US20050215594A1 - 2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists - Google Patents

2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists Download PDF

Info

Publication number
US20050215594A1
US20050215594A1 US11/117,759 US11775905A US2005215594A1 US 20050215594 A1 US20050215594 A1 US 20050215594A1 US 11775905 A US11775905 A US 11775905A US 2005215594 A1 US2005215594 A1 US 2005215594A1
Authority
US
United States
Prior art keywords
amino
methyl
dihydro
chromen
pyridinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/117,759
Inventor
Stephen O'Connor
Gaetan Ladouceur
William Bullock
Ann-Marie Campbell
Miao Dai
Robert Dally
Jacques Dumas
Holia Hatoum-Mokdad
Uday Khire
Wendy Lee
Qingjie Liu
Derek Lowe
Steven Magnuson
Ning Qi
Tatiana Skelekhin
Quanrong Shen
Roger Smith
Ming Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharmaceuticals Corp
Original Assignee
Bayer Pharmaceuticals Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharmaceuticals Corp filed Critical Bayer Pharmaceuticals Corp
Priority to US11/117,759 priority Critical patent/US20050215594A1/en
Publication of US20050215594A1 publication Critical patent/US20050215594A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to novel chroman compounds, pharmaceutical compositions containing such compounds, and methods of treating beta-3 adrenoreceptor-mediated conditions with such compositions.
  • Adrenoreceptors are sites on effector organs that are innervated by postganglionic adrenergic fibers of the sympathetic nervous system, and are classified as either alpha-adrenergic or beta-adrenergic receptors.
  • Alpha-adrenergic receptors respond to norepinephrine and to such blocking agents as phenoxybenzamine and phentolamine, whereas beta-adrenergic receptors respond to epinephrine and to such blocking agents as propranolol.
  • Beta-adrenergic receptors are sub-classified as beta-1, beta-2, and beta-3 adrenoreceptors. Generally, beta-1 stimulation causes cardiostimulation, whereas beta-2 stimulation causes bronchodilation and vasodilation.
  • Beta-3 receptors are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis and energy expenditure.
  • Agonists of beta-3 adrenoreceptors are known to be useful in the treatment of hyperglycemia (diabetes) and obesity in mammals, as well as in the treatment of gastrointestinal disorders and neurogenetic inflammation (U.S. Pat. No. 5,561,142). Additionally, they are known to lower triglyceride and cholesterol levels and to raise high-density lipoprotein levels in mammals (U.S. Pat. No. 5,451,677). Accordingly, they are useful in the treatment of conditions such as hypertriglyceridemia, hypercholesterolemia, and in lowering high-density lipoprotein levels. They also may be useful in treating patients with Syndrome X, impaired fasting glucose, and/or impaired glucose tolerance, as well as in the treatment of atherosclerotic and cardiovascular diseases and related conditions.
  • the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urinary disorders including pollakiuria and incontinence, as well as in the treatment of prostate disease and as topical anti-inflammatory agents.
  • C 1 -C 10 haloalkyl means straight or branched chain alkyl groups having from about one to about ten carbon atoms where any C—C bond may be saturated or unsaturated, the alkyl groups being substituted at any available carbon atom with one or more halogen atoms, and includes such groups as trifluoromethyl, trichloromethyl, pentafluoroethyl, fluoromethyl, 6-chlorohexyl, and the like.
  • C 1 -C 10 alkoxy means straight or branched chain alkoxy groups having from one to about ten carbon atoms where any C—C bond may be saturated or unsaturated, and includes such groups as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
  • C 1 -C 10 alkylthio means straight or branched chain alkylthio groups having from one to about ten carbon atoms where any C—C bond may be saturated or unsaturated, and includes such groups as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.
  • C 3 -C 8 cycloalkyl means saturated mono cyclic alkyl groups of from 3 to about 8 carbon atoms, and includes such groups as cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • Halo includes fluoro, chloro, bromo, and iodo, unless specifically stated otherwise.
  • R, R 2 , Ar, and Y each include any 5- or 6-membered saturated or unsaturated heterocyclic group having any combination of one or more N, S, or O atoms with the point of attachment being at any available position on the heterocyclic ring.
  • each heteroatom shall be chosen independently of any other heteroatom, in each occurrence, with the proviso that any single heterocyclic ring may not contain more than two oxygen or sulfur atoms.
  • moieties include such 5-membered heterocylic groups as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, pyrrolinyl, dihydrothienyl, tetrahydrothienyl, dioxolyl, dithiolanyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, triazolinyl, triazolidinyl, tri
  • 6-membered heterocyclic rings such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, dihydropyranyl, thiopyranyl, triazinyl, dioxanyl, piperidinyl, piperazinyl, pyrazinyl, morpholinyl, and the like
  • Ar and Y also each include phenyl fused to any 5- or 6-membered heterocyclic ring described above to form a bicyclic moiety, which may be saturated or unsaturated and may have any combination of one or more N, S, or O atoms with the point of attachment being any at available position on the phenyl ring.
  • phenyl fused 5-membered heterocyclic groups as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indazolyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzothiadiazolinyl, benzisothiazolyl, benzisothiazolinyl, benzotriazolyl, benzoxadiazolyl, benzoxadiazolinyl, benzothiadiazolyl, benzopyrazolinyl, and the like.
  • It also includes such phenyl fused 6-membered heterocyclic groups as quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
  • Ar also includes phenyl fused to any 5- or 6-membered heterocyclic ring to form a bicyclic moiety as described above, which is further fused on the heterocyclic ring to a second phenyl ring, forming a tricyclic system, with the point of attachment to the core structure of the compound of Formula I being at any available position of the first phenyl ring.
  • Ar also includes any 5- or 6-membered saturated or unsaturated heterocyclic ring having any combination of one or more N, S, or O atoms as described above, which is further fused to a phenyl ring, with the point of attachment to the core molecule of Formula I being at any available position on the heterocyclic ring.
  • phenyl-fused with 5-membered hetero-bicyclic moieties as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indazolyl, indolizinyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzisothiazolyl, benzoisothiazolinyl, benzopyrazolinyl and the like.
  • C 1 -C 10 -alkyl-phenyl means saturated straight or branched chain alkyl groups having from one to about ten carbon atoms where the phenyl moiety is attached at any available position on the alkyl group.
  • these moieties include benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-methyl-2-phenylethyl, 5-phenylpentyl, 4-phenylhexyl, and the like.
  • C 1 -C 10 -alkyl-pyridyl means straight or branched chain saturated alkyl groups having from one to about ten carbon atoms where the pyridyl moiety is attached at any available position on the alkyl group.
  • the pyridyl group may be attached to the alkyl group from any available position on the pyridine ring.
  • Examples of these include pyridyl, 2-(2-pyridyl)ethyl, 3-(4-pyridyl)-propyl, 2-(3-pyridyl)-propyl, 1-methyl-2-(3-pyridyl)-ethyl, 5-(3-pyridyl)-pentyl, 4-(4-pyridyl)-hexyl, and the like.
  • S(O) b -phenyl-CO 2 R 1 means a phenylthio, a phenylsulfinyl, or a phenylsulfonyl group, where the CO 2 R 1 moiety is attached at any available position on the phenyl ring.
  • NR 1 R 1 may represent NH 2 , NHCH 3 , N(CH 3 )CH 2 CH 2 CH 3 , and the like.
  • the present invention includes compounds of Formula I wherein Y is halo; R 6 ; SR 1 ; S(O) b -phenyl-CO 2 R 1 ; or phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR 2 , halo, NO 2 , OR 1 , R 1 , SR 1 , SO 2 NR 1 R 7 , NR 1 R 1 , C 1 -C 10 COR 2 , phenyl, or tetrazolo.
  • Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR 2 , halo, NO 2 , OR 1 , R 1 , SR 1 , SO 2 NR 1 R 7 , NR 1 R 1 , C 1 -C 10 COR 2 , phenyl, or tetrazolo; and d is 1 or 2.
  • Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR 2 , halo, NO 2 , OR 1 , R 1 , SR 1 , SO 2 NR 1 R 7 , NR 1 R 1 , C 1 -C 10 COR 2 , phenyl, or tetrazolo; d is 1 or 2; and Ar is phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N; or a 5- or 6-membered heterocycle containing one
  • Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR 2 halo, OR 1 , R 1 or NR 1 R 1 ; d is 1; Ar is phenyl or a 5- or 6-membered heterocycle containing one or more N atoms; and a is 0, 1, 2, or 3.
  • the present invention specifically includes the following compounds:
  • Representative salts of the compounds of Formula I include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate,
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine.
  • basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, lauryl
  • esters in the present invention are non-toxic, pharmaceutically acceptable esters such as alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl-C 1 -C 5 alkyl may be used, although methyl ester is preferred.
  • the compound of Formula I may be esterified by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the Formula I compound. The appropriate anhydride is reacted with the alcohol in the presence of an acylation catalyst such as 1,8-bis[dimethylamino]naphthalene or N,N-dimethylaminopyridine.
  • An appropriate carboxylic acid may be reacted with the alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and optionally, an acylation catalyst. Esterification may also be reached using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and optionally, pyridine, or in the presence of N,N-carbonyldiimidazole with pyridine. Reaction of an acid chloride with the alcohol may be carried out with an acylation catalyst such as 4-DMAP or pyridine.
  • a dehydrating agent such as dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide or other water soluble dehydrating agents which are used to drive the reaction by the removal of water,
  • Sensitive or reactive groups on the compound of Formula I may need to be protected during any of the above methods for forming esters, and protecting groups may be added and removed by conventional methods well known in the art.
  • the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R,S) configuration, preferably in the (R)- or (S)-configuration, whichever is most active.
  • the configurational isomers of Formula I in which both the hydroxyl group attached to the side chain containing the Ar—X— moiety and the (CH 2 )d group attached to the dihydrochromenyl ring are above the plane, as depicted below, are preferred.
  • protecting groups may be required for the synthesis of compounds containing certain substituents.
  • a description of suitable protecting groups and appropriate methods of adding and removing such groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991.
  • compounds of Formula I wherein R 3 is H may be selectively protected, for example, as a carbamate derivative obtained by, for example, treatment with a reagent such as di-tert-butyl dicarbonate or other means known in the art. After purification, the carbamate group can easily be removed by treatment with an acid such as HCI or trifluoroacetic acid by means known in the art.
  • Formula I compounds may be prepared by standard techniques known in the art and by known processes analogous thereto.
  • three such standard methods may be used, the selection of which may be based, among other considerations, upon the availability of the required individual starting materials. These three methods are illustrated in Reaction Schemes 1, 2, and 3 below.
  • each variable may be any moiety within that variable's definition may be synthesized according to Reaction Scheme 1 wherein an appropriate epoxide 1a or chlorohydrin 1b (preparation of 1a is described in WO 99/32475) is coupled with the appropriate amine 2 (preparation of 2 is described below in Reaction Schemes 12, 13, and 14).
  • This reaction of Reaction Scheme 1 is typically carried out in an aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, or in an alcohol such as ethanol, isopropanol, or propanol at temperature from about ⁇ 10° C. to reflux.
  • an aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, or in an alcohol such as ethanol, isopropanol, or propanol at temperature from about ⁇ 10° C. to reflux.
  • R 3 is other than hydrogen
  • compounds in which R 3 is other than hydrogen may be prepared by reaction of compound I in which R 3 is H, by selective N-alkylation of N-acylation reactions with known compounds of formula R 3 -halo (where R 3 is acyl or alkyl) or [R 3 ] 2 O (where R 3 is acyl). Protection of the hydroxyl group, for example as a TBDMS ether, may be required prior to N-alkylation reactions; O-deprotection is carried out under standard conditions well known in the art.
  • Reaction of an aldehyde of Formula 4 (preparation described below in Reaction Scheme 9) with an amino alcohol of Formula 3 (preparation described in WO 98/32475) followed by reduction gives the desired transformation to Formula Ia compounds.
  • Compounds in which R 3 is other than hydrogen may be prepared by reaction of compound Ia in which R 3 is H by selective N-alkylation or N-acylation reactions with known compounds of formula R 3 -halo (where R 3 is alkyl or acyl) or [R 3 ] 2 O (where R 3 is acyl). Protection of the hydroxyl group, for example, as a TBDMS ether, may be required prior to N-alkylation reactions. O-deprotection is carried out under standard conditions well known in the art.
  • a third general route to Formula I compounds, where each variable may be any moiety within that variable's definition except that d 1, is shown in Reaction Scheme 3.
  • An amino alcohol 3 and a carboxylic acid 5 are coupled to provide an amide of Formula 6.
  • Reduction of the Formula 6 amides with an appropriate reagent such as borane-dimethylsulfide complex provides the Formula I compounds where R 3 is H.
  • Formula I compounds in which R 3 is other than H may be similarly prepared as described above for Reaction Schemes 1 and 2.
  • Reaction Scheme 4 shows that compounds of Formula I or Formula Ia where Y is any alkenyl, cycloalkenyl, phenyl, or a 5-or 6-membered heterocyclic ring may be prepared from compounds of Formula I or Formula Ia where Y is a halogen, using the following additional methods described below.
  • a compound of Formula I, wherein Y is iodo may be prepared by Reaction Scheme 1 using corresponding starting materials 2 or 4, where Y is iodo, each of which may be prepared by Reaction Schemes 12 or 9, respectively.
  • the resulting Formula I compound is then protected by standard methods to give a compound of Formula 7a.
  • the compound of Formula 7a is then converted to the boronic ester 8, which is then subjected to Suzuki coupling reactions with a halo-Y compound, in which Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5-or 6-membered heterocycle to provide Formula 7 compounds as shown in Reaction Scheme 4.
  • a halo-Y compound in which Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5-or 6-membered heterocycle to provide Formula 7 compounds as shown in Reaction Scheme 4.
  • Deprotection of Formula 7 compounds by acid or fluoride-catalyzed hydrolysis provides the corresponding Formula I compounds.
  • the coupling may also be performed in the reverse manner, that is, a boronic ester derivative 10 prepared from a halophenyl compound 9 may be added to the iodo compound of Formula 7b, as shown in Reaction Scheme 5 to give Formula Ib compounds.
  • Formula I compounds in which Y is an aryl group further substituted by a S(O) b R 2 or NHS(O) b R 2 group may be prepared by elaboration of the corresponding Formula 7 compounds in which Y is an aryl group substituted by CO 2 H as shown in Reaction Scheme 6.
  • Formula I compounds wherein Y is and R 1 and R 4 are as described above may be prepared by a sequence shown in Reaction Scheme 7.
  • the iodo compound of Formula 7a may be converted to the carboxylic acid of Formula 7c by palladium-catalyzed carboxylation. This may then be coupled with an amino acid using standard peptide synthesis techniques, deprotected and hydrolyzed to give compounds of Formula Ic. This method may be repeated to give Formula I compounds where Y is by an analogous sequence of reactions performed on the Formula Ic compounds.
  • Other Formula I compounds wherein Y is NR 1 R 1 may be prepared from the nitro compound of Formula Id by reduction to Ie followed by dialkylation with the appropriate alkylating agents, such as R 1 -halo, R 1 -OTs, or R 1 -OMs to If (Reaction Scheme7).
  • Reaction Scheme 9 shows how other Formula I compounds in which Y is S(O) b Ph-CO 2 R 1 and b is 0 may be prepared by diazotization of Ie and nucleophilic displacement with a arylthiol to give arylthioethers of Formula Ih.
  • Formula I compounds in which Y is SR 1 may be similarly prepared by methods analogous to Reaction Scheme 9, by substituting HSR 1 in place of the arylthiol in the first step.
  • the salts and esters of the Formula I compounds of the invention may be readily prepared by conventional chemical processes.
  • the epoxides 1a of Reaction Scheme 1 are commercially available or may be prepared according to one of the many procedures described in the literature known to those skilled in the art.
  • the epoxides of formula 1a may be prepared by the reaction of an aryl methyl ketone with a selective halogenating agent such as NBS, followed by ketone reduction with, for example, sodium borohydride to a give a chlorohydrin 1b (a halo alcohol). Base-catalyzed cyclization of this alcohol with, for example, potassium carbonate, gives the epoxides of formula 1a.
  • This method is general for the conversion of substituted methyl aryl ketones of general formula (R) a —Ar—C( ⁇ O)CH 3 to the corresponding epoxides of formula 1a.
  • the amino alcohols 3 may be prepared by ring opening of the epoxides 1a with a nitrogen nucleophile, such as phthalimide, in the presence of a base to form an intermediate which may be cleaved or hydrolyzed as described in WO 98/32475. This sequence is general for conversion of epoxides of formula 1a to the amino alcohols of formula 3.
  • a nitrogen nucleophile such as phthalimide
  • Synthesis of aldehyde starting materials of Formula 4 may be accomplished from the carboxylic acid of Formula 5 by reduction with borane followed by oxidation, for example, under Swern conditions as shown in Reaction Scheme 10. This method is compatible with a wide variety of Y groups, although in some cases, a protecting group may also be employed and removed in a subsequent step.
  • the carboxylic acids of Formula 5 are generally available from the known unsubstituted chroman carboxylic acid 5a (WO 99/32476) by various aromatic substitution reactions at the 6-position of the chroman ring and further elaboration of these products.
  • halogenation e.g., iodination
  • 5a gives the 6-iodo compound 5b
  • nitration gives predominantly the 6-nitro analog 5c (U.S. Pat. No. 6,051,586) as shown in Reaction Scheme 11.
  • Compounds of Formula 5 where Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5- or 6-membered heterocycle may be prepared by Suzuki coupling of a halo-Y group to an iodo chroman boronic ester 12 prepared from the iodo chroman acid 5b.
  • Formula 2 amines in which Y is other than hydrogen or halo may be prepared by palladium-catalyzed coupling reactions on the N-protected amine of Formula 15a followed by deprotection, as shown in Reaction Scheme 14.
  • Formula 2 amines prepared in this way in which the Y group is substituted by an acid, ester, alcohol, ketone, sulfide, or nitro group may provide additional Formula 2 amines by manipulation of those functional groups by directed hydrolysis, esterification, reduction, oxidation, or reduction reactions of the Y group.
  • the amine 2c after protection, may be directly substituted at the 6-position of the chroman under Friedel-Crafts alkylation conditions to provide the compounds of Formula 15 in which Y is any alkyl or cycloalkyl group.
  • Y is an optionally substituted alkanoic acid group (15c) is shown in Reaction Scheme 15.
  • Alcohol intermediates of Formula 11 in which Y is other than hydrogen or halo may also be prepared from the iodo alcohol 11a by the previously described Suzuki coupling methodology as shown in Reaction Scheme 16. This may be accomplished either directly or via a 4-step sequence involving protection of the alcohol to 16a, for example, as a t-butyldimethylsilyl ether, conversion of the iodide to the boronic ester, Suzuki coupling to 16, and finally deprotection to 11.
  • halo-Y compounds used in Reaction Schemes 12, 14, and 16 where halo is iodo, chloro, or bromo and Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5- or 6-membered heterocycle are either commercially available or synthesized by standard methods known to those skilled in the art.
  • One such standard method is direct halogenation of compounds of formula H—Y which are either commercially available or known in the art.
  • Other methods include the functional group conversion of HO—Y or H 2 N—Y compounds to halo-Y or TfO—Y compounds by standard substitution methods.
  • halo-Y compounds of Formula 9b or 9c where Y represents an oxazole or a thiazole, prepared by direct halogenation of the unsubstituted compound or by diazotization of a corresponding amino group as shown in Reaction Scheme 17.
  • heterocyclic intermediates 17 and 18 used to prepare 9b and 9c are accessible by standard methods from acyclic materials. Three examples of such heterocycles are shown in Reaction Schemes 18, 19, and 20.
  • HPLC-electrospray mass spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro C18 2.0 mm ⁇ 23 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes was used on the HPLC. Buffer A was 98% water, 2% Acetonitrile, and 0.02% TFA. Buffer B was 98% Acetonitrile, 2% water, and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source.
  • Combinatorial/parallel reactions were carried out in 8-mL glass vials with Teflon-lined screw caps, or in a polypropylene reaction block consisting of a 8 ⁇ 12 matrix of ninety-six 2.0-mL reaction wells, with each reaction well incorporating a 15-45 micron polyethylene frit.
  • Reaction blocks of this type are commercially available as FlexChemTM reactor blocks from Robbins Scientific Corporation, Sunnyvale, Calif. The reactor blocks are sealed with rubber gaskets and a clamping device, and can be heated with mixing by rotation in an oven (Robbins Scientific).
  • the carboxamide of Example 9 (25.0 g, 82.5 mmol) was suspended in anhydrous tetrahydrofuran (200 mL) at reflux under argon. To this suspension was then added borane/dimethyl sulfide complex (83 mL, 2M in THF) dropwise. The reaction became a clear solution after the addition which was stirred at reflux for 1 hour. Additional borane reagent (70 mL) was added and the reaction was further refluxed for 1 hour. Heating was removed and the reaction was cooled to 0° C. with an ice-water bath. Methanol (38 mL) was added slowly to quench the reaction. The reaction mixture was concentrated in vacuo to about 40% of its initial volume.
  • the resulting reaction mixture was degassed with argon for an additional 5 minutes before aqueous Na 2 CO 3 (2 M, 26 mmol, 10.5 eq.) was added and the solution was heated at 85° C. overnight.
  • the product mixture was allowed to cool to room temperature, water was added and the two phase mixture was extracted with ethyl acetate.
  • the combined organic extracts were dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexane:ethyl acetate 10:1).
  • the purified product was dissolved in THF (10 mL) and tetrabutylammonium fluoride (1 M, 5 mL) was added in a single portion.
  • the reaction mixture was then heated at 65° C. under argon for 2 hours. It turned into a suspension. Heating was removed and the reaction was allowed to cool to room temperature. The solid (metallic color) was then collected by filtration and dried by suction. The crude was then dissolved in chloroform (2 L) and filtered through a pad of Celite® (100 g) under vacuum slowly to remove palladium.
  • the methanol was removed by rotary evaporation, and the resulting crude was partitioned between ethyl acetate and water.
  • the aqueous layer was adjusted to pH 7 with 1N aqueous sodium hydroxide, and the layers were separated.
  • the organic layer was washed with brine, dried (MgSO 4 ), and concentrated in vacuo to a dark oil.
  • the reaction was quenched with addition of methanol (12 mL) and 2 M hydrochloric acid (95 mL), and then the resulting solution was heated at reflux for 1 hour.
  • the reaction was cooled to room temperature and then the solution was adjusted to pH 9 using 1 M aqueous sodium hydroxide.
  • the mixture was diluted with brine (500 mL) and the layers were separated.
  • the aqueous layer was extracted with ethyl acetate (2 ⁇ 200 mL) and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo.
  • Triphenylphosphine (0.04 g, 0.16 mmol, 0.2 eq.) and palladium (II) acetate (0.01 g, 0.04 mmol, 0.05 eq.) were added, and the mixture was stirred vigorously under argon at 85° C. overnight.
  • the reaction was cooled and filtered through a pad of Celite® with the aid of ethyl acetate.
  • the filtrate was transferred to a separatory funnel where the layers were separated.
  • the organic layer was concentrated in vacuo to remove excess solvents, and the resulting oil was dissolved in ethyl acetate.
  • the ethyl acetate solution was extracted with a 1:1 solution of saturated aqueous sodium bicarbonate and water.
  • Triphenylphosphine (0.04 g, 0.16 mmol, 0.2 eq.) and palladium (II) acetate (0.01 g, 0.04 mmol, 0.05 equivalent) were added, and the mixture was stirred vigorously under argon at 85° C. overnight.
  • the reaction was cooled and filtered through a pad of Celite® with the aid of ethyl acetate. The filtrate was transferred to a separatory funnel where the layers were separated.
  • the organic layer was dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel flushed with ethyl acetate followed by elution with 95:5 chloroform/methanol.
  • Example 73 By employing the methods described in Example 73 and by using the compound of Example 70 with the appropriate amide or sulfonamide as starting materials, the following were similarly prepared and characterized: TABLE 4 Example Calculated MS RT (minutes) No. R′ Y MW [M + H + ] LC-MS 74 418.2 419.2 0.93 75 480.22 481.2 2.01 76 516.2 517.2 2.18 77 482.16 483.1 0.75 78 510.19 511.2 1.03 79 562.17 563.2 2.02 80 574.19 575.2 1.73
  • the mixture was treated with Na 2 CO 3 (1.0 mL of a 2.0 M aq.) and the bi-phase mixture stirred vigorously under Ar at 85° C. for 12 hours.
  • the cooled reaction mixture was filtered through a pad of Celite® and the filtrate was extracted with EtOAc (2 ⁇ 20 mL).
  • the mixture was diluted with 1.0 mL H 2 O and purified via preparative HPLC (gradient of 100:0 0.1% TFA/H 2 0:acetonitrile to 30:70 0.1% TFA/H 2 0:acetonitrile).
  • Example 86 The product of Example 86 (100 mg, 0.16 mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide (36 mg, 0.19 mmol), dimethylaminopyridine (20 mg, 0.16 mmol), and methylsulfonamide (17 mg, 0.18 mmol) were dissolved in 2 mL methylene chloride and stirred overnight at room temperature. The mixture was treated with 0.5 mL 4 M HCl in 1,4-dioxane was added, the solution stirred for 0.5 hours, concentrated to dryness and the residue was purified by preparative HPLC to obtain the title compound (47 mg, 62%).
  • the resulting mixture was then allowed to stir at 0° C. for 1 hour while 270 mg (1.75 mmol) 3-mercaptobenzoic acid, 279 mg (1.75 mmol) copper sulfate, and 1.24 mL water were mixed together at room temperature for 0.5 hour. After this time, the cold (0° C.) solution was added slowly to the room temperature solution. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then added to 100 mL water and extracted 3 times with 25 mL ethyl acetate. The combined organic phases were washed with water and brine, and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was used without further purification.
  • Example 85 By using procedure described in Example 85, the compounds of Example 178 and Example 81 were coupled to provide the desired compound.
  • Benzyl bromide (0.86 g, 5.0 mmol, 1.1 eq.) was added neat to a solution of 4-bromo-2-fluorobenzoic acid. (1.0 g, 4.6 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.36 ml, 9.2 mmol, 2.0 eq.) in anhydrous acetonitrile (20 mL). The reaction was stirred at room temperature for 18 hours before removing the solvent in vacuo. The residue was diluted with ether and washed with water, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, and brine.
  • Phenylmethyl 4-bromo-2-fluorobenzoate (Example 189, 260 mg, 0.84 mmol) was combined with phenol (160 mg, 1.68 mmol, 2.0 eq.) and solid potassium carbonate (580 mg, 4.21 mmol, 5.0 eq.) in anhydrous N,N-dimethylformamide and was heated at 85° C. for 5 hours. The mixture was cooled and partitioned between diethyl ether and water. The aqueous layer was separated and extracted with fresh ether. The organic layers were combined, washed with brine (4 ⁇ ), dried (MgSO 4 ), and concentrated in vacuo to a crude oil.
  • the reaction mixture was cooled and filtered through a pad of Celite® with the aid of ethyl acetate. The filtrate was transferred to a separatory funnel where the water layer was removed. The organic layer was dried (MgSO 4 ) and concentrated in vacuo to a crude oil.
  • the carboxylic acid intermediate (25 mg, 0.04 mmol) was stirred in an excess of 4M HCl in dioxane at room temperature for 18 hours. The volatile components were removed by rotary evaporation, and the residue was washed with dichloromethane.
  • Example 85 By using the procedure described in Example 85, the compounds of Example 200 and Example 178 were coupled to provide the desired compound.
  • Example 204 To a solution of the compound of Example 204 (0.18 g, 0.38 mmol, 1.0 eq.) in isopropanol (4.0 mL) were added the compound of Example 1 (0.09 g, 0.57 mmol, 1.5 eq.) and potassium carbonate (0.16 g, 1.13 mmol, 3.0 eq.) at room temperature. The reaction mixture was allowed to heat up at 95° C. for 16 hours. The mixture was diluted with distilled water (6 mL) and extracted with ethyl acetate (3 ⁇ 6 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by HPLC yielded the intermediate as a colorless oil.
  • Example 212 was converted to the title compound.
  • N-benzyl[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine hydrobromide (2173 g, 6.5 moles, 1.0 eq.) was suspended in 11.4 L formic acid. The suspension was cooled to 16° C., then bromine (1071 g, 6.7 moles, 1.03 eq.) was added over a 60 minutes, maintaining the reaction temperature between 15 and 16° C. After 70 minutes, a HPLC probe indicated the reaction to be complete. To the reaction mixture was then added 15.6 L water (temperature increased to 21° C). The light reaction mixture was then stirred for 30 minutes at room temperature, then the product was filtered and washed with 3.9 L water.
  • the reaction was diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure and the residue was coated on silica.
  • the silica coated product was purified on the MPLC (Biotage) with 30-100% ethyl acetate in hexanes then 2% methanol in methylene chloride to afford 796 mg (1.09 mmol, 63%) of product.
  • Example MS RT (min, No. Structure [M + H + ] LC-MS) 250 518 1.01 251 585 1.91 252 599 1.94 253 517 1.53 254 517 1.44 255 570 1.96 256 541 2.02 257 541 2.02 258 570 1.94 259 586 2.04 260 517 1.55 261 518 1.37 262 625 2.14 263 642 2.17 264 558 2.01 265 523 1.55 266 653 2.32 267 578 1.95 268 532 1.35 269 562 1.53 270 608 1.92 271 592 1.66 272 548 1.3 273 562 1.52 274 662 2.14 275 616 1.74 276 573 2.07 277 571 1.94 278 603 2.03 279 517 1.23 280 588 1.87
  • Example MS RT (min, No. Structure [M + H + ] LC-MS) 284 550.1 1.97 285 508.2 1.75 286 526.2 1.89 287 528.2 0.54 288 618.1 2.04 289 538.3 0.36 290 510.2 0.25 291 512.2 0.21 292 524 2.01 293 574 1.86 294 544 1.55 295 562 1.93 296 558 2.01 297 558 2.01 298 574 2.18 299 558 2.13 300 573 2.15 301 577 2.27 302 577 2.26 303 574 1.94 304 525 0.76 305 496 1.57
  • Example 312 was converted to the title compound.
  • Example 316 80 mg, 0.135 mmol
  • benzene sulfonyl chloride 41 mg, 0.233 mmol
  • pyridine 1.5 mL
  • the reaction was diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate.
  • the crude product was coated on silica and purified on the MPLC (Biotage) with 40-70% ethyl acetate in hexanes to afford the desired product (91 mg, 92%).
  • Example 318 was converted to the title compound.
  • Example 281 To a stirred solution of Example 281 (45 mg) in dichloroethane (10 mL), were added Et 3 N (0.014 mL) and 4-methylphenyl isocyanate (0.013 mL). Stirring was continued at room temperature over a 2-3 hour period. The solvent was removed under reduced pressure. Crude product was purified by combiflash column chromatography to give the free base of the desired product (27 mg, 50% yield). This material was treated with HCl (4 M) in dioxane and stirred at room temperature overnight. The solvent was removed under reduced pressure to provide the crude product, which was purified by preparative HPLC-to provide the title compound.
  • 6-(4-methoxycarbonylphenyl)-(R)-chroman-2-methylamine and 3,4-dimethylphenyl oxirane were reacted by following the procedure described above to provide 4-[(2R)-2-( ⁇ [2-(3,4-dimethylphenyl)-2-hydroxyethyl]amino ⁇ methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid as the trifluoroacetate salt (17% yield).
  • Example 81 Using the method described above for Example 371, the following compounds were similarly prepared using Example 81 and the appropriate halobenzene starting material: TABLE 17 Example MS HPLC No. Structure [M + H + ] RT (min) 372 726.4 5.18 373 765.4 4.85 374 978 5.29
  • Example 372 In similar fashion to that described above for Example 375, the title compound was prepared from Example 372 and used without further purification.
  • the reaction block was sealed with rubber gaskets and clamped, then heated at 80° C. for 72 hours, with mixing by rotation. After allowing the reaction block to cool to room temperature, the block was disassembled, and the reaction well contents were filtered into a collection 96-well deep-well microtiter plate, washing with 2 portion of 200 ⁇ L of dioxane. The filtrate solutions were evaporated to dryness using a multiple sample centrifugal vacuum evaporator. Products were analyzed for purity and correct identity by LC/MS.
  • An embodiment of the present invention is the administration of the compounds of this invention to a human or animal for the treatment of beta-3 adrenergic receptor mediated conditions such as diabetes, obesity, gastrointestinal disorders including irritable bowel syndrome and intestinal hypermotility disorders, peptic ulcerations, esophagitis, gastritis, and duodenitis, intestinal ulcerations including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis, and gastrointestinal ulcerations, as well as neurogenetic inflammation such as cough and asthma, and depression. It is also believed that the compounds of this invention are effective in the treatment of hyper-triglyceridemia, hypercholesterolemia and conditions of low or high density lipoprotein levels, artherosclerotic disease and cardiovascular disease and related conditions.
  • the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urinary disorders including pollakiuria and incontinence, as well as in the treatment of prostate disease and as topical anti-inflammatory agents.
  • An embodiment of this invention includes a method of treating beta-3 adrenergic receptor mediated conditions in a mammal which comprises administering to said mammal a composition containing an amount of the compound of Formula I that is effective in treating the target condition.
  • the specificity of the compounds of this invention as beta-3 adrenergic receptor agonists can readily be determined by evaluating the affinity of the compound for the different beta adrenergic receptor subtypes and comparing the activity with various receptor subtypes affinities to discover specificity as well as activity using standard and well-known procedures. Such a procedure is described in more detail in the specific example below.
  • Chinese hamster ovary (CHO) cells that stably express full-length human beta-3-adrenergic receptor (Granneman et al., Mol. Pharmacol. 44:264-270,1993) can be used in the following procedure.
  • the cell line is grown in 90% F12 nutrient mixture (HAM), 10% fetal bovine serum, 100 units/ml penicillin G sodium, 100 mg/ml streptomycin sulfate, and 2 mM L-glutamine at 37° C. in 95% air and 5% CO 2 .
  • the transfected cell line is maintained with G-418 (800 ⁇ g/ml).
  • CHO cells 100 ⁇ l are plated at 5 ⁇ 10 4 cells/well of a 96-well plate (Costar, Cambridge, Mass.) to achieve 70% confluency the next day. After overnight incubation at 37° C., media is removed and the cells are treated for 30 minutes at 37° C.
  • KRP buffer 120 mM NaCl, 5.1 mM KCl, 0.6 mM MgSO 4 7 H 2 O, 0.8 mM CaCl 2 H 2 O, 12.5 ⁇ M phosphate buffer, 20 ⁇ M Hepes pH 7.4
  • IBMX 100 ⁇ M/well
  • test compounds 10 ⁇ M DMSO stocks. Test compounds are assayed from 10 ⁇ M to 3 nM with 3-fold serial dilutions.
  • the control agonist, isoproterenol (10 mM stock in 1.1 mM ascorbate) is assayed by 3-fold dilution beginning at 1 ⁇ M.
  • the buffer/compound mixture is removed.
  • the cells are lysed and cAMP levels are measured using the cAMP SPA screening assay system (Amersham, Arlington Heights, Ill.). The cAMP values are then plotted to determine the EC 50 of each compound tested.
  • Beta-3 Agonistic Activity Compounds with EC 50 values Compounds with EC 50 values ⁇ 1 ⁇ M >1 ⁇ M (Example No.) (Example No.) 36 39 40 41 47 42 48 43 54 45 184-188 363 192 364 193-198 365 205 367 211 215 216 249A 249B 250-280 283-305 308-311 314 317 319-340 343 344 348 352 362 366 369 381-386
  • Beta-3 adrenergic receptor agonists may be useful for correcting the insulin resistance that underlies two prediabetic states, impaired glucose tolerance (Harris, Diabetes Care 12:464-474, 1989) and impaired fasting glucose (Weyer et al., Diabetes 48:2197-2203,1999).
  • impaired glucose tolerance Harris, Diabetes Care 12:464-474, 1989
  • impaired fasting glucose Weyer et al., Diabetes 48:2197-2203,1999
  • the ability of a beta-3 adrenergic receptor agonist to restore insulin sensitivity has been demonstrated in a diabetic animal model with marked insulin resistance. Treatment of KK-Ay/Ta diabetic obese mice with a beta-3 adrenergic receptor agonist resulted in marked improvement in the animals' responses to insulin (Kato et al., Diabetes 50:113-122, 2001).
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.01 mg/kg to about 100 mg/kg, and preferably from about 0.1 mg/kg to about 20 mg/kg body weight per day.
  • a unit dosage may contain from about 5 mg to about 1500 mg of active ingredient, and may be administered one or more times per day.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician.
  • the compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular beta-3 adrenergic receptor mediated condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or ester thereof.
  • a pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compounds of Formula I may be administered with a pharmaceutically-acceptable carrier using any effective conventional dosage unit forms, including immediate and timed release preparations, orally, parenterally, topically, or the like.
  • the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin; disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum; lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium, or zinc stearate; dyes; coloring agents; and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and
  • Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring, and coloring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring, and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose.
  • Such formulations may also contain a demulcent, and preservative, flavoring, and coloring agents.
  • the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water; saline; aqueous dextrose and related sugar solutions; an alcohol such as ethanol, isopropanol, or hexadecyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol; ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a fatty acid ester or glyceride; or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent; suspending agent such as pectin, carb
  • Suitable fatty acids include oleic acid, stearic acid, and isostearic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, al
  • compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation may range from about 5% to about 15% by weight.
  • the surfactant may be a single component having the above HLB or may be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • compositions may be in the form of sterile injectable aqueous suspensions.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid may be used in the preparation of injectables.
  • composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No. 5,023,252, incorporated herein by reference).
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
  • a capsule formula is prepared from A compound of Formula I 40 mg Starch 109 mg Magnesium stearate 1 mg The components are blended, passed through an appropriate mesh sieve, and filled into hard gelatin capsules.
  • a tablet is prepared from A compound of Formula I 25 mg Cellulose, microcrystalline 200 mg Colloidal silicon dioxide 10 mg Stearic acid 5.0 mg The ingredients are mixed and compressed to form tablets.
  • the compound of this invention may be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compounds of this invention may be combined with known antiobesity or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • compositions which are comprised of an inert carrier and an effective amount of a compound of Formula I, or a salt or ester thereof.
  • An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like, to the compound to be carried.
  • An effective amount of compound is that amount which produces a result or exerts an influence on the particular procedure being performed.

Abstract

This invention relates to novel 2,6-substituted chroman derivatives which are useful in the treatment of beta-3 adrenoreceptor-mediated conditions.

