrite with 2-fiuoro-4-methylsulfonylpheπol in step A. Compound 63: LCMS: 518 (M+H)+, Compound 64: LCMS: 518 (M+H)+.
Example 48
Preparation of Compounds 65 and 66
Figure imgf000126_0001
Using 4,6~dichJoro~5-fiuoropyrimidine as a starting material, Compounds 65 and 66 were prepared using the method described in Example 35 and replacing 3~Chloro- 4-hydroxybenzonitrile with 2-fluoro-4-methylsulfonylphenoi in step A. Compound 65: LCMS: 506 (M-I-H)+, Compound 66: LCMS: 506 (M+H)+.
Example 48
Preparation of Compound 67
Figure imgf000126_0002
48A 48B
Figure imgf000126_0003
Step A - Synthesis of Compound 48A
Compound 48A was synthesized using the method described above for the synthesis of Compound 2F.
Step B - Synthesis of Compound 48B
Compound 48B was synthesized from Compound 48A using the method described above for the synthesis of Compound 7B. Step C - Synthesis of Compound 4BC
To a solution of Compound 48B (0.30 g, 1.0 mrnol) in 7 ml DMF was added HOBT (0.40 g, 3.0 mmot), D-alaninol (0.23 mL, 3.0 mmol), and EDCI (0.57 g, 3.0 mmol). The resulting reaction was allowed to stir at room temperature for 16 hours, after which time water was added and the mixture was extracted with ethyl acetate. [WORKUP] The residue obtained was purified using flash column chromatography on silica gel (3% MeOH in CH2CI2) to provide Compound 48C.
Step D - Synthesis of Compound 67
Compound 67 was synthesized from Compound 48C using the method described in Example 2, Step G. LCMS: 524 (M+H)+.
Example 49
Preparation of Compound 68
Figure imgf000127_0001
Step A: Synthesis of Compound 49C
Compound 49B and Compound 49C were obtained as a 1 :1 mixture from Compound 49A using the method described in Example 6, Step A. Step B: Synthesis of Compound 49D
Compound 49D was prepared from Compound 49C using the method described in Example 35.
Step C: Synthesis of Compound 49E
Compound 49D (0.05 g, 0.12 mmol) was taken up in 0.5 ml AcOH, 0.25 mL conc. H2SO4, and 0.5 mL H2O. The resulting reaction was heated to 100 °C and allowed to stir at this temperature for 16 hours. The reaction mixture was cooled to room temperature and most of the acetic acid was removed in vacuo and the residue was basified using 1N NaOH. The resulting solution was then acidified to pH 5 using 1N HCl and the acidic solution was extracted with dichloromethane (2 x 5 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide Compound 49E, which was used without further purification.
Step D: Synthesis of Compound 68
Compound 68 was prepared from Compound 49E using the method described in Example 2, Step D. LCMS; 518 (M+H)+.
Example 50
Preparation of Compound 69
Figure imgf000128_0001
5OA 5OB
Figure imgf000128_0002
5OC 69
Step A: Synthesis of Compound 5OA To a 0 °C solution of triethylphosphonoacetate (1.78 mL, 8.88 mmol) in 40 mL THF was added 60% NaH (0.36 g, 8.88 mmol). The resulting reaction was allowed to stir for 30 minutes at 0 °C, after which time a solution of Compound 1 A (1.0 g, 4.44 mmol) in 4 mL THF was added. The reaction was allowed to stir for 16 hours, during which time it was allowed to warm to room temperature on its own. The reaction was then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were dried (Na2SO4)t filtered and concentrated in vacuo to provide Compound 5OA which was used without further purification.
Step B: Synthesis of Compound 5OB
To a solution of Compound 5OA in 35 mL MeOH and 35 mL EtOAc was added 400 mg 10% Pd-C and the resulting reaction was hydrogenated under atmospheric pressure at room temperature for 3 hours. The reaction mixture was then filtered through ceiite and the filtrate was concentrated in vacuo to provide Compound 5OB as an oil that was used without further purification.
Step C: Synthesis of Compound 5OC
Compound 5OB was converted to Compound 5OC using the method described in Example 2, Steps E and G.
Step D: Synthesis of Compound 69
Compound 5OC was hydroiyzed to the corresponding acid using the method described for the synthesis of Compound 7B. This acid intermediate was then converted to Compound 69 (unseparabfe mixture of two isomers) using the method described in Example 2, Step D. LCMS: 515 (M+H)+.
Example 51
Preparation of Compound 70
Figure imgf000130_0001
Step A - Synthesis of Compound 51 B
To a solution of Compound 51 A (0.275g, 1.05 mmol, 1 eq), in DCM (10 mL) was added triethylamine (0.44 mL, 3.15 mmol, 3.0 eq) and /so-propyl chlroformate (1.36 mL of a 1 M solution in toluene, 1.36 mmol, 1.3 eq). The resulting reaction was allowed to stir at room temperature for 4 hours then was quenched with water and extracted with DCM. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to provide Compound 51 B which was used without further purification,
Step B - Synthesis of Compound 70
Trifluoroacetic acid (0.32 mL, 4.2 mmol, 4 eq) was added to a solution of Compound 51 B (0.330 g, 1.05 mmol, 1 eq) in dichloromethane 10 mL at room temperature and the resulting reaction was allowed to stir at room temperature for 4 hours then was concentrated in vacuo. The resulting residue was taken up in 1 ,4- dioxane (10 mL) and to the resulting solution was added DIPEA (0.73 mL, 4.2 mmol, 4 eq)» followed by Compound 51 C (0.297 mg, 1.05 mmol, 1 eq). The resulting reaction was heated to 110 °C and allowed to stir at this temperature for 4 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified using preparative TLC (40%EtOAc/hexanes) to provide Compound 70 (0.02Og1 4%). LCMS: 455, 457 (M+Hf .
Example 52
Preparation of Compound 71
Figure imgf000131_0001
Step A - Synthesis of Compound 52B
Compound 52A (1.08 g, 4.8 mmol) was combined with 3-brorno-[1 ,2,4]triazole (0.70 g, 4.7 mmol), trtphenylphosphine (1.49 g, 5.7 mmol) and diisopropyl azodicarboxylate (1.12 mL, 5.7 mmol) in THF (15 mL). The resulting reaction was allowed to stir at room temperature for 18 hours, then the reaction mixture was concentrated in vacuo to provide Compound 52B, which was used without further purification.
Step B - Synthesis of Compound 52C
Compound 52B was taken up in 2:1 CH2CI2/MeOH (15 mL) and treated with 4.0M HCl/dioxane (15 mL). The resulting reaction was allowed to stir at room temperature for 3 hours, then the reaction mixture was partitioned between water and EtOAc. The aqueous layer was bastfied to pH 10 using 1N NaOH, then the basic solution was extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide Compound 52C as a yellow oil which was used without further purification.
Step C - Synthesis of Compound 52D A solution of Compound 52C (0.78 g, 3.0 mmol), 4,6-dichloro-5- methylpyrimidine (0.51 g, 3.1 mmof) and DiPEA (1.06 mL, 6.1 mmol) in 1 ,4-dioxane (6 mL) was sealed and heated in a microwave apparatus at 155 °C for 1 hour. The reaction mixture was then cooled to room temperature and concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica (0-40% EtOAc/hexanes) to provide Compound 52D. Step D - Synthesis of Compound 71
Compound 52D (0.43 g, 1.12 mmol) was combined with 2~fluoro-4- methylsulfonylphenol (0.26 g, 1.4 mmol), K2CO3 (0,31 g, 2.2 mmol), and AgF (0.29 g, 2.3 mmol) in DMSO (3 ml_). The resulting reaction was heated to 130 °C and allowed to stir at this temperature for 96 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified using preparative liquid chromatography to provide Compound 71 as a yellow solid. LCMS: 537, 539 (M+H)+.
Example 53 Preparation of Compound 72
Figure imgf000132_0001
Compound 71 (0.070 g, 0.13 mmo!) was combined with cyclopropaneboronic acid (0.045 g, 0.52 mmol), dppf (0.038 g, 0.052 mmoi), and K2CO3 (0.072 g, 0.52 mmol) in a mixture of THF (2.0 ml) and water (0.20 mL). The resulting reaction was sealed and heated in a microwave apparatus at 110 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resulting residue was purified using preparative TLC to provide Compound 72 as a yellow solid. LCMS: 499 (M+H)+.
Example 54 cAMP assay
The ability of illustrative compounds of the invention to activate GPR119 and stimulate increases in cAMP levels was determined using the LANCE™ cAMP kit (Perkin Elmer). HEK293 cells expressing human GPR119 were maintained in culture flasks at 37 °C/5% CO2 in DMEM containing 10% fetal bovine serum, 100 U/ml Pen/Strep, and 0.5 mg/ml geneticin. The media was changed to Opttmem and cells were incubated overnight at 37 °C /5% CO2. The Optimem was then aspirated and the cells were removed from the flasks using room temperature Hank's balanced saline solution (HBSS). The cells were pelleted using centrifugation (1300 rpm, 7 minutes, room temperature), then resuspended in stimulation buffer (HBSS, 0.1 % BSA, 5 mM HEPES, 15 μM RO-20) at 2.5 x 106 ceils/mL. Alexa Fluor 647-anti cAMP antibody (1 :100) was then added to the cell suspension and incubated for 30 minutes. A representative Bicyclic Heterocycle Derivative (6 μl at 2X concentration) in stimulation buffer containing 2% DMSO were then added to white 384 well Matrix plates. Cell suspension mix (6 μl) was added to each well and incubated with the Bicyclic Heterocycle Derivative for 30 minutes. A cAMP standard curve was also created in each assay according to the kit protocol. Standard concentrations of cAMP in stimulation buffer (6 μl) were added to white 384 well plates. Subsequently, 6 μl of 1 :100 anti-cAMP antibody was added to each well. Following the 30 minute incubation period, 12 μl of detection mix (included in kit) was added to all wells and incubated for 2-3 hours at room temperature. Fluorescence was detected on the plates using an Envision instrument. The level of cAMP in each well is determined by extrapolation from the cAMP standard curve.
Using this assay, EC50 values for various illustrative Bicyclic Heterocycle Derivatives pf the present invention were calculated and range from about 1 nM to about 20 μM.
Example 31
Effect of The Compounds of the Invention in Oral Glucose Tolerance Test
Male C57BI/6NCrI mice (6-8 week old) were fasted overnight and randomly dosed with either vehicle (20% hydroxypropyl-β-cyclodextrin) or a representative compound of the invention (at 3, 10 or 30 mg/kg) via oral gavage (n=8 mice/group). Glucose was administered to the animals 30 minutes post-dosing (3 g/kg p.o.). Blood glucose was measured prior to administration of test compound and glucose, and at 20 minutes after glucose administration using a hand-held glucometer (Ascensia Elite, Bayer).
Using this protocol, the effects of various Bicyclic Heterocycle Derivatives of the present invention were measured and indicate that the Bicyclic Heterocycle
Derivatives of the present invention are effective in lowering blood glucose levels after glucose challenge. Uses of the Bicyclic Heterocycle Derivatives
The Bicyclic Heterocycle Derivatives are useful in human and veterinary medicine for treating or preventing a Condition in a patient. In accordance with the invention, the Bicyciic Heterocycle Derivatives can be administered to a patient in need of treatment or prevention of a Condition.
Treatment of Obesity and Obesity-Related Disorders The Bicyclic Heterocycle Derivatives are useful for treating obesity or an obesity-related disorder.
Accordingly, in one embodiment, the invention provides methods for treating obesity or an obesity-related disorder in a patient, wherein the method comprises administering to the patient an effective amount of one or more Bicycfic Heterocycle Derivatives, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
Treatment of Diabetes
The Bicyclic Heterocycle Derivatives are useful for treating diabetes in a patient. Accordingly, in one embodiment, the present invention provides a method for treating diabetes in a patient, comprising administering to the patient an effective amount of one or more Bicyclic Heterocycle Derivatives.
Non-limiting examples of diabetes treatable or preventable using the Bicyclic Heterocycle Derivatives include, type I diabetes (insulin-dependent diabetes mellitus), type II diabetes (non-insulin dependent diabetes mellitus), gestational diabetes, autoimmune diabetes, insulinopathies, idiopathic type I diabetes (Type 1 b), latent autoimmurnne diabetes in adults, early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition- related diabetes, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), type A insulin resistance syndrome, type B insulin resistance syndrome, lipatrophic diabetes, diabetes induced by β-cell toxins, and diabetes induced by drug therapy (such as diabetes induced by antipsychotic agents).
In one embodiment, the diabetes is type I diabetes. In another embodiment, the diabetes is type Il diabetes,
Treatment of a Diabetic Complication
The Bicyclic Heterocycle Derivatives are useful for treating a diabetic complication in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a diabetic complication in a patient, comprising administering to the patient an effective amount of one or more Bicyciic Heterocycle Derivatives.
Non-limiting examples of diabetic complications treatable or preventable using the Bicyclic Heterocycle Derivatives include diabetic cataract, glaucoma, retinopathy, aneuropathy (such as diabetic neuropathy, polyneuropathy, mononeuropathy, autonomic neuropathy, microaluminuria and progressive diabetic neuropathyl), nephropathy, gangrene of the feet, immune-complex vasculitis, systemic lupsus erythematosus (SLE), atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorumobesity), hyperlipidemia, cataract, hypertension, syndrome of insulin resistance, coronary artery disease, a fungal infection, a bacterial infection, and cardiomyopathy.