Description

  • This application claims benefit of U.S. Provisional Application Ser. No. 60/285,719, filed Apr. 23, 2001, and U.S. Provisional Application Ser. No. 60/324,518, filed on Sep. 26, 2001, the contents of which are incorporated herein by reference in their entirety.
    • FIELD OF THE INVENTION
  • This invention relates to novel chroman compounds, pharmaceutical compositions containing such compounds, and methods of treating beta-3 adrenoreceptor-mediated conditions with such compositions.
    • BACKGROUND OF THE INVENTION
  • Adrenoreceptors, or adrenergic receptors, are sites on effector organs that are innervated by postganglionic adrenergic fibers of the sympathetic nervous system, and are classified as either alpha-adrenergic or beta-adrenergic receptors. Alpha-adrenergic receptors respond to norepinephrine and to such blocking agents as phenoxybenzamine and phentolamine, whereas beta-adrenergic receptors respond to epinephrine and to such blocking agents as propranolol.
  • Beta-adrenergic receptors are sub-classified as beta-1, beta-2, and beta-3 adrenoreceptors. Generally, beta-1 stimulation causes cardiostimulation, whereas beta-2 stimulation causes bronchodilation and vasodilation.
  • Beta-3 receptors are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis and energy expenditure. Agonists of beta-3 adrenoreceptors are known to be useful in the treatment of hyperglycemia (diabetes) and obesity in mammals, as well as in the treatment of gastrointestinal disorders and neurogenetic inflammation (U.S. Pat. No. 5,561,142). Additionally, they are known to lower triglyceride and cholesterol levels and to raise high-density lipoprotein levels in mammals (U.S. Pat. No. 5,451,677). Accordingly, they are useful in the treatment of conditions such as hypertriglyceridemia, hypercholesterolemia, and in lowering high-density lipoprotein levels. They also may be useful in treating patients with Syndrome X, impaired fasting glucose, and/or impaired glucose tolerance, as well as in the treatment of atherosclerotic and cardiovascular diseases and related conditions.
  • Additionally, it is also believed that the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urinary disorders including pollakiuria and incontinence, as well as in the treatment of prostate disease and as topical anti-inflammatory agents.
  • It has now been found that certain novel chroman derivatives are effective as beta-3 agonists and are useful in the treatment of beta-3 adrenoreceptor-mediated conditions.
    • DESCRIPTION OF THE INVENTION
  • Figure US20050215594A1-20050929-C00001
    wherein,
      • R is independently
        • hydroxy,
        • oxo,
        • halo,
        • cyano,
        • nitro,
        • C1-C10 alkyl,
        • C1-C10 haloalkyl,
        • CF3,
        • NR1R1,
        • SR1,
        • OR1,
        • SO2R2,
        • OCOR2,
        • NR1COR2,
        • COR2,
        • NR1SO2R2,
        • phenyl, or
        • a 5- or 6-membered heterocycle with from 1 to 4 heteroatoms selected from O, S, and N;
      • each cyclic moiety being optionally substituted with
        • hydroxy,
        • R1,
        • halo,
        • cyano,
        • NR1R1,
        • SR1,
        • CF3,
        • OR1,
        • C3-C8 cycloalkyl,
        • NR1COR2,
        • COR2,
        • SO2R2,
        • OCOR2,
        • NR1SO2R2,
        • C1-C10 alkyl, or
        • C1-C10 alkoxy;
      • R1 is
        • hydrogen,
        • (CH2)d—O—(CH2)dR5 where each d is selected independently, or
        • C1-C10 alkyl optionally substituted with 1 to 4 substituents each independently selected from
          • hydroxy,
          • halo,
          • CO2C1-C4-alkyl,
          • CO2H,
          • C1-C10 alkoxy,
          • S(O)bC1-C10 alkyl,
          • S(O)b-phenyl optionally substituted with halo, C1-C4alkyl, C1-C4 alkoxy, SO2—C1-C4alkyl, or CO2 C1-C4alkyl; or
          • phenyl optionally substituted with CO2C1-C4-alkyl, CO2H, halo, or C1-C10 alkyl;
          • or
        • C3-C8 cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1 to 4 substituents each independently selected from halo, nitro, oxo, C1-C10 alkyl, C1-C10alkoxy, C1-C10 alkylthio, CO2C1-C4-alkyl, and CO2H, and
      • when two R1 groups are attached to N as NR1R1, these R1 groups may form together with the nitrogen to which they are attached, a heterocyclic ring containing 4 to 7 C atoms, 1 to 2 N atoms, and 0 to 1 O or S atoms;
        • R2is
        • R1,
        • OR1,
        • NR1R1,
        • NHS(O)bphenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo or nitro;
        • NHS(O)bnaphthyl,
        • NHS(O)bC1-C10alkyl optionally substituted with fluoro up to the perfluoro level, or
        • a 5- or 6-membered heterocycle with one or more heteroatoms selected from O, S, and N, said heterocyclic moiety being optionally substituted with R1;
      • R3 is hydrogen, C1-C10 alkyl, or COR2;
      • R4 is hydrogen, C1-C10 alkyl, C1-C10 alkyl-phenyl, or C1-C10 alkyl-pyridyl;
      • R5 is hydrogen or COOH;
      • R6 is
        • hydrogen,
        • C1-C10 alkyl optionally substituted with 1 to 4 substituents each independently selected from halo, phenyl, or phenyl-COR2, or
        • C1-C10 alkyl-S(O)bC1-C10 alkyl optionally substituted with COR2 or C3-C8 cycloalkyl;
      • Ar is
        • phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N, said bicyclic moiety being optionally fused to a phenyl, or
        • a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to phenyl;
      • Y is
        • halo,
        • NO2,
        • R6,
        • SR1,
        • S(O)b-phenyl-CO2R1,
          Figure US20050215594A1-20050929-C00002
          • where, when the two R4 groups attached to the same C are both alkyl, they optionally may be joined so that, when taken together with the C to which they are attached, they form a spiro ring of 3, 5, or 6 C atoms, or where the R4 attached to N and one R4 attached to the adjacent C are both alkyl, they optionally may be joined so that, taken together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic ring;
            • with the proviso that when e is 1, at least one R4 group must be C1-C10 alkyl-phenyl or C1-C10 alkyl-pyridyl, or two R4 groups must form one of said spiro or heterocyclic ring moieties,
        • phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or
        • a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S and O, optionally fused to a phenyl ring,
      • each cyclic moiety being optionally substituted with one or more substituents independently selected from
        • COR2,
        • CONR1S(O)2R9,
        • COCH2SO2-thiazolyl optionally substituted with alkyl or amino,
        • halo,
        • NO2,
        • OR1,
        • R1,
        • SR1,
        • O—C1-C6-alkyl substituted by C3-C6-cycloalkyl,
        • O-phenyl optionally substituted by SO2CH3,
        • SO2NH2,
        • SO2NR1R7,
        • NR1R1,
        • NR1COC1-C6alkyl,
          Figure US20050215594A1-20050929-C00003
        • C1-C10COR2,
        • phenyl optionally substituted with halo, C1-C4 alkyl, or C1-C4 alkoxy,
        • tetrazolo;
      • R7 is
        • phenyl or heteroaryl containing 3-6 C and 1-3 O, N, or S atoms, each optionally substituted by C1-C4alkyl, CN, NO2, CO—C1-C4alkyl, C1-C4alkoxy, or C1-C4 haloalkyl,
        • CO—R8,
          Figure US20050215594A1-20050929-C00004
      • R8 is
        • C1-C6alkyl optionally substituted with C1-C4 alkoxy, N(CH3)2,or one or two CF3,
        • C3-C6-cycloalkyl,
        • phenyl optionally substituted with C1-C4 alkoxy, halo, or C1-C4 alkyl,
        • NH-phenyl optionally substituted with C1-C4alkyl, halo, C1-C4alkoxy, or C1-C4 haloalkoxy,
        • NH-cyclohexyl;
      • R9 is
        • C3-C6 cycloalkyl,
        • thienyl optionally substituted with C1-C4 alkyl or isoxazolyl,
        • pyridyl optionally substituted with —SO2—C1-C4alkyl,
        • pyrazolyl optionally substituted with halo or C1-C4alkyl,
        • isoxazolyl optionally substituted with C1-C4 alkyl, or
          Figure US20050215594A1-20050929-C00005
      • a is 0, 1, 2, 3, 4, or 5;
      • b is 0, 1, or 2;
      • d is 1, 2, or 3;
      • e is 1 or 2;
        and pharmaceutically acceptable salts and esters thereof.
  • The terms identified above have the following meaning throughout:
      • C1-C10 alkyl means straight or branched chain alkyl groups having from one to about ten carbon atoms, which may be saturated, unsaturated, or partially saturated. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, as well as vinyl, allyl, propynyl, butenyl, butadienyl, isopropenyl, methyleneyl, ethylenyl, propenyl, ethynyl, and the like.
  • C1-C10 haloalkyl means straight or branched chain alkyl groups having from about one to about ten carbon atoms where any C—C bond may be saturated or unsaturated, the alkyl groups being substituted at any available carbon atom with one or more halogen atoms, and includes such groups as trifluoromethyl, trichloromethyl, pentafluoroethyl, fluoromethyl, 6-chlorohexyl, and the like.
  • The term C1-C10 alkoxy means straight or branched chain alkoxy groups having from one to about ten carbon atoms where any C—C bond may be saturated or unsaturated, and includes such groups as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
  • The term C1-C10 alkylthio means straight or branched chain alkylthio groups having from one to about ten carbon atoms where any C—C bond may be saturated or unsaturated, and includes such groups as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.
  • C3-C8 cycloalkyl means saturated mono cyclic alkyl groups of from 3 to about 8 carbon atoms, and includes such groups as cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • Halo includes fluoro, chloro, bromo, and iodo, unless specifically stated otherwise.
  • R, R2, Ar, and Y each include any 5- or 6-membered saturated or unsaturated heterocyclic group having any combination of one or more N, S, or O atoms with the point of attachment being at any available position on the heterocyclic ring. Where there is more than one heteroatom in a single cyclic group, each heteroatom shall be chosen independently of any other heteroatom, in each occurrence, with the proviso that any single heterocyclic ring may not contain more than two oxygen or sulfur atoms. These moieties include such 5-membered heterocylic groups as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, pyrrolinyl, dihydrothienyl, tetrahydrothienyl, dioxolyl, dithiolanyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, triazolinyl, triazolidinyl, oxadiazolyl, thiadiazolyl, furazanyl, tetrazolyl, and the like. It also includes such 6-membered heterocyclic rings such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, dihydropyranyl, thiopyranyl, triazinyl, dioxanyl, piperidinyl, piperazinyl, pyrazinyl, morpholinyl, and the like
  • Ar and Y also each include phenyl fused to any 5- or 6-membered heterocyclic ring described above to form a bicyclic moiety, which may be saturated or unsaturated and may have any combination of one or more N, S, or O atoms with the point of attachment being any at available position on the phenyl ring. These include such phenyl fused 5-membered heterocyclic groups as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indazolyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzothiadiazolinyl, benzisothiazolyl, benzisothiazolinyl, benzotriazolyl, benzoxadiazolyl, benzoxadiazolinyl, benzothiadiazolyl, benzopyrazolinyl, and the like. It also includes such phenyl fused 6-membered heterocyclic groups as quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
  • Ar also includes phenyl fused to any 5- or 6-membered heterocyclic ring to form a bicyclic moiety as described above, which is further fused on the heterocyclic ring to a second phenyl ring, forming a tricyclic system, with the point of attachment to the core structure of the compound of Formula I being at any available position of the first phenyl ring. These include such groups as carbazolyl, carbazolinyl, acridinyl, xanthenyl, phenoxathiinyl, phenoxazinyl, phenanthridinyl, dibenzofuryl, dibenzopyranyl, dibenzodioxanoyl, phenazinyl, thianthrenyl, and the like.
  • Ar also includes any 5- or 6-membered saturated or unsaturated heterocyclic ring having any combination of one or more N, S, or O atoms as described above, which is further fused to a phenyl ring, with the point of attachment to the core molecule of Formula I being at any available position on the heterocyclic ring. These include such phenyl-fused with 5-membered hetero-bicyclic moieties as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indazolyl, indolizinyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzisothiazolyl, benzoisothiazolinyl, benzopyrazolinyl and the like. It also includes such phenyl-fused with 6-membered hetero-bicyclic groups as quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
  • C1-C10-alkyl-phenyl means saturated straight or branched chain alkyl groups having from one to about ten carbon atoms where the phenyl moiety is attached at any available position on the alkyl group. Examples of these moieties include benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-methyl-2-phenylethyl, 5-phenylpentyl, 4-phenylhexyl, and the like.
  • C1-C10-alkyl-pyridyl means straight or branched chain saturated alkyl groups having from one to about ten carbon atoms where the pyridyl moiety is attached at any available position on the alkyl group. The pyridyl group may be attached to the alkyl group from any available position on the pyridine ring. Examples of these include pyridyl, 2-(2-pyridyl)ethyl, 3-(4-pyridyl)-propyl, 2-(3-pyridyl)-propyl, 1-methyl-2-(3-pyridyl)-ethyl, 5-(3-pyridyl)-pentyl, 4-(4-pyridyl)-hexyl, and the like.
  • S(O)b-phenyl-CO2R1 means a phenylthio, a phenylsulfinyl, or a phenylsulfonyl group, where the CO2R1 moiety is attached at any available position on the phenyl ring.
  • When any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety. When there are two or more substituents on any moiety, each term shall be defined independently of any other in each occurrence. For example, NR1R1 may represent NH2, NHCH3, N(CH3)CH2CH2CH3, and the like.
  • Examples of the compound of Formula I, which are illustrative of the present invention but not limiting in any way, are listed in Table 1.
    TABLE 1
    (I)
    Figure US20050215594A1-20050929-C00006
    Entry
    No. R a Ar R3 d Y
     1
    Figure US20050215594A1-20050929-C00007
         		1
    Figure US20050215594A1-20050929-C00008
         		H 1
    Figure US20050215594A1-20050929-C00009
     2
    Figure US20050215594A1-20050929-C00010
         		1
    Figure US20050215594A1-20050929-C00011
         		H 2
    Figure US20050215594A1-20050929-C00012
     3
    Figure US20050215594A1-20050929-C00013
         		1
    Figure US20050215594A1-20050929-C00014
         		H 3
    Figure US20050215594A1-20050929-C00015
     4 6-NH2 1
    Figure US20050215594A1-20050929-C00016
         		H 1 l
     5 6-NH2 1
    Figure US20050215594A1-20050929-C00017
         		H 1 Br
     6 6-NH2 1
    Figure US20050215594A1-20050929-C00018
         		H 1 —NO2
     7 6-NH2 1
    Figure US20050215594A1-20050929-C00019
         		H 1 —≡-t-Bu
     8 6-NH2 1
    Figure US20050215594A1-20050929-C00020
         		H 1 —≡-Ph
     9 6-NH2 1
    Figure US20050215594A1-20050929-C00021
         		H 1 —S—CH2—CO3Et
     10 6-NH2 1
    Figure US20050215594A1-20050929-C00022
         		H 2 —S—CH2—CO3H
     11 6-NH2 1
    Figure US20050215594A1-20050929-C00023
         		H 1
    Figure US20050215594A1-20050929-C00024
     12 6-NH2 1
    Figure US20050215594A1-20050929-C00025
         		H 2
    Figure US20050215594A1-20050929-C00026
     13 6-NH2 1
    Figure US20050215594A1-20050929-C00027
         		H 1
    Figure US20050215594A1-20050929-C00028
     14 6-NH2 1
    Figure US20050215594A1-20050929-C00029
         		H 2
    Figure US20050215594A1-20050929-C00030
     15 6-NH2 1
    Figure US20050215594A1-20050929-C00031
         		H 3
    Figure US20050215594A1-20050929-C00032
     16 — 0 Ph H 1
    Figure US20050215594A1-20050929-C00033
     17 — 0 Ph H 1
    Figure US20050215594A1-20050929-C00034
     18 — 0
    Figure US20050215594A1-20050929-C00035
         		H 1
    Figure US20050215594A1-20050929-C00036
     19 — 0
    Figure US20050215594A1-20050929-C00037
         		H 2
    Figure US20050215594A1-20050929-C00038
     20 6-NH2 1
    Figure US20050215594A1-20050929-C00039
         		H 1
    Figure US20050215594A1-20050929-C00040
     21 — 0
    Figure US20050215594A1-20050929-C00041
         		H 1
    Figure US20050215594A1-20050929-C00042
     22 — 0
    Figure US20050215594A1-20050929-C00043
         		H 1
    Figure US20050215594A1-20050929-C00044
     23 — 0
    Figure US20050215594A1-20050929-C00045
         		H 2
    Figure US20050215594A1-20050929-C00046
     24 — 0
    Figure US20050215594A1-20050929-C00047
         		H 1
    Figure US20050215594A1-20050929-C00048
     25 — 0
    Figure US20050215594A1-20050929-C00049
         		H 1
    Figure US20050215594A1-20050929-C00050
     26 — 0 Ph H 1
    Figure US20050215594A1-20050929-C00051
     27 — 0
    Figure US20050215594A1-20050929-C00052
         		H 3
    Figure US20050215594A1-20050929-C00053
     28 — 0
    Figure US20050215594A1-20050929-C00054
         		H 1
    Figure US20050215594A1-20050929-C00055
     29 — 0
    Figure US20050215594A1-20050929-C00056
         		H 1
    Figure US20050215594A1-20050929-C00057
     30 — 0
    Figure US20050215594A1-20050929-C00058
         		H 1
    Figure US20050215594A1-20050929-C00059
     31 — 0
    Figure US20050215594A1-20050929-C00060
         		H 1
    Figure US20050215594A1-20050929-C00061
     32 — 0
    Figure US20050215594A1-20050929-C00062
         		H 1
    Figure US20050215594A1-20050929-C00063
     33 — 0
    Figure US20050215594A1-20050929-C00064
         		H 1
    Figure US20050215594A1-20050929-C00065
     34 — 0
    Figure US20050215594A1-20050929-C00066
         		H 1
    Figure US20050215594A1-20050929-C00067
     35 — 0
    Figure US20050215594A1-20050929-C00068
         		H 1
    Figure US20050215594A1-20050929-C00069
     36 — 0
    Figure US20050215594A1-20050929-C00070
         		H 1
    Figure US20050215594A1-20050929-C00071
     37 — 0
    Figure US20050215594A1-20050929-C00072
         		H 1
    Figure US20050215594A1-20050929-C00073
     38 — 0
    Figure US20050215594A1-20050929-C00074
         		H 1
    Figure US20050215594A1-20050929-C00075
     39 — 0
    Figure US20050215594A1-20050929-C00076
         		H 1
    Figure US20050215594A1-20050929-C00077
     40 — 0
    Figure US20050215594A1-20050929-C00078
         		H 1
    Figure US20050215594A1-20050929-C00079
     41 — 0
    Figure US20050215594A1-20050929-C00080
         		H 1
    Figure US20050215594A1-20050929-C00081
     42 — 0
    Figure US20050215594A1-20050929-C00082
         		H 1
    Figure US20050215594A1-20050929-C00083
     43 — 0
    Figure US20050215594A1-20050929-C00084
         		H 1
    Figure US20050215594A1-20050929-C00085
     44 — 0
    Figure US20050215594A1-20050929-C00086
         		H 1
    Figure US20050215594A1-20050929-C00087
     45 — 0
    Figure US20050215594A1-20050929-C00088
         		H 1
    Figure US20050215594A1-20050929-C00089
     46 — 0
    Figure US20050215594A1-20050929-C00090
         		H 1
    Figure US20050215594A1-20050929-C00091
     47 — 0
    Figure US20050215594A1-20050929-C00092
         		H 1
    Figure US20050215594A1-20050929-C00093
     48 — 0 Ph H 1
    Figure US20050215594A1-20050929-C00094
     49 — 0 Ph H 2
    Figure US20050215594A1-20050929-C00095
     50 — 0 Ph H 3
    Figure US20050215594A1-20050929-C00096
     51 6-NH2 1
    Figure US20050215594A1-20050929-C00097
         		H 1
    Figure US20050215594A1-20050929-C00098
     52 6-NH2 1
    Figure US20050215594A1-20050929-C00099
         		H 2
    Figure US20050215594A1-20050929-C00100
     53 6-NH2 1
    Figure US20050215594A1-20050929-C00101
         		H 3
    Figure US20050215594A1-20050929-C00102
     54 — 0
    Figure US20050215594A1-20050929-C00103
         		H 1
    Figure US20050215594A1-20050929-C00104
     55 — 0
    Figure US20050215594A1-20050929-C00105
         		H 1
    Figure US20050215594A1-20050929-C00106
     56 — 0
    Figure US20050215594A1-20050929-C00107
         		H 1
    Figure US20050215594A1-20050929-C00108
     57 — 0
    Figure US20050215594A1-20050929-C00109
         		H 1
    Figure US20050215594A1-20050929-C00110
     58 — 0
    Figure US20050215594A1-20050929-C00111
         		H 1
    Figure US20050215594A1-20050929-C00112
     59 — 0
    Figure US20050215594A1-20050929-C00113
         		H 1
    Figure US20050215594A1-20050929-C00114
     60 — 0
    Figure US20050215594A1-20050929-C00115
         		H 1
    Figure US20050215594A1-20050929-C00116
     61 — 0
    Figure US20050215594A1-20050929-C00117
         		H 1
    Figure US20050215594A1-20050929-C00118
     62 — 0
    Figure US20050215594A1-20050929-C00119
         		H 1
    Figure US20050215594A1-20050929-C00120
     63 — 0
    Figure US20050215594A1-20050929-C00121
         		H 1
    Figure US20050215594A1-20050929-C00122
     64 — 0
    Figure US20050215594A1-20050929-C00123
         		H 1
    Figure US20050215594A1-20050929-C00124
     65 — 0
    Figure US20050215594A1-20050929-C00125
         		H 1
    Figure US20050215594A1-20050929-C00126
     66 — 0
    Figure US20050215594A1-20050929-C00127
         		H 1
    Figure US20050215594A1-20050929-C00128
     67 — 0
    Figure US20050215594A1-20050929-C00129
         		H 1
    Figure US20050215594A1-20050929-C00130
     68 — 0
    Figure US20050215594A1-20050929-C00131
         		H 1
    Figure US20050215594A1-20050929-C00132
     69 — 0
    Figure US20050215594A1-20050929-C00133
         		H 1
    Figure US20050215594A1-20050929-C00134
     70 — 0
    Figure US20050215594A1-20050929-C00135
         		H 1
    Figure US20050215594A1-20050929-C00136
     71 — 0
    Figure US20050215594A1-20050929-C00137
         		H 1
    Figure US20050215594A1-20050929-C00138
     72 — 0
    Figure US20050215594A1-20050929-C00139
         		H 1
    Figure US20050215594A1-20050929-C00140
     73 — 0
    Figure US20050215594A1-20050929-C00141
         		H 1
    Figure US20050215594A1-20050929-C00142
     74 — 0
    Figure US20050215594A1-20050929-C00143
         		H 1
    Figure US20050215594A1-20050929-C00144
     75 — 0
    Figure US20050215594A1-20050929-C00145
         		H 1
    Figure US20050215594A1-20050929-C00146
     76 — 0
    Figure US20050215594A1-20050929-C00147
         		H 1
    Figure US20050215594A1-20050929-C00148
     77 — 0
    Figure US20050215594A1-20050929-C00149
         		H 1
    Figure US20050215594A1-20050929-C00150
     78 — 0
    Figure US20050215594A1-20050929-C00151
         		H 1
    Figure US20050215594A1-20050929-C00152
     79 — 0
    Figure US20050215594A1-20050929-C00153
         		H 1
    Figure US20050215594A1-20050929-C00154
     80 — 0
    Figure US20050215594A1-20050929-C00155
         		H 2
    Figure US20050215594A1-20050929-C00156
     81 — 0
    Figure US20050215594A1-20050929-C00157
         		H 3
    Figure US20050215594A1-20050929-C00158
     82 — 0
    Figure US20050215594A1-20050929-C00159
         		—CO2- t- Bu 1
    Figure US20050215594A1-20050929-C00160
     83 — 0
    Figure US20050215594A1-20050929-C00161
         		H 1
    Figure US20050215594A1-20050929-C00162
     84 6-NH2 1
    Figure US20050215594A1-20050929-C00163
         		H 1
    Figure US20050215594A1-20050929-C00164
     85 — 0 Ph h 1
    Figure US20050215594A1-20050929-C00165
     86 — 0
    Figure US20050215594A1-20050929-C00166
         		—CO2- t- Bu 1
    Figure US20050215594A1-20050929-C00167
     87 — 0
    Figure US20050215594A1-20050929-C00168
         		H 1
    Figure US20050215594A1-20050929-C00169
     88 — 0
    Figure US20050215594A1-20050929-C00170
         		H 1
    Figure US20050215594A1-20050929-C00171
     89 — 0
    Figure US20050215594A1-20050929-C00172
         		H 1
    Figure US20050215594A1-20050929-C00173
     90 — 0
    Figure US20050215594A1-20050929-C00174
         		H 1
    Figure US20050215594A1-20050929-C00175
     91 — 0
    Figure US20050215594A1-20050929-C00176
         		H 1
    Figure US20050215594A1-20050929-C00177
     92 — 0
    Figure US20050215594A1-20050929-C00178
         		H 1
    Figure US20050215594A1-20050929-C00179
     93 — 0
    Figure US20050215594A1-20050929-C00180
         		H 1
    Figure US20050215594A1-20050929-C00181
     94 — 0
    Figure US20050215594A1-20050929-C00182
         		H 1
    Figure US20050215594A1-20050929-C00183
     95 — 0
    Figure US20050215594A1-20050929-C00184
         		H 1
    Figure US20050215594A1-20050929-C00185
     96 — 0
    Figure US20050215594A1-20050929-C00186
         		H 1
    Figure US20050215594A1-20050929-C00187
     97 — 0
    Figure US20050215594A1-20050929-C00188
         		H 1
    Figure US20050215594A1-20050929-C00189
     98 — 0
    Figure US20050215594A1-20050929-C00190
         		H 1
    Figure US20050215594A1-20050929-C00191
     99 — 0
    Figure US20050215594A1-20050929-C00192
         		H 1
    Figure US20050215594A1-20050929-C00193
    100 — 0
    Figure US20050215594A1-20050929-C00194
         		H 1
    Figure US20050215594A1-20050929-C00195
    101 — 0
    Figure US20050215594A1-20050929-C00196
         		H 1
    Figure US20050215594A1-20050929-C00197
    102 — 0
    Figure US20050215594A1-20050929-C00198
         		H 1
    Figure US20050215594A1-20050929-C00199
    103 — 0
    Figure US20050215594A1-20050929-C00200
         		H 1
    Figure US20050215594A1-20050929-C00201
    104 — 0
    Figure US20050215594A1-20050929-C00202
         		H 1
    Figure US20050215594A1-20050929-C00203
    105 — 0
    Figure US20050215594A1-20050929-C00204
         		H 1
    Figure US20050215594A1-20050929-C00205
    106 — 0
    Figure US20050215594A1-20050929-C00206
         		H 1
    Figure US20050215594A1-20050929-C00207
    107 4-OH 1 Ph H 1
    Figure US20050215594A1-20050929-C00208
    108 6-OH 1
    Figure US20050215594A1-20050929-C00209
         		H 1
    Figure US20050215594A1-20050929-C00210
    109 4-CN 1 Ph H 1
    Figure US20050215594A1-20050929-C00211
    110 2-Me 1 Ph H 1
    Figure US20050215594A1-20050929-C00212
    111 3-Et 1 Ph H 1
    Figure US20050215594A1-20050929-C00213
    112 3-CF3 1 Ph H 1
    Figure US20050215594A1-20050929-C00214
    113 3-NH2 1 Ph H 1
    Figure US20050215594A1-20050929-C00215
    114 3-NH—Me 1 Ph H 1
    Figure US20050215594A1-20050929-C00216
    115 3-N(Et)2 1 Ph H 1
    Figure US20050215594A1-20050929-C00217
    116 4-OMe 1 Ph H 1
    Figure US20050215594A1-20050929-C00218
    117 2,3,5,6-tetra-Cl 4 Ph H 1
    Figure US20050215594A1-20050929-C00219
    118 4-OEt 1 Ph H 1
    Figure US20050215594A1-20050929-C00220
    119 4-O-cyc-Pr 1 Ph H 1
    Figure US20050215594A1-20050929-C00221
    120 2,3,4,5,6-penta-F 5 Ph H 1
    Figure US20050215594A1-20050929-C00222
    121 2,4-di-Cl 2 Ph H 1
    Figure US20050215594A1-20050929-C00223
    122 2,4-di-Me 2 Ph H 1
    Figure US20050215594A1-20050929-C00224
    123 2,4-di-Cl 2 Ph —CO2-t- Bu 1
    Figure US20050215594A1-20050929-C00225
    124 2,4,5-tri-Cl 3 Ph H 1
    Figure US20050215594A1-20050929-C00226
    125 3-CONH-i-Bu 1 Ph H 1
    Figure US20050215594A1-20050929-C00227
    126 2,4-di-Me-6-Cl 3 Ph H 1
    Figure US20050215594A1-20050929-C00228
    127
    Figure US20050215594A1-20050929-C00229
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00230
    128 3-NO2 1 Ph H 1
    Figure US20050215594A1-20050929-C00231
    129 2-Cl 1 Ph H 1
    Figure US20050215594A1-20050929-C00232
    130 4-SMe 1 Ph H 1
    Figure US20050215594A1-20050929-C00233
    131 3-SO2Me 1 Ph H 1
    Figure US20050215594A1-20050929-C00234
    132 4-O—C(═O)Me 1 Ph H 1
    Figure US20050215594A1-20050929-C00235
    133 4-C(═O)Me 1 Ph H 1
    Figure US20050215594A1-20050929-C00236
    134 3-CO2H 1 Ph H 1
    Figure US20050215594A1-20050929-C00237
    135 3-NH-SO2Me 1 Ph H 1
    Figure US20050215594A1-20050929-C00238
    136 4-NH-C(═O)Me 1 Ph H 1
    Figure US20050215594A1-20050929-C00239
    137 — 0
    Figure US20050215594A1-20050929-C00240
         		H 1
    Figure US20050215594A1-20050929-C00241
    138 — 0
    Figure US20050215594A1-20050929-C00242
         		H 1
    Figure US20050215594A1-20050929-C00243
    139 — 0
    Figure US20050215594A1-20050929-C00244
         		H 1
    Figure US20050215594A1-20050929-C00245
    140 2-Me 1
    Figure US20050215594A1-20050929-C00246
         		H 1
    Figure US20050215594A1-20050929-C00247
    141 — 0
    Figure US20050215594A1-20050929-C00248
         		H 1
    Figure US20050215594A1-20050929-C00249
    142 — 0
    Figure US20050215594A1-20050929-C00250
         		H 1
    Figure US20050215594A1-20050929-C00251
    143 — 0
    Figure US20050215594A1-20050929-C00252
         		H 1
    Figure US20050215594A1-20050929-C00253
    144 — 0
    Figure US20050215594A1-20050929-C00254
         		H 1
    Figure US20050215594A1-20050929-C00255
    145 — 0
    Figure US20050215594A1-20050929-C00256
         		H 1
    Figure US20050215594A1-20050929-C00257
    146 — 0 Ph CO2- t- Bu 1
    Figure US20050215594A1-20050929-C00258
    147 6-NH2 1
    Figure US20050215594A1-20050929-C00259
         		CO2Me 1
    Figure US20050215594A1-20050929-C00260
    148 — 0 Ph CO NH2 1
    Figure US20050215594A1-20050929-C00261
    149 — 0 Ph Me 1
    Figure US20050215594A1-20050929-C00262
    150 6-NH2 1
    Figure US20050215594A1-20050929-C00263
         		Et 1
    Figure US20050215594A1-20050929-C00264
    151 — 0
    Figure US20050215594A1-20050929-C00265
         		CO Me 1
    Figure US20050215594A1-20050929-C00266
    152 6-NH2 1
    Figure US20050215594A1-20050929-C00267
         		H 1
    Figure US20050215594A1-20050929-C00268
    153 — 0
    Figure US20050215594A1-20050929-C00269
         		H 1
    Figure US20050215594A1-20050929-C00270
    154 — 0
    Figure US20050215594A1-20050929-C00271
         		H 1
    Figure US20050215594A1-20050929-C00272
    155 — 0
    Figure US20050215594A1-20050929-C00273
         		H 1
    Figure US20050215594A1-20050929-C00274
    156 — 0
    Figure US20050215594A1-20050929-C00275
         		H 1
    Figure US20050215594A1-20050929-C00276
    157 — 0
    Figure US20050215594A1-20050929-C00277
         		H 1
    Figure US20050215594A1-20050929-C00278
    158 — 0
    Figure US20050215594A1-20050929-C00279
         		H 1
    Figure US20050215594A1-20050929-C00280
    159 — 0
    Figure US20050215594A1-20050929-C00281
         		H 1
    Figure US20050215594A1-20050929-C00282
    160 — 0
    Figure US20050215594A1-20050929-C00283
         		H 1
    Figure US20050215594A1-20050929-C00284
    161 — 0
    Figure US20050215594A1-20050929-C00285
         		H 1
    Figure US20050215594A1-20050929-C00286
    162 — 0
    Figure US20050215594A1-20050929-C00287
         		H 2
    Figure US20050215594A1-20050929-C00288
    163 — 0
    Figure US20050215594A1-20050929-C00289
         		H 2
    Figure US20050215594A1-20050929-C00290
    164 — 0
    Figure US20050215594A1-20050929-C00291
         		H 1
    Figure US20050215594A1-20050929-C00292
    165 — 0
    Figure US20050215594A1-20050929-C00293
         		H 1
    Figure US20050215594A1-20050929-C00294
    166 — 0
    Figure US20050215594A1-20050929-C00295
         		H 2
    Figure US20050215594A1-20050929-C00296
    167 — 0
    Figure US20050215594A1-20050929-C00297
         		H 1
    Figure US20050215594A1-20050929-C00298
    168 — 0
    Figure US20050215594A1-20050929-C00299
         		H 1
    Figure US20050215594A1-20050929-C00300
    169 — 0
    Figure US20050215594A1-20050929-C00301
         		H 1
    Figure US20050215594A1-20050929-C00302
    170 — 0
    Figure US20050215594A1-20050929-C00303
         		H 1
    Figure US20050215594A1-20050929-C00304
    171 — 0
    Figure US20050215594A1-20050929-C00305
         		H 1
    Figure US20050215594A1-20050929-C00306
    172 — 0
    Figure US20050215594A1-20050929-C00307
         		H 1
    Figure US20050215594A1-20050929-C00308
    173 — 0
    Figure US20050215594A1-20050929-C00309
         		H 1
    Figure US20050215594A1-20050929-C00310
    174 — 0
    Figure US20050215594A1-20050929-C00311
         		H 1
    Figure US20050215594A1-20050929-C00312
    175 — 0
    Figure US20050215594A1-20050929-C00313
         		H 2
    Figure US20050215594A1-20050929-C00314
    176 2-oxo-3-CH3— 2
    Figure US20050215594A1-20050929-C00315
         		H 1
    Figure US20050215594A1-20050929-C00316
    177 — 0
    Figure US20050215594A1-20050929-C00317
         		H 1
    Figure US20050215594A1-20050929-C00318
    178 3,5-Cl2— 2
    Figure US20050215594A1-20050929-C00319
         		H 1
    Figure US20050215594A1-20050929-C00320
    179 4-Ph 1 Ph H 1
    Figure US20050215594A1-20050929-C00321
    180
    Figure US20050215594A1-20050929-C00322
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00323
    181
    Figure US20050215594A1-20050929-C00324
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00325
    182
    Figure US20050215594A1-20050929-C00326
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00327
    183 4-Br 1 Ph H 1
    Figure US20050215594A1-20050929-C00328
    184 3-l 1 Ph H 1
    Figure US20050215594A1-20050929-C00329
    185 3-CF3CF2— 1 Ph H 1
    Figure US20050215594A1-20050929-C00330
    186 4-CH2═CHCH2— 1 Ph H 1
    Figure US20050215594A1-20050929-C00331
    187 4-t-Bu- 1 Ph H 1
    Figure US20050215594A1-20050929-C00332
    188 4-n-hexyl- 1 Ph H 1
    Figure US20050215594A1-20050929-C00333
    189 4-n-docecyl- 1 Ph H 1
    Figure US20050215594A1-20050929-C00334
    190 2-CF3(CH2)3— 1 Ph H 1
    Figure US20050215594A1-20050929-C00335
    191
    Figure US20050215594A1-20050929-C00336
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00337
    192
    Figure US20050215594A1-20050929-C00338
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00339
    193
    Figure US20050215594A1-20050929-C00340
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00341
    194
    Figure US20050215594A1-20050929-C00342
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00343
    195
    Figure US20050215594A1-20050929-C00344
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00345
    196
    Figure US20050215594A1-20050929-C00346
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00347
    197 4-CH3OCH2CH2N(Me)— 1 Ph H 1
    Figure US20050215594A1-20050929-C00348
    198 3-Ph-NH— 1 Ph H 1
    Figure US20050215594A1-20050929-C00349
    199
    Figure US20050215594A1-20050929-C00350
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00351
    200
    Figure US20050215594A1-20050929-C00352
         		1 Ph H 1
    Figure US20050215594A1-20050929-C00353
    201 — 0
    Figure US20050215594A1-20050929-C00354
         		H 1
    Figure US20050215594A1-20050929-C00355
    202 — 0
    Figure US20050215594A1-20050929-C00356
         		H 1
    Figure US20050215594A1-20050929-C00357
    203 — 0
    Figure US20050215594A1-20050929-C00358
         		H 1
    Figure US20050215594A1-20050929-C00359
    204 — 0
    Figure US20050215594A1-20050929-C00360
         		H 1
    Figure US20050215594A1-20050929-C00361
    205 — 0
    Figure US20050215594A1-20050929-C00362
         		H 1
    Figure US20050215594A1-20050929-C00363
    206 — 0
    Figure US20050215594A1-20050929-C00364
         		H 1
    Figure US20050215594A1-20050929-C00365
    207 2-Me 1
    Figure US20050215594A1-20050929-C00366
         		H 1
    Figure US20050215594A1-20050929-C00367
    208 — 0
    Figure US20050215594A1-20050929-C00368
         		H 1
    Figure US20050215594A1-20050929-C00369
    209 — 0
    Figure US20050215594A1-20050929-C00370
         		H 1
    Figure US20050215594A1-20050929-C00371
    210 2-Me 1
    Figure US20050215594A1-20050929-C00372
         		H 1
    Figure US20050215594A1-20050929-C00373
    211 2-Me— 1
    Figure US20050215594A1-20050929-C00374
         		H 1
    Figure US20050215594A1-20050929-C00375
    212 2-Me— 1
    Figure US20050215594A1-20050929-C00376
         		H 1
    Figure US20050215594A1-20050929-C00377
    213 2-Me 1
    Figure US20050215594A1-20050929-C00378
         		H 1
    Figure US20050215594A1-20050929-C00379
    214 — 0
    Figure US20050215594A1-20050929-C00380
         		H 1
    Figure US20050215594A1-20050929-C00381
    215 — 0
    Figure US20050215594A1-20050929-C00382
         		H 1
    Figure US20050215594A1-20050929-C00383
    216 — 0
    Figure US20050215594A1-20050929-C00384
         		H 1
    Figure US20050215594A1-20050929-C00385
    217 — 0
    Figure US20050215594A1-20050929-C00386
         		H 1
    Figure US20050215594A1-20050929-C00387
    218 — 0
    Figure US20050215594A1-20050929-C00388
         		H 1
    Figure US20050215594A1-20050929-C00389
    219 5-Me 1
    Figure US20050215594A1-20050929-C00390
         		H 1
    Figure US20050215594A1-20050929-C00391
    220 — 0
    Figure US20050215594A1-20050929-C00392
         		H 1
    Figure US20050215594A1-20050929-C00393
    221 — 0
    Figure US20050215594A1-20050929-C00394
         		H 1
    Figure US20050215594A1-20050929-C00395
    222 — 0
    Figure US20050215594A1-20050929-C00396
         		H 1
    Figure US20050215594A1-20050929-C00397
    223 5-Me— 1
    Figure US20050215594A1-20050929-C00398
         		H 1
    Figure US20050215594A1-20050929-C00399
    224 5-Me— 1
    Figure US20050215594A1-20050929-C00400
         		H 1
    Figure US20050215594A1-20050929-C00401
    225 — 0
    Figure US20050215594A1-20050929-C00402
         		H 1
    Figure US20050215594A1-20050929-C00403
    226 — 0
    Figure US20050215594A1-20050929-C00404
         		H 1
    Figure US20050215594A1-20050929-C00405
    227 — 0
    Figure US20050215594A1-20050929-C00406
         		H 1
    Figure US20050215594A1-20050929-C00407
    228 — 0
    Figure US20050215594A1-20050929-C00408
         		H 1
    Figure US20050215594A1-20050929-C00409
    229 — 0
    Figure US20050215594A1-20050929-C00410
         		H 1
    Figure US20050215594A1-20050929-C00411
    230 — 0
    Figure US20050215594A1-20050929-C00412
         		H 1
    Figure US20050215594A1-20050929-C00413
    231 5-Me 1
    Figure US20050215594A1-20050929-C00414
         		H 1
    Figure US20050215594A1-20050929-C00415
    232 — 0
    Figure US20050215594A1-20050929-C00416
         		H 1
    Figure US20050215594A1-20050929-C00417
    233 — 0
    Figure US20050215594A1-20050929-C00418
         		H 1
    Figure US20050215594A1-20050929-C00419
    234 — 0
    Figure US20050215594A1-20050929-C00420
         		H 1
    Figure US20050215594A1-20050929-C00421
    235 — 0
    Figure US20050215594A1-20050929-C00422
         		H 1
    Figure US20050215594A1-20050929-C00423
    236 — 0
    Figure US20050215594A1-20050929-C00424
         		H 1
    Figure US20050215594A1-20050929-C00425
    237 — 0
    Figure US20050215594A1-20050929-C00426
         		H 1
    Figure US20050215594A1-20050929-C00427
    238 — 0
    Figure US20050215594A1-20050929-C00428
         		H 1
    Figure US20050215594A1-20050929-C00429
    239 — 0
    Figure US20050215594A1-20050929-C00430
         		H 1
    Figure US20050215594A1-20050929-C00431
    240 H 0
    Figure US20050215594A1-20050929-C00432
         		H 1
    Figure US20050215594A1-20050929-C00433
    241 3-Me 1
    Figure US20050215594A1-20050929-C00434
         		H 1
    Figure US20050215594A1-20050929-C00435
    242 — 0
    Figure US20050215594A1-20050929-C00436
         		H 1
    Figure US20050215594A1-20050929-C00437
    243 — 0
    Figure US20050215594A1-20050929-C00438
         		H 1
    Figure US20050215594A1-20050929-C00439
    244 — 0
    Figure US20050215594A1-20050929-C00440
         		H 1
    Figure US20050215594A1-20050929-C00441
    245 3-Me 1
    Figure US20050215594A1-20050929-C00442
         		H 1
    Figure US20050215594A1-20050929-C00443
    246 — 0
    Figure US20050215594A1-20050929-C00444
         		H 1
    Figure US20050215594A1-20050929-C00445
    247 3-Me 1
    Figure US20050215594A1-20050929-C00446
         		H 1
    Figure US20050215594A1-20050929-C00447
    248 3-Me 1
    Figure US20050215594A1-20050929-C00448
         		H 1
    Figure US20050215594A1-20050929-C00449
    249 6-NH2 1
    Figure US20050215594A1-20050929-C00450
         		H 1
    Figure US20050215594A1-20050929-C00451
    250 6-NH2 1
    Figure US20050215594A1-20050929-C00452
         		H 1
    Figure US20050215594A1-20050929-C00453
    251 6-NH2 1
    Figure US20050215594A1-20050929-C00454
         		H 2
    Figure US20050215594A1-20050929-C00455
    252 2-NH2 1
    Figure US20050215594A1-20050929-C00456
         		H 1
    Figure US20050215594A1-20050929-C00457
    253 2-NH2 1
    Figure US20050215594A1-20050929-C00458
         		H 1
    Figure US20050215594A1-20050929-C00459
    254 2-NH2 1
    Figure US20050215594A1-20050929-C00460
         		H 1
    Figure US20050215594A1-20050929-C00461
    255 2-NH2 1
    Figure US20050215594A1-20050929-C00462
         		H 1
    Figure US20050215594A1-20050929-C00463
    256 2-NH2 1
    Figure US20050215594A1-20050929-C00464
         		H 2
    Figure US20050215594A1-20050929-C00465
    257 2-NH2 1
    Figure US20050215594A1-20050929-C00466
         		H 2
    Figure US20050215594A1-20050929-C00467
    258 4-NH2 1
    Figure US20050215594A1-20050929-C00468
         		H 1
    Figure US20050215594A1-20050929-C00469
    259 4-NH2 1
    Figure US20050215594A1-20050929-C00470
         		H 1
    Figure US20050215594A1-20050929-C00471
    260 4-NH2 1
    Figure US20050215594A1-20050929-C00472
         		H 1
    Figure US20050215594A1-20050929-C00473
    261 4-NH2 1
    Figure US20050215594A1-20050929-C00474
         		H 2
    Figure US20050215594A1-20050929-C00475
    262 4-NH2 1
    Figure US20050215594A1-20050929-C00476
         		H 2
    Figure US20050215594A1-20050929-C00477
    263 4-NH2 1
    Figure US20050215594A1-20050929-C00478
         		H 2
    Figure US20050215594A1-20050929-C00479
    264 — 0
    Figure US20050215594A1-20050929-C00480
         		H 1
    Figure US20050215594A1-20050929-C00481
    265 — 0
    Figure US20050215594A1-20050929-C00482
         		H 1
    Figure US20050215594A1-20050929-C00483
    266 — 0
    Figure US20050215594A1-20050929-C00484
         		H 1
    Figure US20050215594A1-20050929-C00485
    267 — 0
    Figure US20050215594A1-20050929-C00486
         		H 1
    Figure US20050215594A1-20050929-C00487
    268 — 0
    Figure US20050215594A1-20050929-C00488
         		H 1
    Figure US20050215594A1-20050929-C00489
    269 — 0
    Figure US20050215594A1-20050929-C00490
         		H 1
    Figure US20050215594A1-20050929-C00491
    270 — 0
    Figure US20050215594A1-20050929-C00492
         		H 1
    Figure US20050215594A1-20050929-C00493
    271 — 0
    Figure US20050215594A1-20050929-C00494
         		H 1
    Figure US20050215594A1-20050929-C00495
    272 — 0
    Figure US20050215594A1-20050929-C00496
         		H 1
    Figure US20050215594A1-20050929-C00497
    273 — 0
    Figure US20050215594A1-20050929-C00498
         		H 1
    Figure US20050215594A1-20050929-C00499
    274 — 0
    Figure US20050215594A1-20050929-C00500
         		H 2
    Figure US20050215594A1-20050929-C00501
    275 — 0
    Figure US20050215594A1-20050929-C00502
         		H 2
    Figure US20050215594A1-20050929-C00503
    276 — 0
    Figure US20050215594A1-20050929-C00504
         		H 2
    Figure US20050215594A1-20050929-C00505
    277 — 0
    Figure US20050215594A1-20050929-C00506
         		H 1
    Figure US20050215594A1-20050929-C00507
    278 — 0
    Figure US20050215594A1-20050929-C00508
         		H 2
    Figure US20050215594A1-20050929-C00509
    279 — 0
    Figure US20050215594A1-20050929-C00510
         		H 1
    Figure US20050215594A1-20050929-C00511
    280 — 0
    Figure US20050215594A1-20050929-C00512
         		H 2
    Figure US20050215594A1-20050929-C00513
  • The present invention includes compounds of Formula I wherein Y is halo; R6; SR1; S(O)b-phenyl-CO2R1; or phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR2, halo, NO2, OR1, R1, SR1, SO2NR1R7, NR1R1, C1-C10COR2, phenyl, or tetrazolo.
  • Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR2, halo, NO2, OR1, R1, SR1, SO2NR1R7, NR1R1, C1-C10COR2, phenyl, or tetrazolo; and d is 1 or 2.
  • Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR2, halo, NO2, OR1, R1, SR1, SO2NR1R7, NR1R1, C1-C10COR2, phenyl, or tetrazolo; d is 1 or 2; and Ar is phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N; or a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to phenyl.
  • Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR2 halo, OR1, R1 or NR1R1; d is 1; Ar is phenyl or a 5- or 6-membered heterocycle containing one or more N atoms; and a is 0, 1, 2, or 3.
  • In addition, the present invention specifically includes the following compounds:
    • 2-[4-(ethoxycarbonyl)phenoxy]-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 197);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutylbenzoic acid (Example 211);
    • N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-2-methylbenzenesulfonamide (Example 91);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutoxybenzoic acid (Example 183);
    • N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-4-methoxybenzenesulfonamide (Example 92);
    • N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-1-propanesulfonamide (Example 97);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxybenzoyl)benzenesulfonamide (Example 300);
    • N-(2-cyano-4-nitrophenyl)-3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 259);
    • 2-(4-chlorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 194);
    • N-(4,6-dimethoxy-2-pyrimidinyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluoromethoxy)benzenesulfonamide (Example 274);
    • 2-(4-fluorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 193);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3-methoxybenzoyl)benzenesulfonamide (Example 293);
    • 4-fluoro-N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}benzenesulfonamide (Example 295);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(4-methylphenoxy)benzoic acid (Example 195);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(2-phenylethyl)benzoic acid (Example 213);
    • 3-chloro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 124);
    • N-(4-fluorobenzoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 295);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methoxybenzoic acid (Example 125);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-phenoxybenzoic acid (Example 192);
    • N-(4-cyanophenyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluoromethoxy)benzenesulfonamide (Example 262);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxy-6-methyl-2-pyrimidinyl)-2-(trifluoromethoxy)benzenesulfonamide (Example 275);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3,3,3-trifluoropropanoyl)benzenesulfonamide (Example 284);
    • 2-hydroxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-15 chromen-6-yl]benzoic acid (Example 180);
    • 3-((1R)-2-{[((2R)-6-{4-[({[(4-fluorophenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1-hydroxyethyl)pyridine (Example 327);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide (Example 249);
    • N-benzoyl-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 294);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-propoxybenzoic acid (Example 186);
    • N-({4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinyl}carbonyl)-4-methoxybenzenesulfonamide (Example 80);
    • 3-((1R)-1-hydroxy-2-{[((2R)-6-{4-[({[(4-methylphenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}ethyl)pyridine (Example 326);
    • 3-((1R)-2-{[((2R)-6-{4-[({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1-hydroxyethyl)pyridine (Example 330);
    • N-(ethoxyacetyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 286);
    • N-(3,3-dimethylbutanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 287);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methyl-2-pyrimidinyl)benzenesulfonamide (Example 268);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-[4-(methylsulfonyl)phenoxy]benzoic acid (Example 198);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methylbenzoic acid (Example 88);
    • 4-{2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid (Example 215);
    • N-(2,2-dimethylpropanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 292);
    • 3-[(1R)-2-({[(2R)-6-(4-{[(anilinocarbonyl)amino]sulfonyl}phenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-hydroxyethyl]pyridine (Example 328);
    • 2-ethoxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 185);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxy-6-methyl-2-pyrimidinyl)benzenesulfonamide (Example 273);
    • 3-{(1R)-2-[({(2R)-6-[4-({[(cyclohexylamino)carbonyl]amino}sulfonyl)phenyl]-3,4-dihydro-2H-chromen-2-yl}methyl)amino]-1-hydroxyethyl}pyridine (Example 329);
    • N-(cyclopropylcarbonyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 285);
    • 2-chloro-5-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 122);
    • 4-[(4-[R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 148);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-methylbenzoic acid (Example 149);
    • 2-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 150);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-propoxybenzoic acid (Example 130);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isopropoxybenzoic acid (Example 188);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(1,3-thiazol-2-yl)benzenesulfonamide (Example 265);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(4-methoxyphenoxy)benzoic acid (Example 196);
    • 3-(cyclopropylmethoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 132);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 325);
    • 5-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-4′-methyl-1,1′-biphenyl-2-carboxylic acid (Example 205);
    • N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide (Example 319);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3-pyridinyl)benzenesulfonamide (Example 253);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-methoxybenzoic acid (Example 184);
    • 4-chloro-N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide (Example 320);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-isobutoxybenzoic acid (Example 133);
    • N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}methanesulfonamide (Example 321);
    • 3-{2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid (Example 216);
    • 3-[(1E)-1-hexenyl]-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 128);
    • 3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide (Example 261);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(2-methoxyethoxy)benzoic acid (Example 187);
    • 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2,6-dimethylbenzoic acid (Example 121);
    • 4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 385);
    • 3-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 386);
    • (1R)-1-(6-amino-3-pyridinyl)-2-[({(2R)-6-[4-(1H-tetraazol-5-yl)phenyl]-3,4-dihydro-2H-chromen-2-yl}methyl)amino]ethanol (Example 384);
    • 5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-3-phenyl-1,2I5,3I5,4-thiatriazole-2-carboxylic acid (Example 166);
    • 5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-furoic acid (Example 159);
    • 5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid (Example 154);
    • 5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-3-thiophenecarboxylic acid (Example 156);
    • 4-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid (Example 157);
    • 6-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]nicotinic acid (Example 151);
    • 5-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]nicotinic acid (Example 142);
    • 2-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-4-pyridinecarboxylic acid (Example 158);
    • 1-({[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]carbonyl}amino)cyclopropanecarboxylic acid (Example 366); and
    • 4-[(2R)-2-({[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 344).
  • Representative salts of the compounds of Formula I include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • The esters in the present invention are non-toxic, pharmaceutically acceptable esters such as alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl-C1-C5 alkyl may be used, although methyl ester is preferred. The compound of Formula I may be esterified by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the Formula I compound. The appropriate anhydride is reacted with the alcohol in the presence of an acylation catalyst such as 1,8-bis[dimethylamino]naphthalene or N,N-dimethylaminopyridine. An appropriate carboxylic acid may be reacted with the alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and optionally, an acylation catalyst. Esterification may also be reached using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and optionally, pyridine, or in the presence of N,N-carbonyldiimidazole with pyridine. Reaction of an acid chloride with the alcohol may be carried out with an acylation catalyst such as 4-DMAP or pyridine.
  • Sensitive or reactive groups on the compound of Formula I may need to be protected during any of the above methods for forming esters, and protecting groups may be added and removed by conventional methods well known in the art.
  • One skilled in the art would readily know how to successfully carry out these as well as other methods of esterification of alcohols.
  • The compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R,S) configuration, preferably in the (R)- or (S)-configuration, whichever is most active. The configurational isomers of Formula I, in which both the hydroxyl group attached to the side chain containing the Ar—X— moiety and the (CH2)d group attached to the dihydrochromenyl ring are above the plane, as depicted below, are preferred.
    Figure US20050215594A1-20050929-C00514
  • All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this invention are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art.
  • Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (=Z-) or trans (=E-) form, and both isomeric forms are encompassed within the scope of this invention.
  • The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific Ar and Y moieties and the specific substituents on the various moieties, all play a role in the path to be followed in the preparation of the specific compounds of this invention. These factors are readily recognized by one of ordinary skill in the art.
  • For synthesis of any particular compound, one skilled in the art will recognize that the use of protecting groups may be required for the synthesis of compounds containing certain substituents. A description of suitable protecting groups and appropriate methods of adding and removing such groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991. For example, after preparation of a compound according to Reaction Scheme 1, in order to enable purification of the end product by, for example, flash chromatography, compounds of Formula I wherein R3 is H, may be selectively protected, for example, as a carbamate derivative obtained by, for example, treatment with a reagent such as di-tert-butyl dicarbonate or other means known in the art. After purification, the carbamate group can easily be removed by treatment with an acid such as HCI or trifluoroacetic acid by means known in the art.
  • In the Reaction Schemes below, one skilled in the art will recognize that reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents. When specific reagents or solvents are shown in a Reaction Scheme, therefore, they are meant to be illustrative examples of conditions desirable for the execution of that particular Reaction Scheme. Abbreviations not identified in accompanying text are listed later in this disclosure under “Abbreviations and Acronyms.”
  • General Methods of Preparation of Formula I Compounds
  • In general, Formula I compounds may be prepared by standard techniques known in the art and by known processes analogous thereto. In particular, three such standard methods may be used, the selection of which may be based, among other considerations, upon the availability of the required individual starting materials. These three methods are illustrated in Reaction Schemes 1, 2, and 3 below.
  • The compounds of Formula I where each variable may be any moiety within that variable's definition may be synthesized according to Reaction Scheme 1 wherein an appropriate epoxide 1a or chlorohydrin 1b (preparation of 1a is described in WO 99/32475) is coupled with the appropriate amine 2 (preparation of 2 is described below in Reaction Schemes 12, 13, and 14). This reaction of Reaction Scheme 1 is typically carried out in an aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, or in an alcohol such as ethanol, isopropanol, or propanol at temperature from about −10° C. to reflux. Compounds in which R3 is other than hydrogen may be prepared by reaction of compound I in which R3 is H, by selective N-alkylation of N-acylation reactions with known compounds of formula R3-halo (where R3 is acyl or alkyl) or [R3]2O (where R3 is acyl). Protection of the hydroxyl group, for example as a TBDMS ether, may be required prior to N-alkylation reactions; O-deprotection is carried out under standard conditions well known in the art.
    Figure US20050215594A1-20050929-C00515
  • Alternatively, Formula I compounds, where each variable may be any moiety within that variables definition, except that d=1, may be prepared by a reductive amination as shown in Reaction Scheme 2. Reaction of an aldehyde of Formula 4 (preparation described below in Reaction Scheme 9) with an amino alcohol of Formula 3 (preparation described in WO 98/32475) followed by reduction gives the desired transformation to Formula Ia compounds. Compounds in which R3 is other than hydrogen may be prepared by reaction of compound Ia in which R3 is H by selective N-alkylation or N-acylation reactions with known compounds of formula R3-halo (where R3 is alkyl or acyl) or [R3]2O (where R3 is acyl). Protection of the hydroxyl group, for example, as a TBDMS ether, may be required prior to N-alkylation reactions. O-deprotection is carried out under standard conditions well known in the art.
    Figure US20050215594A1-20050929-C00516
  • A third general route to Formula I compounds, where each variable may be any moiety within that variable's definition except that d=1, is shown in Reaction Scheme 3. An amino alcohol 3 and a carboxylic acid 5 (preparation described in Reaction Schemes 10 and 11) are coupled to provide an amide of Formula 6. Reduction of the Formula 6 amides with an appropriate reagent such as borane-dimethylsulfide complex provides the Formula I compounds where R3 is H. Formula I compounds in which R3 is other than H may be similarly prepared as described above for Reaction Schemes 1 and 2.
    Figure US20050215594A1-20050929-C00517
  • Reaction Scheme 4 shows that compounds of Formula I or Formula Ia where Y is any alkenyl, cycloalkenyl, phenyl, or a 5-or 6-membered heterocyclic ring may be prepared from compounds of Formula I or Formula Ia where Y is a halogen, using the following additional methods described below. For example, a compound of Formula I, wherein Y is iodo, may be prepared by Reaction Scheme 1 using corresponding starting materials 2 or 4, where Y is iodo, each of which may be prepared by Reaction Schemes 12 or 9, respectively. The resulting Formula I compound is then protected by standard methods to give a compound of Formula 7a. The compound of Formula 7a is then converted to the boronic ester 8, which is then subjected to Suzuki coupling reactions with a halo-Y compound, in which Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5-or 6-membered heterocycle to provide Formula 7 compounds as shown in Reaction Scheme 4. Deprotection of Formula 7 compounds by acid or fluoride-catalyzed hydrolysis provides the corresponding Formula I compounds.
    Figure US20050215594A1-20050929-C00518
  • The coupling may also be performed in the reverse manner, that is, a boronic ester derivative 10 prepared from a halophenyl compound 9 may be added to the iodo compound of Formula 7b, as shown in Reaction Scheme 5 to give Formula Ib compounds.
    Figure US20050215594A1-20050929-C00519
  • Formula I compounds in which Y is an aryl group further substituted by a S(O)bR2 or NHS(O)bR2 group may be prepared by elaboration of the corresponding Formula 7 compounds in which Y is an aryl group substituted by CO2H as shown in Reaction Scheme 6.
    Figure US20050215594A1-20050929-C00520
  • Formula I compounds wherein Y is
    Figure US20050215594A1-20050929-C00521
    and R1 and R4 are as described above, may be prepared by a sequence shown in Reaction Scheme 7. The iodo compound of Formula 7a may be converted to the carboxylic acid of Formula 7c by palladium-catalyzed carboxylation. This may then be coupled with an amino acid using standard peptide synthesis techniques, deprotected and hydrolyzed to give compounds of Formula Ic. This method may be repeated to give Formula I compounds where Y is
    Figure US20050215594A1-20050929-C00522
    by an analogous sequence of reactions performed on the Formula Ic compounds.
    Figure US20050215594A1-20050929-C00523
  • Formula Id compounds of Reaction Scheme 8 may be prepared according to Reaction Scheme 1 or 3, starting from the known Formula 5 compound (U.S. Pat. No. 6,051,586) in which Y=NO2. Other Formula I compounds wherein Y is NR1R1 may be prepared from the nitro compound of Formula Id by reduction to Ie followed by dialkylation with the appropriate alkylating agents, such as R1-halo, R1-OTs, or R1-OMs to If (Reaction Scheme7).
    Figure US20050215594A1-20050929-C00524
  • Reaction Scheme 9 shows how other Formula I compounds in which Y is S(O)bPh-CO2R1 and b is 0 may be prepared by diazotization of Ie and nucleophilic displacement with a arylthiol to give arylthioethers of Formula Ih. Oxidation of the Formula Ih compound with mCPBA or Oxone® gives the Formula Ii compound in which Y is —S(O)bPh—CO2R1 and b=1 or the Formula Ij compound in which Y is —S(O)bPh—CO2R1 and b=2, depending on the number of equivalents of oxidant used in the reaction.
  • Formula I compounds in which Y is SR1 may be similarly prepared by methods analogous to Reaction Scheme 9, by substituting HSR1 in place of the arylthiol in the first step.
    Figure US20050215594A1-20050929-C00525
  • The salts and esters of the Formula I compounds of the invention may be readily prepared by conventional chemical processes.
  • General Method of Preparation of Intermediates
  • The starting materials required to carry out the above described reactions (e.g., epoxides 1a, chlorohydrins 1b, amines 2, amino alcohols 3, aldehydes 4, and carboxylic acids 5) are in many cases commercially available or may be readily prepared by methods known to those skilled in the art. The following routes are exemplary of such methods, but are not intended to be limiting in any way.
  • The epoxides 1a of Reaction Scheme 1 are commercially available or may be prepared according to one of the many procedures described in the literature known to those skilled in the art. For example, as described in WO 99/32475, the epoxides of formula 1a may be prepared by the reaction of an aryl methyl ketone with a selective halogenating agent such as NBS, followed by ketone reduction with, for example, sodium borohydride to a give a chlorohydrin 1b (a halo alcohol). Base-catalyzed cyclization of this alcohol with, for example, potassium carbonate, gives the epoxides of formula 1a. This method is general for the conversion of substituted methyl aryl ketones of general formula (R)a—Ar—C(═O)CH3 to the corresponding epoxides of formula 1a.
  • The amino alcohols 3 may be prepared by ring opening of the epoxides 1a with a nitrogen nucleophile, such as phthalimide, in the presence of a base to form an intermediate which may be cleaved or hydrolyzed as described in WO 98/32475. This sequence is general for conversion of epoxides of formula 1a to the amino alcohols of formula 3.
  • Synthesis of aldehyde starting materials of Formula 4 may be accomplished from the carboxylic acid of Formula 5 by reduction with borane followed by oxidation, for example, under Swern conditions as shown in Reaction Scheme 10. This method is compatible with a wide variety of Y groups, although in some cases, a protecting group may also be employed and removed in a subsequent step.
    Figure US20050215594A1-20050929-C00526
  • The carboxylic acids of Formula 5 are generally available from the known unsubstituted chroman carboxylic acid 5a (WO 99/32476) by various aromatic substitution reactions at the 6-position of the chroman ring and further elaboration of these products. For example, halogenation (e.g., iodination) of 5a gives the 6-iodo compound 5b and nitration gives predominantly the 6-nitro analog 5c (U.S. Pat. No. 6,051,586) as shown in Reaction Scheme 11.
    Figure US20050215594A1-20050929-C00527
  • Compounds of Formula 5 where Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5- or 6-membered heterocycle may be prepared by Suzuki coupling of a halo-Y group to an iodo chroman boronic ester 12 prepared from the iodo chroman acid 5b.
    Figure US20050215594A1-20050929-C00528
  • The amine starting materials of Formula 2, in which d=1, are generally available by standard methods involving conversion of a carboxylic acid 5 to an amide of Formula 13. Reduction with borane or further conversion of the Formula 13 amide to the nitrile of Formula 14 and then reduction by hydrogenation gives the desired Formula 2a compounds. This sequence is shown in Reaction Scheme 13 for Formula 2 amines wherein d=1 and R3 is H. Formula 2 amines in which R3 is other than H may be prepared by standard alkylation or acylation methods known in the art.
    Figure US20050215594A1-20050929-C00529
  • Formula 2 amines in which d is 2 or 3 may be prepared by standard homologation sequences of a variety of known intermediates where d=1. For example, aldehydes of Formula 4 can undergo an alkyl chain extension according to well known procedures such as that described by Wittig et al., (Chem. Ber., 2514, 1962) and the process may be repeated in order to prepare the acetic and propionic acid homologues of Formula 5 by a method analogous to Reaction Scheme 13, to provide a variety of Formula 2 amines in which d=2 or 3.
  • Formula 2 amines in which Y is other than hydrogen or halo may be prepared by palladium-catalyzed coupling reactions on the N-protected amine of Formula 15a followed by deprotection, as shown in Reaction Scheme 14. Formula 2 amines prepared in this way in which the Y group is substituted by an acid, ester, alcohol, ketone, sulfide, or nitro group may provide additional Formula 2 amines by manipulation of those functional groups by directed hydrolysis, esterification, reduction, oxidation, or reduction reactions of the Y group.
    Figure US20050215594A1-20050929-C00530
  • Similarly, the amine 2c, after protection, may be directly substituted at the 6-position of the chroman under Friedel-Crafts alkylation conditions to provide the compounds of Formula 15 in which Y is any alkyl or cycloalkyl group. An example of this where Y is an optionally substituted alkanoic acid group (15c) is shown in Reaction Scheme 15.
    Figure US20050215594A1-20050929-C00531
  • Alcohol intermediates of Formula 11 in which Y is other than hydrogen or halo may also be prepared from the iodo alcohol 11a by the previously described Suzuki coupling methodology as shown in Reaction Scheme 16. This may be accomplished either directly or via a 4-step sequence involving protection of the alcohol to 16a, for example, as a t-butyldimethylsilyl ether, conversion of the iodide to the boronic ester, Suzuki coupling to 16, and finally deprotection to 11.
    Figure US20050215594A1-20050929-C00532
  • The halo-Y compounds used in Reaction Schemes 12, 14, and 16 where halo is iodo, chloro, or bromo and Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5- or 6-membered heterocycle, are either commercially available or synthesized by standard methods known to those skilled in the art. One such standard method is direct halogenation of compounds of formula H—Y which are either commercially available or known in the art. Other methods include the functional group conversion of HO—Y or H2N—Y compounds to halo-Y or TfO—Y compounds by standard substitution methods.
  • Particular illustrations of this are the preparation of halo-Y compounds of Formula 9b or 9c, where Y represents an oxazole or a thiazole, prepared by direct halogenation of the unsubstituted compound or by diazotization of a corresponding amino group as shown in Reaction Scheme 17.
    Figure US20050215594A1-20050929-C00533
  • The heterocyclic intermediates 17 and 18 used to prepare 9b and 9c are accessible by standard methods from acyclic materials. Three examples of such heterocycles are shown in Reaction Schemes 18, 19, and 20.
    Figure US20050215594A1-20050929-C00534
    Figure US20050215594A1-20050929-C00535
    Figure US20050215594A1-20050929-C00536
  • Using a combination of the above Reaction Schemes and the knowledge of one skilled in the art, all of compounds of Formula I may be prepared.
  • The following specific examples are presented to further illustrate the invention described herein, but they are not intended nor should they be construed to limit the scope of the invention in any way.
  • Abbreviations and Acronyms
  • When the following abbreviations are used herein, they have the following meaning:
    • Ac2O acetic anhydride
    • anhy anhydrous
    • BH3 borane
    • BOC tert-butyloxycarbonyl
    • BTMAICl2 benzyltrimethylammonium dichloriodate
    • n-BuLi n-butyllithium
    • t-BuLi t-butyllithium
    • Cbz benzyloxycarbonyl
    • CDI carbonyldiimidazole
    • Celite® diatomaceous earth filter agent, ®Celite Corp.
    • CI-MS chemical ionization mass spectroscopy
    • conc. concentrated
    • mCPBA 3-chloroperoxybenzoic acid
    • dec. decomposition
    • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
    • DMAP 4-dimethylaminopyridine
    • DME dimethoxyethane
    • DMF N,N-dimethylformamide
    • DMSO dimethylsulfoxide
    • EDCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
    • EtOAc ethyl acetate
    • EtOH ethanol (100%)
    • Et2O diethyl ether
    • Et3N triethylamine
    • HPLC ES-MS high performance liquid chromatography-electrospray mass spectroscopy
    • HOBT 1-hydroxybenzotriazole hydrate
    • KOtBu potassium tert-butoxide
    • LiAlH4 lithium aluminum hydride
    • LiBH4 lithium borohydride
    • LiHMDS lithium bis(trimethylsilyl)amide
    • MeOH methanol
    • MSTFA N-methyl-N-(trimethylsilyl)trifluoroacetamide
    • NaBH4 sodium borohydride
    • Na(OAc)3BH sodium triacetoxyborohydride
    • NMM 4-methylmorpholine
    • Oxone® potassium peroxymonosulfate, ®E.I. du Pont de Nemours & Co., Inc.Corp.
    • Ph3P triphenylphosphine
    • Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
    • Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)
    • Pd(OAc)2 palladium acetate
    • rt room temperature
    • TBAF tetrabutylammonium fluoride
    • TBDMS tert-butyldimethylsilyl
    • TBDMSCl tert-butyldimethylsilyl chloride
    • TBDMSOTf tert-butyldimethylsilyl trifluoromethanesulfonate
    • THF tetrahydrofuran
    • TFA trifluoroacetic acid
    • TLC thin layer chromatography
    • Tf trifluoroacetyl
      General Experimental Procedures
  • HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro C18 2.0 mm×23 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes was used on the HPLC. Buffer A was 98% water, 2% Acetonitrile, and 0.02% TFA. Buffer B was 98% Acetonitrile, 2% water, and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source.
  • Combinatorial/parallel reactions were carried out in 8-mL glass vials with Teflon-lined screw caps, or in a polypropylene reaction block consisting of a 8×12 matrix of ninety-six 2.0-mL reaction wells, with each reaction well incorporating a 15-45 micron polyethylene frit. Reaction blocks of this type are commercially available as FlexChem™ reactor blocks from Robbins Scientific Corporation, Sunnyvale, Calif. The reactor blocks are sealed with rubber gaskets and a clamping device, and can be heated with mixing by rotation in an oven (Robbins Scientific).
    • EXAMPLE 1
  • Method A. Preparation of Racemic 2-chloro-1-(3-pyridinyl)ethanol
    Figure US20050215594A1-20050929-C00537
  • Sodium borohydride (198 mg, 5.2 mmol) was added to a 0° C. suspension of 2-chloro-1-(3-pyridinyl)ethanone hydrochloride (500 mg, 2.6 mmol) in ethanol (13 mL). After stirring at 0° C. for 1 hour, the reaction was adjusted to pH 5 with 1 N aqueous HCl. The solution was concentrated in vacuo to remove ethanol, and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried (Na2SO4), and concentrated to provide the title compound as a crude material that was used directly in following steps: 1H NMR (CDCl3) δ 8.54 (s, 1 H), 8.48 (d, J=6.2 Hz, 1 H), 7.76 (d, J=7.9 Hz, 1 H), 7.32-7.28 (m, 1 H), 4.95-4.91 (m, 1 H), 3.75-3.62 (m, 2 H).
    Method B: Preparation of (1R)-2-chloro-1-(3-pyridinyl)ethanol
    Figure US20050215594A1-20050929-C00538
  • To a cold (ice bath) solution of 3-(2-chloroacetyl)pyridine hydrochloride (120 g, 624 mmol) in 500 mL of H2O, was added NaHCO3 (52.8 g, 624 mmol) slowly. After addition, 500 mL of CH2Cl2 was added, and this mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was washed with CH2Cl2 (2×150 mL). The combined organic layers were dried over anhydrous Na2SO4, the solids removed by filtration, and solvent removed in vacuo at room temperature. Anhydrous THF (600 mL) was added to the residue, and the resulting solution of this crude chloroketone was kept cold (dry ice) under Ar, until used as described below.
  • In an oven-dried 5 L round bottom flask, a solution of (R)-(+)-2-(α,α)-diphenylprolinol (7.8 g, 31.2 mmol) in 600 mL anhydrous THF was stirred at room temperature under Ar and to it, was added B(OCH3)3 (4.8 mL, 42 mmol), and the solution was stirred at room temperature for one hour. BH3S(CH3)2 2M/THF (624 mL, 1.25 mol) was then added. After the solution was stirred at room temperature for 20 minutes, the cold chloroketone THF solution was then slowly added at a rate of 30 mL/hour at room temperature. After the addition, HPLC analysis showed the reaction was complete providing 97% for the desired enantiomer of chlorohydrin. MeOH (200 mL) was added slowly and solution was maintained at a temperature below 20° C. The reaction mixture was concentrated in vacuo below 40° C. The product was used without further purification.
    • EXAMPLE 2 Preparation of (2R)-3,4-dihydro-2H-chromene-2-carboxamide
  • Figure US20050215594A1-20050929-C00539
  • To a solution of (2R)-3,4-dihydro-2H-chromene-2-carboxylic acid (WO 99/32476) (17.8 g, 0.1 mol) in anhydrous dichloromethane (170 mL), cooled in an ice-water bath containing 4 drops of N,N-dimethylformamide, were added oxalyl chloride (13.4 mL, 0.16 mol) via a syringe in 10 minutes under argon. The resulting mixture was then stirred at room temperature for 15 hours. Solvent was removed in vacuo to afford the acid chloride cleanly: 1H NMR (CDCl3, δ): 2.31-2.51 (m, 2H), 2.72-2.91 (m, 2H), 5.01 (t, J=4.2 Hz, 1H), 7.04-7.06 (t, J=8.7 Hz, 2H), 7.03-7.06 (d, J=6.9 Hz, 1H); 7.13-7.18 (t, J=8.1 Hz, 1H).