Treatment of a Metabolic Disorder The Bicyclic Heterocycle Derivatives are useful for treating a metabolic disorder. Accordingly, in one embodiment, the invention provides methods for treating a metabolic disorder in a patient, wherein the method comprises administering to the patient an effective amount of one or more Bicyclic Heterocycle Derivatives, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof. Non-limiting examples of metabolic disorders treatable include metabolic syndrome (also known as "Syndrome X"), impaired glucose tolerance, impaired fasting glucose, hypercholesterolemia, hyperiipidemia, hypertriglyceridemia, low HDL levels, hypertension, phenylketonuria, post-prandial lipidemia, a glycσgen-storage disease, Gaucher's Disease, Tay-Sachs Disease, Niernann-Pick Disease, ketosis and acidosis. in one embodiment, the metabolic disorder is hypercholesterolemia. in another embodiment, the metabolic disorder is hyperlipidemia.
In another embodiment, the metabolic disorder is hypertriglyceridemia.
In still another embodiment the metabolic disorder is metabolic syndrome.
In a further embodiment, the metabolic disorder is low HDL levels.
Methods For Treating a Cardiovascular Disease
The Bicyclic Heterocycle Derivatives are useful for treating or preventing a cardiovascular disease in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a cardiovascular disease in a patient, comprising administering to the patient an effective amount of one or more Bicyclic Heterocycle Derivatives.
Non-iimitng examples of cardiovascular diseases treatable or preventable using the present methods include atherosclerosis, congestive heart failure, cardiac arrhythmia, myocardial infarction, atrial fibrillation, atrial flutter, circulatory shock, left ventricular hypertrophy, ventricular tachycardia, supraventricular tachycardia, coronary artery disease, angina, infective endocarditis, non-infective endocarditis, cardiomyopathy, peripheral artery disease, Reynaud's phenomenon, deep venous thrombosis, aortic stenosis, mitral stenosis, pulmonic stenosis and tricuspid stenosis.
In one embodiment, the cardiovascular disease is atherosclerosis.
In another embodiment, the cardiovascular disease is congestive heart failure. In another embodiment, the cardiovascular disease is coronary artery disease.
Combination Therapy
In one embodiment, the present invention provides methods for treating a Condition in a patient, the method comprising administering to the patient one or more Bicyclic Heterocycle Derivatives, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof and at least one additional therapeutic agent that is not a Bicyclic Heterocycle Derivative, wherein the amounts administered are together effective to treat or prevent a Condition.
Non-iirniting examples of additional therapeutic agents useful in the present methods for treating or preventing a Condition include, anti-obesity agents, antidiabetic agents, any agent useful for treating metabolic syndrome, any agent useful for treating a cardiovascular disease, cholesterol biosynthesis inhibitors, cholesterol absorption inhibitors, bile acid sequestrants, probucol derivatives, IBAT inhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors, choiesteryl ester transfer proten (CETP) inhibitors, low-denisity lipoprotein (LDL) activators, fish oil, water-soluble fibers, plant sterols, plant stands, fatty acid esters of plant stanols, or any combination of two or more of these additional therapeutic agents.
Non-limiting examples of anti-obesity agents useful in the present methods for treating a Condition include CB 1 antagonists or inverse agonists such as rimonabant, neuropeptide Y antagonists, MCR4 agonists, MCH receptor antagonists, histamine H3 receptor antagonists or inverse agonists, metaboiic rate enhancers, nutrient absorption inhibitors, leptin, appetite suppressants and lipase inhibitors.
Non-limiting examples of appetite suppressant agents useful in the present methods for treating or preventing a Condition include cannabinoid receptor 1 (CBi) antagonists or inverse agonists (e.g., rimonabant); Neuropeptide Y (NPY1 , NPY2, NPY4 and NPY5) antagonists; metabotropic glutamate subtype 5 receptor (mGluR5) antagonists (e.g., 2-methyl-6-(phenyIethynyl)-pyridine and 3[(2-methyl-1 ,4-thiazol-4- yl)ethynyl]pyridine); melanin-concentrating hormone receptor (MCH1 R and MCH2R) antagonists; melanocortin receptor agonists (e.g., Melanotan-ll and Mc4r agonists); serotonin uptake inhibitors (e.g., dexfenfluramine and fluoxetine); serotonin (5HT) transport inhibitors (e.g., paroxetine, fluoxetine, fenfluramine, fluvoxarnine, sertaline and imipramine); norepinephrine (NE) transporter inhibitors (e.g., desipramine, taisupram and nomifensine); ghrelin antagonists; leptin or derivatives thereof; opioid antagonists (e.g., nalmefene, 3-methoxynaltrexone, naloxone and nalterxone); orexin antagonists; bombesin receptor subtype 3 (BRS3) agonists; Cholecystokinin-A (CCK- A) agonists; ciliary neurotrophic factor (CNTF) or derivatives thereof (e.g., butabindide and axokine); monoamine reuptake inhibitors (e.g., sibutramine); gfucagon-itke peptide 1 (GLP-1 ) agonists; topiramate; and phytopharm compound 57. Non-timiting examples of metabolic rate enhancers useful in the present methods for treating or preventing a Condition include acetyl-CoA carboxylase-2 (ACC2) inhibitors; beta adrenergic receptor 3 (β3) agonists; diacylglyceroi acyltransferase inhibitors (DGAT1 and DGAT2); fatty acid synthase (FAS) inhibitors (e.g., Cerulenin); phosphodiesterase (PDE) inhibitors (e.g., theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram and cilomϋast); thyroid hormone β agonists; uncoupling protein activators (UCP-1 ,2 or 3) (e.g., phytanic acid, 4-[(E}-2-(5,6,7,84etramethyl-2-naphthalenyl)-1-propenyl]benzoic acid and retinoic acid); acyl-estrogens (e.g., oleoyl-estrone); glucocorticoid antagonists; 11 -beta hydroxy steroid dehydrogenase type 1 (11 β HSD-1) inhibitors; melanocortin-3 receptor (Mc3r) agonists; and stearoyl-CoA desaturase-1 (SCD-1) compounds.
Non-limiting examples of nutrient absorption inhibitors useful in the present methods for treating or preventing a Condition include lipase inhibitors (e.g., oriistat, lipstatin, tetrahydrolipstatin, teasaponin and diethylumbellϊferyl phosphate); fatty acid transporter inhibitors; dicarboxylate transporter inhibitors; glucose transporter inhibitors; and phosphate transporter inhibitors.