  • To a 2-L 3-necked round-bottomed flask containing ethyl acetate (633 mL) and ammonium hydroxide (158.2 mL), cooled in an ice-water bath with vigorous stirring, was added a solution of the above acid chloride in ethyl acetate (159 mL) dropwise in 15 minutes. The reaction mixture was stirred for additional 20 minutes. The organic layer was separated and washed with water (200 mL), brine (200 mL), and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded the chroman amide as a white solid (16.9 g, 95% yield): 1H NMR (CDCl3, δ): 2.01-2.14 (m, 1H), 2.37-2.46 (m, 1H), 2.75-2.95 (m, 2H), 4.53-4.57 (dd, J=9.3, 2.7 Hz, 1H), 5.75 (s, broad, 1H), 6.60 (s, broad, 1H), 6.86-6.93 (m, 2H); 7.07-7.16 (m, 2H); Cl-MS m/z=178 (M+H+).
    • EXAMPLE 3 Preparation of (2R)-3,4-dihydro-2H-chromen-2-ylmethylamine hydrochloride
  • Figure US20050215594A1-20050929-C00540
  • In a dry 1-L 3-necked round-bottomed flask were charged the amide of Example 2 (16.9 g, 95 mmol) and tetrahydrofuran (100 mL). The mixture was heated to reflux under argon with stirring to obtain a clear solution. To this solution was then added borane/dimethyl sulfide complex (95 mL, 2M in THF) in about 30 minutes. After completion of addition, the reaction was further refluxed for 1 hour. Additional borane/dimethyl sulfide (80 mL) was then added to the reaction and the mixture was further refluxed for 1 hour. Heating was removed and replaced with an ice-water bath to cool the reaction mixture to room temperature. Methanol (43 mL) was then added to the reaction and it was stirred for 30 minutes. The reaction mixture was then concentrated in vacuo to remove 140 mL of liquid. The residue was then treated with ether/HCl (1 M) carefully to obtain a white suspension which was cooled in an ice-water bath for 30 minutes before vacuum filtration to obtain the product as a white powder (16.3 g, 87% yield): 1H NMR (DMSO-d6, δ): 1.60-1.77 (m, 1H), 2.00-2.08 (m, 1H), 2.65-2.85 (m, 2H), 2.95-3.20 (m, 2H), 4.20-4.30 (m, 1H), 6.75-6.85 (m, 2H), 7.04-7.09 (m, 2H); 8.30 (s, broad, 3H); Cl-MS m/z=164 (M+H+).
    • EXAMPLE 4 Preparation of N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-2,2,2-trifluoroacetamide
  • Figure US20050215594A1-20050929-C00541
  • The amine HCl salt of Example 3 (16.3 g, 82.6 mmol) was dissolved in 1N aqueous sodium hydroxide solution (91 mL) followed by extraction with dichloromethane (90 mL×3). The combined organic layer was washed with brine (50 mL) and dried over anhydrous sodium sulfate. Removal of solvent in vacuo afforded the free base chroman amine as colorless oil which was mixed with pyridine (14.2 mL) in dichloromethane (136 mL) under argon.
  • To this mixture cooled in an ice-water bath was then added trifluoroacetic anhydride (23.3 mL) carefully in about 10 minutes. Cooling bath was removed and the reaction was stirred at room temperature for 4 hours. It was then poured onto crushed ice (130 g). The organic layer was separated, washed with brine (50 mL), and dried over anhydrous sodium sulfate. Removal of solvent in vacuo afforded the product cleanly (19.7 g, 92% yield): 1H NMR (CDCl3, δ): 1.75-1.86 (m, 1H), 1.99-2.12 (m, 1H), 2.76-2.97 (m, 2H), 3.46-4.26 (m, 3H), 6.80-6.91 (m, 2H), 7.03-7.14 (m, 2H); Cl-MS m/z=260 (M+H+). The crude product was used for next step without further purification.
    • EXAMPLE 5 Preparation of ethyl (methylsulfanyl)[(2R)-2-(3,3,3-trifluoro-2-oxopropyl)-3,4-dihydro-2H-chromen-6-yl]acetate
  • Figure US20050215594A1-20050929-C00542
  • To a solution of N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-2,2,2-trifluoroacetamide (Example 4,12.96 g, 50 mmol) and α-chloro-2-(methylthio) acetate (9.28 g, 55 mmol) in dichloromethane (75 mL) at 0° C. was slowly added tin(IV) chloride (55 mL, 1M in CH2Cl2) via a syringe. The mixture became yellow rapidly and precipitation started to form. After completion of addition, the reaction was stirred at room temperature for 30 minutes. It was then quenched by addition of water (100 mL). The organic layer was separated and dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product as a brown oil (diastereomeric mixture): 1H NMR (CDCl3, δ): 1.30 (m, 3H), 1.76 (m, 2H), 2.18 (m, 4H), 2.90 (m, 2H), 4.20 (m, 5H), 6.65-6.79 (dd, J=8.1, 7.8 Hz, 1H), 7.18 (m, 2H); Cl-MS m/z=392 (M+H+). The crude was used without further purification.
    • EXAMPLE 6 Preparation of (2R)-6-bromo-3,4-dihydro-2H-chromene-2-carboxylic Acid
  • Figure US20050215594A1-20050929-C00543
    Step 1. Preparation of isobutyl (2R)-6-bromo-3,4-dihydro-2H-chromene-2-carboxylate
    Figure US20050215594A1-20050929-C00544
  • To dichloromethane (2.2 L) in a round-bottom flask equipped with a mechanical stirrer, argon gas inlet, and condensor were charged 255.8 g (1.092 moles, 98% ee) isobutyl (2R)-3,4-dihydro-2H-chromene-2-carboxylate [prepared by esterification of (2R)-3,4-dihydro-2H-chromene-2-carboxylic acid (WO 99/32476)], 156.3 g (0.55 moles) 1,3-dibromo-5,5-dimethylhydantoin, and 10.49 g (0.109 moles) methanesulfonic acid. The mixture was stirred in the dark overnight at room temperature. The reaction mixture was concentrated to 700 ml and the solid hydantoin was filtered and washed once with 50 ml of dichloromethane. The filtrate was concentrated to afford 355.7 g (104% crude yield) of a light brown solid, which by H-NMR, contained residual hydantoin: 1H-NMR (DMSO-d6, 300 MHz) δ 0.85 (d, 6H), 1.86 (m, 1H), 2.13 (m, 2H), 2.59 (m, 1H), 2.81 (m, 1H), 3.90 (d, 2H), 4.98 (t, 1H), 6.80 (d, 1H), 7.22-7.27 (m, 2H); El-MS m/z 312, 314.
    Step 2. Preparation of (2R)-6-bromo-3,4-dihydro-2H-chromene-2-carboxylic Acid
    Figure US20050215594A1-20050929-C00545
  • The crude product from step 1 above (1.092 moles) was dissolved in THF (2.1 L) and charged to a round-bottom flask, followed by 700 ml of methanol. A solution of LiOH (32.76 g, 1.365 moles) in 700 ml of water was then added over five minutes, resulting in a 10 degree rise in temperature. The reaction was stirred for five minutes and a sample analyzed by HPLC indicated excellent conversion of the starting material. After stirring for twenty minutes at 50° C., THF and methanol were removed in vacuo. Water (1.1 L) was added to the resulting solution, which was then charged to a round-bottom flask. 1.4 L of 1N HCl was slowly added to the solution to precipitate the product. The mixture was filtered to obtain 342 g of a white solid that was still wet. Water was removed by azeotroping with 700 ml of toluene and the compound was allowed to crystallize upon cooling from refluxing toluene to room temperature overnight. Upon breaking up the solid crystal, the reaction mixture was filtered, and the solid was dried in a vacuum oven overnight to obtain 185 g (66%) of an off-white solid: 1H-NMR (DMSO-d6, 300 MHz) δ 2.07 (m, 2H), 2.61 (m, 1H), 2.78 (m, 1H), 4.81 (t, 1H), 6.77 (d, 1H), 7.21-7.25 (m, 2H), 13.08 (s, 1H).
    • EXAMPLE 7
  • Method A. Preparation of (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic Acid
    Figure US20050215594A1-20050929-C00546
  • (2R)-3,4-Dihydro-2H-chromene-2-carboxylic acid (WO 99/32476) (26.7 g, 150 mmol), benzyltrimethyl-ammonium dichloroiodate (50.1 g, 144 mmol), and zinc chloride (25.3 g, 186 mmol) were stirred in glacial acetic acid (500 mL) under argon at room temperature for 18 hours. The solid was removed by vacuum filtration and then washed with acetic acid (100 mL). The filtrate was concentrated in vacuo to obtain a solid which was slurried in water (300 mL). The crude product was obtained as a pink solid after vacuum filtration and dried (38.3 g, 84%): 1H NMR (DMSO-d6, δ): 1.95-2.10 (m, 1H), 2.60 (m, 1H), 2.70-2.80 (m, 1H), 4.79 (dd, J=6.0, 3.9 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H). Cl-MS m/z=305 (M+H+). The crude was used for next step directly.
    Method B. Preparation of (2S)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic Acid
    Figure US20050215594A1-20050929-C00547
  • Using the same procedure described in for Method A and (2S)-3,4-dihydro-2H-chromene-2-carboxylic acid as starting material, the title compound was obtained in 89% yield: 1H NMR (DMSO-d6) δ 1.95-2.10 (m, 1H), 2.60 (m, 1H), 2.70-2.80 (m, 1H), 4.79 (dd, J=6.0, 3.9 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H).
    • EXAMPLE 8 Preparation of [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methanol
  • Figure US20050215594A1-20050929-C00548
  • To a solution of (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, 19.5 mmol, 1.0 eq.) in THF (45 mL) at 10° C. was added dropwise a solution of borane-THF complex (1M in THF, 23.4 mmol, 1.2 eq). The resulting reaction mixture was stirred at 45° C. for 1.5 hours and was then cooled to 10° C. Next, water was added followed by saturated NaHCO3 solution. The resulting two-phase mixture was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated to afford the product as a white solid in quantitative yield that was used without further purification. GC-MS m/z 290 (M+)
    • EXAMPLE 9 Preparation of (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide
  • Figure US20050215594A1-20050929-C00549
  • The crude carboxylic acid of Example 7 (30.4 g, 100 mmol) and CDI (19.5 g, 120 mmol) were stirred in N,N-dimethylformamide (300 mL) at room temperature for 2 hours to obtain a yellow solution. To this solution was then added ammonium acetate (23.1 g, 300 mmol). The resulting mixture was stirred for 3 hours. It was then cooled in an ice-water bath and water (400 mL) was then added dropwise to the reaction mixture to obtain a fine white precipitation which was stirred for 12 hours. The solid was collected by vacuum filtration, washed with water, and dried by suction (25.8 g, 85%): 1H NMR (DMSO-d6, δ): 1.75-1.90 (m, 1H), 2.00-2.15 (m, 1H), 2.55-2.80 (m, 2H), 4.43-4.47 (dd, J=8.7, 3.3 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 7.35 (m, 2H). Cl-MS m/z=304 (M+H+)
    • EXAMPLE 10 Preparation of [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylamine Hydrochloride
  • Figure US20050215594A1-20050929-C00550
  • The carboxamide of Example 9 (25.0 g, 82.5 mmol) was suspended in anhydrous tetrahydrofuran (200 mL) at reflux under argon. To this suspension was then added borane/dimethyl sulfide complex (83 mL, 2M in THF) dropwise. The reaction became a clear solution after the addition which was stirred at reflux for 1 hour. Additional borane reagent (70 mL) was added and the reaction was further refluxed for 1 hour. Heating was removed and the reaction was cooled to 0° C. with an ice-water bath. Methanol (38 mL) was added slowly to quench the reaction. The reaction mixture was concentrated in vacuo to about 40% of its initial volume. The residue was then treated with ether/HCl (1 M) to obtain white precipitate which was filtered, washed with ether, and dried by suction (11.7 g, 44%): 1H NMR (DMSO-d6,δ): 1.65 (m, 1H), 2.00 (m, 1H), 2.75 (m, 2H), 2.99 (dd, J=13.2, 8.1 Hz, 1H), 3.09-3.1
    • EXAMPLE 11 Preparation of benzyl [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylcarbamate
  • Figure US20050215594A1-20050929-C00551
  • To a mixture of (R)-6-iodo-chroman-2-methylamine hydrochloride of Example 10 (3.3 g, 10 mmol) and benzylchloroformate (1.57 mL, 11 mmol) in tetrahydrofuran (30 mL) cooled in an ice-water bath was added slowly 1N aqueous sodium hydroxide in 20 minutes. The resulting mixture was stirred for 1 hour. The organic layer was separated and concentrated in vacuo. The aqueous layer was extracted with ethyl acetate (50 mL×2). The combined ethyl acetate layer was combined with the above residue and washed with water (50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded the crude product as a white solid (4.2 g, 99%). 1H nmr (DMSO d6) δ 1.5-1.6 (m, 2H), 1.9, 2.0 (m, 1H), 2.7 (m, 2H), 3.3 (m, 2H), 4.0 (m, 1H), 5.0 (s, 2H), 6.5 (d, 1H), 7.3 (m, 7H), 7.5 (t, 1H).
    • EXAMPLE 12 Preparation of tert-butyl [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylcarbamate
  • Figure US20050215594A1-20050929-C00552
  • [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylamine hydrochloride (Example 10, 3.52 g, 10.83 mmol) was dissolved in THF (20 mL), and treated with 0.91 g (10.83 mmol) of sodium bicarbonate in 2 mL of water, followed by the addition of 2.36 g (10.83 mmol) of di-t-butyldicarbonate. The resulting solution was allowed to stir for 16 hours at room temperature. At this point the solution was concentrated in vacuo and the resulting residue was treated with water and extracted with ethyl acetate. The dried (Na2SO4) ethyl acetate layers were concentrated in vacuo to obtain 4.02 g of product as a yellowish solid; m/z=389.8 [M+].
    • EXAMPLE 13 Preparation of tert-butyl(dimethyl)silyl[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl ether
  • Figure US20050215594A1-20050929-C00553
  • A reaction mixture containing [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methanol (Example 8, 5 g, 17.2 mmol, 1.0 eq), tert-butyldimethylsilyl chloride (20.6 mmol, 1.2 eq), and imidazole (43 mmol, 2.5 eq) in anhydrous DMF (35 mL) was stirred at 27° C. overnight. The resulting mixture was then cooled to room temperature, poured into water, and extracted with diethyl ether. The organic extract was washed with water, brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column) providing the product in 79% yield; m/z=405 [MH=].
    • EXAMPLE 14 Preparation of tert-butyl(dimethyl)silyl[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl ether
  • Figure US20050215594A1-20050929-C00554
  • Argon was bubbled through a solution of tert-butyl(dimethyl)silyl[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl ether (Example 13, 11.1 mmol, 1.0 eq.) in dioxane (45 mL) for 10 minutes before Pd(dppf)Cl2 (0.306 mmol, 0.03 eq.), triethylamine (33.4 mmol, 3.0 eq.), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.8 mmol, 1.6 eq.) were added. The resulting reaction mixture was stirred at 80° C. overnight. The mixture was then filtered through a Celite® pad. The filtrate was concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=10:1). The product was obtained as a pale brown waxy solid in 94% yield. MH+=405.3, retention time (LC-MS)=4.79 min.
    • EXAMPLE 15 Preparation of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
  • Figure US20050215594A1-20050929-C00555
  • A solution of methyl 4-iodobenzoate (2.00 g, 7.63 mmol) in 30 mL of dioxane was degassed with argon for 10 minutes. Then, 171 mg (3 mol %) Pd(dppf)Cl2, 3.27 mL triethylamine, and 1.47 g (11.45 mmol) pinacolborane were added. The resulting solution was stirred at 85° C. for 16 hours. The mixture was allowed to cool to ambient temperature, filtered through a pad of Celite®, and concentrated in vacuo to obtain 3.97 g of product which was used without further purification. m/z=263 [M+H]+
    • EXAMPLE 16 Preparation of methyl 4-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate
  • Figure US20050215594A1-20050929-C00556
    Method (1)
  • Argon was bubbled through a solution of tert-butyl(dimethyl)silyl[(2R)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl ether, Example 14, 2.47 mmol, 1.0 eq.) in toluene (60 mL) for 10 minutes. Next, Pd(dppf)Cl2 (0.164 mmol, 0.07 eq.) and methyl 4-iodobenzoate (3.71 mmol, 1.5 eq.) were added in a single portion. The resulting reaction mixture was degassed with argon for an additional 5 minutes before aqueous Na2CO3 (2 M, 26 mmol, 10.5 eq.) was added and the solution was heated at 85° C. overnight. The product mixture was allowed to cool to room temperature, water was added and the two phase mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexane:ethyl acetate 10:1). The purified product was dissolved in THF (10 mL) and tetrabutylammonium fluoride (1 M, 5 mL) was added in a single portion. The resulting mixture was stirred at room temperature for 1 hour. The solvents were evaporated and the resulting residue was purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=5:1 to 2:1). The product was obtained as a white solid in yield of 46% (two step yield). MH+=299.2, retention time (LC-MS)=2.79 min.
  • Method (2)
  • To a 5-L 3-necked round-bottomed flask were charged 4-methoxycarbonyl phenylboronic acid (72.0 g, 0.4 mol), potassium carbonate (124.4 g, 0.9 mol), and water (900 mL) to obtain a suspension. To this suspension was then added a solution of [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methanol (Example 8, 105.5 g, 0.36 mol) in acetone (720 mL). The resultant mixture became a near homogeneous solution (internal temperature rose from 20 to 28° C.). Palladium acetate (1.5 g, 0.0067 mol) was then added in one portion. The reaction mixture was then heated at 65° C. under argon for 2 hours. It turned into a suspension. Heating was removed and the reaction was allowed to cool to room temperature. The solid (metallic color) was then collected by filtration and dried by suction. The crude was then dissolved in chloroform (2 L) and filtered through a pad of Celite® (100 g) under vacuum slowly to remove palladium. Removal of solvent in vacuo afforded the desired compound as a white solid (90 g, 84% yield): 1H NMR (CDCl3, δ): 1.82-2.12 (m, 3 H), 2.80-3.02 (m, 2H), 3.75-3.90 (m, 2H), 3.92 (s, 3H), 4.20 (m, 1H), 6.91 (d, J=8.1 Hz, 1H), 7.33 (s, 1 H), 7.37 (dd, J=8.1, 2.7 Hz, 1H), 7.60 (d, J=9 Hz, 2H), 8.06 (d, J=8.7 Hz, 2H).
    • EXAMPLE 17 Preparation of methyl 3-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate
  • Figure US20050215594A1-20050929-C00557
  • Using essentially the same procedure as Example 16, Method (1), and substituting the appropriate starting materials, methyl 3-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate was prepared in yield of 68% (two steps). MH+=313.1, retention time (LC-MS)=3.00 min.
    • EXAMPLE 18 Preparation of methyl 4-((2R)-2-{[(tert-butoxycarbonyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl) benzoate
  • Figure US20050215594A1-20050929-C00558
  • A solution of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Example 15, 1.67 g, 6.36 mmol) in 130 mL toluene and 27 mL 1,4-dioxane was degassed with argon for 10 minutes. tert-Butyl [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylcarbamate (Example 12, 1.65 g) and 265 mg (3 mol %) Pd(dppf)Cl2 were then added, and the solution was degassed with argon for an additional 5 minutes. Finally, 26.5 mL of 2M aqueous sodium carbonate was added and the solution was stirred at 85° C. for 16 hours. This mixture was then cooled to ambient temperature, filtered through a pad of Celite®, and concentrated in vacuo. The product was then purified by Biotage (100% methylene chloride to 3% MeOH:methylene chloride) to obtain 1.40 g of product. m/z=397.9 [M+].
    • EXAMPLE 19 Preparation of methyl 4-[(2 R)-2-(aminomethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate
  • Figure US20050215594A1-20050929-C00559
  • To a solution of methyl 4-((2R)-2-{[(tert-butoxycarbonyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl) benzoate (Example 18, 0.94 g, 2.37 mmol) in 5 mL 1,4-dioxane was added 1 mL of 4M hydrochloric acid in 1,4-dioxane dropwise. The resulting solution was allowed to stir at room temperature for 16 hours, followed by concentration in vacuo. At this point, diethyl ether was added and the solid was collected to provide 587 mg of product as a white solid. m/z=298.2 [MH+].
    • EXAMPLE 20 Preparation of methyl 4-[(2R)-2-formyl-3,4-dihydro-2H-chromen-6-yl]benzoate
  • Figure US20050215594A1-20050929-C00560
  • To a solution of 33 mg (0.425 mmol) dimethyl sulfoxide in 2 mL of methylene chloride at −78° C., was added 0.14 mL (0.272 mmol) 2M oxalyl chloride. After the solution had stirred at this temperature for 10 minutes, a solution of 50 mg (0.17 mmol) methyl 4-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 16) in 2 mL of methylene chloride was added dropwise and the resulting mixture was stirred at −78° C. for an additional 1.6 hours. At this time, 0.14 mL (1.02 mmol) triethylamine was added to the mixture slowly, and then it was allowed to warm to room temperature over 15 minutes. The solution of desired product was used without further purification.
    • EXAMPLE 21 Preparation of methyl 4-chloro-2-pyridinecarboxylate
  • Figure US20050215594A1-20050929-C00561
  • To 5020 C. thionyl chloride (14.8 mL, 203.1 mmol, 5.0 eq.) was added dry N,N-dimethylformamide (0.62 mL, 8.12 mmol, 0.20 eq.). The solution was stirred for 15 minutes before picolinic acid (5.0 g, 40.6 mmol) was added as a solid. The reaction was immediately warmed to reflux. After 16 hours at reflux, the mixture was cooled to room temperature and concentrated by rotary evaporation. The residue was diluted with toluene and concentrated again. The resulting oil was poured into a molar excess of methanol and stirred for 1 hour at room temperature. The methanol was removed by rotary evaporation, and the resulting crude was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH 7 with 1N aqueous sodium hydroxide, and the layers were separated. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo to a dark oil. Purification by flash chromatography on silica gel eluted on a gradient from 100:0 to 70:30 hexanes/ethyl acetate provided the title compound as a pale orange solid (3.5 g, 50%): 1H NMR (300 MHz, CDCl3) δ 8.61 (d, 1 H), 8.10 (s, 1 H), 7.46 (d, 1 H), 3.98 (s, 3 H); MS m/z 172.1 (MH+).
    • EXAMPLE 22 Preparation of 4-chloro-2-pyridinecarboxamide
  • Figure US20050215594A1-20050929-C00562
  • Using the same procedure described in Example 21 and substituting aqueous ammonia (28%) for methanol, the title compound was obtained by filtration (1.91 g, 76% yield): MS m/z 157.8 (MH+), retention time (LC-MS)=1.08 minutes.
    • EXAMPLE 23 Preparation of ethyl 2-chloro-3-oxo-3-phenylpropanoate
  • Figure US20050215594A1-20050929-C00563
  • A solution of sulfuryl chloride (12.4 mmol) in toluene (5 mL) was added dropwise via an additional funnel to a solution of ethyl benzoylacetate (12.4 mmol) in toluene (20 mL) over 5 minutes at room temperature. The resulting mixture was stirred at room temperature overnight. Water was added slowly and resulting two-phase mixture was basified with saturated NaHCO3 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and evaporated to afford 2.2 g (84%) of product as a pale yellow oil; MH+=227.0, retention time (LC-MS)=2.77 min.
    • EXAMPLE 24 Preparation of ethyl 2-chloro-4-methyl-3-oxopentanoate
  • Figure US20050215594A1-20050929-C00564
  • Utilizing the method described for Example 23, the product was obtained in 67% yield (crude). MH+=193.0, retention time (LC-MS)=2.45 min.
    • EXAMPLE 25 Preparation of methyl 2-amino-5-phenyl-1,3-thiazole-4-carboxylate
  • Figure US20050215594A1-20050929-C00565
  • A solution of 25 wt % NaOMe in MeOH (13.4 mmol) was added to a solution of methyl dichloroacetate (13.4 mmol) and benzaldehyde (14.8 mmol, 1.1 eq.) in diethyl ether (8 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hour before diethyl ether and brine were added. The organic layer was separated, dried over anhydrous sodium sulfate, and evaporated to give a crude material which was dissolved in MeOH (16 mL) containing thiourea (11.4 mmol, 0.85 eq.). The resulting reaction mixture was heated to reflux for 18 hours. The crude product mixture was concentrated in vacuo, neutralized with 18M-NH4OH at which time the product precipitated as a white solid. The product was washed with CH2Cl2 (2×), water and was collected by filtration to afford 1.88 g (70%) of product; MH+=235.1, Rf=0.18 (Hexanes:EtOAc=1:1), retention time (LC-MS)=1.86 min.
    • EXAMPLE 26 Preparation of methyl 2-amino-5-isopropyl-1,3-thiazole-4-carboxylate
  • Figure US20050215594A1-20050929-C00566
  • The title compound was prepared according to method of Example 25 in 88% yield. MH+=201.0, retention time (LC-MS)=1.48 min.
    • EXAMPLE 27 Preparation of ethyl 2-amino-4-phenyl-1,3-thiazole-5-carboxylate
  • Figure US20050215594A1-20050929-C00567
  • A solution of ethyl 2-chloro-3-oxo-3-phenylpropanoate (Example 23, 9.73 mmol) and thiourea (9.73 mmol) in EtOH (25 mL) was heated at reflux overnight. The resulting mixture was concentrated in vacuo, neutralized with 18M-NH4OH, and extracted with CH2Cl2. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to afford a yellow solid that was washed with MeOH (3 mL) and dried to afford the product in 89% yield as a pale yellow solid. MH+=249.1, Rf=0.29 (Hexanes:EtOAc=1:1). MH+=249.1, retention time (LC-MS)=2.37 min.
    • EXAMPLE 28 Preparation of ethyl 2-amino-4-isopropyl-1,3-thiazole-5-carboxylate
  • Figure US20050215594A1-20050929-C00568
  • The title compound was prepared according to method of Example 27 in 65% yield. MH+=215.1, Rf=0.66 (hexanes:EtOAc=1:1), retention time (LC-MS)=1.98 min.
    • EXAMPLE 29 Preparation of ethyl 5-phenyl-1,3-oxazole-4-carboxylate
  • Figure US20050215594A1-20050929-C00569
  • To a mixture of ethyl isocyanoacetate (8.74 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (8.84 mmol) in THF (12 mL) was added a solution of benzoic anhydride (8.84 mmol) in THF (2 mL) at 10° C. with stirring. The resulting mixture was maintained with vigorous stirring for 18 hours at room temperature. The solvent was evaporated to afford a residue that was partitioned between EtOAc and water. The organic extract was dried over anhydrous sodium sulfate and concentrated to afford an amber oil which was purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=6:1 to 4:1 to 2:1). The product was obtained as a clear oil in 42%. MH+=218.1, retention time (LC-MS)=2.52 min.
    • EXAMPLE 30 Preparation of methyl 2-bromo-5-phenyl-1,3-thiazole-4-carboxylate
  • Figure US20050215594A1-20050929-C00570
  • To a dark brown solution of copper(II) bromide (3.85 mmol, 3 eq.) in acetonitrile (5 mL) in a two-neck round-bottomed flask equipped with a condenser was added tert-butyl nitrite (1.92 mmol, 1.5 eq.) slowly at room temperature. The resulting mixture was heated to 60° C. at which time a suspension of methyl 2-amino-5-phenyl-1,3-thiazole-4-carboxylate (Example 25, 1.28 mmol) in acetonitrile (7 mL) was added dropwise. The resulting reaction mixture was heated at 60° C. for 3 hours, allowed to cool to room temperature, poured to 1M NaOH aqueous, and extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=5:1). The product was obtained as a pale yellow oil in 88%. MH+=298.0, Rf=0.74 (hexanes:EtOAc=2:1), retention time (LC-MS)=3.01 min.
    • EXAMPLES 31-33 Preparation of methyl 2-bromo-5-isopropyl-1,3-thiazole-4-carboxylate, ethyl 2-bromo-4-phenyl-1,3-thiazole-5-carboxylate and ethyl 2-bromo-4-isopropyl-1,3-thiazole-5-carboxylate
  • Using essentially the same procedure and substituting the appropriate starting amino compound, the following bromothiazoles were prepared and characterized according to method of Example 30:
    TABLE 2
    Starting
    Ex. MS Material RT (min.
    No. Structure [M + H+] (Ex. No.) Rf LC-MS)
    31
    Figure US20050215594A1-20050929-C00571
         		264.0 28 0.51 hexanes: EtOAc 6:1 2.83
    32
    Figure US20050215594A1-20050929-C00572
         		312.1 26 0.65 hexanes: EtOAc 6:1 3.46
    33
    Figure US20050215594A1-20050929-C00573
         		278.2 27 0.74 hexanes: EtOAc 6:1 3.54
    • EXAMPLE 34 Preparation of ethyl 2-iodo-5-phenyl-1,3-oxazole-4-carboxylate
  • Figure US20050215594A1-20050929-C00574
  • To a solution of ethyl 5-phenyl-1,3-oxazole-4-carboxylate (Example 29, 0.921 mmol, 1 eq.) in THF (7 mL) at −78° C. was added a solution of lithium bis(trimethylsilyl)amide in THF (1M, 1.11 mmol, 1.2 eq.) dropwise by syringe. The resulting solution was stirred at −78° C. for 1 hour at which time a solution of iodine (1.38 mmol, 1.5 eq. in 2 mL THF) was added dropwise by a syringe. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 1.5 hours. The resulting solution was poured onto 10% aqueous NaS2O3 (15 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=9:1). The product was obtained as a pale yellow solid in 82% yield. MH+=344.0, Rf=0.31 (hexanes:EtOAc=6:1), retention time (LC-MS)=3.01 min.
    • EXAMPLE 35
  • Method A. Preparation of (2R)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide
    Figure US20050215594A1-20050929-C00575
  • (1R)-2-Amino-1-(3-pyridinyl)ethanol dihydrochloride (U.S. Pat. No. 6,051,586) (5.73 g, 27.1 mmol), 1-hydroxybenzotriazole (6.67 g, 49.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcabodiimide hydrochloride (9.46 g, 49.3 mmol), and triethylamine (13.8 mL, 9.98 g, 98.7 mmol) were added successively to a stirred solution of (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, Method A, 7.50 g, 24.7 mmol) in dichloromethane (100 mL). The reaction was stirred for 18 hours and then diluted with dichloromethane (300 mL). The solution was washed with saturated aqueous sodium bicarbonate (300 mL) and then the aqueous layer was back-extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 5-10% methanol/ethyl acetate gave the product (7.80 g, 74%) as a white solid: 1H NMR (acetone-d6, δ): 8.55 (d, J=1.6 Hz, 1 H), 8.44 (dd, J=4.7, 1.6 Hz, 1 H), 7.71 (ddd, J=7.9, 1.8, 1.8 Hz, 1H), 7.59 (s, 1 H), 7.35-7.42 (m, 2 H), 7.27 (dd, J=7.9, 4.7 Hz, 1 H), 6.63 (d, 9.6 Hz, 1 H), 4.98 (d, J=4.2 Hz, 1 H), 4.85-4.93 (m, 1 H), 4.53 (dd, J=8.8, 3.4 Hz, 1 H), 3.38-3.70 (m, 2 H), 2.61-2.91 (m, 4 H), 2.16-2.28 (m, 2 H), 1.85-1.99 (m, 1 H); mass spectroscopy gave m/z=425.1 [M+H]+.
    Method B. Preparation of (2S)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide
    Figure US20050215594A1-20050929-C00576
  • Using the same procedure described in Method A, using (2S)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, Method B) and (1R)-2-amino-1-(3-pyridinyl)ethanol dihydrochloride (U.S. Pat. No. 6,051,586), the title compound was obtained as a white solid in 87% yield. 1H NMR (DMSO-d6) δ 8.47 (d, J=2.2 Hz, 1 H), 8.43 (dd, J=6.6, 1.8 Hz, 1 H), 7.90 (t, J=7.1 Hz, 1 H), 7.69-7.60 (m, 1 H), 7.40-7.37 (m, 2 H), 7.30-7.26 (m, 1 H), 6.66 (d, J=9.1 Hz, 1 H), 5.66 (d, J=4.6 Hz, 1 H), 4.72 (q, J=5.0 Hz, 1 H), 4.52 (dd, J=8.3, 3.3 Hz, 1 H), 4.12 (dd, J=6.1, 1.8 Hz, 1 H), 3.36-3.32 (m, 1 H), 2.77-2.65 (m, 1 H), 2.58-2.52 (m, 1 H), 2.08-2.00 (m, 1 H), 1.85-1.73 (m, 1 H). LC-MS m/z 425.1 (MH+), RT=2.07 minutes.
    • EXAMPLE 36 Method A. Preparation of (1R)-2-({[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-(3-pyridinyl)ethanol
  • Figure US20050215594A1-20050929-C00577
  • Borane-dimethylsulfide complex (2.0 M in tetrahydrofuran, 46 mL, 92 mmol) was added dropwise (20 minutes) to a cooled (0° C.) and stirred solution of (2R)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide (Example 35, Method A, 7.75 g, 18.3 mmol) in tetrahydrofuran (300 mL). The solution was warmed to reflux for 1 hour and then cooled to room temperature. The reaction was quenched with addition of methanol (12 mL) and 2 M hydrochloric acid (95 mL), and then the resulting solution was heated at reflux for 1 hour. The reaction was cooled to room temperature and then the solution was adjusted to pH 9 using 1 M aqueous sodium hydroxide. The mixture was diluted with brine (500 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×200 mL) and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 30-50% ethyl acetate/hexane afforded product (6.32 g, 84%) as a waxy yellow solid: 1H NMR (acetone-d6, δ): 8.59 (d, J=1.9 Hz, 1 H), 8.44 (dd, J=5.0, 1.5 Hz, 1 H), 7.77 (ddd, J=8.0, 1.8, 1.8 Hz, 1 H), 7.25-7.39 (m, 3 H), 6.56 (d, J=8.4 Hz, 1 H), 4.80 (dd, J=8.4, 4.0 Hz, 1 H), 4.08-4.18 (m, 1 H), 2.67-3.00 (m, 10 H), 1.67-1.82 (m, 1 H); mass spectroscopy gave m/z=410.9 [M+H]+.
    Method B. Preparation of (1R)-2-({[(2S)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-(3-pyridinyl)ethanol
    Figure US20050215594A1-20050929-C00578
  • Using the same procedure described in Method A using (2S)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide (Example 35, Method B), the title compound was obtained as a crude oil after quench and extractive workup. The crude material was not purified before carrying on to the next step. LC-MS m/z 411.3 (MH+), RT=2.23 minutes.
    • EXAMPLE 37
  • Method A. Preparation of tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
    Figure US20050215594A1-20050929-C00579
  • A solution of di-tert-butyl dicarbonate (3.46 g, 15.9 mmol) in tetrahydrofuran (20+5 mL rinse) was added to a cooled (0° C.) and stirred solution of (1R)-2-({[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-(3-pyridinyl)ethanol (Example 36, Method A, 6.20 g, 15.1 mmol) in tetrahydrofuran (75 mL). The mixture was stirred at 0° C. for 1 hour, warmed to room temperature, and stirred for 18 hours. The solution was concentrated in vacuo and then flash chromatography of the residue over silica gel using ethyl acetate gave product (7.23 g, 93%) as a glassy white solid: 1H NMR (acetone-d6, δ): 8.57 (s, 1 H), 8.46 (s, 1 H), 7.70 (d, J=7.5 Hz, 1 H), 7.27-7.40 (m, 3 H), 6.57 (d, J=8.5 Hz, 1 H), 4.76-5.11 (m, 2 H), 4.17-4.28 (m, 1 H), 3.42-3.75 (m, 4 H), 2.69-2.90 (m, 1 H), 1.94-2.06 (m, 1 H), 1.58-1.75 (m, 1 H), 1.41 (d, J=7.6 Hz, 9 H); mass spectroscopy gave m/z=510.9 [M+H]+.
    Method B. Preparation of tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2S)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
    Figure US20050215594A1-20050929-C00580
  • Using the same procedure described in Method A, with (1R)-2-({[(2S)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-(3-pyridinyl)ethanol (Example 36, Method B), the title compound was obtained (55% overall yield for the reduction to the amine and protection as the carbamate). LC-MS m/z 511.1 (MH+), RT=2.59 minutes.
    • EXAMPLE 38
  • Method A. Preparation of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl]ethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
    Figure US20050215594A1-20050929-C00581
  • A mixture of tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 37, Method A, 6.35 g, 12.4 mmol), TBDMSCl (2.25 g, 14.9 mmol) and imidazole (2.10 g, 30.9 mmol) in DMF (10 mL) was stirred at room temperature under argon for 24 hours. The reaction mixture was then poured into a saturated NaHCO3 solution (50 mL). The mixture was extracted with ether (100 mL×2). The ether layer was washed with water (50 mL) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded a near white syrup which was purified by column chromatography (silica gel, hexanes/ethyl acetate (5/1, v/v)) giving the desired compound as a colorless oil. LC-MS m/z 625.0 (MH+), RT=4.09 minutes.
    Method B. Preparation of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl]ethyl{[(2S)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
    Figure US20050215594A1-20050929-C00582
  • Using the same procedure described in Method A, using tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2S)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 37, Method B) as starting material, the title compound was obtained in 65% yield. LC-MS m/z 625.3 (MH+), RT=3.54 minutes.
    • EXAMPLE 39 Preparation of (1R)-2-({[(2R)-6-(3,4-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-(3-pyridinyl)ethanol
  • Figure US20050215594A1-20050929-C00583
  • 3,4-Dichlorophenylboronic acid (34 mg, 0.18 mmol), a solution of palladium acetate (3 mg, 0.01 mmol) and triphenylphosphine (12 mg, 0.05 mmol) in toluene (1 mL), and 2 M aqueous sodium carbonate (1 mL) were added successively to a solution of tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 37, 60 mg, 0.12 mmol) in toluene (2 mL). The mixture was heated (80° C.) and stirred for 16 hours. After cooling the reaction was diluted with dichloromethane (5 mL) and the layers were separated. The organic layer was concentrated in vacuo and the residue was dissolved in a solution of 4 M hydrogen chloride in dioxane (4 mL). The solution was stirred for 16 hours and then concentrated in vacuo. Preparative reverse phase HPLC of the residue using acetonitrile/water afforded 10.3 mg (20%) of the desired product (retention time=2.19 min.): 1H NMR (CD3OD, δ): 8.71 (d, J=2.2 Hz, 1 H), 8.59 (dd, J=5.1, 1.5 Hz, 1 H), 8.11 (ddd, J=7.9, 1.7, 1.7 Hz, 1 H), 7.71 (d, J=2.3 Hz, 1 H), 7.61 (dd, J=7.9, 5.1 Hz, 1 H), 7.37-7.56 (m, 4 H), 6.99 (d, 9.2 Hz, 1 H), 5.22 (dd, J=10.5, 2.9 Hz, 1 H), 4.43-4.54 (m, 1 H), 3.26-3.55 (m, 4 H), 2.87-3.10 (m, 2 H), 2.11-2.22 (m, 1 H), 1.76-1.92 (m, 1 H); mass spectroscopy gave m/z=429.2 [M+H]+.
  • Using essentially the same method as described for Example 39 and using Example 37 and the appropriate substituted phenylboronic acid as starting materials, the following compounds were prepared and characterized in Table 3.
    TABLE 3
    Figure US20050215594A1-20050929-C00584
    HPLC
    Example MS RT
    No. Y [M + H+] (min)
    40
    Figure US20050215594A1-20050929-C00585
         		429.2 2.00
    41
    Figure US20050215594A1-20050929-C00586
         		395.2 2.03
    42
    Figure US20050215594A1-20050929-C00587
         		406.2 1.86
    43
    Figure US20050215594A1-20050929-C00588
         		391.2 1.75
    44
    Figure US20050215594A1-20050929-C00589
         		429.2 2.07
    45
    Figure US20050215594A1-20050929-C00590
         		375.2 1.94
    46
    Figure US20050215594A1-20050929-C00591
         		395.2 1.99
    47
    Figure US20050215594A1-20050929-C00592
         		437.3 2.27
    48
    Figure US20050215594A1-20050929-C00593
         		379.2 1.86
    49
    Figure US20050215594A1-20050929-C00594
         		407.2 1.98
    50
    Figure US20050215594A1-20050929-C00595
         		405.2 1.80
    51
    Figure US20050215594A1-20050929-C00596
         		429.2 2.14
    52
    Figure US20050215594A1-20050929-C00597
         		413.2 2.04
    53
    Figure US20050215594A1-20050929-C00598
         		451.2 1.72
    54
    Figure US20050215594A1-20050929-C00599
         		411.2 2.09
    55
    Figure US20050215594A1-20050929-C00600
         		411.2 2.15
    56
    Figure US20050215594A1-20050929-C00601
         		367.2 1.77
    57
    Figure US20050215594A1-20050929-C00602
         		367.2 1.74
    58
    Figure US20050215594A1-20050929-C00603
         		417.2 2.09
    59
    Figure US20050215594A1-20050929-C00604
         		401.2 2.04
    60
    Figure US20050215594A1-20050929-C00605
         		375.2 1.92
    61
    Figure US20050215594A1-20050929-C00606
         		395.2 1.95
    62
    Figure US20050215594A1-20050929-C00607
         		439.2 2.06
    63
    Figure US20050215594A1-20050929-C00608
         		405.2 1.95
    64
    Figure US20050215594A1-20050929-C00609
         		439.2 2.06
    65
    Figure US20050215594A1-20050929-C00610
         		497.2 2.30
    66
    Figure US20050215594A1-20050929-C00611
         		429.1 2.20
    67
    Figure US20050215594A1-20050929-C00612
         		455.2 1.93
    68
    Figure US20050215594A1-20050929-C00613
         		461.3 2.32
    69
    Figure US20050215594A1-20050929-C00614
         		420.2 1.99
    • EXAMPLE 70 Preparation of 4-{(2R)-2-[([(2R)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}-2-pyridinecarboxylic Acid
  • Figure US20050215594A1-20050929-C00615
  • Argon was bubbled through a mixture of (1R)-1-(3-pyridinyl)-2-({[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol (Example 81, I, 0.50 g, 0.80 mmol) and methyl 4-chloro-2-pyridinecarboxylate (Example 21, 0.15 g, 0.88 mmol, 1.1 eq.) in toluene (2 mL), ethanol (2 mL), and 2M aqueous sodium carbonate (2 mL) for 15 minutes. Triphenylphosphine (0.04 g, 0.16 mmol, 0.2 eq.) and palladium (II) acetate (0.01 g, 0.04 mmol, 0.05 eq.) were added, and the mixture was stirred vigorously under argon at 85° C. overnight. The reaction was cooled and filtered through a pad of Celite® with the aid of ethyl acetate. The filtrate was transferred to a separatory funnel where the layers were separated. The organic layer was concentrated in vacuo to remove excess solvents, and the resulting oil was dissolved in ethyl acetate. The ethyl acetate solution was extracted with a 1:1 solution of saturated aqueous sodium bicarbonate and water. The aqueous layer was adjusted to pH 4 with 1N aqueous HCl, then extracted with chloroform (2×). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to provide the title compound as an orange oil (0.24 g, 48%): 1H NMR (300 MHz, CDCl3) δ 8.62 (d, 1 H), 8.55 (broad s, 1 H), 8.39 (s, 1 H), 7.78-7.66 (m, 2 H), 7.51-7.48 (m, 1 H), 7.42 (broad s, 2 H), 7.34-7.31 (m, 1 H), 6.82 (dd, 1 H), 5.15-4.97 (m, 1 H), 4.24-4.12 (m, 3 H), 3.76-3.61 (m, 1 H), 3.46-3.30 (m, 1 H), 2.88-2.83 (m, 1 H), 2.05-1.95 (m, 1 H), 1.72-1.62 (m, 2 H), 1.21 (s, 9 H), 0.86 (s, 9 H), 0.03 (s, 3 H), −0.15 (s, 3 H); MS m/z 620.3 (MH+).
    • EXAMPLE 71 Preparation of 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinecarboxylic Acid
  • Figure US20050215594A1-20050929-C00616
  • 4-{[(2R)-2-[([(2R)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}-2-pyridinecarboxylic acid (Example 70, 29 mg, 0.05 mmol) was stirred in an excess of 4M HCl in dioxane at room temperature for 18 hours. The volatile components were removed by rotary evaporation, and the residue was washed with dichloromethane. After drying under vacuum, the title compound was collected as the tri-hydrochloride salt (23 mg, 93%): 1H NMR (300 MHz, CD3OD) δ 9.07 (broad s, 1 H), 8.90 (d, 1 H), 8.83-8.78 (m, 3 H), 8.49 (d, 1 H), 8.18 (t, 1 H), 7.94-7.89 (m, 2 H), 7.20 (d, 1 H), 5.52-5.46 (m, 1 H), 4.67-4.61 (m, 1 H), 3.76-3.57 (m, 2 H), 3.51-3.39 (m, 2 H), 3.10-3.05 (m, 2 H), 2.29-2.20 (m, 1 H), 1.95-1.83 (m, 1 H); MS m/z 406.2 (MH+ of the free base).
    • EXAMPLE 72 Preparation of methyl 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinecarboxylate
  • Figure US20050215594A1-20050929-C00617
  • Argon was bubbled through a mixture of (1R)-1-(3-pyridinyl)-2-({[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol (Example 81, 0.50 g, 0.80 mmol) and methyl 4-chloro-2-pyridinecarboxylate (Example 21, 0.15 g, 0.88 mmol, 1.1 eq.) in toluene (2 mL), ethanol (2 mL), and 2M aqueous sodium carbonate (2 mL) for 15 minutes. Triphenylphosphine (0.04 g, 0.16 mmol, 0.2 eq.) and palladium (II) acetate (0.01 g, 0.04 mmol, 0.05 equivalent) were added, and the mixture was stirred vigorously under argon at 85° C. overnight. The reaction was cooled and filtered through a pad of Celite® with the aid of ethyl acetate. The filtrate was transferred to a separatory funnel where the layers were separated. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel flushed with ethyl acetate followed by elution with 95:5 chloroform/methanol. The coupling product was obtained as a yellow oil (63 mg, 12%); MS m/z 634.3 (MH+). The intermediate oil was stirred in 4N HCl in dioxane overnight at room temperature. The reaction was concentrated in vacuo and the residue was washed with dichloromethane to provide the title compound as the tri-hydrochloride salt (32 mg, 77%): 1H NMR (300 MHz, DMSO-d6) δ 9.51 (broad s, 1 H), 9.36 (broad s, 1 H), 8.95 (s, 1 H), 8.89 (d, 1 H), 8.71 (d, 1 H), 8.62 (d, 1 H), 8.27 (s, 1 H), 8.10-8.06 (m, 1 H), 7.96-7.94 (m, 1 H), 7.70-7.65 (m, 2 H), 6.98 (d, 1 H), 5.42-5.39 (m, 2 H), 4.60-4.55 (m, 1 H), 3.91 (s, 3 H), 3.46-3.30 (m, 4 H), 2.94-2.88 (m, 1 H), 2.16-2.12 (m, 1 H), 1.83-1.68 (m, 1 H); MS m/z 420.1 (MH+ of the free base).
    • EXAMPLE 73 Preparation of trifluoro-N-({4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinyl}carbonyl)methanesulfonamide
  • Figure US20050215594A1-20050929-C00618
  • Into a solution of 4-{(2R)-2-[([(2R)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}-2-pyridinecarboxylic acid (Example 70, 113 mg, 0.18 mmol) in dichloromethane (2 mL) was added trifluoromethylsulfonamide (30 mg, 0.20 mmol, 1.1 eq.), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (42 mg, 0.22 mmol, 1.2 eq.), and N,N-dimethylaminopyridine (22 mg, 0.18 mmol, 1.0 eq.). The solution was stirred overnight at room temperature before being concentrated in vacuo to remove volatile components. The crude residue was purified by flash chromatography on silica gel flushed with ethyl acetate followed by elution with 3:1 ethyl acetate/methanol. The coupling product was obtained as a yellow oil (36 mg, 27%); MS m/z 751.2 (MH+). The protected intermediate was stirred in an excess of 4N HCl in dioxane overnight at room temperature. The reaction was concentrated in vacuo, and the residue was washed with dichloromethane to provide the title compound as the tri-hydrochloride salt (19 mg, 61%): 1H NMR (300 MHz, CD3OD) δ 9.11 (s, 1 H), 8.89 (d, 1 H), 8.75-8.60 (m, 2 H), 8.34 (d, 1 H), 8.18 (t, 1 H), 7.92-7.74 (m, 2 H), 7.68-7.54 (m, 1 H), 7.20-7.08 (m, 1 H), 4.70-4.60 (m, 1 H), 3.74-3.59 (m, 5 H), 3.02-2.90 (m, 2 H), 2.24-2.16 (m, 1 H), 1.89-1.77 (m, 1 H); MS m/z 537.1 (MH+ of the free base).
  • By employing the methods described in Example 73 and by using the compound of Example 70 with the appropriate amide or sulfonamide as starting materials, the following were similarly prepared and characterized:
    TABLE 4
    Figure US20050215594A1-20050929-C00619
    Example Calculated MS RT (minutes)
    No. R′ Y MW [M + H+] LC-MS
    74
    Figure US20050215594A1-20050929-C00620
    Figure US20050215594A1-20050929-C00621
         		418.2  419.2 0.93
    75
    Figure US20050215594A1-20050929-C00622
    Figure US20050215594A1-20050929-C00623
         		480.22 481.2 2.01
    76
    Figure US20050215594A1-20050929-C00624
    Figure US20050215594A1-20050929-C00625
         		516.2  517.2 2.18
    77
    Figure US20050215594A1-20050929-C00626
    Figure US20050215594A1-20050929-C00627
         		482.16 483.1 0.75
    78
    Figure US20050215594A1-20050929-C00628
    Figure US20050215594A1-20050929-C00629
         		510.19 511.2 1.03
    79
    Figure US20050215594A1-20050929-C00630
    Figure US20050215594A1-20050929-C00631
         		562.17 563.2 2.02
    80
    Figure US20050215594A1-20050929-C00632
    Figure US20050215594A1-20050929-C00633
         		574.19 575.2 1.73
    • EXAMPLE 81
  • Method A. Preparation of (1R)-1-(3-pyridinyl)-2-({[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol
    Figure US20050215594A1-20050929-C00634
  • According to the procedure of Murata et al., (J. Org. Chem. 62:6458, 1997), Ar was bubbled into a dioxane solution (40 mL) of (tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 38, Method A, 3.90 g, 6.126 mmol) for 10 minutes. To this solution was then added Pd(dppf)Cl2 (100 mg) and Et3N (4.0 mL), and then pinacolborane (2.0 mL, 13.78 mmol, Aldrich Chemical Co.) was added slowly via syringe. The reaction mixture was stirred at 80° C. for 12 hours and allowed to cool to room temperature. It was filtered through a pad of Celite® and concentrated in vacuo to an oily residue. The residue was purified on silica gel with EtOAc-Hexane (1:4) as the eluant to provide (II) (3.73 g, 97%): 1H NMR (CDCl3, δ): −0.1 (s, 3H), 0.10 (s, 3 H), 0.90 (s, 9 H), 1.32 (s, 12 H), 1.50 (s, 9 H), 1.60-1.80 (m, 1 H), 1.95-2.10 (m, 1 H), 2.80 (dd, 2 H), 3.30-3.50 (m, 2 H), 3.60-3.64 (dd, 1 H), 3.76-3.80(dd, 1 H), 4.20-4.26 (m, 1 H), 5.02 (bs, 1 H), 6.78 (d, 1 H), 7.40 (s, 1 H), 7.50 (m, 2 H), 7.75 (m, 1 H), 8.54 (m, 2 H); m/z=625.4 [M+H]+.
    Method B. Preparation of (1R)-1-(3-pyridinyl)-2-({[(2S)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol
    Figure US20050215594A1-20050929-C00635
  • Using the same procedure described in Method A, with tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl{[(2S)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 38, Method B), the title compound was obtained in 63% yield. 1H NMR (DMSO-d6) δ 8.52-8.48 (m, 2 H), 7.72-7.67 (m, 1 H), 7.40-7.32 (m, 3 H), 6.67 (d, J=8.2 Hz, 1 H), 5.09-5.00 (m, 1 H), 4.26-4.16 (m, 1 H), 3.56-3.38 (m, 4 H), 2.76-2.69 (m, 2 H), 1.95-1.89 (m, 1 H), 1.63-1.52 (m, 1 H), 1.25 (s, 9 H), 0.82 (s, 9 H), 0.00 s, 3 H), −0.15 (s, 3 H). LC-MS m/z 625.4 (MH+), RT=3.66 minutes.
    • EXAMPLE 82 Preparation of methyl 2-[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate
  • Figure US20050215594A1-20050929-C00636
  • Argon gas was bubbled through a solution of (1 R)-1-(3-pyridinyl)-2-({[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol (Example 81, 115 mg, 0.184 mmol) in toluene (5 mL) and dioxane (1 mL) for 10 minutes and then Pd(dppf)Cl2(10 mg) and methyl 2-iodobenzoate (72 mg, 0.276 mmol, Aldrich Chemical Co.) were added and the mixture was bubbled with argon for an additional 5 minutes. The mixture was treated with Na2CO3 (1.0 mL of a 2.0 M aq.) and the bi-phase mixture stirred vigorously under Ar at 85° C. for 12 hours. The cooled reaction mixture was filtered through a pad of Celite® and the filtrate was extracted with EtOAc (2×20 mL). Concentration of the organic extracts in vacuo and purification on silica gel using a gradient of 20-30% EtOAc/Hexanes provided the product as colorless oil (61 mg, 52%); 1H NMR (CDCl3, δ): 0.01 (s, 3H), 0.20 (s, 3 H), 0.99 (s, 9 H), 1.59 (s, 9 H), 1.64-1.82 (m, 1 H), 1.98-2.10 (m, 1 H), 2.80-3.00 (dd, 2 H), 3.40-3.58 (m, 2 H), 3.80 (s, 3 H), 3.80-3.90 (dd, 1 H), 4.20-4.40 (m, 2 H), 5.02 (bs, 1 H), 6.78 (d, 1 H), 7.10 (bs, 2 H), 7.40-7.60 (m, 3 H), 7.90-8.00 (m, 3 H), 8.60-8.80 (m, 2 H); MS: [M+H]+ 633.3
    • EXAMPLE 83 Preparation of methyl 2-[(2 R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate
  • Figure US20050215594A1-20050929-C00637
  • A stirred solution of methyl 2-[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 82, 61 mg, 0.096 mmol) in MeOH (0.50 mL) was treated with HCl in dioxane (1 mL of a 4N solution in dioxane, Aldrich Chemical Co.) at room temperature and stirring continued for 60 minutes. The mixture was concentrated in vacuo and purified on silica gel using a gradient of 5-10% MeOH/EtOAc to provide 31 mg of product as colorless oil (77%); 1H NMR (DMSO-d6, δ): 1.65-2.04 (m, 2 H), 2.50-3.10 (m, 6 H), 3.65 (s, 3 H), 4.10 (dd, 1 H), 4.80 (d, 1 H), 6.80 (d, 1 H), 7.00 (bs, 2 H), 7.25-7.40 (m, 3 H), 7.42-7.52 (m, 1 H), 7.78-7.80 (m, 2 H), 8.52 (s, 1 H), 8.60 (s, 1 H); MS: m/z=419.3 [M+H]+.
    • EXAMPLE 84 Preparation of 2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic Acid
  • Figure US20050215594A1-20050929-C00638
  • To a solution of methyl 2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}-methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 83, 60 mg, 0.143 mmol) in THF (0.50 mL) and MeOH (0.50 mL) was added LiOH (1.0 mL of a 2.0 M aq solution), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with 1.0 mL H2O and purified via preparative HPLC (gradient of 100:0 0.1% TFA/H20:acetonitrile to 30:70 0.1% TFA/H20:acetonitrile). The peak of interest was collected and concentrated in vacuo to provide 41 mg of desired final product as a bis-trifluoroacetic acid (TFA) salt; 1H NMR (DMSO-d6, δ): 1.68-1.80 (m, 1 H), 2.04-2.18 (m, 1 H), 2.72-2.90 (m, 2 H), 3.22-3.50 (m, 4 H), 4.58 (dd, 1 H), 5.41 (d, 1 H), 6.82 (d, 1 H), 7.02 (d, 1 H), 7.04 (s, 1 H), 7.30-7.40 (m, 2 H), 7.50 (t, 1 H), 7.62 (d, 1 H), 8.01 (t, 1 H), 8.58 (d, 1 H), 8.82 (d, 1 H), 8.90 (s, 1 H), 9.44 (bs, 1 H), 9.64 (bs, 1 H) MS: m/z=415.2 [M+H]+.
    • EXAMPLE 85 Preparation of Methyl 3-[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl) silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate
  • Figure US20050215594A1-20050929-C00639
  • Argon was bubbled through a solution of the compound of Example 81 (5 g, 8 mmol) in toluene (100 mL) for 10 minutes. Then, [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (460 mg, 0.56 mmol) and methyl 3-bromobenzoate (2.6 g, 12 mmol) were added in a single portion. The resulting reaction mixture was degassed with argon for an additional 5 minutes before aqueous Na2CO3 (2M, 40 mL, 80 mmol) was added and the solution was heated at 85° C. overnight. The product mixture was allowed to cool to room temperature, water was added and the biphasic mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated and purified with a Biotage column, gradient 10-30% ethyl acetate/hexanes to obtain 3.83 g (77%) of the title compound. MH+=633.5
    • EXAMPLE 86 Preparation of 3-[(2R)-2-({(tert-Butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic Acid
  • Figure US20050215594A1-20050929-C00640
  • The product from Example 85 (3.0 g, 4.8 mmol) was diluted with 10 mL each of tetrahydrofuran, water, and methanol; 15 mL of 1 N sodium hydroxide (14.4 mmol) was added; and allowed solution to stir overnight at room temperature. The solution was concentrated, water added, and neutralized with 1 N phosphoric acid. The aqueous layer was extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purified by Biotage in gradient 10-30% ethyl acetate/hexanes, then flushed column with ethyl acetate to 5% methanol/ethyl acetate. Yielded 2.3 g (78%) of product. MH+=619.6
    • EXAMPLE 87 Preparation of N-{3-[(2R)-2-({[(2R)-2-Hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}methanesulfonamide
  • Figure US20050215594A1-20050929-C00641
  • The product of Example 86 (100 mg, 0.16 mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide (36 mg, 0.19 mmol), dimethylaminopyridine (20 mg, 0.16 mmol), and methylsulfonamide (17 mg, 0.18 mmol) were dissolved in 2 mL methylene chloride and stirred overnight at room temperature. The mixture was treated with 0.5 mL 4 M HCl in 1,4-dioxane was added, the solution stirred for 0.5 hours, concentrated to dryness and the residue was purified by preparative HPLC to obtain the title compound (47 mg, 62%). 1H NMR (CD3CN-d3) δ 8.91 (s, 1 H), 8.76 (d, 1 H), 8.51 (d, 1 H), 8.07 (s, 1 H), 7.97 (t, 1 H), 7.88-7.83 (m, 2 H), 7.62-7.56 (m, 1 H), 7.50-7.47 (m, 2 H), 6.98 (d, 1 H), 5.46 (d, 1 H), 4.54-4.47 (m, 1 H), 3.52 (dd, 2 H), 3.37 (s, 3 H), 3.39-3.25 (m, 2 H), 2.99-2.90 (m, 2 H), 2.14-2.09 (m, 1 H), 1.86-1.79 (m, 1 H). MH+=482.2
    • EXAMPLE 88
  • Method A. Preparation of 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methylbenzoic Acid
    Figure US20050215594A1-20050929-C00642
  • Argon was bubbled through a solution of Example 81 (100 mg, 0.16 mmol) in toluene (2 mL) for 10 minutes. Then, palladium acetate (2 mg, 0.008 mmol), 2-(di-tert-butylphosphino)biphenyl (5 mg, 0.016 mmol), and methyl 4-bromo-3-methylbenzoate (55 mg, 0.24 mmol) were added in a single portion. The resulting reaction mixture was degassed with argon for an additional 5 minutes before aqueous Na2CO3 (2M, 1 mL, 1.68 mmol) was added and the solution was heated at 85° C. overnight. The product mixture was allowed to cool to room temperature, water was added, and the biphasic mixture was extracted with ethyl acetate. 1 mL of 4 M HCl/dioxane was added to the combined organic extracts, stirred for 0.5 hour, and concentrated in vacuo. Then, 1 mL of 1 N sodium hydroxide was added, stirred for 0.5 hour, filtered, and purified by preparative HPLC to obtain 8 (7 mg, 11%). MH+=419.3
    Method B. Preparation of 4-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methylbenzoic Acid
    Figure US20050215594A1-20050929-C00643
  • Using the same procedure described in Method A with (1R)-1-(3-pyridinyl)-2-({[(2S)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol (Example 81, Method B), the title compound was obtained in 38% yield: 1H NMR (CD3OD) δ 7.08 (d, J=2.3 Hz, 1 H), 6.95 (dd, J=5.1, 1.8 Hz, 1 H), 6.41-6.37 (m, 1 H), 6.30-6.28 (m, 1 H), 6.24-6.21 (m, 1 H), 5.94-5.89 (m, 1 H), 5.60 (d, J=8.0 Hz, 1 H), 5.50-5.47 (m, 2 H), 5.33 (d, J=8.8 Hz, 1 H), 3.52 (dd, J=9.6, 3.6 Hz, 1 H), 3.38-3.33 (m, 1 H), 2.84-2.78 (m, 1 H), 1.78 (s, 3 H), 1.75-1.72 (m, 1 H), 1.68-1.60 (m, 1 H), 1.43-1.33 (m, 1 H), 1.31-1.25 (m, 1 H), 0.58-0.52 (m, 1 H), 0.32-0.23 (m, 1 H). LC-MS m/z 419.2 (MH+).
    Method C. Preparation of 4-[(2S)-2-({[2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methylbenzoic Acid
    Figure US20050215594A1-20050929-C00644
  • Starting with the (2S)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, Method B) and racemic 2-amino-1-(3-pyridinyl)ethanol dihydrochloride, and using the procedures described in Examples 35-38 and Method A above, the title compound was prepared. LC-MS m/z 419.2 (MH+), RT=1.45 minutes.
  • Using the procedures outlined in Examples 69-88 and using the appropriate aryl halides, trifluoromethanesulfonates, sulfonamides and/or benzoates, the following compounds were prepared and characterized.
    TABLE 5
    Figure US20050215594A1-20050929-C00645
    Calculated MS RT (minutes)
    Example R′ Y MW [M + H+] LC-MS
     89
    Figure US20050215594A1-20050929-C00646
    Figure US20050215594A1-20050929-C00647
         		481 482.2 1.33
     90
    Figure US20050215594A1-20050929-C00648
    Figure US20050215594A1-20050929-C00649
         		557 558.2 2.05
     91
    Figure US20050215594A1-20050929-C00650
    Figure US20050215594A1-20050929-C00651
         		557  558.31 2.01
     92
    Figure US20050215594A1-20050929-C00652
    Figure US20050215594A1-20050929-C00653
         		573 574.2 1.98
     93
    Figure US20050215594A1-20050929-C00654
    Figure US20050215594A1-20050929-C00655
         		561 562.2 2  
     94
    Figure US20050215594A1-20050929-C00656
    Figure US20050215594A1-20050929-C00657
         		577 578.2 2.15
     95
    Figure US20050215594A1-20050929-C00658
    Figure US20050215594A1-20050929-C00659
         		591 592.2 2.25
     96
    Figure US20050215594A1-20050929-C00660
    Figure US20050215594A1-20050929-C00661
         		644 645.2 2.24
     97
    Figure US20050215594A1-20050929-C00662
    Figure US20050215594A1-20050929-C00663
         		509 510.2 1.76
     98
    Figure US20050215594A1-20050929-C00664
    Figure US20050215594A1-20050929-C00665
         		509 510   1.75
     99
    Figure US20050215594A1-20050929-C00666
    Figure US20050215594A1-20050929-C00667
         		481 482.2 1.14
    100
    Figure US20050215594A1-20050929-C00668
    Figure US20050215594A1-20050929-C00669
         		543 544.2 1.88
    101
    Figure US20050215594A1-20050929-C00670
    Figure US20050215594A1-20050929-C00671
         		573 574.2 1.86
    102
    Figure US20050215594A1-20050929-C00672
    Figure US20050215594A1-20050929-C00673
         		561 562.2 1.89
    103
    Figure US20050215594A1-20050929-C00674
    Figure US20050215594A1-20050929-C00675
         		557 558.3 1.96
    104
    Figure US20050215594A1-20050929-C00676
    Figure US20050215594A1-20050929-C00677
         		557 558.2 1.9 
    105
    Figure US20050215594A1-20050929-C00678
    Figure US20050215594A1-20050929-C00679
         		577 578.2 2.02
    106
    Figure US20050215594A1-20050929-C00680
    Figure US20050215594A1-20050929-C00681
         		584 583,585 2.01
    107
    Figure US20050215594A1-20050929-C00682
    Figure US20050215594A1-20050929-C00683
         		509 510 0.39
    108
    Figure US20050215594A1-20050929-C00684
    Figure US20050215594A1-20050929-C00685
         		495 496 0.17
    109
    Figure US20050215594A1-20050929-C00686
    Figure US20050215594A1-20050929-C00687
         		596 595,597 1.68
    110
    Figure US20050215594A1-20050929-C00688
    Figure US20050215594A1-20050929-C00689
         		616 617 1.89
    111
    Figure US20050215594A1-20050929-C00690
    Figure US20050215594A1-20050929-C00691
         		636 637 1.16
    112
    Figure US20050215594A1-20050929-C00692
    Figure US20050215594A1-20050929-C00693
         		558 559 0.47
    113
    Figure US20050215594A1-20050929-C00694
    Figure US20050215594A1-20050929-C00695
         		549 550 1.79
    114
    Figure US20050215594A1-20050929-C00696
    Figure US20050215594A1-20050929-C00697
         		509 510 2.04
    115
    Figure US20050215594A1-20050929-C00698
    Figure US20050215594A1-20050929-C00699
         		523 524 2.12
    116
    Figure US20050215594A1-20050929-C00700
    Figure US20050215594A1-20050929-C00701
         		535 536 0.8 
    117
    Figure US20050215594A1-20050929-C00702
    Figure US20050215594A1-20050929-C00703
         		507 508 1.9 
    118
    Figure US20050215594A1-20050929-C00704
    Figure US20050215594A1-20050929-C00705
         		562 563 3.4 
  • TABLE 6
    Figure US20050215594A1-20050929-C00706
    HPLC
    Example MS RT
    No Y [M + H]+ (min)
    119
    Figure US20050215594A1-20050929-C00707
         		419.3 1.61
    120
    Figure US20050215594A1-20050929-C00708
         		465.1 1.37
    121
    Figure US20050215594A1-20050929-C00709
         		433   1.42
    122
    Figure US20050215594A1-20050929-C00710
         		457   1.68
    123
    Figure US20050215594A1-20050929-C00711
         		462   1.56
    124
    Figure US20050215594A1-20050929-C00712
         		439   1.1 
    125
    Figure US20050215594A1-20050929-C00713
         		435   0.92
    126
    Figure US20050215594A1-20050929-C00714
         		477.2
    127
    Figure US20050215594A1-20050929-C00715
         		537.3 2.30
    128
    Figure US20050215594A1-20050929-C00716
         		487.4 2.21
    129
    Figure US20050215594A1-20050929-C00717
         		479.2 1.74
    130
    Figure US20050215594A1-20050929-C00718
         		463.2 1.86
    131
    Figure US20050215594A1-20050929-C00719
         		463.1 1.88
    132
    Figure US20050215594A1-20050929-C00720
         		475.2 1.95
    133
    Figure US20050215594A1-20050929-C00721
         		477.2 2.08
    134
    Figure US20050215594A1-20050929-C00722
         		491.2 2.17
    135
    Figure US20050215594A1-20050929-C00723
         		435.2 1.66
    136
    Figure US20050215594A1-20050929-C00724
         		449.2 1.87
    137
    Figure US20050215594A1-20050929-C00725
         		464.2 1.91
    138
    Figure US20050215594A1-20050929-C00726
         		450.2 1.59
    139
    Figure US20050215594A1-20050929-C00727
         		419.5 1.68
    140
    Figure US20050215594A1-20050929-C00728
         		405.2 1.68
    141
    Figure US20050215594A1-20050929-C00729
         		419.2 1.91
    142
    Figure US20050215594A1-20050929-C00730
         		406.2 0.79
    143
    Figure US20050215594A1-20050929-C00731
         		458.2 1.95
    144
    Figure US20050215594A1-20050929-C00732
         		479.3 1.55
    145
    Figure US20050215594A1-20050929-C00733
         		465.3 1.13
    146
    Figure US20050215594A1-20050929-C00734
         		420.2 1.15
    147
    Figure US20050215594A1-20050929-C00735
         		495.3 1.63
    148
    Figure US20050215594A1-20050929-C00736
         		405.2 1.53
    149
    Figure US20050215594A1-20050929-C00737
         		419.2 1.55
    150
    Figure US20050215594A1-20050929-C00738
         		423.2 1.26
    151
    Figure US20050215594A1-20050929-C00739
         		406.2 0.62
    152
    Figure US20050215594A1-20050929-C00740
         		419.3 1.58
    153
    Figure US20050215594A1-20050929-C00741
         		419.2 1.69
    154
    Figure US20050215594A1-20050929-C00742
         		411.1 1.18
    155
    Figure US20050215594A1-20050929-C00743
         		433.3 1.94
    156
    Figure US20050215594A1-20050929-C00744
         		411.3 1.52
    157
    Figure US20050215594A1-20050929-C00745
         		411.3 1.33
    158
    Figure US20050215594A1-20050929-C00746
         		406.3 0.62
    159
    Figure US20050215594A1-20050929-C00747
         		395.2 1.07
    160
    Figure US20050215594A1-20050929-C00748
         		455.3 1.99
    161
    Figure US20050215594A1-20050929-C00749
         		451.3 1.17
    162
    Figure US20050215594A1-20050929-C00750
         		423.3 0.63
    163
    Figure US20050215594A1-20050929-C00751
         		500.6 2.27
    164
    Figure US20050215594A1-20050929-C00752
         		472.4 1.99
    165
    Figure US20050215594A1-20050929-C00753
         		516.5 2.38
    166
    Figure US20050215594A1-20050929-C00754
         		488.3 1.96
    • EXAMPLE 167 Preparation of methyl 4-[((2R)-2-{[(tert-butoxycarbonyl)((2R)-2-(3-pyridinyl)-2-{[(1,1,2,2-tetramethylpropyl)-silyl]oxy}ethyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl)methyl]benzoate
  • Figure US20050215594A1-20050929-C00755
  • A solution of 100 mg (0.16 mmol) of (1R)-1-(3-pyridinyl)-2-({[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol Example 81) dissolved in 5 mL of toluene and 1 mL 1,4-dioxane, was bubbled under argon for 10 minutes. Then, 10 mg (0.0122 mmol) of Pd(dppf)Cl2 complex with methylene chloride (1:1) and 54.98 mg (0.24 mmol) of methyl 4-(bromomethyl)benzoate (Aldrich Chemical Co.) were added, and the mixture was bubbled under argon for another 5 minutes. Finally, 1.0 mL (2.0 mmol) of 2M aqueous sodium carbonate was added, and the mixture was stirred under argon at 85° C. for 16 hours. After this time, the mixture was allowed to cool to ambient temperature, filtered through Celite®, rinsed with ethyl ether, and concentrated in vacuo. The product was purified by flash chromatography using 30% ethyl acetate/hexanes as the eluant to provide 77.2 mg of product; MH+ 647.4.
    • EXAMPLE 168 Preparation of 4-{[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino□methyl)-3,4-dihydro-2H-chromen-6-yl]methyl}benzoic Acid
  • Figure US20050215594A1-20050929-C00756
  • To a solution of 77.2 mg (0.11 mmol) methyl 4-[((2R)-2-{[(tert-butoxycarbonyl)((2R)-2-(3-pyridinyl)-2-{[(1,1,2,2-tetramethylpropyl)silyl]oxy}ethyl)amino]-methyl}-3,4-dihydro-2H-chromen-6-yl)methyl]benzoate (Example 167) in 1 mL of tetrahydrofuran was added 0.54 mL of 1M LiOH and 0.27 mL methanol. The mixture was stirred at room temperature for 3 hours after which point 0.5 mL of 1N phosphoric acid was added to the solution. The mixture was partitioned between ethyl acetate (3×5 mL) and water (5 mL). The organic layer was washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated. To the residue was added 0.4 mL of hydrochloric acid in dioxane. This solution was stirred at room temperature for 0.5 hour. The solution was then washed with water and concentrated in vacuo, followed by purification by preparative HPLC (gradient of 100:0 0.1% TFA/H20:acetonitrile to 30:70 0.1% TFA/H20:acetonitrile) to obtain 16.4 mg of product as the TFA salt. MH+ 419.3. 1H NMR (DMSO d6, δ): 8.89 (br. s, 1 H), 8.63 (s, 1 H), 8.57 (d, 1 H), 7.88 (dt, 1 H), 7.85 (s, 1 H), 7.82 (s, 1 H), 7.50 (dd, 1 H), 7.32 (s, 1 H), 7.29 (s, 1 H), 6.96 (m, 2 H), 6.73 (d, 1 H), 6.38 (br. s, 1 H), 5.08 (m, 1 H), 4.38 (m, 1 H), 2.76 (m, 1 H), 2.71 (m, 1 H), 1.99 (m, 1 H), 1.67 (m, 1 H).
    • EXAMPLE 169 Preparation of (2R)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-nitro-3,4-dihydro-2H-chromene-2-carboxamide
  • Figure US20050215594A1-20050929-C00757
  • (2R)-6-Nitro-3,4-dihydro-2H-chromene-2-carboxylic acid (4.1 g, 18 mmol) and (1R)-2-amino-1-(3-pyridinyl)ethanol (5.0 g, 24 mmol) (both described in U.S. Pat. No. 6,051,586) were suspended in CH2Cl2 and stirred vigorously. Triethylamine (9.2 mL, 66 mmol) was added followed by hydroxybenzotriazole (4.9 g, 36 mmol) and EDCl (6.9 g, 36 mmol), and the reaction was stirred overnight. After 18 hours, TLC showed no remaining acid starting material, so the reaction was partitioned between water and CH2Cl2 and the organic layer was washed 3×100 mL of water. The organic layer was washed with 1N HCl, which removed the product into the aqueous layer. This aqueous layer was washed with CH2Cl2 and the organic was discarded. The aqueous solution was then basified and became cloudy with a white precipitate. The basified mixture was extracted with 3×100 mL of CH2C2.
  • The combined organic layer was concentrated, affording the product (4.5 g) as a light yellow foam. 1H NMR (DMSO-d6, δ): 8.4 (d, 2H), 8.1 (t, 1H), 8.0 (m, 2H), 7.6 (d, 1H), 7.3 (m, 1H), 7.0 (d, 1H), 5.6 (s, 1H), 4.7 (m, 2H), 3.3 (m, 2H) 2.8 (m, 1H), 2.6 (m, 1H), 2.2 (m, 1H), 1.9 (m, 1H); LC/MS: m/z 343, MH+344.
    • EXAMPLE 170 Preparation of (1 R)-2-({[(2R)-6-nitro-3,4-dihydro-2H-chromen-2-yl]methyl}amino)- 1-(3-pyridinyl)ethanol
  • Figure US20050215594A1-20050929-C00758
  • (2R)-N-[(2R)-2-Hydroxy-2-(3-pyridinyl)ethyl]-6-nitro-3,4-dihydro-2H-chromene-2-carboxamide (Example 169, 1.0 g, 3 mmol) was dissolved in 15 mL of THF and borane-dimethylsulfide complex (1.4 mL, 12.6 mmol) was added dropwise. The reaction was refluxed for one hour after which TLC showed no remaining starting material. Methanol (0.5 mL) was then added dropwise followed by 6N HCl (0.5 mL) and the reaction was refluxed an additional 1.5 hours. The solution was then cooled and diluted with water and ethyl acetate, and adjusted to about pH 9 with 1N NaOH. The organic layer was dried and evaporated to afford the product (650 mg) as a yellow solid. 1H NMR (DMSO-d6, δ): 8.6 (s, 1H), δ 8.5 (d, 1H), δ 8.1 (s, 1H), δ 8.0 (d, 1H), δ 7.8 (d, 1H), δ 7.4 (m, 1H), δ 7.0 (d, 1H), δ 5.6 (s, 1 H), δ4.8 (m, 1H), δ 4.3 (m, 1H), δ 3.2 (s, 1H), δ 2.9 (m, 2H), δ 2.8 (m, 2H), δ 2.1 (m, 1H), δ 1.8 (m, 1H); LC/MS: m/z 329, MH+330
    • EXAMPLE 171 Preparation of tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2R)-6-nitro-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
  • Figure US20050215594A1-20050929-C00759
  • (1 R)-2-({[(2R)-6-nitro-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-(3-pyridinyl)ethanol (Example 170, 650 mg, 2 mmol) was dissolved in 12 mL THF, di-tert-butyl-dicarbonate (440 mg, 2 mmol) was added, and the reaction was stirred and monitored by TLC. Upon completion, when the disappearance of starting material was observed, the reaction was partitioned between water and ethyl acetate. The crude product obtained by concentration of the organic layer was purified by filtration through a silica plug to give 777 mg of material as a white foam. 1H NMR (DMSO-d6, δ): 8.4 (m, 2H), 8.1 (s, 1H), 7.9 (d, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 6.9 (d, 1H), 5.6 (d, 1H), 4.8 (m, 1H), 4.4 (m, 1H), 3.5 (m, 4H), 2.8 (m, 2H), 2.0 (m, 1H), 1.6 (m, 1H), 1.2 (s, 9H); LC/MS: m/z 429, MH+430.
    • EXAMPLE 172 Preparation of tert-butyl [(2R)-6-amino-3,4-dihydro-2H-chromen-2-yl]methyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate
  • Figure US20050215594A1-20050929-C00760
  • tert-Butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2R)-6-nitro-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 171, 500 mg, 1.2 mmol) was dissolved in degassed THF, and to the solution was added Pd/C (50 mg, 10%) under argon and cooled to 0° C. NaBH4 was dissolved in ethanol and added to the reaction slowly to avoid excessive bubbling. After gas evolution had stopped, the reaction was warmed to room temperature and monitored by TLC. When complete, the reaction was cooled to 0° C. and quenched by the addition of ice. The black precipitate was then filtered through Celite® and the filtrate was concentrated in vacuo until cloudy. The filtrate was then extracted with ethyl acetate and the crude material was purified via flash chromatography to yield the product (30%). 1H NMR (DMSO-d6, δ): 8.4 (m, 2H), 7.7 (m, 1 H), 7.4 (m, 1H), 6.4 (d, 1H), 6.3 (s, 1H), 6.2 (d, 1H), 5.6 (d, 1H), 4.8 (m, 1H), 4.5 (m, 1H), 3.5 (m, 2H), 3.4 (m, 2H), 2.8 (m, 2H), 1.8 (m, 1H), 1.5 (m, 1H), 1.2 (d, 9H); LC/MS: m/z 399, MH+ 400
    • EXAMPLE 173 Preparation of 3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoic acid
  • Figure US20050215594A1-20050929-C00761
  • Utilizing a procedure reported by Schutze (EP 0067352 B2), a solution of 510 mg (1.25 mmol) of Example 172 in 15 mL of acetone was cooled to 0° C., and 1.3 mL (2.5 mmol) of 2N hydrochloric acid was added. Sodium nitrite (95 mg, 1.38 mmol) dissolved in 1.3 mL of water at 0° C. was added slowly to the reaction flask.
  • The resulting mixture was then allowed to stir at 0° C. for 1 hour while 270 mg (1.75 mmol) 3-mercaptobenzoic acid, 279 mg (1.75 mmol) copper sulfate, and 1.24 mL water were mixed together at room temperature for 0.5 hour. After this time, the cold (0° C.) solution was added slowly to the room temperature solution. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then added to 100 mL water and extracted 3 times with 25 mL ethyl acetate. The combined organic phases were washed with water and brine, and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was used without further purification.
    • EXAMPLE 174 Preparation of 3-{[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoic acid
  • Figure US20050215594A1-20050929-C00762
  • To 670 mg (1.25 mmol) of crude 3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]aminomethyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoic acid (Example 173) diluted in 5 mL 1,4-dioxane, was added 0.5 mL of 6N hydrochloric acid slowly. The resulting mixture was stirred at 45° C. for 2 hours. After this time the mixture was concentrated in vacuo, dissolved in 2 mL of 1:1 methanol to water, and purified by HPLC (0-70% acetonitrile/0.1% TFA) to afford 28.5 mg (5% yield) of the desired product as the bis TFA salt. MH+437.3. 1H NMR (CDCl3, δ): 8.91 (br. S, 1 H), 8.63 (d, 1 H), 8.56 (dd, 1 H), 7.89 (m, 1 H), 7.72 (dt, 1 H), 7.62 (m, 1 H), 7.49 (m, 1 H), 7.39 (m, 1 H), 7.31 (m, 1 H), 7.27 (m, 1 H), 7.24 (dd, 1 H), 6.90 (d, 1 H), 6.35 (br. S, 1 H), 5.07 (m, 1 H), 4.48 (m, 1 H), 3.32 (m, 4 H), 3.16 (m, 1 H), 2.78 (m, 2 H), 2.04 (m, 1 H), 1.71 (m, 1 H).
    • EXAMPLE 175 Preparation of methyl 3-[{(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoate
  • Figure US20050215594A1-20050929-C00763
  • To 650 mg (1.25 mmol) of 3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoic acid (Example 173) dissolved in 10 mL 1:1 methanol/ethyl acetate, was added 3 mL of 2M trimethylsilyl diazomethane dropwise. The resulting solution was then allowed to stir at room temperature for 16 hours. The solution was then diluted with ethyl acetate, washed with water and brine, and concentrated in vacuo. The crude mixture was purified by Biotage with 75% ethyl acetate/hexanes to obtain 223 mg (33% yield) of product; MH+ 551.2.
    • EXAMPLE 176 Preparation of methyl 3-{[(2 R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfonyl}benzoate
  • Figure US20050215594A1-20050929-C00764
  • A solution of 0.5 mL (3.6 mmol) of trifluoroacetic anhydride in 2 mL methylene chloride was cooled to 0° C., and then 0.11 mL (1.1 mmol) of 30% hydrogen peroxide was added to the solution slowly, allowing the solution to stir at this temperature for 5 minutes. Then a solution of 200 mg (0.36 mmol) methyl 3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoate (Example 175) in 1 mL of methylene chloride was added to the cold solution dropwise and the reaction mixture was stirred at 0° C. for 1 hour, followed by stirring at room temperature for 0.5 hour. The mixture was diluted with 10 mL ethyl ether and washed with 20 mL of 1N aqueous sodium hydroxide. The aqueous layer was extracted with ethyl ether, and the organic phase was washed sequentially with 20% aqueous sodium sulfite, water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to obtain 66.3 mg (21% yield) of crude product; MH+ 583.2.
    • EXAMPLE 177 Preparation of 3-{[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfonyl}benzoic acid
  • Figure US20050215594A1-20050929-C00765
  • To a solution of 66.3 mg (0.11 mmol) methyl 3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfonyl}benzoate (Example 176) diluted in 5 mL 1,4-dioxane, was slowly added 0.05 mL of 6N hydrochloric acid. The resulting mixture was then stirred at 45° C. for 2 hours. The crude mixture was concentrated in vacuo, then purified by preparative HPLC. The purified intermediate product was then treated with 0.8 mL of 2N sodium hydroxide and allowed to stir for 36 hours and then concentrated in vacuo. The crude product was then purified by preparative HPLC (0-70% Acetonitrile/0.1% aq TFA) to obtain 6.5 mg of product as the bis-TFA salt. MH+ 469.3 (free base)
    • EXAMPLE 178 Preparation of 2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl trifluoromethanesulfonate
  • Figure US20050215594A1-20050929-C00766
  • To 2,4-dihydroxybenzoic acid (Aldrich) (10.0 g, 64.9 mmol, 1.0 eq.) was added trifluoroacetic acid (80 mL), trifluoroacetic anhydride (50 mL), and acetone (10 mL) at 0° C. The reaction mixture was allowed to warm up slowly to room temperature and stirred for 48 hours. The mixture was then concentrated under reduced pressure. The resulting residue was washed with saturated sodium bicarbonate (100 mL), extracted with ethyl acetate (3×100 mL). The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give crude product 9.2 g as yellow solid.