Non-limiting examples of cholesterol biosynthesis inhibitors useful in the present methods for treating or preventing a Condition include HMG-CoA reductase inhibitors, squalene synthase inhibitors, squalene epoxidase inhibitors, and mixtures thereof.
Non-limiting examples of cholesterol absorption inhibitors useful in the present methods for treating or preventing a Condition include ezetimibe. In one embodiment, the cholesterol absorption inhibitor is ezetimibe. HMG-CoA reductase inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, statins such as iovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, cerivastatin, CI-981 , resuvastatin, rivastatin, pravastatin, rosuvastatin or L-659,699 ((E,E)-11-[3'R-(hydroxy-methyl)-4'- oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoic acid). Squalene synthesis inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, squalene synthetase inhibitors; squalestatin 1 ; and squalene epoxidase inhibitors, such as NB-598 ((E)-N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yf)methoxy]benzene- methanamine hydrochloride).
BtIe acid sequestrants useful in the present methods for treating or preventing a Condition include, but are not limited to, cholestyramine (a styrene-dϊvinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available from Bristol-Myers Squibb), colestipol (a copolymer of diethyϊenetriamine and 1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are available from Pharmacia), coiesevelam hydrochloride (such as WelChol® Tablets (poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1- bromodecane and {6-bromohexyl)-trimethylammonium bromide) which are available from Sankyo), water soluble derivatives such as 3,3-ioene, N-(cycloalkyl) alkylamϊnes and poliglusam, insoluble quaternized polystyrenes, saponins and mixtures thereof. Suitable inorganic cholesterol sequestrants include bismuth salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids. Probucol derivatives useful in the present methods for treating or preventing a Condition include, but are not limited to, AG 1-1067 and others disclosed in U.S. Patent Nos. 6,121 ,319 and 6,147,250.
IBAT inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, benzothiepines such as therapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1 ,1-dioxide structure such as are disclosed in International Publication No. WO 00/38727. Nicotinic acid receptor agonists useful in the present methods for treating or preventing a Condition include, but are not limited to, those having a pyridine-3- carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers, where available. Other examples of nicotinic acid receptor agonists useful in the present methods include nicotinic acid, niceritrol, nicofuranose and acipimox. An example of a suitable nicotinic acid product is NIASPAN® (niacin extended-release tablets) which are available from Kos Pharmaceuticals, Inc. (Cranbury, NJ). Further nicotinic acid receptor agonists useful in the present methods for treating or preventing a Condition include, but are not limited to, the compounds disclosed in U.S. Patent Publication Nos, 2006/0264489 and 2007/0066630, and U.S. Patent Application No. 11/771538, each of which is incorporated herein by reference.
ACAT inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, avasimibe, HL-004, lecimibide and CL- 277082 (N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyI)phenyl]-methyl]-N- heptylurea). See P. Chang er al., "Current, New and Future Treatments in Dysiipidaemia and Atherosclerosis", Drugs 2000 Jul;60(1); 55-93, which is incorporated by reference herein.
CETP inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, those disclosed in International Publication No. WO 00/38721 and U.S. Patent No. 6,147,090, each of which are incorporated herein by reference.
LDL-receptor activators useful in the present methods for treating or preventing a Condition include, but are not limited to, include HOE-402, an imidazolidinyl- pyrimidine derivative that directly stimulates LDL receptor activity. See M. Huettinger et ai, "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb. 1993; 13:1005-12.
Natural water-soluble fibers useful in the present methods for treating or preventing a Condition include, but are not limited to, psyllium, guar, oat and pectin. Fatty acid esters of plant stands useful in the present methods for treating or preventing a Condition include, but are not limited to, the sitostanol ester used in BENECOL® margarine.
Non-limiting examples of antidiabetic agents useful in the present methods for treating a Condition include insulin sensitizers, α-glucostdase inhibitors, DPP-IV inhibitors, insulin secretogogues, hepatic glucose output lowering compounds, antihypertensive agents, sodium glucose uptake transporter 2 fSGLT-2) inhibitors, insulin and insulin-containing compositions, and anti-obesity agents as set forth above.
In one embodiment, the antidiabetic agent is an insulin secretagogue. In one embodiment, the insulin secretagogue is a sulfonylurea. Non-limiting examples of sulfonylureas useful in the present methods include glipizide, tolbutamide, glyburide, glimeptrtde, chlorpropamide, acetohexamide, gliamilide, gliclazide, giiquidone, glibenclamide and tolazamide.
In another embodiment, the insulin secretagogue is a meglitinide. Non-limiting examples of meglitinides useful in the present methods for treating a Condition include repaglinide, mitiglinide, and nateglinide.
In still another embodiment, the insulin secretagogue is GLP- 1 or a GLP- 1 mimetic.
Non-limiting examples of GLP-1 mimetics useful in the present methods include Byetta-Exanatide, Liraglutinide, CJC-1131 (ConjuChem, Exanatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and compounds disclosed in International Publication No. WO 00/07617.
Other non-limiting examples of insulin secretagogues useful in the present methods include exendin, GIP and secretin. In another embodiment, the antidiabetic agent is an insulin sensitizer.
Non-limiting examples of insulin sensitizers useful in the present methods include PPAR activators or agonists, such as troglitazone, rosiglitazone, pioglitazone and englitazone; biguanidines such as metformin and phenformin; PTP- 1 B inhibitors; and glucokinase activators. In another embodiment, the antidiabetic agent is a α-Glucosidase inhibitor.
Non-limiting examples of α-Glucosidase inhibitors useful the present methods include miglitol, acarbose, and voglibose.
In another embodiment, the antidiabetic agent is an hepatic glucose output lowering agent. Non-limiting examples of hepatic glucose output lowering agents useful in the present methods include Glucophage and Glucophage XR.
In yet another embodiment, the antidiabetic agent is insulin, including all formualtions of insulin, such as long acting and short acting forms of insulin. Non-limiting examples of orally administrable insulin and insulin containing compositions include AL-401 from Autoimmune, and the compositions disclosed in U.S. Patent Nos. 4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632; 6,191 ,105; and International Publication No. WO 85/05029, each of which is incorporated herein by reference.
In another embodiment, the antidiabetic agent is a DPP-(V inhibitor.
Non-limiting examples of DPP-IV inhibitors useful in the present methods include sitagϋptin, saxagliptin (Januvia™, Merck), denagliptin, vildagliptin (Galvus™, Novartis), alogiiptin, alogliptin benzoate, ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph), Bl-A and Bl-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513 (Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) or a combination of sitagliptin/metformin HCl (Janumet™, Merck), in a further embodiment, the antidiabetic agent is a SGLT-2 inhibitor.
Non-limiting examples of SGLT-2 inhibitors useful in the present methods include dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) and T-1095 (Tanabe Seiyaku),
Non-limiting examples of antihypertensive agents useful in the present methods for treating a Condition include β-biockers and calcium channel blockers (for example diltiazern, verapamil, nifedipine, amlopidine, and mybefradil), ACE inhibitors (for example captopril, lisinopril, enalapril, spiraprii, ceranopril, zefenopril, fosinopril, cilazoprii, and quinapril), AT-1 receptor antagonists (for example losartan, irbesartan, and valsartan), renin inhibitors and endotheiin receptor antagonists (for example sitaxsentan).
In one embodiment, the antidiabetic agent is an agent that slows or blocks the breakdown of starches and certain sugars.
Non-limiting examples of antidiabetic agents that slow or block the breakdown of starches and certain sugars and are suitable for use in the compositions and methods of the present invention include alpha-glucosidase inhibitors and certain peptides for increasing insulin production. Atpha-glucosidase inhibitors help the body to lower blood sugar by delaylng the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. Non-limiting examples of suitable alpha-giucosidase inhibitors include acarbose; migiitol; camiglibose; certain polyamines as disclosed in WO 01/47528 (incorporated herein by reference); voglibose. Non-limiting examples of suitable peptides for increasing insulin production including amlintide (CAS Reg. No. 122384-88-7 from Amylin; pramlintide, exendin, certain compounds having Glucagon-like peptide-1 (GLP- 1 ) agonistic activity as disclosed in Internationa! Publication No. WO 00/07617.
Other specific additional therapeutic agents useful in the present methods for treating or preventing a Condition include, but are not limited to, rimonabant, 2-methyl- 6-{phenylethynyl)-pyridine, 3[(2-methyl-1 ,4-thiazol-4-yl)ethynyl]pyridine, Melanotan-SI, dexfenfiuramine, fluoxetine, paroxetine, fenfluramine, fluvoxamine, sertaline, imipramine, desipramine, talsupram, nomifensine, leptin, naimefene, 3- methoxynaltrexone, naloxone, nalterxone, butabindide, axokine, sibutramine, topiramate, phytopharm compound 57, Cerulenin, theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, cilomilast, phytanic acid, 4-[(E)-2-(5,6,7,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid, retinoic acid, oleoyl-estrone, orlistat, lipstatin, tetrahydrolipstatin, teasaponin and diethylumbelliferyl phosphate.
In one embodiment, the present combination therapies for treating or preventing diabetes comprise administering a Bicyclic Heterocycle Derivative, an antidiabetic agent and/or an antiobesity agent.
In another embodiment, the present combination therapies for treating or preventing diabetes comprise administering a Bicyclic Heterocycle Derivative and an antidiabetic agent. In another embodiment, the present combination therapies for treating or preventing diabetes comprise administering a Bicyclic Heterocycle Derivative and an anti-obesity agent.
In one embodiment, the present combination therapies for treating or preventing obesity comprise administering a Bicycfic Heterocycle Derivative, an antidiabetic agent and/or an antiobesity agent. in another embodiment, the present combination therapies for treating or preventing obesity comprise administering a Bicyclic Heterocycle Derivative and an antidiabetic agent,
In another embodiment, the present combination therapies for treating or preventing obesity comprise administering a Bicyclic Heterocycle Derivative and an anti-obesity agent. In one embodiment, the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative and one or more additional therapeutic agents selected from: anti-obesity agents, antidiabetic agents, any agent useful for treating metabolic syndrome, any agent useful for treating a cardiovascular disease, cholesterol biosynthesis inhibitors, sterol absorption inhibitors, bile acid sequestrants, probucol derivatives, !BAT inhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors, cholesteryl ester transfer proten (CETP) inhibitors, low-denisity lipoprotein (LDL) activators, fish oil, water-soluble fibers, plant sterols, plant stanols and fatty acid esters of plant stanols. In one embodiment, the additional therapeutic agent is a cholesterol biosynthesis inhibitor. In another embodiment, the cholesterol biosynthesis inhibitor is a squalene synthetase inhibitor, In another embodiment, the cholesterol biosynthesis inhibitor is a squalene epoxidase inhibitor, In still another embodiment, the cholesterol biosynthesis inhibitor is an HMG-CoA reductase inhibitor, In another embodiment, the HMG-CoA reductase inhibitor is a statin. In yet another embodiment, the statin is lovastatin, pravastatin, simvastatin or atorvastatin. in one embodiment, the additional therapeutic agent is a cholesterol absorption inhibitor, In another embodiment, the cholesterol absorption inhibitor is ezetimibe. In one embodiment, the additional therapeutic agent comprises a cholesterol absorption inhibitor and a cholesterol biosynthesis inhibitor. In another embodiment, the additional therapeutic agent comprises a cholesterol absorption inhibitor and a statin. In another embodiment, the additional therapeutic agent comprises ezetimibe and a statin. In another embodiment, the additionai therapeutic agent comprises ezetimibe and simvastatin. In one embodiment, the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative, an antidiabetic agent and/or an antiobesity agent.
In another embodiment, the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative and an antidiabetic agent. In another embodiment, the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative and an anti-obesity agent.
(n one embodiment, the present combination therapies for treating or preventing a cardiovascular disease comprise administering one or more Bicyclic Heterocycle Derivatives, and an additional agent useful for treating or preventing a cardiovascular disease.
When administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). In one embodiment, the one or more Bicyclic Heterocycle Derivatives are administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
In another embodiment, the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a Condition.
In another embodiment, the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition. In stifl another embodiment, the one or more Bicycϋc Heterocycie Derivatives and the additional therapeutic agent(s) act synergisticaϋy and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
In one embodiment, the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration. The one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
In one embodiment, the administration of one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) may inhibit the resistance of a Condition to these agents. In one embodiment, when the patient is treated for diabetes or a diabetic complication, the additional therapeutic agent is an antidiabetic agent which is not a Bicyclic Heterocycle Derivative. In another embodiment, the additional therapeutic agent is an agent useful for reducing any potential side effect of a Bicyclic Heterocycle Derivative. Such potential side effects include, but are not limited to, nausea, vomiting, headache, fever, lethargy, muscle aches, diarrhea, general pain, and pain at an injection site.
!n one embodiment, the additional therapeutic agent is used at its known therapeutically effective dose. In another embodiment, the additional therapeutic agent is used at its normally prescribed dosage. In another embodiment, the additional therapeutic agent is used at less than its normally prescribed dosage or its known therapeutically effective dose.