  • The crude product was treated with trifluoromethanesulfonic anhydride (8.8 mL, 52.11 mmol, 1.1 eq.) in the presence of pyridine (50 mL) at 0° C. for 8 hours. The resulting mixture was then diluted with distilled water (100 mL), extracted with ethyl acetate (3×50 mL), and washed with saturated sodium bicarbonate (60 mL) and brine (100 mL). The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give brown oil. Purification by flash chromatography on a silica gel column (20%-40% ethyl acetate/hexanes) yielded the desired product as a white solid (8.3 g, 40%). 1H NMR (CDCl3) δ 8.08 (d, 1H), 7.03 (d, 1H), 6.94 (s, 1H), 1.77 (s, 6H), GC-MS: 326 (M+), retention time: 7.557 min.
    • EXAMPLE 179 Preparation of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl{[(2S)-6-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
  • Figure US20050215594A1-20050929-C00767
  • By using procedure described in Example 85, the compounds of Example 178 and Example 81 were coupled to provide the desired compound. LC-MS: 421.4 (MH+-Boc), retention time: 1.54 min.
    • EXAMPLE 180 Preparation of 2-hydroxy-4-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid
  • Figure US20050215594A1-20050929-C00768
  • To a solution of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl) ethyl{[(2S)-6-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 179, 0.07 g, 0.104 mmol, 1.0 eq.) in tetrahydrofuran (3 mL) was added 4N hydrochloric acid in 1,4-dioxane (2 mL) at room temperature. The reaction mixture was allowed to stir at room temperature for 16 hours. The mixture was then concentrated under reduced pressure. Purification by HPLC afforded the desired HCl salt as a white solid (0.005 g, 10%). LC-MS: 421.4 (MH+), retention time: 1.54 min.
    • EXAMPLE 181 Preparation of methyl 4-[(2S)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl) silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-hydroxybenzoate
  • Figure US20050215594A1-20050929-C00769
  • To a solution of the compound of Example 179 in methanol (10 mL) was added potassium carbonate (0.12 g) at room temperature. The reaction mixture was allowed to stir at room temperature for 18 hours and then concentrated under reduced pressure. The resulting residue was washed with distilled water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the desired product as pale yellow oil (0.68 g, 94%). LC-MS: 649.8 (MH+), retention time: 3.80 min.
    • EXAMPLE 182 Preparation of methyl 4-[(2S)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl) silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]2-isobutoxybenzoate
  • Figure US20050215594A1-20050929-C00770
  • To a solution of the compound of Example 181 (0.097 g, 0.0015 mmol, 1.0 eq.) in N,N-dimethylformamide (0.5 mL) were added 1-iodo-2-methylpropane (0.10 ml) and potassium carbonate (0.10 g). The reaction mixture was stirred at 60° C. for 16 hours. The mixture was diluted with distilled water (2 mL) and extracted with ethyl acetate (3×2 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as clear oil (0.076 g, 74%). LC-MS: 705.3 (MH+), retention time: 4.01 min.
    • EXAMPLE 183 Preparation of 4-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutoxybenzoic acid
  • Figure US20050215594A1-20050929-C00771
  • To a solution of the compound of Example 182 (0.076 g, 0.11 mmol, 1.0 eq.) in methanol (1.0 mL) was added 1M lithium hydroxide (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was neutralized by 1N hydrochloric acid and then extracted with ethyl acetate (3×2 mL). The extracts were concentrated under reduced pressure to give white solid. To this crude was added 4N hydrochloric acid in 1,4-dioxane (1.5 mL) and the mixture was stirred for 3 hours at room temperature. The resulting mixture was concentrated under reduced pressure to give white solid. Purification by HPLC yielded the desired HCl salt as a white solid (15.7 mg, 26%). LC-MS: 477.2 (MH+), retention time: 1.97 min.
  • By using procedure described in Examples 182 and 183, the following analogs were prepared.
    TABLE 7
    Figure US20050215594A1-20050929-C00772
    Calcu- RT
    lated MS (minutes)
    Example R′ MW [M + H+] LC-MS
    184
    Figure US20050215594A1-20050929-C00773
         		434 435.1 1.45
    185
    Figure US20050215594A1-20050929-C00774
         		448 449.1 1.73
    186
    Figure US20050215594A1-20050929-C00775
         		462 463.2 1.87
    187
    Figure US20050215594A1-20050929-C00776
         		478 479.2 1.63
    188
    Figure US20050215594A1-20050929-C00777
         		462 463.2 1.83
    • EXAMPLE 189 Preparation of phenylmethyl 4-bromo-2-fluorobenzoate
  • Figure US20050215594A1-20050929-C00778
  • Benzyl bromide (0.86 g, 5.0 mmol, 1.1 eq.) was added neat to a solution of 4-bromo-2-fluorobenzoic acid. (1.0 g, 4.6 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.36 ml, 9.2 mmol, 2.0 eq.) in anhydrous acetonitrile (20 mL). The reaction was stirred at room temperature for 18 hours before removing the solvent in vacuo. The residue was diluted with ether and washed with water, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, and brine. The organic layer was dried (MgSO4) and concentrated in vacuo to provide the title compound as a pale yellow oil that crystallized into long needles upon standing (1.4 g, 99%): 1H NMR (300 MHz, CDCl3) δ 7.82 (t, 1H), 7.42-7.31 (m, 7 H), 5.35 (s, 2 H); GC/MS m/z 308/310 (M+ and M+2).
    • EXAMPLE 190 Preparation of phenylmethyl 4-bromo-2-(phenyloxy)benzoate
  • Figure US20050215594A1-20050929-C00779
  • Phenylmethyl 4-bromo-2-fluorobenzoate (Example 189, 260 mg, 0.84 mmol) was combined with phenol (160 mg, 1.68 mmol, 2.0 eq.) and solid potassium carbonate (580 mg, 4.21 mmol, 5.0 eq.) in anhydrous N,N-dimethylformamide and was heated at 85° C. for 5 hours. The mixture was cooled and partitioned between diethyl ether and water. The aqueous layer was separated and extracted with fresh ether. The organic layers were combined, washed with brine (4×), dried (MgSO4), and concentrated in vacuo to a crude oil. The crude was purified by flash chromatography on silica gel eluted with 95:5 hexanes/ether to provide the title compound as a colorless oil that crystallized upon standing (110 mg, 34%): 1H NMR (300 MHz, CDCl3) δ 7.84 (d, 1 H), 7.39-7.27 (m, 7 H), 7.17-7.10 (m, 1 H), 6.98-6.91 (m, 2 H), 6.85 (d, 2 H), 5.30 (s, 2 H); Rf0.51 (4:1 hexanes/diethyl ether).
    • EXAMPLE 191 Preparation of phenylmethyl 4-{(2R)-2-[([(2R)-2-{[(1,1-dimethylethyl) (dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]}[(1,1-dimethylethyl)oxy]carbonyl}amino) methyl]-3,4-dihydro-2H-chromen-6-yl}-2-(phenyloxy)benzoate
  • Figure US20050215594A1-20050929-C00780
  • Argon gas was bubbled through a solution of the compound of Example 81 (160 mg, 0.25 mmol) in toluene (5 mL), dioxane (1 mL), and aqueous Na2CO3 (0.5 mL of a 2.0 M solution) for 10 minutes. Pd(dppf)Cl2(20 mg, 0.025 mmol, 0.1 eq.) and phenylmethyl 4-bromo-2-(phenyloxy)benzoate (Example 190, 110 mg, 0.27 mmol, 1.1 eq.) were added, and argon was bubbled through the mixture for an additional 5 minutes before being stirred vigorously at 85° C. for 3 hours. The reaction mixture was cooled and filtered through a pad of Celite® with the aid of ethyl acetate. The filtrate was transferred to a separatory funnel where the water layer was removed. The organic layer was dried (MgSO4) and concentrated in vacuo to a crude oil. The crude was purified by flash chromatography on silica gel eluted on a gradient from 100:0 to 70:30 hexanes/ethyl acetate to provide the title compound as a colorless oil (69 mg, 34%): 1H NMR (300 MHz, CDCl3) δ 8.58-8.47 (m, 2 H), 7.96 (d, 1 H), 7.64 (dd, 1 H), 7.32 (d, 1 H), 7.27-7.20 (m, 10 H), 7.17-7.12 (m, 1 H), 7.00 (t, 1 H), 6.89 (d, 2 H), 6.72 (d, 1 H), 5.20 (s, 2 H), 5.11-4.90 (m, 1 H), 4.21-4.03 (m, 1 H), 3.73 (d, 1 H), 3.63-3.54 (m, 1 H), 3.42-3.14 (m, 2 H), 2.81-2.70 (m, 2 H), 1.98-1.89 (m, 1 H), 1.68-1.60 (m, 1 H), 1.42 (s, 9 H), 0.83 (s, 9 H), −0.01 (s, 3 H), −0.018 (s, 3 H); MS m/z 801.2 (MH+).
    • EXAMPLE 192 Preparation of 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(phenyloxy)benzoic acid
  • Figure US20050215594A1-20050929-C00781
  • Phenylmethyl 4-{(2R)-2-[([(2R)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}-2-(phenyloxy)benzoate (Example 191, 69 mg, 0.086 mmol) was stirred over a suspension of 10% Pd/C (7 mg) in ethanol (5 mL) under a hydrogen atmosphere for 15 hours. Solids were removed by filtration through Celite®, and the filtrate was concentrated in vacuo. The carboxylic acid intermediate was collected as a colorless oil (25 mg, 41%): 1H NMR (300 MHz, CD3OD) δ 8.66-8.58 (m, 2 H), 7.99 (d, 1 H), 7.92 (d, 1 H),7.58-7.54 (m, 2 H), 7.51-7.41 (m, 2 H), 7.37-7.34 (m, 2 H), 7.21-7.16 (m, 2 H), 7.10 (d, 2 H), 6.86 (d, 1 H), 5.27-5.15 (m, 1 H), 4.38-4.31 (m, 1 H), 3.86-3.54 (m, 4 H), 2.96-2.90 (m, 2 H), 2.13-2.00 (m, 1 H), 1.87-1.75 (m, 1 H), 1.56 (d, 9 H), 1.00 (s, 9 H), 0.18 (d, 3 H), 0.00 (s, 3 H). The carboxylic acid intermediate (25 mg, 0.04 mmol) was stirred in an excess of 4M HCl in dioxane at room temperature for 18 hours. The volatile components were removed by rotary evaporation, and the residue was washed with dichloromethane. After drying under vacuum, the title compound was collected as the di-hydrochloride salt (16 mg, 80%): 1H NMR (300 MHz, CD3OD) δ 9.04 (broad s, 1 H), 8.89 (broad s, 1 H), 8.77 (d, 1 H), 8.15 (t, 1 H), 8.00 (d, 1 H), 7.46 (d, 1 H), 7.38-7.33 (m, 4 H), 7.14-7.08 (m, 2 H), 6.98 (d, 3 H), 5.45 (d, 1 H), 4.50 (t, 1 H), 3.76-3.55 (m, 5 H), 3.52-3.35 (m, 2 H), 2.99-2.85 (m, 2 H), 2.18-2.11 (m, 1 H), 1.85-1.75 (m, 1 H); MS m/z 497.2 (MH+ of the free base).
  • By employing the methods described above for Examples 190-192, the following were similarly prepared and characterized:
    TABLE 8
    Figure US20050215594A1-20050929-C00782
    Example Calculated MS LC-MS
    No. R″ MW [M + H+] RT (min)
    193 —F 514.19 515.1 1.88
    194 —Cl 530.16 531.2 2.01
    195 —CH3 510.22 511.2 1.96
    196 —OCH3 526.21 527.2 1.94
    197 —CO2Et 568.22 569.2 1.99
    198 —SO2CH3 574.18 575.1 1.77
    • EXAMPLE 199 Preparation of tert-butyl benzyl{[(2S)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
  • Figure US20050215594A1-20050929-C00783
  • To a solution of N-benzyl[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl] methanamine (Example 217, 20.0 g, 60.2 mmol, 1.0 mmol) in tetrahydrofuran (200 mL) was added di-tert-butyl dicarbonate (14.45 g, 66.22 mmol, 1.1 eq.) at room temperature. The reaction mixture was stirred at room temperature for 18 hours and then quenched with distilled water (100 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL) and washed with saturated sodium bicarbonate (50 mL) and brine (80 mL). The combined extracts were dried over magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure to yield the desired product as colorless oil which was used without further purification (25 g, 100%).
    • EXAMPLE 200 Preparation of tert-butyl benzyl{[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
  • Figure US20050215594A1-20050929-C00784
  • To a degassed solution of the compound of Example 199 (15.0 g, 57.24 mmol, 1.0 mmol) in dimethyl sulfoxide (120 mL) was added bis(pinacolato)diboron (15.0 g, 57.24 mmol, 1.0 eq.), dichloro[1,1′-bis(diphenylphospphino)ferrocene]palladium(II) dichloromethane adduct (1.46 g, 1.72 mmol, 0.03 eq.) and potassium acetate (17.0 g, 171.72 mmol, 3.0 eq.) under argon atmosphere at room temperature. The reaction mixture was allowed to heat up at 85° C. under argon atmosphere for 24 hours. The mixture was then allowed to cool down to room temperature and filter through silica gel. The filtrates were extracted with diethyl ether (3×100 mL). The combined extracts were washed with saturated sodium bicarbonate (50 mL) and brine (80 mL), dried over magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure to yield yellow oil. Purification by flash chromatography on a silica gel column (5%-10% ethyl acetate/hexanes) yielded the desired product as yellow oil (13.5 g, 81%). LC-MS: 479.9 (MH+), retention time: 4.41 min.
    • EXAMPLE 201 Preparation of tert-butyl benzyl{[(2R)-6-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
  • Figure US20050215594A1-20050929-C00785
  • By using the procedure described in Example 85, the compounds of Example 200 and Example 178 were coupled to provide the desired compound. LC-MS: 529.9 (MH+), retention time: 4.36 min.
    • EXAMPLE 202 Preparation of methyl 4-((2R)-2-{[benzyl(tert-butoxycarbonyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl)-2-hydroxybenzoate
  • Figure US20050215594A1-20050929-C00786
  • By using the procedure described in Example 181, the title compound was prepared. LC-MS: 503.7 (MH+), retention time: 4.51 min.
    • EXAMPLE 203 Preparation of methyl 4-((2R)-2-{[benzyl(tert-butoxycarbonyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate
  • Figure US20050215594A1-20050929-C00787
  • By using the procedure described in Example 12, the compound of Example 202 was converted into the title compound. LC-MS: 635.6 (MH+), retention time: 4.48 min.
    • EXAMPLE 204 Preparation of methyl 5-{(2R)-2-[(benzylamino)methyl]-3,4-dihydro-2H-chromen-6-yl}-4′-methyl-1,1′-biphenyl-2-carboxylate
  • Figure US20050215594A1-20050929-C00788
  • To a degassed solution of the compound of Example 203 (0.31 g, 0.49 mmol, 1.0 eq.) in toluene (1.0 mL) was added 4-methylphenylboronic acid (0.10 g, 0.73 mmol, 1.5 eq.), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.028 g, 0.034 mmol, 0.07 eq.) and 2M sodium carbonate (2.4 mL, 4.88 mmol, 10.0 eq.) under argon atmosphere at room temperature. The reaction mixture was allowed to heat up at 80° C. under argon atmosphere for 18 hours. The mixture was diluted with distilled water (3 mL) and extracted with diethyl ether (3×2 mL). The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was then treated with 4N hydrochloric acid (1.0 mL) in tetrahydrofuran (3 ml) and stirred at room temperature for 48 hours. The mixture was concentrated under reduced pressure to give white solid. Purification by HPLC followed yielded the desired product as clear oil (0.18 g, 77%). LC-MS: 578.0 (MH+), retention time: 4.63 min.
    • EXAMPLE 205 Preparation of 5-[(2R)-2-([(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-4′-methyl-1,1′-biphenyl-2-carboxylic acid
  • Figure US20050215594A1-20050929-C00789
  • To a solution of the compound of Example 204 (0.18 g, 0.38 mmol, 1.0 eq.) in isopropanol (4.0 mL) were added the compound of Example 1 (0.09 g, 0.57 mmol, 1.5 eq.) and potassium carbonate (0.16 g, 1.13 mmol, 3.0 eq.) at room temperature. The reaction mixture was allowed to heat up at 95° C. for 16 hours. The mixture was diluted with distilled water (6 mL) and extracted with ethyl acetate (3×6 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by HPLC yielded the intermediate as a colorless oil. The pure intermediate was then treated with 1M lithium hydroxide (1.0 mL) in the presence of methanol (2.0 mL) and stirred at 80° C. for 15 hours. The mixture was neutralized by 1N hydrochloric acid and then extracted with ethyl acetate (3×2 mL). The extracts were concentrated under reduced pressure to give white solid. To this crude in methanol (1 mL) was added palladium hydroxide (0.04 g) and ammonium formate(0.045 g) under argon atmosphere and the mixture was stirred at 65° C. for 14 hours. The resulting mixture was filtered through celite and concentrated under reduced pressure to give white solid. Purification by HPLC yielded the desired TFA salt as a white solid (10 mg, 10%). LC-MS: 585.3 (MH+), retention time: 2.35 min.
    • EXAMPLE 206 Preparation of methyl 4-(benzyloxy)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate
  • Figure US20050215594A1-20050929-C00790
  • To a solution of methyl-4-benzyloxy-2-hydroxybenzoate (5.34 g, 21 mmol) and pyridine (2.5 g, 31.5 mmol) in dichloromethane (100 mL) was added trifluoromethanesulfonic anhydride (8.17 g, 29 mmol) slowly. The resulting mixture was stirred overnight, washed with 1N HCl, brine, dried, evaporated to afford 4.3 g yellow solid. (53% yield). 1HNMR Chloroform-d δ 4.01 (d, 3H), 5.17 (d, 2H), 6.89 (d, 1H), 7.2 (d, 1H), 7.30-7.41 (m, 5H), 8.10 (t, 1H). Rf=0.37 ethyl acetate/hexane (1/9).
    • Example 207 Preparation of methyl 4-(benzyloxy)-2-isobutylbenzoate
  • Figure US20050215594A1-20050929-C00791
  • To a condensed liquid 2-methyl-1-propene in THF (10 mL) at −78° C. was added 0.5 M 9-BBN (3 mL, 1.5 mmol), the mixture was allowed to warm up to room temperature with stirring. The mixture was transferred via a syringe to a degassed solution containing the compound of Example 206 (0.5 g, 1.3 mmol), Pd(dppf)Cl2 (82 mg, 0.1 mmol), K2CO3 (0.23 g, 1.7 mmol), water (2 mL) in DMF (21 mL). The resulting mixture was heated at 60° C. overnight. After removal of solvent, the residue was purified by chromatography to afford the title compound (0.11 g, 31% yield). 1HNMR Chloroform-d δ 0.85 (d, 6H), 1.75-1.80 (m, 1H), 2.88 (d, 2H), 3.78 (s, 3H), 5.13 (s, 2H), 6.71-6.80 (m, 2H), 7.30-7.41 (m, 5H), 7.90 (d, 1H). Rf=0.65 ethyl acetate/hexane (1/9).
    • EXAMPLE 208 Preparation of methyl 4-(hydroxy)-2-isobutylbenzoate
  • Figure US20050215594A1-20050929-C00792
  • A solution of the compound of Example 207 (0.8 g, 2.6 mmol), 10% Pd-C in MeOH (30 mL) was hydrogenated overnight. The mixture passed through Celite® and concentrated to yellow residue (0.5 g, 89% yield). 1HNMR Chloroform-d δ 0.90 (d, 6H), 1.82-1.90 (m, 1H), 2.89 (d, 2H), 3.90 (s, 3H), 6.73-6.80 (m, 2H), 7.88 (d, 1H). Rf=0.41 ethyl acetate/hexane (4/6).
    • EXAMPLE 209 Preparation of methyl 2-isobutyl-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate
  • Figure US20050215594A1-20050929-C00793
  • To a solution of the compound of Example 198 (0.5 g, 2.4 mmol) and pyridine (0.21 g, 2.6 mmol) in dichloromethane (50 mL) was added trifluoromethanesulfonic anhydride (0.75 g, 2.6 mmol) slowly. The resulting mixture was stirred overnight, washed with 1N HCl, brine, dried, evaporated to afford 0.51 g yellow solid. (64% yield). Rf=0.63 ethyl acetate/hexane (1/9).
    • EXAMPLE 210 Preparation of methyl 4-{(2S)-2-[(4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-4-(3-pyridinyl)butyl]-3,4-dihydro-2H-chromen-6-yl}-2-isobutylbenzoate
  • Figure US20050215594A1-20050929-C00794
  • The reaction mixture of the compound of Example 81 (1.3 g, 2.1 mmol), the compound of Example 209 (0.7 g, 2.1 mmol) and potassium carbonate (0.9 g, 6.3 mmol) in toluene (20 mL) was flushed with Ar for 5 minutes, and Pd(PPh3)4 was added quickly to the reaction. The reaction mixture was refluxed overnight at 45° C. After removal of solvent in vacuo, the crude product was purified by silica gel chromatography to afford 0.32 g of white solid in 23% yield. Rf=0.63 ethyl acetate/hexane (3/7), MS: m/z (M+1) 690.43.
    • EXAMPLE 211 Preparation 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutylbenzoic acid
  • Figure US20050215594A1-20050929-C00795
  • The compound of Example 210 (0.3 g, 0.4 mmol) was dissolved in 4.0 M HCl in dioxane (30 mL) and stirred overnight. After removal of the solvent, the residue was dissolved in MeOH-THF (1:1) (26 mL). NaOH (0.6 g), water (3 mL) was added to the solution and refluxed for 3 hours. After the reaction cooled to room temperature, 2N HCl was added to pH=3. White solid was formed and filtered to collect the white solid. The solid was purified by HPLC to afford 0.15 g yellow solid (50% yield). 1HNMR Methanol-d4 δ 0.93 (d, 2H), 1.81-1.91 (m, 2H), 2.20-2.25 (m, 1H), 2.91-3.08 (m, 4H), 3.35-3.41 (m, 4H), 4.53 (t, 1H), 5.43 (d, 1H), 7.03 (d, 1H), 7.43-7.50 (m, 4H), 7.95 (d, 1H), 8.09 (t, 1H), 8.70 (d, 1H), 8.87 (s, 1H), 9.0 (s, 1H). Rf=0.21 methanol/dichloromethane (2/8), MS: m/z (M+1) 461.30.
    • EXAMPLE 212 Preparation of methyl 4-(benzyloxy)-2-(2-phenylethyl)benzoate
  • Figure US20050215594A1-20050929-C00796
  • To a solution of styrene in THF (50 mL), 9-BBN was added slowly, stirring at room temperature for overnight. The solution was degassed for 5 minutes and the compound of Example 206, Pd(dppf)Cl2, and Et3N were added at once. The reaction mixture was heated to reflux for 3-4 hours. The solvent was stripped. Residue was partitioned between EtOAc and H2O (100 ml/50 mL), aqueous layer was extracted with EtOAc (2×100 mL). Organic solvent was dried over anhydrous Na2SO4 and removed under the reduced pressure. The crude product was purified by column chromatography to give 0.40 g of the desired compound (25%). 1H NMR (MeOH-d4, δ ppm): 8.10-8.18 (m, 2H), 10.28-10.32 (m, 2H), 3.90 (s, 3H), 7.11-7.18 (m, 2H), 7.10-7.31 (m, 10H), 8.20-8.91 (m, 2H), 8.01 (d, 1 H). Rf=0.51 (CH2Cl2:MeOH=95:5)
    • EXAMPLE 213 4-[(2R)-2-([{(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(2-phenylethyl)benzoic acid
  • Figure US20050215594A1-20050929-C00797
  • Using the procedures outlined in Examples 208-211, Example 212 was converted to the title compound. MS [M+H]+ 508.2, Rf=0.24 (CH2Cl2:MeOH=95:5). H1 NMR (MeOD-d4,δ ppm): 1.64 (2H, d), 1.73-1.85 (1H, m), 2.07-2.10 (1H, m), 2.90-2.96 (2H, m), 3.31 (2H, d), 3.36-3.56 (4H, m), 4.47 (1H, m), 5.38 (1H, dd), 6.95 (1H, dd), 7.13-7.46 (9H, m), 7.87 (1H, d), 8.03-8.05 (1H, m), 8.60 (1H, d), 8.82 (1H, br.s.), 8.95 (1H, br.s.)
    • EXAMPLE 214 Preparation of methyl 4-{2-[(2S)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl) silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoate
  • Figure US20050215594A1-20050929-C00798
  • Using the procedure outlined in Example 212, methyl 4-vinylbenzoate was hydroborated with 9-BBN and coupled with the compound of Example 38 to provide the title compound. MS [M+H]+661.4, Rf=0.43 (Hex:EtOAc=2:1). H1 NMR (CDCl3,δ ppm): 0.12 (s, 6H), 0.67-0.72 (s, 9H), 1.43 (s, 9H), 1.55-1.59 (m, 1H), 1.81-1.95 (m, 2H), 2.68-2.93 (m, 5H), 3.15-3.72 (m, 4H), 3.80 (s, 3H), 4.01-4.21 (m, 1H), 4.91-5.02 (m, 1H), 6.55-6.60 (m, 1 H), 6.70-6.78 (m, 2H), 7.25-7.38 (m, 3H), 7.60-7.73 (m, 1 H), 7.83-7.92 (m, 2H), 8.41-8.58 (m, 2H).
    • EXAMPLE 215 Preparation of 4-{2-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid
  • Figure US20050215594A1-20050929-C00799
  • Using the procedures outlined in Examples 208-211, the compound of Example 214 was converted to the title compound. MS [M+H]+432.2, Rf=0.5 (CH2Cl2:MeOH=7:3) H1 NMR (MeOH-d4, δ ppm): 1.66-1.80 (1H, m), 2.01-2.12 (1H, m), 2.82-2.92 (6H, m), 3.18-3.30 (6H, m), 4.32 (1H, t), 5.10 (1H, dd), 6.72 (1H, d), 6.85-6.88 (2H, m), 7.16 (2H, d), 7.48 (1H, dd), 7.84 (2H, d), 7.94 (1H, d), 8.51 (1H, d), 8.63 (1H, s)
    • EXAMPLE 216 Preparation of 3-{2-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid
  • Figure US20050215594A1-20050929-C00800
  • Using the procedures outlined in Examples 208-211, the compound of Example 215 was converted to the title compound. MS [M+H]+432.2, Rf=0.5 (CH2C2:MeOH=7:3) H1 NMR (MeOH-d4, δ ppm): 1.66-1.80 (1H, m), 1.99-2.12 (1H, m), 2.80-2.92 (6H, m), 3.18-3.30 (6H, m), 4.32 (1H, t), 5.10 (1H, dd), 6.72 (1H, d), 6.85-6.88 (2H, m), 7.15-7.17 (2H, m), 7.46 (1H, dd), 7.81-7.85 (2H, m), 7.94 (1H, d), 8.51 (1H, d), 8.63 (1H, s)
    • EXAMPLE 217 Preparation of N-benzyl-N-{[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methyl}amine
  • Figure US20050215594A1-20050929-C00801
  • In a 30 L reaction vessel, N-benzyl[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine hydrobromide (2173 g, 6.5 moles, 1.0 eq.) was suspended in 11.4 L formic acid. The suspension was cooled to 16° C., then bromine (1071 g, 6.7 moles, 1.03 eq.) was added over a 60 minutes, maintaining the reaction temperature between 15 and 16° C. After 70 minutes, a HPLC probe indicated the reaction to be complete. To the reaction mixture was then added 15.6 L water (temperature increased to 21° C). The light reaction mixture was then stirred for 30 minutes at room temperature, then the product was filtered and washed with 3.9 L water. The 3.14 kg of light gray moist product was then suspended in 9.75 L dichloromethane. To this suspension was added 13 L 1M NaHCO3. Foaming ensued and the suspension became a bi-phasic solution. The aqueous phase was separated (14.5 L; pH=8) and the organic phase was washed with 6.5 L water. The phases were separated and the organic phase evaporated at 45° C. to yield 1820 g of N-benzyl-N-{[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methyl}amine.
    • EXAMPLE 218 Preparation of 4-bromo-N-(2-pyrimidinyl)benzene-sulfonamide
  • Figure US20050215594A1-20050929-C00802
  • A mixture of 4-bromobenzene sulfonyl chloride (3.0 g, 11.74 mmol) and 2-aminopyrimidine (1.17 g, 12.3 mmol, 1.05 eq) in anhydrous pyridine (23 mL) was stirred at 50° C. for 17 hours. The reaction was quenched with 2N aqueous hydrochloric acid (100 mL) and the resultant reaction mixture was extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (1×100 mL) and brine (1×100 mL), dried (Na2SO4), filtered, and evaporated under reduced pressure. Recrystallization from ethyl acetate—dichloromethane gave the desired product as a white solid (2.95 g, 80%). LC-MS (ES MH+=314/316); TLC (Rf=0.42, 75% ethyl acetate—hexane).
  • Using the procedure outline in Example 208 and the appropriate amine and sulfonyl chloride, the following sulfonamides were prepared.
    TABLE 9
    Example
    No. Structure
    219
    Figure US20050215594A1-20050929-C00803
    220
    Figure US20050215594A1-20050929-C00804
    221
    Figure US20050215594A1-20050929-C00805
    222
    Figure US20050215594A1-20050929-C00806
    223
    Figure US20050215594A1-20050929-C00807
    224
    Figure US20050215594A1-20050929-C00808
    225
    Figure US20050215594A1-20050929-C00809
    226
    Figure US20050215594A1-20050929-C00810
    227
    Figure US20050215594A1-20050929-C00811
    228
    Figure US20050215594A1-20050929-C00812
    229
    Figure US20050215594A1-20050929-C00813
    230
    Figure US20050215594A1-20050929-C00814
    231
    Figure US20050215594A1-20050929-C00815
    232
    Figure US20050215594A1-20050929-C00816
    233
    Figure US20050215594A1-20050929-C00817
    234
    Figure US20050215594A1-20050929-C00818
    235
    Figure US20050215594A1-20050929-C00819
    236
    Figure US20050215594A1-20050929-C00820
    237
    Figure US20050215594A1-20050929-C00821
    238
    Figure US20050215594A1-20050929-C00822
    239
    Figure US20050215594A1-20050929-C00823
    240
    Figure US20050215594A1-20050929-C00824
    241
    Figure US20050215594A1-20050929-C00825
    242
    Figure US20050215594A1-20050929-C00826
    243
    Figure US20050215594A1-20050929-C00827
    244
    Figure US20050215594A1-20050929-C00828
    245
    Figure US20050215594A1-20050929-C00829
    246
    Figure US20050215594A1-20050929-C00830
    • EXAMPLE 247 Preparation of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl[((2R)-6-{4-[(2-pyrimidinylamino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]carbamate
  • Figure US20050215594A1-20050929-C00831
  • A solution of the compound of Example 81, (1.08 g, 1.73 mmol) in toluene (10 mL) and ethanol (10 mL) was degassed with argon for 10 minutes. At this time, the compound of Example 218 (815 mg, 2.59 mmol) was added followed by [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (98 mg, 0.12 mmol) and 2M aqueous Na2CO3 (8.5 mL). The reaction was bubbled with argon for another 10 minutes and then heated to 80° C. overnight. The reaction was diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure and the residue was coated on silica. The silica coated product was purified on the MPLC (Biotage) with 30-100% ethyl acetate in hexanes then 2% methanol in methylene chloride to afford 796 mg (1.09 mmol, 63%) of product. LC-MS (ES MH+=732, Rt=3.27 min); TLC (Rf=0.31,100% ethyl acetate).
    • EXAMPLE 248 Preparation of tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl[((2 R)-6-{3-[(2-pyrimidinylamino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]carbamate
  • Figure US20050215594A1-20050929-C00832
  • A solution of the compound of Example 247 (796 mg, 1.09 mmol) in tetrahydrofuran (20 mL) was treated with a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (4.4 mL, 4.40 mmol). The reaction was stirred at room temperature for 2 hours. At this time, the product was coated on silica, concentrated at reduced pressure, and purified on the MPLC (Biotage) with 2-4% methanol in methylene chloride to afford 650 mg (1.05 mmol, 96%) of the desired product. TLC (Rf=0.13, 100% ethyl acetate).
    • EXAMPLE 249
  • Method A. Preparation of 4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide
    Figure US20050215594A1-20050929-C00833
  • A solution of the compound of Example 248 (1.32 g, 2.13 mmol) in ethyl acetate (20 mL) and methylene chloride (2 mL) was treated with 4 N HCl in 1,4-dioxane (5.5 mL, 22.0 mmol). A suspension was formed and was allowed to stir at room temperature under argon overnight. The reaction was then diluted with diethyl ether and decanted. The solid was rinsed several times with diethyl ether and dried on high vacuum to afford 1.13 g (1.80 mmol, 85%) of product as the hydrochloride salt. 1H-NMR (CD3OD-d6) δ 9.04 (s, 1H), 8.88 (d, J=5.7 Hz, 1H), 8.79 (d, J=8.1 Hz, 1 H), 8.44 (d, J=4.8Hz, 2H), 8.17 (dd, J=5.8 Hz, 8.0 Hz, 1H), 8.09 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.9 Hz, 2H), 7.46-7.42 (m, 2H), 7.02-6.96 (m, 2H), 5.44 (dd, J=3.0 Hz, 10.5 Hz, 1H), 4.50 (t, J=9.8 Hz, 1H), 3.62-3.35 (m, 4H), 3.02-2.94 (m, 2H), 2.21-2.14 (m, 1H), 1.87-1.80 (m, 1H); LC-MS (ES MH+=518), Rt=1.05 min.
    Method B. Preparation of 4-[(2S)-2-({[-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide
    Figure US20050215594A1-20050929-C00834
  • Starting with the (2S)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, Method B) and 2-amino-1-(3-pyridinyl)ethanol dihydrochloride and following the procedures described in Examples 247-248 and Method A above, the title compound was prepared. 1H NMR (CD3OD) δ 9.10 (s, 1 H), 8.93-8.85 (m, 1 H), 8.61 (d, J=5.2 Hz, 2 H), 8.55 (d, J=4.6 Hz, 1 H), 8.23-8.17 (m, 1 H), 8.11 (d, J=8.0 Hz, 1 H), 7.74 (d, J=8.3, 1 H), 7.44 (s, 1 H), 7.12-7.08 (m, 1 H), 7.06-7.01 (m, 1 H), 5.58-5.53 (m, 1 H), 4.60-452 (m, 1 H), 3.75-3.50 (m, 3 H), 3.52-3.41 (m, 1 H), 3.08-2.88 (m, 2 H), 2.22-2.18 (m, 1 H). 1.90-1.75 (m, 1 H). LC-MS m/z 518.2 (MH+), Rt=0.71 minutes.
  • Using the procedures described in Examples 247-248, and the starting materials described in Examples 218-246, the following compounds were prepared:
    TABLE 10
    Example MS RT (min,
    No. Structure [M + H+] LC-MS)
    250
    Figure US20050215594A1-20050929-C00835
         		518 1.01
    251
    Figure US20050215594A1-20050929-C00836
         		585 1.91
    252
    Figure US20050215594A1-20050929-C00837
         		599 1.94
    253
    Figure US20050215594A1-20050929-C00838
         		517 1.53
    254
    Figure US20050215594A1-20050929-C00839
         		517 1.44
    255
    Figure US20050215594A1-20050929-C00840
         		570 1.96
    256
    Figure US20050215594A1-20050929-C00841
         		541 2.02
    257
    Figure US20050215594A1-20050929-C00842
         		541 2.02
    258
    Figure US20050215594A1-20050929-C00843
         		570 1.94
    259
    Figure US20050215594A1-20050929-C00844
         		586 2.04
    260
    Figure US20050215594A1-20050929-C00845
         		517 1.55
    261
    Figure US20050215594A1-20050929-C00846
         		518 1.37
    262
    Figure US20050215594A1-20050929-C00847
         		625 2.14
    263
    Figure US20050215594A1-20050929-C00848
         		642 2.17
    264
    Figure US20050215594A1-20050929-C00849
         		558 2.01
    265
    Figure US20050215594A1-20050929-C00850
         		523 1.55
    266
    Figure US20050215594A1-20050929-C00851
         		653 2.32
    267
    Figure US20050215594A1-20050929-C00852
         		578 1.95
    268
    Figure US20050215594A1-20050929-C00853
         		532 1.35
    269
    Figure US20050215594A1-20050929-C00854
         		562 1.53
    270
    Figure US20050215594A1-20050929-C00855
         		608 1.92
    271
    Figure US20050215594A1-20050929-C00856
         		592 1.66
    272
    Figure US20050215594A1-20050929-C00857
         		548 1.3 
    273
    Figure US20050215594A1-20050929-C00858
         		562 1.52
    274
    Figure US20050215594A1-20050929-C00859
         		662 2.14
    275
    Figure US20050215594A1-20050929-C00860
         		616 1.74
    276
    Figure US20050215594A1-20050929-C00861
         		573 2.07
    277
    Figure US20050215594A1-20050929-C00862
         		571 1.94
    278
    Figure US20050215594A1-20050929-C00863
         		603 2.03
    279
    Figure US20050215594A1-20050929-C00864
         		517 1.23
    280
    Figure US20050215594A1-20050929-C00865
         		588 1.87
    • EXAMPLE 281 tert-Butyl {(2S)-6-[3-(aminosulfonyl)phenyl]-3,4-dihydro-2H-chromen-2-yl}methyl [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]carbamate
  • Figure US20050215594A1-20050929-C00866
  • The solution of Na2CO3 (2 N, 6 mL), toluene (6 mL), and ethanol (6 mL) was degassed for 10 minutes. Then the compound of Example 81 (1001 mg, 1.62 mmol), 3-bromobenzenesulphonamide (458 mg, 1.94 mmol) and PdCl2(dppf) (132 mg, 0.16 mmol) were added to the above solution and it was degassed for another 5 minutes. Then, the reaction mixture was heated to reflux overnight. After it was allowed to cool down, the reaction mixture was poured into water and was extracted with EtOAc. The combined organic layer was washed by water, brine, dried over Na2SO4, and concentrated. Chromatography with 20% -30% ethyl acetate in hexane provided the title compound (670 mg) as a pale yellow oil. ESLC-MS: m/z=654 (MH+); 1H NMR (MeOH-d4): 8.576-8.451 (m, 2H), 8.077 (s, 1H), 7.906˜7.752 (m, 3H), 7.565 (t, 1H), 7.459 (m, 1H), 7.383(m, 2H), 6.813 (d, 1H), 5.185˜5.050 (m, 1H), 4.251 (t, 1H), 3.772˜3.348 (m, 4H), 2.879 (m, 2H), 2.045 (m, 1 H), 1.741 (m, 1 H), 1.447(d, 9H), 0.897 (s, 9H), 0.083 (s, 3H), −0.102 (s, 3H).
    • EXAMPLE 282 tert-Butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl{[(2S)-6-(3-}[(methoxyacetyl)amino]sulfonyl}phenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
  • Figure US20050215594A1-20050929-C00867
  • A solution of the compound of Example 281 (60 mg, 0.091 mmol), methoxyacetic acid (13 mg, 0.13 mmol), EDCI (26 mg, 0.14 mmol), and DMAP (11 mg, 0.091 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated down and the crude product was purified by preparative TLC plate with CH2Cl2: MeOH: NH4OH (90:15:2) to obtain (60 mg). ESLC-MS: m/z=725 (MH+); 1H NMR (MeOH-d4): 8.566˜8.439 (m, 2H), 8.077 (s, 1 H), 7.889˜7.780 (m, 1H), 7.675 (m, 1H), 7.453 (m, 2H), 7.313(m, 2H), 6.767 (d, 1H), 5.180˜5.035 (m, 1H), 4.220 (s, b, 1H), 3.907 (s, 2H), 3.760˜3.333 (m, 4H), 2.835 (m, 2H), 2.041 (m, 1H), 1.711 (m, 1H), 1.445 (d, 9H), 0.892 (s, 9H), 0.076 (s, 3H), −0.109 (s, 3H).
    • EXAMPLE 283 3-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(methoxyacetyl)benzenesulfonamide
  • Figure US20050215594A1-20050929-C00868
  • Using the procedure described in Example 249, the title compound was prepared. ESLC-MS m/z=512 (MH+), HPLC retention time=1.53 min.
  • Using the procedures described in Examples 281-283, the compounds described below were similarly prepared.
    TABLE 11
    Example MS RT (min,
    No. Structure [M + H +] LC-MS)
    284
    Figure US20050215594A1-20050929-C00869
         		550.1 1.97
    285
    Figure US20050215594A1-20050929-C00870
         		508.2 1.75
    286
    Figure US20050215594A1-20050929-C00871
         		526.2 1.89
    287
    Figure US20050215594A1-20050929-C00872
         		528.2 0.54
    288
    Figure US20050215594A1-20050929-C00873
         		618.1 2.04
    289
    Figure US20050215594A1-20050929-C00874
         		538.3 0.36
    290
    Figure US20050215594A1-20050929-C00875
         		510.2 0.25
    291
    Figure US20050215594A1-20050929-C00876
         		512.2 0.21
    292
    Figure US20050215594A1-20050929-C00877
         		524   2.01
    293
    Figure US20050215594A1-20050929-C00878
         		574 1.86
    294
    Figure US20050215594A1-20050929-C00879
         		544 1.55
    295
    Figure US20050215594A1-20050929-C00880
         		562 1.93
    296
    Figure US20050215594A1-20050929-C00881
         		558 2.01
    297
    Figure US20050215594A1-20050929-C00882
         		558 2.01
    298
    Figure US20050215594A1-20050929-C00883
         		574 2.18
    299
    Figure US20050215594A1-20050929-C00884
         		558 2.13
    300
    Figure US20050215594A1-20050929-C00885
         		573 2.15
    301
    Figure US20050215594A1-20050929-C00886
         		577 2.27
    302
    Figure US20050215594A1-20050929-C00887
         		577 2.26
    303
    Figure US20050215594A1-20050929-C00888
         		574 1.94
    304
    Figure US20050215594A1-20050929-C00889
         		525 0.76
    305
    Figure US20050215594A1-20050929-C00890
         		496 1.57
    • EXAMPLE 306 Preparation of 1-(4-bromophenyl)-2-[(phenyl)sulfonyl]ethan-1-one
  • Figure US20050215594A1-20050929-C00891
  • To benzenesulfonyl chloride (0.5 mL, 3.92 mmol) in 4:1 v/v tetrahydrofuran—water (20 mL) was added powdered zinc (282 mg, 4.31 mmol, 1.1 eq.) followed by 4-bromophenacyl bromide (1.31 g, 4.70 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 17 hours. The volatile solvent was evaporated under reduced pressure and poured into water. The reaction was extracted with ethyl acetate (2×150 mL), and the combined organic layers were washed with brine (1×100 mL), dried (MgSO4), filtered, and evaporated under reduce pressure. The crude product was purified using MPLC (Biotage) eluted with 5:1 v/v hexane—ethyl acetate. Crystallization from dichloromethane—hexane gave the desired product as a white fluffy solid (486 mg, 36.6% yield). MS LC-MS (ES MH+=340); TLC (Rf=0.30, 25% ethyl acetate—hexane)
    • EXAMPLE 307 Preparation of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl [((2R)-6-{4-[(phenylsulfonyl)acetyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl] carbamate
  • Figure US20050215594A1-20050929-C00892
  • The procedure was analogous to that described in Example 247 except 1-(4-bromophenyl)-2-[(phenyl)sulfonyl]ethan-1-one was used instead of 4-bromo-N-(2-pyrimidinyl)benzene-sulfonamide. TLC (Rf=0.16, 40% ethyl acetate—hexane); LC-MS (ES MH+=757), Rt=3.70 min.