The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a Condition can be determined by the attending clinician, taking into consideration the the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder. When administered in combination, the Bicyclic Heterocycle Derivative(s) and the other agent(s) for treating diseases or conditions listed above can be administered simultaneously or sequentially. This particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another every six hours, or when the preferred pharmaceutical compositions are different, e.g. one is a tablet and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous. Generally, a total daily dosage of the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s)can when administered as combination therapy, range from about 0.1 to about 2000 mg per day, although variations will necessarily occur depending on the target of the therapy, the patient and the route of administration. In one embodiment, the dosage is from about 0.2 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses, (n still another embodiment, the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses, in a further embodiment, the dosage is from about 1 to about 20 mg/day, administered in a single dose or in 2-4 divided doses.
Compositions and Administration
In one embodiment, the invention provides compositions comprising an effective amount of one or more Bicyclic Heterocycle Derivatives or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier.
For preparing compositions comprising one or more Btcyclic Heterocycle Derivatives, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.)s Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, PA. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
In one embodiment, a Bicyclic Heterocycle Derivative is administered orally.
In another embodiment, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation is from about 0.1 to about 2000 mg. Variations will necessarily occur depending on the target of the therapy, the patient and the route of administration, in one embodiment, the unit dose dosage is from about 0.2 to about 1000 mg. In another embodiment, the unit dose dosage is from about 1 to about 500 mg. In another embodiment, the unit dose dosage is from about 1 to about 100 mg/day. In still another embodiment, the unit dose dosage is from about 1 to about 50 mg. In yet another embodiment, the unit dose dosage is from about 1 to about 10 mg.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, the condition and size of the patient, as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 1000 mg/day, 1 mg/day to about 500 mg/day, 1 mg/day to about 300 mg/day, 1 mg/day to about 75 mg/day, 1 mg/day to about 50 mg/day, or 1 mg/day to about 20 mg/day, in one dose or in two to four divided doses.
When the invention comprises a combination of one or more Bicyclic Heterocycle Derivatives and an additional therapeutic agent, the two active components may be co-administered simultaneously or sequentially, or a single composition comprising one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) in a pharmaceutically acceptable carrier can be administered. The components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc. The dosage of the additional therapeutic agent can be determined from published material, and may range from about 1 to about 1000 mg per dose. In one embodiment, when used in combination, the dosage levels of the individual components are lower than the recommended individual dosages because of an advantageous effect of the combination.
In one embodiment, the components of a combination therapy regimen are to be administered simultaneously, they can be administered in a single composition with a pharmaceutically acceptable carrier.
In another embodiment, when the components of a combination therapy regimen are to be administered separately or sequentially, they can be administered in separate compositions, each containing a pharmaceutically acceptable carrier.
Kits
In one aspect, the present invention provides a kit comprising an effective amount of one or more Bicyclic Heterocycle Derivatives, or a pharmaceutically acceptable salt or solvate of the compound and a pharmaceutically acceptable carrier, vehicle or diluent.
In another aspect the present invention provides a kit comprising an amount of one or more Bicycitc Heterocycle Derivatives, and an amount of one or more additional therapeutic agents, wherein the combined amounts are effective for enhancing the memory of a patient or effective for treating or preventing a cognitive disorder in a patient.
When the components of a combination therapy regimen are to are to be administered in more than one composition, they can be to provide in a kit comprising comprising: (a) one or more Bicyclic Heterocycle Derivatives together in a pharmaceutically acceptable carrier in a single container, or (b) one or more Bicyclic
Heterocycle Derivatives in separate containers, each in a pharmaceutically acceptable carrier, and (c) one or more additional therapeutic agents together in a pharmaceutically acceptable carrier in a single contatiner or (d) one or more additional therapeutic agents in separate containers, each in a pharmaceutically acceptable carrier; such that the active components of the combination therapy are present in amounts that render the combination therapeutically effective.
The present invention is not to be limited by the specific embodiments disclosed in the examples that are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparant to those skilled in the art and are intended to fall within the scope of the appended claims. A number of references have been cited herein, the entire disclosures of which are incorporated herein by reference.

Claims

WHAT IS CLAIMED IS:
1. A compound having the formula:
Figure imgf000151_0001
or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
A is aryl or heteroaryf, each of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, halo, -OH1 -O-haloalkyl, -O-alkyl, -O- alkyl-OH, -O-alkyl-O-alkyl, -O-aryl, -alkylene-O-alkyl, -CN, -N(R4)2, -C(O)H, -C(O)R4, - C(O)OR4, -C(O)N(R4)2, -NHC(O)R4, -NHS(O)mR4, -S(O)nR4 and -S(O)mN(R4)2;
B is aryl or heteroaryl, each of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, -OH, -O-haloalkyl, - O-alkyl, -0-aryl, -alkylene-O-alkyl, -alkylene-S(O)2-alkyl, -SF5, -CN, -N(R4)2, -C(O)H, - C(O)R4, -C(O)OR4, -C(O)N(R4)2, -NHC(O)R4, -NHS(O)mR4, -S(O)nR4 and - S(O)mN(R4)2, wherein a cycloalkyl, aryl or heteroaryl substituent group can be unsubstituted or optionally substituted with R9, and wherein when B is aryl, the aryl group can be optionally fused to a 4 to 7-membered cycloalkyl group or cycloalkanoyl group;
G is -C(R1)- or -N-;
W is a bond, -O1 -C(O)O-, -C(R12)-, -alkyleπe-O, alkylene, -C(O)-,-S(O)- - S(O)2-, -S(O)2-N(R10)-, -N(R12)-, -NHC(O)- Or -C(O)-N(R10)-. such that W is other than -O- when G is -N-, and such that when G is -C(R1)- and W is -C(R12)-, these R1 and R12 groups can combine to form a C1-C3 alkylene bridge between G and W and form a spirocycie;
X is a bond, -C(R1)2-, -O1 -N(R10)- or -S-;
Z is a single bond, a double bond, ~C{0)-, -C(=NOR12}-, -C=C(R14)2, -C(R1)2-, - O-, -N(R10)- or -S(O)n-, such that when q is O1 Z is other than a double bond; each occurrence of R1 is independently H1 alkyl, cycloalkyl, halo or -OR7; wherein an alkyl group can be unsubstituted or optionally substituted with one or more of the following groups: -O-alkyl, -OH or -N(R4)2; and wherein any two geminal R1 groups, together with the common carbon atom to which they are attached, can join to form a spirocyclic 3- to 6-membered cycloalkyl group, a spirocyclic 3- to 6-membered heterocycloalkyl group or a spirocyclic 3- to 6-membered heterocycloalkenyl group; and wherein any two R1 groups present on separate ring carbon atoms can join to form an alkylene or heteroalkylene bridge between the ring carbon atoms to which they are attached; and wherein when any R1 group is -OR7, then the carbon atom to which the R1 group is attached is not also attached to another oxygen atom or to a nitrogen or halogen atom; each occurrence of R2 is Independently H or alkyl;
R3 is alkyl, -(alkylene )ralkenyl, -(alkylene)ralkynyl, -(alkylene)rC(O)R4, - (alkylene)t-haloalkyl, -alkylene-O-alkyl, -aIkyIene-O-(aIkylene)t-aryl, -alkylene-S-aryl, - alkylene-N(R4)C(O)O-alkyl, -CH(cycloaIkyl)2) -CH(heterocycloalkyl)2l -(alkylene)raryl, - (alkylene)t-cycloalkyl, -(alkylene)rcycloalkenyl, -(alkylenejt-heterocycloalkyl, - (alkylenejj-heterocycloalkenyl or -(alkylene)t-heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be unsubstituted or optionally substituted with R9; each occurrence of R4 is H1 alkyl, haloalkyl, cycloalkyl, heteroaryl, aryl or alkenyl, any of which is unsubstituted or optionally substituted with one or more groups, which can be the same or different and are selected from halo, alkyl, -OH and -O-alkyl; each occurrence of R7 is independently H or alkyl; R9 represents from 1 to 4 optional substituents, which can be the same or different, and which are selected from alkyl, hydroxyalkyl, -(alkylene)t-O-R13, alkenyl, alkynyl, halo, haloalkyl, -CN1 -NO2, -O-(aIkylene)rR13, -S-(alkylene)rR13, -N(R13)- (alkylene)rR13, -(alkylene)rR13, -(alkylene)rN(R7)2) -C(OHalkylene)rR13, -C(O)O- (alkylene)t-R13, -N(R7)C(O)-(alkylene)rR13, -C(O)N(R7)-(alkyIene)t-R13, -OC(O)- (alkylene)rR13, ~N(R7)C(O)N{R7Malkylene)rR13, -N(R7)C(O)O-(alkylene)t-R13, -SF5, - S(OHalkylene)rR13 or ~S(O)2(alkylene)rR13; R10 is H, alkyl, aryl, or -C(O)OR4, wherein an alkyl group is unsubstituted or optionally substituted with -OH or -O-alkyl;
R12 Js H, alkyl or aryt; each occurrence of R13 is independently H1 haloalkyl, aryl, cycloalkyl, cycloalkanoyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be optionally substituted with up to 3 groups, which can be the same or different and which are selected from alkyl, alkenyl, halo, haloalkyl, -CN, - N(R7)2, -OH, -O-alkyl or -O-haloalkyl; each occurrence of R14 is independently H, alkyl or aryl, or both R14 groups, and the carbon atom to which they are attached, combine to form a cycioalkyl or heterocycloalkyl group; each occurrence of m is independently 1 or 2; each occurrence of n is independently O, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2, such that when Z is -O- or -N(R10)-, then at least one of p and q is other than 0; r is 0, 1 or 2, such that when G is -N-, then at least one of p and r is other than 0; s is 0, 1 or 2; each occurrence of t is independently 0 or 1 ; and u is 0, 1 or 2, such that when G is -N-, then at least one of s and u is other than 0.
2. The compound of claim 1 , wherein p and u are each 0.
3. The compound of claim 2, wherein r and s are each 1.
4. The compound of claim 3, wherein q is 1.
5. The compound of claim 1 , wherein Z is a single bond or -O-,
6. The compound of claim 1 , wherein G is -CH- and W is a bond, -O- or - alkylene-O-.
7. The compound of claim 6, wherein W is a bond.
8. The compound of claim 6, wherein W is -O-.
9. The compound of claim 6, wherein W is -alkylene-O-.
10. The compound of claim 7, wherein R3 is heteroaryl.
11. The compound of claim 10, wherein R3 is:
Figure imgf000155_0001
12. The compound of claim 8, wherein R3 is phenyl,
13. The compound of claim 9, wherein W is -CH2O-.
14. The compound of claim 13, wherein R3 is alkyl.
15. The compound of claim 1 wherein G is -N-.
16. The compound of claim 1 , wherein the group:
Figure imgf000156_0001
Figure imgf000156_0002
17. The compound of claim 16, wherein the group
Figure imgf000156_0003
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000158_0002
Figure imgf000158_0004
Figure imgf000158_0003
18. The compound of claim 1 , wherein X is -O- .
19. The compound of claim 1 , wherein X is -NH-.
20. The compound of claim 1 , wherein A is heteroaryl.
21. The compound of claim 20, wherein A is pyrimidinyt.
22, The compound of claim 21 , wherein A is:
Figure imgf000158_0005
and Q is H1 alkyl, halo or -O-alkyl.
23. The compound of claim 22, wherein Q is H, F, methyl or methoxy.
24. The compound of claim 1 , wherein B is aryl or heteroaryl.
25. The compound of claim 24, wherein B is pyridyf.
26. The compound of claim 24, wherein B is phenyl.
27, The compound of claim 1 , wherein B is:
Figure imgf000159_0001
28. The compound of claim 20, wherein B is aryl or heteroaryl,
29. The compound of claim 27, wherein A is:
Figure imgf000159_0002
, and wherein Q is H, F, methyl or methoxy.
30. The compound of claim 1 , wherein the group B-X-A- is:
Figure imgf000160_0001
and wherein Q is H, alkyl, halo or -O-alkyl.
31. The compound of claim 30, wherein the group B-X-A- is:
Figure imgf000161_0001
32. The compound of claim 30, wherein the group:
Figure imgf000161_0002
Figure imgf000161_0003
33, The compound of claim 31 , wherein the group
Figure imgf000162_0001
Figure imgf000162_0002
Figure imgf000162_0004
Figure imgf000162_0003
Figure imgf000163_0001
34. A compound having the formula:
Figure imgf000164_0001
(Ia)
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein
A is -5- or 6-membered heteroaryf, any of which can be optionally substituted with an alkyl, halo or -O-alkyl group;
B is aryl or heteroaryl, any of which can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from; alkyl, halo, heteroaryl, -CN or -S(O)2alkyl;
W is a bond, -O-, alkylene or -alkylene-O-;
X is -O- or -NH-;
R3 is alkyl, aryl or heteroaryl, wherein an aryl or heteroaryl group can be unsubstituted or optionally substituted with an alkyl, cycloalkanoyl, cycioalkyl, hydroxyalkyl, -alkylene-N{alkyl)2, or -alkylene-O-alkyl group, wherein a cycloalkyl substituent can be further and optionally substituted with up to 3 groups, which can be the same or different, and are selected from alkyl, alkenyl, halo, haloalkyl, -OH or -O- alkyl.
35. The compound of claim 34, wherein A is 6-membered heteroaryl, which can be optionally substituted with an alkyl group; B is phenyl, which can be optionally substituted with up to 2 substituents, which can be the same or different and are selected from halo and -S(O)2-alkyl; W is a bond; X is -O- ; and R3 is heteroaryl, which can be optionally substituted with an alkyl group.