    • EXAMPLE 308 Preparation of 1-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-(phenylsulfonyl)ethanone dihydrochloride
  • Figure US20050215594A1-20050929-C00893
  • Using the procedure described in Examples 248 and 249, the title compound was prepared. 1H-NMR (CD3OD-d6) δ 9.02 (s, 1H), 8.86 (d, J=5.6 Hz, 1H), 8.73 (d, J=8.0 Hz, 1H), 8.15-8.08 (m, 2H), 7.92-7.41 (m, 10H), 7.02 (d, J=9.0 Hz, 1H), 5.44 (dd, J=2.9 Hz, 10.7 Hz, 1H), 4.52 (t, J=10.2 Hz, 1H), 3.65-3.33 (m, 6H), 3.15-2.89 (m, 2H), 2.22-2.15 (m, 1H), 1.93-1.80 (m, 1H); LC-MS (ES MH+=543), Rt=2.06 min.
  • Using the procedures described in Examples 306-308 and using the appropriate sulfonyl chlorides, the following compounds were similarly prepared.
    TABLE 12
    Example MS RT (min,
    No. Structure [M + H ]+ LC-MS)
    309
    Figure US20050215594A1-20050929-C00894
         		557 2.06
    310
    Figure US20050215594A1-20050929-C00895
         		578 1.83
    311
    Figure US20050215594A1-20050929-C00896
         		543 2.06
    • EXAMPLE 312 Preparation of 1-(3-bromophenyl)-5-hydroxy-4-methyl-1,2-dihydro-3H-pyrazol-3-one
  • Figure US20050215594A1-20050929-C00897
  • To a suspension of 1-(3-bromophenyl)hydrazine hydrochloride (1.0 g, 4.47 mmol) in ethanol (8.9 mL) was added dropwise 2.0 M sodium ethoxide in ethanol (0.77 mL, 9.84 mmol, 2.2 eq.). Diethyl 2-methylmalonate (0.85 mL, 4.92 mmol, 1.1 eq.) was then added. The reaction mixture was stirred at 90° C. for 16 hours and then quenched with 2 N aqueous hydrochloric acid (50 mL). The reaction was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried (MgSO4), filtered, and evaporated under reduced pressure. Purification using MPLC (Biotage) eluted with 3:1 V/V ethyl acetate—hexane gave the desired product as a white solid (125 mg, 0.46 mmol, 10.4% yield). MS LC-MS (ES MH+=269/271); TLC (Rf=0.10, 50% ethyl acetate—hexane).
    • EXAMPLE 313 Preparation of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl ({(2S)-6-[3-(4-hydroxy-4-methyl-3,5-dioxo-1-pyrazolidinyl)phenyl]-3,4-dihydro-2H-chromen-2-yl}methyl)carbamate
  • Figure US20050215594A1-20050929-C00898
  • Using the procedures described in Example 247, Example 312 was converted to the title compound. LC-MS (ES MH+=783); TLC (Rf=0.19, 20% methanol—dichloromethane).
    • EXAMPLE 314 Preparation of 4-hydroxy-1-{3-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-4-methyl-3,5-pyrazolidinedione dihydrochloride
  • Figure US20050215594A1-20050929-C00899
  • Using the procedure described in Examples 248 and 249, the title compound was prepared. 1H-NMR (CD3OD-d6) δ 8.96 (s, 1H), 8.84 (d, J=5.4 Hz, 1H), 8.64 (d, J=8.1 Hz, 1H), 8.07 (dd, J=8.07Hz, 6.0 Hz, 1H), 7.91 (s, 1H), 7.58 (dt, J=7.2Hz, 2.1 Hz, 1H), 7.49 to 7.41 (m, 4H), 7.00 (d, J=9.6 Hz, 1H),5.38 (dd, J=10.8 Hz, 2.7 Hz, 1H), 4.48 (t, J=7.2 Hz, 1H), 3.65 to 3.35 (m, 4H), 3.13 to 2.95 (m, 3H), 2.19 to 2.14 (m, 1H), 1.87 to 1.75 (m, 1H), 1.70 to 1.64 (m, 1H), 1.51 (s, 3H), 1.44 to 1.28 (m, 2H); LC-MS (ES MH+=489), Rt=1.10 min.
    • EXAMPLE 315 Preparation of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl {[(2R)-6-(5-nitro-2-pyridinyl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
  • Figure US20050215594A1-20050929-C00900
  • The procedure was analogous to that of Example 247 except methyl 2-chloro-5-nitropyridine was used instead of 3-bromo-N-(2-pyrimidinyl)benzene-sulfonamide. LC-MS (ES MH+=621), Rt=3.68 min; TLC (Rf=0.05, 25% ethyl acetate—hexane).
    • EXAMPLE 316 Preparation of tert-butyl [(2R)-6-(5-amino-2-pyridinyl)-3,4-dihydro-2H-chromen-2-yl]methyl[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]carbamate
  • Figure US20050215594A1-20050929-C00901
  • A dry flask under argon was charged with 10% Pd on C (50 mg) and ethanol (10 mL) followed by the addition of Example 315 (700 mg, 1.13 mmol). The reaction was stirred under hydrogen (1 atm) overnight. TLC analysis showed complete reaction. The reaction was then filtered through celite and the filtrate was concentrated at reduced pressure. The crude product was then purified on the MPLC (biotage) with 100% ethyl acetate to afford the desired product (610 mg, 91%). LC-MS (ES MH+=591), Rt=2.57 min; TLC (Rf=0.27, 100% ethyl acetate).
    • EXAMPLE 317 Preparation of (1R)-2-({[(2R)-6-(5-amino-2-pyridinyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-(3-pyridinyl)ethanol tetrahydrochloride
  • Figure US20050215594A1-20050929-C00902
  • Using the procedure described in Examples 248 and 249, the title compound was prepared. 1H-NMR (CD3OD-d6) δ 9.06 (s, 1H), 8.89 (d, J=5.6 Hz, 1H), 8.82 (d, J=7.9 Hz, 1H), 8.18 (dd, J=6.1 and 8.2 Hz, 1H), 7.96-7.91 (m, 2H), 7.75 (dd, J=2.6 Hz and 9.2 Hz, 1H), 7.60-7.56 (m, 2H), 7.14 (d, J=8.1 Hz, 1H), 5.49 (d, J=10.2 Hz, 1H), 4.59 5 (t, J=8.5 Hz, 1H), 3.75-3.36 (m, 4H), 3.13-2.92 (m, 2H), 2.26-2.20 (m, 1H), 1.91-1.84 (m, 1H); LC-MS (ES MH+=377), Rt=0.70 min.
    • EXAMPLE 318 Preparation of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl[((2R)-6-{5-[(phenylsulfonyl)amino]-2-pyridinyl}-3,4-dihydro-2H-chromen-2-yl)methyl]carbamate
  • Figure US20050215594A1-20050929-C00903
  • A solution of Example 316 (80 mg, 0.135 mmol) and benzene sulfonyl chloride (41 mg, 0.233 mmol) in pyridine (1.5 mL) was stirred at 50° C. overnight. The reaction was diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The crude product was coated on silica and purified on the MPLC (Biotage) with 40-70% ethyl acetate in hexanes to afford the desired product (91 mg, 92%). LC-MS (ES MH+=731), Rt=3.32 min, TLC Rf=0.25 60% ethyl acetate in hexanes).
    • EXAMPLE 319 Preparation of N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide trihydrochloride
  • Figure US20050215594A1-20050929-C00904
  • Using the procedure described in Examples 248 and 249, Example 318 was converted to the title compound. 1H-NMR (CD3OD-d6) δ 9.05 (s, 1H), 8.88 (d, J=5.2 Hz, 1H), 8.79 (d, J=7.8 Hz, 1H), 8.43 (d, J=1.7, 1H), 8.18-7.90 (m, 5H), 7.70-7.55 (m, 5H), 7.15 (d, J=8.3 Hz, 1H), 5.47 (d, J=9.2 Hz, 1H), 4.60 (t, J=10.0 Hz, 1H), 3.67-3.32 (m, 4H), 3.11-2.92 (m, 2H), 2.26-2.19 (m, 1H), 1.91-1.84 (m, 1H); LC-MS (ES MH+=517), Rt=1.70 min.
  • Using the procedures described in Examples 318 and 319, and using the appropriate acyl or sulfonyl chloride, the following compounds were prepared.
    TABLE 13
    Example MS RT (min,
    No. Structure [M + H+] LC-MS)
    320
    Figure US20050215594A1-20050929-C00905
         		551 1.98
    321
    Figure US20050215594A1-20050929-C00906
         		455 0.8 
    322
    Figure US20050215594A1-20050929-C00907
         		481 1.41
    323
    Figure US20050215594A1-20050929-C00908
         		419 0.74
    • EXAMPLE 324 Preparation of 3-((1R)-1-hydroxy-2-{[((2R)-6-{3-[({[(4-methylphenyl)aminolcarbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl) methyl]amino}ethyl)pyridine hydrochloride
  • Figure US20050215594A1-20050929-C00909
  • To a stirred solution of Example 281 (45 mg) in dichloroethane (10 mL), were added Et3N (0.014 mL) and 4-methylphenyl isocyanate (0.013 mL). Stirring was continued at room temperature over a 2-3 hour period. The solvent was removed under reduced pressure. Crude product was purified by combiflash column chromatography to give the free base of the desired product (27 mg, 50% yield). This material was treated with HCl (4 M) in dioxane and stirred at room temperature overnight. The solvent was removed under reduced pressure to provide the crude product, which was purified by preparative HPLC-to provide the title compound. MS [M+H]+ 573.21, Rf=0.68 (CH2Cl2:MeOH=50:50); H1 NMR (MeOH-d4,δ ppm): 2.25 (s, 3H), 2.85-3.08 (m, 2H), 3.38-3.67 (m, 6H), 4.50 4.54(m, 1H), 5.45-5.47 (m, 1H), 7.04-7.07 (m, 4H), 7.24 (d, 2H, J=6.3 Hz), 7.40 (dd, 1H, J=6.3 Hz), 7.42-7.45 (m, 2H), 7.63 (t, 1H, J=6.0 Hz), 7.87 (d, 1H, J=6.0 Hz), 7.93 (d, 1H, J=6.0 Hz), 8.10-8.20 (m, 1H), 8.22 (s, 1H), 8.78-8.79 (m, 1H).
  • Using the procedures outline in Examples 281 and 324, the following compounds were similarly prepared.
    TABLE 14
    Ex-
    ample MS HPLC TLC
    No. Structure [M + H]+ (RT) Rf (solvent)
    325
    Figure US20050215594A1-20050929-C00910
         		654.3 0.22 (7:3 ethyl acetate/hexanes)
    326
    Figure US20050215594A1-20050929-C00911
         		573.2 0.25 (1:9 MeOH CH2Cl2)
    327
    Figure US20050215594A1-20050929-C00912
         		577.3 0.21 (1:9 MeOH CH2Cl2)
    328
    Figure US20050215594A1-20050929-C00913
         		559.3 0.23 (1.9 MeOH CH2Cl2)
    329
    Figure US20050215594A1-20050929-C00914
         		565.37 0.31 (1:9 MeOH CH2Cl2)
    330
    Figure US20050215594A1-20050929-C00915
         		629.34 0.21 (1:9 MeOH CH2Cl2)
    331
    Figure US20050215594A1-20050929-C00916
         		595.42 0.22 (1:9 MeOH CH2Cl2)
    332
    Figure US20050215594A1-20050929-C00917
         		559.2  8.2 min
    333
    Figure US20050215594A1-20050929-C00918
         		577.2 9.3
    334
    Figure US20050215594A1-20050929-C00919
         		589.2 6.6
    335
    Figure US20050215594A1-20050929-C00920
         		592.2 10.1 
    336
    Figure US20050215594A1-20050929-C00921
         		577.2 6.4
    337
    Figure US20050215594A1-20050929-C00922
         		627.2 5.7
    338
    Figure US20050215594A1-20050929-C00923
         		577.31 0.23 (1:9 MeOH CH2Cl2)
    339
    Figure US20050215594A1-20050929-C00924
         		525.32 0.27 (1:9 MeOH CH2Cl2)
    340
    Figure US20050215594A1-20050929-C00925
         		593.31 0.31 (1:9 MeOH CH2Cl2)
    • EXAMPLE 341 Preparation of 3,4-Dimethylphenyloxirane
  • Figure US20050215594A1-20050929-C00926
  • The procedure was based on methods described by Brandes and Jacobsen, (Tetrahedron Asym. 8:3927,1997); and Kaufman (Syn. Commun. 23:473,1993). A solution of trimethylsulfonium methylsulfate (3.95 g, 0.021 mol) in 8 mL water was added slowly to a biphasic mixture of 50% NaOH (20 mL), 3,4-dimethyl-benzaldehyde (1.34 g, 0.01 mmol), tetrabutylammonium bromide (0.025 g, 0.0782 mmol), and CH2Cl2 (26 mL). The reaction was heated at 50° C. for 13 hours and then cooled to room temperature. The reaction was diluted carefully with brine (50 mL) and diethyl ether (3×70 mL), then filtered to remove the solids. The aqueous layer was extracted with diethyl ether (3×70 mL), and the combined organic layers were washed with brine (50 mL) and dried over Na2SO4, filtered, and concentrated in vacuo to afford the product 3,4-dimethylphenyl oxirane as a light yellow oil (1.15 g, yield 78%). TLC Rf=0.9 (1:2 EtOAc/Hexane); 1H NMR (300 MHz, CDCl3) δ 7.39 (s, 1 H), 7.21 (d, 1 H), 7.19 (s, 1 H), 3.80 (m, 1 H), 3.17 (m, 1 H), 2.80 (m, 1 H), 2.23 (s, 6 H).
    • EXAMPLE 342-354 General Procedure for Coupling Epoxides (4-[(2R)-2-({[2-(3,4-dimethylphenyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic Acid)
  • Step 1: Condensation of the Chroman Amine with Epoxides
  • Into an 8-mL screw-cap vial were dispensed 200 μL of a 0.5 M solution of 6-(4-methoxycarbonylphenyl)-(R)-chroman-2-methylamine (Example 19 free base, 0.01 mmol) and 200 μL of the appropriate epoxide solution (commercial or prepared as in Example 341, 0.01 mmol). Dioxane (500 μL) and water (100 μL) were then added to each vial, and the mixture was heated at 80° C. with mixing by orbital shaking for 2 days. After the mixture was allowed to cool to room temperature, the solvent was removed under reduced pressure by using a multiple sample evaporator (GeneVac).
  • Step 2: Hydrolysis of the Methyl Ester
  • The residue obtained from the previous procedure was heated in 1 mL 2 M lithium hydroxide solution in 3:1 methanol/water at 60° C. overnight. After allowing the reaction mixture to cool to room temperature, 1.1 mL hydrochloric acid (2 N) was slowly added to each vial. Precipitate was formed in the vial. The solvent was removed under reduced pressure by using a multiple sample evaporator (GeneVac). The residue was dissolved in 1 mL MeOH, and then purified by preparative reversed phase HPLC, using aqueous MeCN containing 0.1% trifluoroacetic acid as eluant.
  • In a typical example, 6-(4-methoxycarbonylphenyl)-(R)-chroman-2-methylamine and 3,4-dimethylphenyl oxirane were reacted by following the procedure described above to provide 4-[(2R)-2-({[2-(3,4-dimethylphenyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid as the trifluoroacetate salt (17% yield). 1H NMR (300 MHz, DMSO) δ 7.95 (d, 2 H), 7.72 (d, 2 H), 7.50 (d, 2 H), 7.15-7.00 (m, 3 H), 6.95 (m, 1 H), 4.45 (m, 2 H), 3.80 (m, 1 H), 3.30 (s, 4 H), 2.95-2.80 (m, 2 H), 2.10 (d, 6 H), 1.70 (m, 1 H); LC-MS m/z 432 (MH+), ret. time 2.19 min.
  • Using the procedure outlined above, Examples 342-354 were prepared.
    TABLE 15
    Example LC/MS MS+
    No. Structure RT (min) [M + H]+
    342
    Figure US20050215594A1-20050929-C00927
         		2.19 432
    343
    Figure US20050215594A1-20050929-C00928
         		1.82 435
    344
    Figure US20050215594A1-20050929-C00929
         		2.12 438
    345
    Figure US20050215594A1-20050929-C00930
         		2.04 404
    346
    Figure US20050215594A1-20050929-C00931
         		2.04 404
    347
    Figure US20050215594A1-20050929-C00932
         		2.09 449
    348
    Figure US20050215594A1-20050929-C00933
         		2.19 474
    349
    Figure US20050215594A1-20050929-C00934
         		2.12 456
    350
    Figure US20050215594A1-20050929-C00935
         		2.19 436
    351
    Figure US20050215594A1-20050929-C00936
         		2.13 448
    352
    Figure US20050215594A1-20050929-C00937
         		2.25 456
    353
    Figure US20050215594A1-20050929-C00938
         		2.27 472
    354
    Figure US20050215594A1-20050929-C00939
         		2.32 472
    • EXAMPLE 355 Preparation of (2R)-N-{(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide
  • Figure US20050215594A1-20050929-C00940
  • A reaction mixture containing (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, 5.39 mmol, 1.0 eq.), (1R)-2-amino-1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethanol dihydrochloride (U.S. Pat. No. 6,051,586) (6.47 mmol, 1.2 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl, 10.8 mmol, 2.0 eq.), 1-hydroxybenzotriazole hydrate (HOBT, 10.8 mmol, 2.0 eq.), and triethylamine (16.2 mmol, 3.0 eq.) in CH2Cl2 (30 mL) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the resulting two-phase mixture was extracted with CH2Cl2. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, CH2Cl2:MeOH=100:4). The product was obtained as a pale yellow foam in 56% yield. MH+=518.2, RT=3.74 min.
    • EXAMPLE 356 Preparation of (1R)-1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-({[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol
  • Figure US20050215594A1-20050929-C00941
  • To a solution of (2R)-N{(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide (Example 355, 7.67 mmol, 1 eq.) in THF (150 mL) at room temperature was added slowly borane-methyl sulfide complex (2M in THF, 38.4 mmol, 5.0 eq.). After completion of the addition, the reaction mixture was heated to reflux for 2 hours and was then cooled to room temperature. The excess borane was quenched by the dropwise addition of EtOH (9 mL) followed by the slow addition of 2 M HCl (40 mL). The resulting mixture was heated to reflux for 1 hour and was then allow to cool to room temperature. The mixture was basified with 1N NaOH and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, using a gradient of 1:4 hexanes:EtOAc to 1:10 MeOH:EtOAc). The product was obtained as a pale yellow oil in 63% yield. MH+=503.9, RT=3.23 min.
    • EXAMPLE 357 Preparation of tert-butyl (2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
  • Figure US20050215594A1-20050929-C00942
  • A reaction mixture containing (1R)-1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-({[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol (Example 356, 3.28 mmol, 1.0 eq.) and di-tert-butyl dicarbonate (3.44 mmol, 1.05 eq.) in THF (15 mL) was stirred at room temperature for 18 hours.
  • The solvent was evaporated and the residue was purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, 2:1 hexanes:EtOAc). The product was obtained as a beige foam in 68% yield. MH+=603.9, RT=4.43 min.
    • EXAMPLE 358 Preparation of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
  • Figure US20050215594A1-20050929-C00943
  • A mixture of tert-butyl (2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 357, 7.5 g, 12.4 mmol), TBDMSCl (2.25 g, 14.9 mmol), and imidazole (2.10 g, 30.9 mmol) in DMF (10 mL) was stirred at room temperature under argon for 24 hours. The reaction mixture was then poured into a saturated NaHCO3 solution (50 mL). The mixture was extracted with ether (100 mL×2). The ether layer was washed with water (50 mL) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded a near white syrup which was purified by column chromatography (silica gel, hexanes/ethyl acetate (5/1, v/v)) and gave the desired compound as a colorless oil (6.5 g, 72%).
    • EXAMPLE 359 Preparation of ethyl (2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromene-6-carboxylate
  • Figure US20050215594A1-20050929-C00944
  • A solution of tert-butyl (2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 357,1.72 mmol, 1.0 eq.) in EtOH (6.5 mL) was treated with Pd(OAc)2 (0.09 mmol, 0.05 eq.) and triethylamine (4.31 mmol, 2.5 eq.). The reaction mixture was vigorously stirred and degassed with argon. This suspension was heated to reflux for 18 hours under 1 atmosphere of carbon monoxide. The resulting solution was cooled to room temperature and filtered through a Celite® pad, washing with more EtOH. The filtrate was concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, using a gradient of 8:1 to 2:1 hexanes:EtOAc). The product was obtained as a colorless oil in 62%. MH+=550.3, 3.79 min.
    • EXAMPLE 360 Preparation of (2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-Pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromene-6-carboxylic Acid
  • Figure US20050215594A1-20050929-C00945
  • A solution of ethyl (2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromene-6-carboxylate (Example 359, 0.21 mmol, 1.0 eq.) and 1N NaOH (0.63 mmol, 3.0 eq.) in EtOH (2 mL) was heated to reflux for 1.5 hours. The reaction mixture was allowed to cool to room temperature and was concentrated in vacuo to afford a residue that was purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, 100:5 CH2Cl2:MeOH). The product was obtained as a white foam in 72% yield. MH+=522.3, RT=3.11 min.
    • EXAMPLE 361 Preparation of ethyl N-({(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}carbonyl)glycinate
  • Figure US20050215594A1-20050929-C00946
  • The product was obtained in 44% yield via a coupling reaction between (2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromene-6-carboxylic acid (Example 360) and glycine ethyl ester hydrochloride utilizing the method described for Example 355; MH+=607.3, RT=3.18 min.
    • EXAMPLE 362 Preparation of N-{[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]carbonyl}glycine
  • Figure US20050215594A1-20050929-C00947
  • A mixture of ethyl N-({(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}carbonyl)glycinate (Example 361, 0.08 mmol, 1.0 eq.) in EtOH/H2O (0.8 mL /0.2 mL) was treated with 2 N HCl (0.42 mmol, 5.0 eq), followed by hydroxylamine hydrochloride (0.084 mmol, 10.0 eq.). The resulting reaction mixture was heated at reflux for 18 hours. Solvents were evaporated in vacuo and the brown residue was purified by reverse phase HPLC. The product was obtained as the TFA salt in 15%. MH+=401.1, RT=0.79 min.
  • Following the procedures described above for Examples 361-362, and using Example 360 and the appropriate amino acid esters as starting materials, the following compounds were similarly prepared:
    TABLE 16
    Figure US20050215594A1-20050929-C00948
    Example RT (LC- MS
    No. R″ MS min,) [M + H]+
    363
    Figure US20050215594A1-20050929-C00949
         		0.79 441.2
    364
    Figure US20050215594A1-20050929-C00950
         		0.78 455.2
    365
    Figure US20050215594A1-20050929-C00951
         		0.76 492.2
    366
    Figure US20050215594A1-20050929-C00952
         		0.77
    367
    Figure US20050215594A1-20050929-C00953
         		0.62 441.3
    368
    Figure US20050215594A1-20050929-C00954
         		1.26 505.2
    369
    Figure US20050215594A1-20050929-C00955
         		1.52 491.2
    • EXAMPLE 370 Preparation of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl{[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
  • Figure US20050215594A1-20050929-C00956
  • The product was prepared from tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 358) according to the method described for Example 81.
    • EXAMPLE 371 Preparation of methyl 4-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-{[tert-butyl(dimethyl)silyl]-oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoate
  • Figure US20050215594A1-20050929-C00957
  • Argon was bubbled through a solution of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl{[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 370, 395 mg, 0.55 mmol) in toluene (15 mL) and 1,4-dioxane (3 mL) for 10 minutes. Bis(diphenylphosphino)ferrocene-palladium (40 mg) and methyl 4-iodobenzoate (216 mg, 0.83 mmol) were added, and bubbling with argon was continued for another 5 minutes. 2 N aq. sodium carbonate solution (3 mL, 6 mmol) was added and the reaction mixture was heated (85° C.) for 16 hours. After cooling, the mixture was filtered through a pad of silica gel and Celite® using ethyl acetate to rinse. The filtrate was concentrated in vacuo and then flash chromatography of the residue over silica gel using 20% ethyl acetate/hexanes afforded 276 mg (69%) of the desired product. The product had: 1H NMR (CDCl3, δ): 8.65 (d, J=20.0 Hz, 1 H), 8.13 (d, J=7.9 Hz, 2 H), 7.91 (dd, J=16.8, 8.1 Hz, 1 H), 7.67 (d, J=7.6 Hz, 2 H), 7.24-7.47 (m, 3 H), 6.93 (dd, J=8.1, 1.8 Hz, 1 H), 5.98 (d, J=3.9 Hz, 1 H), 5.23 (dd, J=43.5, 5.5 Hz, 1 H), 4.21-4.43 (m, 1 H), 4.00 (s, 3 H), 3.37-3.95 (m, 4 H), 2.84-3.09 (m, 2 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 2.03-2.18 (m, 1 H), 1.74-1.91 (m, 1 H), 1.59 (d, J=10.4 Hz, 9 H), 0.99 (s, 9 H), 0.17 (s, 3 H), 0.00 (s, 3 H); mass spectroscopy gave m/z=726.4 [M+H]+ (calc'd exact mass for C42H55N3O6Si=725.4).
  • Using the method described above for Example 371, the following compounds were similarly prepared using Example 81 and the appropriate halobenzene starting material:
    TABLE 17
    Example MS HPLC
    No. Structure [M + H+] RT (min)
    372
    Figure US20050215594A1-20050929-C00958
         		726.4 5.18
    373
    Figure US20050215594A1-20050929-C00959
         		765.4 4.85
    374
    Figure US20050215594A1-20050929-C00960
         		978   5.29
    • EXAMPLE 375 Preparation of methyl 4-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoate
  • Figure US20050215594A1-20050929-C00961
  • To a solution of methyl 4-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-{[tert-butyl(dimethyl)silyl]-oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl}-amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoate (Example 371, 213 mg, 0.29 mmol) in THF (5 mL) was added a solution of 1 M tetrabutylammonium fluoride (0.59 mL, 0.59 mmol). The mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. Flash chromatography of the residue over silica gel using 40% ethyl acetate/hexanes afforded 213 mg (92%) of the desired product. The product had: 1H-NMR (CDCl3δ): 8.62 (s, 1 H), 8.06 (d, J=8.9 Hz, 2 H), 7.92 (d, J=7.2 Hz, 1 H), 7.58 (d, J=8.8 Hz, 2 H), 7.31-7.40 (m, 2 H), 7.22 (d, J=7.8 Hz, 1 H), 6.89 (d, J=7.9 Hz, 1 H), 5.89 (s, 2 H), 5.10-5.26 (m, 2 H), 4.21-4.50 (m, 1 H), 3.93 (s, 3 H), 3.56-3.88 (m, 4 H), 3.15-3.42 (m, 1 H), 2.78-3.04 (m, 2 H), 2.12 (s, 6 H), 1.65-1.83 (m, 2 H), 1.50 (s, 9 H).
    • EXAMPLE 376 Preparation of methyl 3-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoate
  • Figure US20050215594A1-20050929-C00962
  • In similar fashion to that described above for Example 375, the title compound was prepared from Example 372 and used without further purification.
    • EXAMPLE 377 Preparation of methyl 4-((2R)-2-{[[(2 R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl](tert-butoxycarbonyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl)benzoate
  • Figure US20050215594A1-20050929-C00963
  • To a solution of methyl 4-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoate (Example 375, 162 mg, 0.26 mmol) in ethanol (4 mL) was added hydroxylamine monohydrate (182 mg, 2.65 mmol) and 2 N aq. potassium hydroxide (0.66 mL, 1.32 mmol). vThe mixture was stirred at room temperature for 70 hours and then concentrated in vacuo. Flash chromatography of the residue using 10% methanol/ethyl acetate afforded 80 mg (43%) of the desired product containing trace impurities. This material was taken on without further purification. Mass spectroscopy gave m/z=534.3 [M+H]+ (calc'd exact mass for C30H35N3O6=533.3).
  • Using the method described above for Example 377 and substituting the appropriate starting materials, the following compounds were made and characterized:
    TABLE 18
    HPLC
    Example MS Starting RT
    No. Structure [M + H+] Material (min)
    378
    Figure US20050215594A1-20050929-C00964
         		used crude 370 —
    379
    Figure US20050215594A1-20050929-C00965
         		687.4 367 3.08
    380
    Figure US20050215594A1-20050929-C00966
         		658.3 368 2.95
    • EXAMPLE 381 Preparation of methyl 4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}-methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate
  • Figure US20050215594A1-20050929-C00967
  • Methyl 4-((2R)-2-{[[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl](tert-butoxycarbonyl)-amino]methyl}-3,4-dihydro-2H-chromen-6-yl)benzoate (Example 377, 80 mg, 0.15 mmol) was added to 4 M hydrochloric acid in dioxane (3 mL, 12 mmol). The solution was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was purified by prep. HPLC, afforded 40 mg (62%) of the desired product. The product had: 1H NMR (CD3ODδ): 8.04 (d, J=8.1 Hz, 2 H); 7.89-8.03 (m, 2 H), 7.68 (d, J=7.8 Hz, 2 H), 7.42-7.49 (m, 2 H), 6.95-7.07 (m, 2 H), 5.02-5.10 (m, 1 H), 4.24-4.52 (m, 1 H), 3.91 (s, 3 H), 3.20-3.52 (m, 4 H), 2.81-3.04 (m, 2 H), 2.11-2.24 (m, 1 H), 1.74-1.92 (m, 1 H); mass spectroscopy gave m/z=434.2 [M+H]+ (calc'd exact mass for C25H27N3O4=433.2).
  • Using the method described above for Example 381 and substituting the appropriate starting materials, the following compounds were made and characterized:
    TABLE 19
    Example MS Starting HPLC
    No. Structure [M + H+] Material RT (min)
    382
    Figure US20050215594A1-20050929-C00968
         		434.2 372 1.95
    383
    Figure US20050215594A1-20050929-C00969
         		473.3 373 1.56
    384
    Figure US20050215594A1-20050929-C00970
         		444.2 374 1.46
    • EXAMPLE 385 Preparation of 4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic Acid
  • Figure US20050215594A1-20050929-C00971
  • To a solution of methyl 4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}-methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 381, 40 mg, 0.1 mmol) in THF (2 mL) and methanol (2 mL) was added 2 M aq. lithium hydroxide (0.5 mL, 1 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. Prep. HPLC of the residue afforded 10.8 mg (28%) of the desired product. The product had: 1H NMR (CDCl3, δ): 7.96 (d, J=8.2 Hz, 2 H), 7.90 (d, J=2.2 Hz, 1 H), 7.49-7.56 (m, 3 H), 7.32-7.39 (m, 2 H), 6.82 (d, J=9.0 Hz, 1 H), 6.59 (d, J=8.6 Hz, 1 H), 4.70 (dd, J=8.3, 4.4 Hz, 1 H), 4.14-4.23 (m, 1 H), 2.75-3.02 (m, 6 H), 1.99-2.10 (m, 1 H), 1.70-1.85 (m, 1 H); mass spectroscopy gave m/z=420.2 [M+H]+ (calc'd exact mass for C 24H25N3O4=419.2).
    • EXAMPLE 386 Preparation of 3-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic Acid
  • Figure US20050215594A1-20050929-C00972
  • The title compound was made from Example 382 and characterized using the method described above for Example 385; m/z=420.2 [M+H]+; RT1.9 min.
    • EXAMPLES 387-388 Reaction of Chroman-2-Methylamines with Epoxides: Method for Combinatorial/Parallel Synthesis
  • Figure US20050215594A1-20050929-C00973
  • The apparatus used was as described in the general experimentals methods above. In a typical procedure, a solution of (2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylamine (Example 10) and an epoxide (commercially-available or prepared as described in WO99/32475) were freshly prepared as a 0.5 M solution in dioxane. To each reaction well in a polypropylene reaction block was added a solution of the desired amine (200 μL, 0.1 mmol), a solution of the desired epoxide (200 μL, 0.1 mmol), and 500 μL of dioxane as well as 100 μL of water. The reaction block was sealed with rubber gaskets and clamped, then heated at 80° C. for 72 hours, with mixing by rotation. After allowing the reaction block to cool to room temperature, the block was disassembled, and the reaction well contents were filtered into a collection 96-well deep-well microtiter plate, washing with 2 portion of 200 μL of dioxane. The filtrate solutions were evaporated to dryness using a multiple sample centrifugal vacuum evaporator. Products were analyzed for purity and correct identity by LC/MS.
  • Utilizing the above procedures and starting from (2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylamine (Example 10) and the appropriate epoxide starting material, the following compounds were prepared and characterized:
    TABLE 20
    Example RT (min) MS m/z
    No. Structure LC/MS [M + H]+
    387
    Figure US20050215594A1-20050929-C00974
         		2.52 410
    388
    Figure US20050215594A1-20050929-C00975
         		2.63 444
  • An embodiment of the present invention is the administration of the compounds of this invention to a human or animal for the treatment of beta-3 adrenergic receptor mediated conditions such as diabetes, obesity, gastrointestinal disorders including irritable bowel syndrome and intestinal hypermotility disorders, peptic ulcerations, esophagitis, gastritis, and duodenitis, intestinal ulcerations including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis, and gastrointestinal ulcerations, as well as neurogenetic inflammation such as cough and asthma, and depression. It is also believed that the compounds of this invention are effective in the treatment of hyper-triglyceridemia, hypercholesterolemia and conditions of low or high density lipoprotein levels, artherosclerotic disease and cardiovascular disease and related conditions. Additionally, it is also believed that the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urinary disorders including pollakiuria and incontinence, as well as in the treatment of prostate disease and as topical anti-inflammatory agents.
  • Therefore, the compounds of this invention are expected to be valuable as therapeutic agents. An embodiment of this invention includes a method of treating beta-3 adrenergic receptor mediated conditions in a mammal which comprises administering to said mammal a composition containing an amount of the compound of Formula I that is effective in treating the target condition.
  • The specificity of the compounds of this invention as beta-3 adrenergic receptor agonists can readily be determined by evaluating the affinity of the compound for the different beta adrenergic receptor subtypes and comparing the activity with various receptor subtypes affinities to discover specificity as well as activity using standard and well-known procedures. Such a procedure is described in more detail in the specific example below.
    • EXAMPLE 389 Biological Evaluation of Compounds
  • The utility of the compounds of this invention can be demonstrated by the following procedure.
  • Chinese hamster ovary (CHO) cells that stably express full-length human beta-3-adrenergic receptor (Granneman et al., Mol. Pharmacol. 44:264-270,1993) can be used in the following procedure. The cell line is grown in 90% F12 nutrient mixture (HAM), 10% fetal bovine serum, 100 units/ml penicillin G sodium, 100 mg/ml streptomycin sulfate, and 2 mM L-glutamine at 37° C. in 95% air and 5% CO2. The transfected cell line is maintained with G-418 (800 μg/ml).
  • To test the agonist activity, cells are exposed to test compound and then assayed for cAMP production. CHO cells (100 μl) are plated at 5×104 cells/well of a 96-well plate (Costar, Cambridge, Mass.) to achieve 70% confluency the next day. After overnight incubation at 37° C., media is removed and the cells are treated for 30 minutes at 37° C. with KRP buffer (120 mM NaCl, 5.1 mM KCl, 0.6 mM MgSO47 H2O, 0.8 mM CaCl2H2O, 12.5 μM phosphate buffer, 20 μM Hepes pH 7.4) +0.2 μM IBMX (100 μM/well), +1% DMSO, +/− test compounds (10 μM DMSO stocks). Test compounds are assayed from 10 μM to 3 nM with 3-fold serial dilutions. The control agonist, isoproterenol (10 mM stock in 1.1 mM ascorbate), is assayed by 3-fold dilution beginning at 1 μM. After a 30-minute incubation with the test compounds, the buffer/compound mixture is removed. The cells are lysed and cAMP levels are measured using the cAMP SPA screening assay system (Amersham, Arlington Heights, Ill.). The cAMP values are then plotted to determine the EC50 of each compound tested.
  • In tests utilizing the above described procedure, the compounds of the present invention were found to have beta-3 adrenergic agonist activity with levels of activity summarized in Table 21.
    TABLE 21
    Beta-3 Agonistic Activity
    Compounds with EC50 values Compounds with EC50 values
    ≦1 μM >1 μM
    (Example No.) (Example No.)
     36 39
     40 41
     47 42
     48 43
     54 45
    184-188 363
    192 364
    193-198 365
    205 367
    211
    215
    216
    249A
    249B
    250-280
    283-305
    308-311
    314
    317
    319-340
    343
    344
    348
    352
    362
    366
    369
    381-386
  • Beta-3 adrenergic receptor agonists may be useful for correcting the insulin resistance that underlies two prediabetic states, impaired glucose tolerance (Harris, Diabetes Care 12:464-474, 1989) and impaired fasting glucose (Weyer et al., Diabetes 48:2197-2203,1999). The ability of a beta-3 adrenergic receptor agonist to restore insulin sensitivity has been demonstrated in a diabetic animal model with marked insulin resistance. Treatment of KK-Ay/Ta diabetic obese mice with a beta-3 adrenergic receptor agonist resulted in marked improvement in the animals' responses to insulin (Kato et al., Diabetes 50:113-122, 2001). Insulin resistance in human subjects with impaired glucose tolerance has been treated by troglitazone, another class of insulin sensitizers (Saltiel et al., Diabetes 45:1661-1669,1996; Saleh et al., Diabetes Rev. 7:55-76,1999). In such studies, improvement in the insulin responses of these subjects were demonstrated. These overall findings support treating the insulin resistance in prediabetic conditions with insulin sensitizers, including beta-3 adrenergic receptor agonists, to delay or prevent the onset of type 2 diabetes.
  • Based upon the above and other standard laboratory techniques known to evaluate compound receptor site inhibition, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the beta-3 adrenergic receptor mediated conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • The total amount of the active ingredient to be administered will generally range from about 0.01 mg/kg to about 100 mg/kg, and preferably from about 0.1 mg/kg to about 20 mg/kg body weight per day. A unit dosage may contain from about 5 mg to about 1500 mg of active ingredient, and may be administered one or more times per day. Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician.
  • The compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular beta-3 adrenergic receptor mediated condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or ester thereof. A pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds of Formula I may be administered with a pharmaceutically-acceptable carrier using any effective conventional dosage unit forms, including immediate and timed release preparations, orally, parenterally, topically, or the like.
  • For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin; disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum; lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium, or zinc stearate; dyes; coloring agents; and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring, and coloring agents described above, may also be present.
  • The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring, and coloring agents.
  • The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water; saline; aqueous dextrose and related sugar solutions; an alcohol such as ethanol, isopropanol, or hexadecyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol; ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a fatty acid ester or glyceride; or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent; suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose; or emulsifying agent and other pharmaceutical adjuvants.
  • Illustrative of oils which may be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation may range from about 5% to about 15% by weight. The surfactant may be a single component having the above HLB or may be a mixture of two or more components having the desired HLB.
  • Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example, polyoxyethylene sorbitan monooleate.
  • The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
  • A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.
  • Another formulation employed in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No. 5,023,252, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in U.S. Pat. No. 5,011,472.
  • The compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
    • EXAMPLE 390
  • A capsule formula is prepared from
    A compound of Formula I  40 mg
    Starch 109 mg
    Magnesium stearate  1 mg