36. A compound having the formula:
Figure imgf000164_0002
(H) or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
A is aryl or heteroaryl, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, halo, -OH, -O-haloalkyl, -O-alkyl, -O- alkyl-OH, -O-alkyl-O-alkyl, -O-aryl, -alkylene-O-alkyl, -CN, -N(R4)2l -C(O)H, -C(O)R4, - C(O)OR4, -C(O)N(R4)2, -NHC(O)R4, -NHS(O)mR4, -S(O)nR4 and -S(O)mN(R4)2;
B is aryl or heteroaryl, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haioalkyl, hydroxyalkyl, heteroaryl, halo, -OH1 -O-haloalkyl, - O-alkyl, -O-aryl, -alkylene-O-alkyl, -alkylene-S(O)2-alkyl, -SF5, -CN, -N(R4)2, -C(O)H, - C(O)R4, -C(O)OR4, -C(O)N(R4)2, -NHC(O)R4, -NHS(O)mR4, -S(O)nR4 and - S(O)mN(R4)2) wherein a cycloalkyl or heteroaryl substituent group can be unsubstituted or optionally substituted with R9, and wherein when B is aryl, the aryl group can be optionally fused to a 4 to 7-membered cycloalkyl group or cycloalkanoyl group;
G is -CH- or -N-;
W is a bond, -O-, -C(O)O-, -alkylene-O-, alkylene, -C(O)-,-S(O)-, -S(O)2-, - S(O)2-N(R1V or -C(O)-N(R10)-- such that when G is -N-, then W is other than -O-;
X is -C(RV, -O-, -N(R10)- or -S-; each occurrence of R1 is independently H, alkyl, cycloalkyl, halo or -OR7;
R3 is alkyl, -(alkylene)ralkenyl, -(alkylene)t-alkynyl, -(alkylene)rC(O)R4, - (alkylene)t-haloalkyl, -alkylene-O-alkyl, -alkylene-O-(alkylene)t-aryl, -alkylene-S-aryl, - alkylene-N(R4)C(O)O-alkyl1 -CH(cycloalkyl)2, -CH(heterocycloalkyl)2, -(alkylene)t-aryl, - (alkylene)t-cycloalkyl, -(alkylene)t-cyc!oalkenyl, -(alkylene)rheterocycloalkyl, - (alkylene)rheterocyc!oalkenyl or -(alkylene)t-heteroaryl, wherein an aryl, cycloalkyl, cycioalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be unsubstituted or optionally substituted with R9; each occurrence of R4 is H, alkyl, haloalkyl, hydroxyalkyl, -alkylene-O-alkyl, cycioalkyl, heteroaryl or alkenyl; each occurrence of R7 is independently H or alkyl; R9 represents from 1 to 4 optional substituents, which can be the same or different, and which are selected from alkyl, hydroxyalkyl, -(alkylene)t-O-R13, alkenyl, alkynyl, halo, haloalkyl, -CN5 -NO2, -O-(alkylene)rR13, -S-(alkylene),-R13, -N(R13)- (aIkyϊene)rR13, -(alkylene)rR13, -{alkylene)rN(R7)2) -C(O)-(alkylene)rR13, -C(O)O- (alkylene)t-R13, -N(R7)C(OMalkylene)rR13, -C(O)N(R7)-(alkylene)rR13, -OC(O)- (alkylene)rR13, -N(R7)C(O)N(R7)-(alkyIene)rR13, -N(R7)C(O)O-(alkyIene)rR13, -SF5, - S(O)-(alkylene)t-R13 or -S(O)2(alkylene)rR13;
R10 is H, alkyl, aryl, or -C(O)OR4, wherein an alkyl group is unsubstituted or optionally substituted with -OH or -O-alkyl; each occurrence of R13 is independently H, hatoalkyl, aryl, cycloalkyl, cycloalkanoyl, cycloalkenyl, heterocycloalkyl, heterocycioalkenyl or heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycSoalkenyl or heteroaryl group can be optionally substituted with up to 3 groups, which can be the same or different, and which are selected from alkyl, halo, haloalkyl, -CN, -N(R7)2, - OH, -O-alkyl or -O-haloalkyl; each occurrence of m is independently 1 or 2; each occurrence of n is independently O, 1 or 2; p is an integer ranging from O to 3, such that the sum of p and q is at least 1 ; q is an integer ranging from O to 3; r is is an integer ranging from O to 3, such that the sum of r and s is at least 1 ; s is an integer ranging from O to 3; and each occurrence of t is independently O or 1.
37, A compound having the structure:
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
38. A composition comprising an effective amount of one or more compounds of claim 1 or a pharmaceutically acceptable sait, solvate, ester, prodrug or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.
39. A composition comprising an effective amount of one or more compounds of claim 37 or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.
40. A method for treating diabetes, obesity or metabolic syndrome in a patient, the method comprising administering to the patient an effective amount of one or more compounds of claim 1 or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
41. A method for treating diabetes, obesity or metabolic syndrome in a patient, the method comprising administering to the patient an effective amount of one or more compounds of claim 37 or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
42. The method of claim 40, wherein the treating is for diabetes.
43. The method of claim 43, wherein the treating is for type Il diabetes.
44, The method of claim 40, wherein the treating is for obesity.
45. The composition of claim 38, further comprising an effective amount of one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from antidiabetic agents and antiobesity agents.
46. The composition of claim 45, wherein the antidiabetic agents are selected from an insulin sensitizer, a β-glucosidase inhibitor, a DPP-IV inhibitor, an insulin secretagogue, an hepatic glucose output lowering compound, an antihypertensive agent, a sodium glucose uptake transporter 2 (SGLT-2) inhibitor, insulin and an insulin-containing composition.
47. The composition of claim 45, wherein the antiobesity agents are selected from a neuropeptide Y antagonist, an MCR4 agonist, an MCH receptor antagonist, a protein hormone, an AMP kinase activator, a CB1 antagonist, a GLP-1 agonist and a lipase inhibitor.
48. The method of claim 40, further comprising an effective amount of one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from antidiabetic agents and antϊobesity agents.
49. The method of claim 48, wherein the antidiabetic agents are selected from an insulin sensitizer, a β-glucosidase inhibitor, a DPP-IV inhibitor, an insulin secretagogue, an hepatic glucose output lowering compound, an antihypertensive agent, a sodium glucose uptake transporter 2 (SGLT-2) inhibitor, insulin and an insulin-containing composition.
50. The method of claim 48, wherein the antiobesity agents are selected from a neuropeptide Y antagonist, an MCR4 agonist, an MCH receptor antagonist, a protein hormone, an AMP kinase activator, a CB 1 antagonist, a GLP-1 agonist and a lipase inhibitor.
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