    The components are blended, passed through an appropriate mesh sieve, and filled into hard gelatin capsules.
    • EXAMPLE 391
  • A tablet is prepared from
    A compound of Formula I 25 mg
    Cellulose, microcrystalline 200 mg 
    Colloidal silicon dioxide 10 mg
    Stearic acid 5.0 mg 

    The ingredients are mixed and compressed to form tablets.
  • The compound of this invention may be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention may be combined with known antiobesity or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • The compounds of Formula I may also be utilized, in free base form or in compositions, in research and diagnostics, or as analytical references standards, and the like. Therefore, the present invention includes compositions which are comprised of an inert carrier and an effective amount of a compound of Formula I, or a salt or ester thereof. An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like, to the compound to be carried. An effective amount of compound is that amount which produces a result or exerts an influence on the particular procedure being performed.
  • It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set froth herein.

Claims (30)

1. A compound of Formula I
Figure US20050215594A1-20050929-C00976
wherein,
R is independently
hydroxy,
oxo,
halo,
cyano,
nitro,
C1-C10 alkyl,
C1-C10 haloalkyl,
CF3,
NR1R1,
SR1,
OR1,
SO2R2,
OCOR2,
NR1COR2,
COR2,
NR1SO2R2,
phenyl, or
a 5- or 6-membered heterocycle with from 1 to 4 heteroatoms selected from O, S, and N;
each cyclic moiety being optionally substituted with
hydroxy,
R1,
halo,
cyano,
NR1R1,
SR1,
CF3,
OR1,
C3-C8 cycloalkyl,
NR1COR2,
COR2,
SO2R2,
OCOR2,
NR1SO2R2
C1-C10 alkyl, or
C1-C10 alkoxy;
R1 is
hydrogen,
(CH2)d—O—(CH2)dR5 where each d is selected independently, or
C1-C10 alkyl optionally substituted with 1 to 4 substituents each independently selected from
hydroxy,
halo,
CO2C1-C4-alkyl,
CO2H,
C1-C10 alkoxy,
S(O)bC1-C10 alkyl,
S(O)b-phenyl optionally substituted with halo, C1-C4 alkyl, C1-C4 alkoxy, SO2-C1-C4alkyl, or CO2 C1-C4alkyl; or
phenyl optionally substituted with CO2C1-C4-alkyl, CO2H, halo, or C1-C10 alkyl; or
C3-C8 cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1 to 4 substituents each independently selected from halo, nitro, oxo, C1-C10 alkyl, C1-C10alkoxy, C1-C10 alkylthio, CO2C1-C4-alkyl, and CO2H, and
when two R1 groups are attached to N as NR1R1, these R1 groups may form together with the nitrogen to which they are attached, a heterocyclic ring containing 4 to 7 C atoms, 1 to 2 N atoms, and 0 to 1 O or S atoms;
R2is
R1,
OR1,
NR1R1,
NHS(O)bphenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo or nitro;
NHS(O)bnaphthyl,
NHS(O)bC1-C10alkyl optionally substituted with fluoro up to the perfluoro level, or
a 5- or 6-membered heterocycle with one or more heteroatoms selected from O, S, and N, said heterocyclic moiety being optionally substituted with R1;
R3 is hydrogen, C1-C10 alkyl, or COR2;
R4 is hydrogen, C1-C10 alkyl, C1-C10 alkyl-phenyl, or C1-C10 alkyl-pyridyl;
R5 is hydrogen or COOH;
R6 is
hydrogen,
C1-C10 alkyl optionally substituted with 1 to 4 substituents each independently selected from halo, phenyl, or phenyl-COR2, or
C1-C10 alkyl-S(O)bC1-C10 alkyl optionally substituted with COR2 or C3-C8 cycloalkyl;
Ar is
phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N, said bicyclic moiety being optionally fused to a phenyl, or
a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to phenyl;
Y is
halo,
NO2,
R6
SR1,
S(O)b-phenyl-CO2R1,
Figure US20050215594A1-20050929-C00977
where, when the two R4 groups attached to the same C are both alkyl, they optionally may be joined so that, when taken together with the C to which they are attached, they form a Spiro ring of 3, 5, or 6 C atoms, or where the R4 attached to N and one R4 attached to the adjacent C are both alkyl, they optionally may be joined so that, taken together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic ring;
with the proviso that when e is 1, at least one R4 group must be C1-C10 alkyl-phenyl or C1-C10 alkyl-pyridyl, or two R4 groups must form one of said spiro or heterocyclic ring moieties;
a phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or
a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S and O, optionally fused to a phenyl ring, each cyclic moiety being optionally substituted with one or more substituents independently selected from
COR2,
CONR1S(O)2R9,
COCH2SO2-thiazolyl optionally substituted with alkyl or amino,
halo,
NO2,
OR1,
R1,
SR1,
O—C1-C6-alkyl substituted by C3-C6-cycloalkyl,
O-phenyl optionally substituted by SO2CH3,
SO2NH2,
SO2NR1R7,
NR1R1,
NR1COC1-C6alkyl,
Figure US20050215594A1-20050929-C00978
C1-C10COR2,
phenyl optionally substituted with halo, C1-C4 alkyl, or C1-C4 alkoxy,
tetrazolo;
R7 is
phenyl or heteroaryl containing 3-6 C and 1-3 O, N, or S atoms, each optionally substituted by C1-C4 alkyl, CN, NO2, CO-C1-C4alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl,
CO—R8,
Figure US20050215594A1-20050929-C00979
R8 is
C1-C6 alkyl optionally substituted with C1-C4 alkoxy, N(CH3)2,or one or two CF3,
C3-C6-cycloalkyl,
phenyl optionally substituted with C1-C4alkoxy, halo, or C1-C4alkyl,
NH-phenyl optionally substituted with C1-C4 alkyl, halo, C1-C4 alkoxy, or C1-C4 haloalkoxy,
NH-cyclohexyl;
R9 is
C3-C6cycloalkyl,
thienyl optionally substituted with C1-C4 alkyl or isoxazolyl,
pyridyl optionally substituted with —SO2—C1-C4alkyl,
pyrazolyl optionally substituted with halo or C1-C4 alkyl,
isoxazolyl optionally substituted with C1-C4 alkyl, or
Figure US20050215594A1-20050929-C00980
a is 0, 1, 2, 3, 4, or 5;
b is 0, 1, or 2;
d is 1, 2, or 3;
e is 1 or 2;
and pharmaceutically acceptable salts and esters thereof.
2. The compound of claim 1 wherein Y is
halo,
R6,
SR1,
S(O)b-phenyl-CO2R1,
phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or
a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S and O, optionally fused to a phenyl ring,
each cyclic moiety being optionally substituted with one or more substituents independently selected from
COR2,
halo,
NO2,
OR1,
R1,
SR1,
SO2NR1R7,
NR1R1,
NR1COC1-C6alkyl,
C1-C10COR2,
phenyl,
tetrazolo;
and pharmaceutically acceptable salts and esters thereof.
3. The compound of claim 1 wherein Y is
phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or
a 5- or 6- membered heterocycle containing one or more heteroatoms each independently selected from N, S and O, optionally fused to a phenyl ring, each cyclic moiety being optionally substituted with one or more substituents independently selected from
COR2,
halo,
NO2,
OR1,
R1,
SR1,
SO2NR1R7,
NR1R1,
NR1COC1-C6alkyl,
C1-C10COR2,
phenyl,
tetrazolo;
and d is 1or 2;
and pharmaceutically acceptable salts and esters thereof.
4. The compound of claim 1 wherein
Y is
phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or
a 5- or 6- membered heterocycle containing one or more heteroatoms each
independently selected from N, S and O, optionally fused to a phenyl ring, each cyclic moiety being optionally substituted with one or more substituents independently selected from
COR2,
halo,
NO2,
OR1,
R1,
SR1,
SO2NR1R7,
NR1R1,
C1-C10COR2,
phenyl,
tetrazolo;
Ar is
phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N, said bicyclic moiety being optionally fused to a phenyl, or
a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to phenyl;
and d is 1 or 2;
and pharmaceutically acceptable salts and esters thereof.
5. The compound of claim 1 wherein
Y is
phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or
a 5- or 6- membered-heterocycle containing one or more heteroatoms each
independently selected from N, S and O, optionally fused to a phenyl ring, each cyclic moiety being optionally substituted with one or more substituents independently selected from
COR2,
halo,
OR1,
R1,
NR1R1,
Ar is
phenyl or
a 5- or 6-membered heterocycle containing one or more N atoms;
a is 0, 1, 2, or 3; and
d is 1;
and pharmaceutically acceptable salts and esters thereof.
6. A compound selected from the group consisting of:
2-[4-(ethoxycarbonyl)phenoxy]-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutylbenzoic acid;
N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-2-methylbenzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutoxybenzoic acid;
N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-4-methoxybenzenesulfonamide;
N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-1-propanesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxybenzoyl)benzenesulfonamide;
N-(2-cyano-4-nitrophenyl)-3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
2-(4-chlorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
N-(4,6-dimethoxy-2-pyrimidinyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluoromethoxy)benzenesulfonamide;
2-(4-fluorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3-methoxybenzoyl)benzenesulfonamide;
4-fluoro-N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(4-methylphenoxy)benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(2-phenylethyl)benzoic acid;
3-chloro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
N-(4-fluorobenzoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methoxybenzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-phenoxybenzoic acid;
N-(4-cyanophenyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluoromethoxy)benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxy-6-methyl-2-pyrimidinyl)-2-(trifluoromethoxy)benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3,3,3-trifluoropropanoyl)benzenesulfonamide;
2-hydroxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
3-((1R)-2-{[((2R)-6-{4-[({[(4-fluorophenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1-hydroxyethyl)pyridine;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide;
N-benzoyl-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-propoxybenzoic acid;
N-({4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinyl}carbonyl)-4-methoxybenzenesulfonamide;
3-((1R)-1-hydroxy-2-{[((2R)-6-{4-[({[(4-methylphenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}ethyl)pyridine;
3-((1R)-2-{[((2R)-6-{4-[({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1-hydroxyethyl)pyridine;
N-(ethoxyacetyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
N-(3,3-dimethylbutanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methyl-2-pyrimidinyl)benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-[4-(methylsulfonyl)phenoxy]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methylbenzoic acid;
4-{2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid;
N-(2,2-dimethylpropanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
3-[(1R)-2-({[(2R)-6-(4-{[(anilinocarbonyl)amino]sulfonyl}phenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-hydroxyethyl]pyridine;
2-ethoxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxy-6-methyl-2-pyrimidinyl)benzenesulfonamide;
3-{(1R)-2-[({(2R)-6-[4-({[(cyclohexylamino)carbonyl]amino}sulfonyl)phenyl]-3,4-dihydro-2H-chromen-2-yl}methyl)amino]-1-hydroxyethyl}pyridine;
N-(cyclopropylcarbonyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
2-chloro-5-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(4-[R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-methylbenzoic acid;
2-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-propoxybenzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isopropoxybenzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(1,3-thiazol-2-yl)benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(4-methoxyphenoxy)benzoic acid;
3-(cyclopropylmethoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
5-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-4′-methyl-1,1′-biphenyl-2-carboxylic acid;
N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3-pyridinyl)benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-methoxybenzoic acid;
4-chloro-N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-isobutoxybenzoic acid;
N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}methanesulfonamide;
3-{2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid;
3-[(1E)-1-hexenyl]-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(2-methoxyethoxy)benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2,6-dimethylbenzoic acid;
4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
3-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
(1R)-1-(6-amino-3-pyridinyl)-2-[({(2R)-6-[4-(1H-tetraazol-5-yl)phenyl]-3,4-dihydro-2H-chromen-2-yl}methyl)amino]ethanol;
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-3-phenyl-1,2I5,3I5,4-thiatriazole-2-carboxylic acid;
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-furoic acid;
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid;
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-3-thiophenecarboxylic acid;
4-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid;
6-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]nicotinic acid;
5-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]nicotinic acid;
2-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-4-pyridinecarboxylic acid;
1-({[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]carbonyl}amino)cyclopropanecarboxylic acid; and
4-[(2R)-2-({[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 344).
7. A method of treating a beta-3 adrenergic receptor-mediated condition comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 1.
8. A method of treating obesity comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 1.
9. A method of treating diabetes comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 1.
10. A method of treating a patient with impaired fasting glucose or impaired glucose tolerance comprising the step of administering to said patient in need thereof a pharmaceutically effective amount of a compound of claim 1.
11. A method of treating gastrointestinal disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 1.
12. A method of treating hypertriglyceridemia, hypercholesteolemia, atherosclerotic disorders, or cardiovascular disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 1.
13. A method for lowering high-density lipoprotein levels comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 1.
14. A method for treating urinary disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 1.
15. The method of claim 14, wherein said urinary disorders is selected from the group consisting of pollakiuria and incontinence.
16. A method of treating a beta-3 adrenergic receptor-mediated condition comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 6.
17. A method of treating obesity comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 6.
18. A method of treating diabetes comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 6.
19. A method of treating a patient with impaired fasting glucose or impaired glucose tolerance comprising the step of administering to said patient in need thereof a pharmaceutically effective amount of a compound of claim 6.
20. A method of treating gastrointestinal disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 6.
21. A method of treating hypertriglyceridemia, hypercholesteolemia, atherosclerotic disorders, or cardiovascular disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 6.
22. A method for lowering high-density lipoprotein levels comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 6.
23. A method for treating urinary disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of claim 6.
24. The method of claim 23, wherein said urinary disorders is selected from the group consisting of pollakiuria and incontinence.
25. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt and esters thereof in combination with a pharmaceutically acceptable carrier.
26. A pharmaceutical composition for the treatment of obesity, diabetes, gastrointestinal disorders, hypertriglyceridaemia, hypercholesterolaemia, atherosclerosis, cardiovascular diseases, or urinary disorders comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt and ester thereof in combination with a pharmaceutically acceptable carrier.
27. A composition comprising an effective amount of a compound of claim 1 or a salt and esters thereof in combination with an inert carrier.
28. A pharmaceutical composition comprising an effective amount of a compound of claim 6 or a pharmaceutically acceptable salt and esters thereof in combination with a pharmaceutically acceptable carrier.
29. A pharmaceutical composition for the treatment of obesity, diabetes, gastrointestinal disorders, hypertriglyceridaemia, hypercholesterolaemia, atherosclerosis, cardiovascular diseases, or urinary disorders comprising an effective amount of a compound of claim 6 or a pharmaceutically acceptable salt and ester thereof in combination with a pharmaceutically acceptable carrier.
30. A composition comprising an effective amount of a compound of claim 6 or a salt and esters thereof in combination with an inert carrier.
US11/117,759 2001-04-23 2005-04-28 2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists Abandoned US20050215594A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/117,759 US20050215594A1 (en) 2001-04-23 2005-04-28 2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US28571901P 2001-04-23 2001-04-23
US32451801P 2001-09-26 2001-09-26
US10/131,448 US6660752B2 (en) 2001-04-23 2002-04-22 2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists
US10/666,903 US6919371B2 (en) 2001-04-23 2003-09-17 2,6-substituted chroman derivatives useful as beta-3 adrenoreceptor agonists
US11/117,759 US20050215594A1 (en) 2001-04-23 2005-04-28 2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/666,903 Division US6919371B2 (en) 2001-04-23 2003-09-17 2,6-substituted chroman derivatives useful as beta-3 adrenoreceptor agonists

Publications (1)

Publication Number Publication Date
US20050215594A1 true US20050215594A1 (en) 2005-09-29

Family

ID=26963345

Family Applications (3)

Application Number Title Priority Date Filing Date
US10/131,448 Expired - Fee Related US6660752B2 (en) 2001-04-23 2002-04-22 2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists
US10/666,903 Expired - Fee Related US6919371B2 (en) 2001-04-23 2003-09-17 2,6-substituted chroman derivatives useful as beta-3 adrenoreceptor agonists
US11/117,759 Abandoned US20050215594A1 (en) 2001-04-23 2005-04-28 2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US10/131,448 Expired - Fee Related US6660752B2 (en) 2001-04-23 2002-04-22 2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists
US10/666,903 Expired - Fee Related US6919371B2 (en) 2001-04-23 2003-09-17 2,6-substituted chroman derivatives useful as beta-3 adrenoreceptor agonists

Country Status (9)

Country Link
US (3) US6660752B2 (en)
EP (1) EP1389202B1 (en)
JP (1) JP2004532227A (en)
AR (1) AR035858A1 (en)
DE (1) DE60201437T2 (en)
DO (1) DOP2002000385A (en)
ES (1) ES2230487T3 (en)
PE (1) PE20021073A1 (en)
WO (1) WO2002085891A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070099908A1 (en) * 2005-11-03 2007-05-03 Jacob Berger Arylsulfonyl chromans as 5-HT6 inhibitors

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005049593A2 (en) * 2003-11-13 2005-06-02 Abbott Laboratories N-acylsulfonamide apoptosis promoters
BRPI0510642A (en) * 2004-05-05 2007-11-20 Hoffmann La Roche arylsulfonyl benzodioxanes useful for modulating 5-ht6 receptor, 5ht2a receptor or both
PL1831152T3 (en) * 2004-12-21 2009-03-31 Hoffmann La Roche Tetralin and indane derivatives and uses thereof as 5-ht antagonists
ATE455755T1 (en) * 2004-12-21 2010-02-15 Hoffmann La Roche TETRALIN AND INDANDE DERIVATIVES AND THEIR APPLICATIONS
CA2592001A1 (en) * 2004-12-21 2006-06-29 F. Hoffmann-La Roche Ag Chroman derivatives and their use as 5-ht receptor ligands
AU2005318516B2 (en) 2004-12-21 2011-02-17 F. Hoffmann-La Roche Ag Chroman derivatives and uses thereof in the treatment of CNS disorders
WO2006066745A1 (en) * 2004-12-21 2006-06-29 F.Hoffmann-La Roche Ag Tetralin and indane derivatives and uses thereof
AU2006214233A1 (en) 2005-02-17 2006-08-24 Wyeth Cycloalkylfused indole, benzothiophene, benzofuran and indene derivatives
GB0526252D0 (en) * 2005-12-22 2006-02-01 Novartis Ag Organic compounds
EP2402319B1 (en) 2006-03-31 2017-08-30 Novartis AG DGAT Inhibitors
EP2035370A2 (en) * 2006-06-20 2009-03-18 F. Hoffmann-Roche AG Tetralin and indane derivatives and uses thereof
MX2008015511A (en) * 2006-06-20 2008-12-18 Hoffmann La Roche Arylsulfonyl naphthalene derivatives and uses thereof.
KR101064001B1 (en) * 2006-06-20 2011-09-08 에프. 호프만-라 로슈 아게 Arylsulfonamidyl tetralin derivatives and uses thereof
US9981918B2 (en) * 2011-08-30 2018-05-29 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
UA122520C2 (en) 2013-01-09 2020-11-25 Басф Агро Б.В. CRYSTAL FORM 2- [4- (4-CHLOROPHENOXY) -2- (TRIFLUOROMETHYL) PHENYL] -1- (1,2,4-TRIAZOL-1-YL) PROPAN-2-OL, AGROCHEMICAL COMPOSITION, COMPOSITION HARMFUL MUSHROOMS
AU2014300629A1 (en) * 2013-06-24 2015-12-24 Lupin Limited Chromane and chromene derivatives and their use as CRAC modulators
US10512267B2 (en) 2013-07-08 2019-12-24 BASF Agro, B.V. Compositions comprising a triazole compound and a biopesticide
EA201990522A1 (en) * 2013-12-12 2019-07-31 Басф Агро Б.В. METHOD FOR PRODUCING SUBSTITUTED OXYRANES AND TRIAZOLE
EP3269245B1 (en) 2014-06-25 2023-08-16 BASF Agro B.V. Pesticidal compositions
BR112017000304B1 (en) 2014-07-08 2021-06-29 BASF Agro B.V. PROCESS FOR THE PREPARATION OF COMPOUNDS OF FORMULA II
PE20170770A1 (en) 2014-07-17 2017-07-04 Chdi Foundation Inc METHODS AND COMPOSITIONS FOR TREATING HIV-RELATED DISORDERS
UA120628C2 (en) 2014-11-07 2020-01-10 Басф Се Pesticidal mixtures
BR112017023950A2 (en) 2015-05-08 2018-07-24 Basf Agro Bv process for the preparation of limonen-4-ol
DK3294720T3 (en) 2015-05-08 2021-02-15 Basf Agro Bv PROCEDURE FOR THE PREPARATION OF TERPINOLENE POXIDE
US10336733B2 (en) 2015-11-30 2019-07-02 Merk Sharp & Dohme Corp. Aryl acylsulfonamides as BLT1 antagonists
US10370368B2 (en) 2015-11-30 2019-08-06 Merck Sharp & Dohme Corp. Aryl acylsulfonamides as BLT1 antagonists
CA3015456A1 (en) 2016-03-16 2017-09-21 Basf Se Use of tetrazolinones for combating resistant phytopathogenic fungi on fruits
WO2017157916A1 (en) 2016-03-16 2017-09-21 Basf Se Use of tetrazolinones for combating resistant phytopathogenic fungi on soybean
CA3015744A1 (en) 2016-03-16 2017-09-21 Basf Se Use of 1-[2-[[1-(4-chlorophenyl)pyrazol-3-yl]oxymethyl]-3-methyl-phenyl]-4-methyl-tetrazol-5-one for combating resistant phytopathogenic fungi on cereals
MX2018015764A (en) 2016-06-15 2019-08-29 Basf Agro Bv Process for the epoxidation of a tetrasubstituted alkene.
MX2018015765A (en) 2016-06-15 2019-08-29 Basf Agro Bv Process for the epoxidation of a tetrasubstituted alkene.
GB201803394D0 (en) * 2018-03-02 2018-04-18 Inflazome Ltd Novel compounds

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4727877A (en) * 1984-12-18 1988-03-01 Medtronic, Inc. Method and apparatus for low energy endocardial defibrillation
US5117824A (en) * 1990-11-14 1992-06-02 Medtronic, Inc. Apparatus for monitoring electrical physiologic signals
US5129392A (en) * 1990-12-20 1992-07-14 Medtronic, Inc. Apparatus for automatically inducing fibrillation
US5163427A (en) * 1990-11-14 1992-11-17 Medtronic, Inc. Apparatus for delivering single and multiple cardioversion and defibrillation pulses
US5674254A (en) * 1995-05-22 1997-10-07 Vitatron Medical, B.V. Cardiac pacemaker system and method for determining a measure of pacing threshold without incurring loss of capture
US5741312A (en) * 1997-03-12 1998-04-21 Vitatron Medical, B.V. Pacemaker system and method with improved capture detection and threshold search
US6052621A (en) * 1998-01-27 2000-04-18 Vitatron Medical B.V. System and method for inducing tachycardia
US6393316B1 (en) * 1999-05-12 2002-05-21 Medtronic, Inc. Method and apparatus for detection and treatment of cardiac arrhythmias
US6647292B1 (en) * 2000-09-18 2003-11-11 Cameron Health Unitary subcutaneous only implantable cardioverter-defibrillator and optional pacer
US6675042B2 (en) * 2002-04-15 2004-01-06 Charles D. Swerdlow Defibrillation shock strength determination technology

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3706764A (en) 1969-04-16 1972-12-19 Yoshitomi Pharmaceutical Phenethylaminomethyl-chromanones and- thiochromanones
US3803176A (en) 1969-05-09 1974-04-09 Novo Terapeutisk Labor As Sulfonylurea derivatives
GB1499323A (en) 1974-03-22 1978-02-01 Fisons Ltd 6-substituted chromones and chromanones
EP0079637B1 (en) 1981-11-12 1987-01-28 FISONS plc Anti-srs-a carboxylic acid derivatives, processes for their production, and pharmaceutical formulation containing them
EP0091749A3 (en) 1982-04-08 1984-12-05 Beecham Group Plc Ethanolamine derivatives, process for their preparation and pharmaceutical compositions containing them
ZA844519B (en) 1983-06-24 1985-02-27 Hoffmann La Roche Dihydrobenzopyran derivatives
US4654362A (en) 1983-12-05 1987-03-31 Janssen Pharmaceutica, N.V. Derivatives of 2,2'-iminobisethanol
DE3411992A1 (en) 1984-03-31 1985-10-10 Bayer Ag, 5090 Leverkusen SUBSTITUTED 4-HYDROXY BENZOPYRANS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS
GB8801306D0 (en) 1988-01-21 1988-02-17 Ici Plc Chemical compounds
FR2695387B1 (en) 1992-09-09 1994-10-21 Adir New benzopyran compounds, process for their preparation and pharmaceutical compositions containing them.
US5451677A (en) 1993-02-09 1995-09-19 Merck & Co., Inc. Substituted phenyl sulfonamides as selective β 3 agonists for the treatment of diabetes and obesity
AU675536B2 (en) 1993-06-14 1997-02-06 Pfizer Inc. Secondary amines as antidiabetic and antiobesity agents
GB9405019D0 (en) 1994-03-15 1994-04-27 Smithkline Beecham Plc Novel compounds
IL113410A (en) 1994-04-26 1999-11-30 Merck & Co Inc Substituted sulfonamides having an asymmetric center and pharmaceutical compositions containing them
US5561142A (en) 1994-04-26 1996-10-01 Merck & Co., Inc. Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
US5541197A (en) 1994-04-26 1996-07-30 Merck & Co., Inc. Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
US5516917A (en) 1994-06-08 1996-05-14 G. D. Searle & Co. Leukotriene B4 antagonists
JPH08198866A (en) 1995-01-20 1996-08-06 Tokyo Tanabe Co Ltd New 2-amino-1-phenylethanol compound
US5663194A (en) 1995-07-25 1997-09-02 Mewshaw; Richard E. Chroman-2-ylmethylamino derivatives
ZA967892B (en) 1995-09-21 1998-03-18 Lilly Co Eli Selective β3 adrenergic agonists.
FR2746395B1 (en) 1996-03-22 1998-04-17 Adir NOVEL ARYLETHANOLAMINE AND ARYLOXYPROPANOLAMINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
JP3708624B2 (en) 1996-03-27 2005-10-19 キッセイ薬品工業株式会社 3,4-disubstituted phenylethanolaminotetralin carboxylic acid derivative
EP0801060A1 (en) 1996-04-09 1997-10-15 Pfizer Inc. Heterocyclic Beta-3 Adrenergenic Agonists
WO1997046556A1 (en) 1996-06-07 1997-12-11 Merck & Co., Inc. OXADIAZOLE BENZENESULFONAMIDES AS SELECTIVE β3 AGONISTS FOR THE TREATMENT OF DIABETES AND OBESITY
AU728812B2 (en) 1997-01-28 2001-01-18 Merck & Co., Inc. Thiazole benzenesulfonamides as beta3 agonists for the treatment of diabetes and obesity
DE69807523T2 (en) * 1997-12-19 2003-01-09 Bayer Ag CARBOXYL-SUBSTITUTED CHROMANE DERIVATIVES FOR USE AS BETA 3 ADRENORE RECEPTOR AGONISTS
US6469031B1 (en) * 1998-12-18 2002-10-22 Bayer Corporation Carboxyl substituted chroman derivatives useful as beta 3 adrenoreceptor agonists
US6051586A (en) 1997-12-19 2000-04-18 Bayer Corporation Sulfonamide substituted chroman derivatives useful as beta 3 adrenoreceptor agonists
GB9812709D0 (en) 1998-06-13 1998-08-12 Glaxo Group Ltd Chemical compounds

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4727877A (en) * 1984-12-18 1988-03-01 Medtronic, Inc. Method and apparatus for low energy endocardial defibrillation
US5117824A (en) * 1990-11-14 1992-06-02 Medtronic, Inc. Apparatus for monitoring electrical physiologic signals
US5163427A (en) * 1990-11-14 1992-11-17 Medtronic, Inc. Apparatus for delivering single and multiple cardioversion and defibrillation pulses
US5129392A (en) * 1990-12-20 1992-07-14 Medtronic, Inc. Apparatus for automatically inducing fibrillation
US5674254A (en) * 1995-05-22 1997-10-07 Vitatron Medical, B.V. Cardiac pacemaker system and method for determining a measure of pacing threshold without incurring loss of capture
US5741312A (en) * 1997-03-12 1998-04-21 Vitatron Medical, B.V. Pacemaker system and method with improved capture detection and threshold search
US6052621A (en) * 1998-01-27 2000-04-18 Vitatron Medical B.V. System and method for inducing tachycardia
US6393316B1 (en) * 1999-05-12 2002-05-21 Medtronic, Inc. Method and apparatus for detection and treatment of cardiac arrhythmias
US6647292B1 (en) * 2000-09-18 2003-11-11 Cameron Health Unitary subcutaneous only implantable cardioverter-defibrillator and optional pacer
US6675042B2 (en) * 2002-04-15 2004-01-06 Charles D. Swerdlow Defibrillation shock strength determination technology

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070099908A1 (en) * 2005-11-03 2007-05-03 Jacob Berger Arylsulfonyl chromans as 5-HT6 inhibitors
WO2007051735A1 (en) * 2005-11-03 2007-05-10 F. Hoffmann-La Roche Ag Arylsulfonylchromans as 5-ht6 inhibitors indolylmaleimide derivatives as protein kinase inhibitors
US7754759B2 (en) 2005-11-03 2010-07-13 Roche Palo Alto Llc Arylsulfonyl chromans as 5-HT6 inhibitors

Also Published As

Publication number Publication date
DE60201437T2 (en) 2005-12-15
JP2004532227A (en) 2004-10-21
US6919371B2 (en) 2005-07-19
DOP2002000385A (en) 2004-01-31
US6660752B2 (en) 2003-12-09
ES2230487T3 (en) 2005-05-01
EP1389202B1 (en) 2004-09-29
DE60201437D1 (en) 2004-11-04
US20030078260A1 (en) 2003-04-24
US20040072828A1 (en) 2004-04-15
EP1389202A1 (en) 2004-02-18
WO2002085891A1 (en) 2002-10-31
AR035858A1 (en) 2004-07-21
PE20021073A1 (en) 2002-12-12

Similar Documents

Publication Publication Date Title
US6919371B2 (en) 2,6-substituted chroman derivatives useful as beta-3 adrenoreceptor agonists
US6780859B2 (en) Benzofuran and dihydrobenzofuran derivatives useful as beta-3 adrenoreceptor agonists
EP0420511B1 (en) Heterocyclic derivatives
US6699860B2 (en) Di-substituted aminomethyl-chroman derivative beta-3 adrenoreceptor agonists
NO175591B (en) Analogous Process for Preparation of Therapeutically Active Substituted Derivatives of Pyridine, Quinoline, Isoquinoline, Quinazoline, or Quinoxaline
US20220324847A1 (en) 2-hydroxycycloalkane-1-carbamoyl derivatives
US8163901B2 (en) Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
CA2314925A1 (en) Novel sulfonamide substituted chroman derivatives useful as beta-3 adrenoreceptor agonists
US6903218B2 (en) Sulfonamide substituted chroman derivatives
EP1040106B1 (en) Carboxyl substituted chroman derivatives useful as beta 3 adrenoreceptor agonists
CA2058651A1 (en) Sulphonamide derivatives
EP1701942A1 (en) Non-nucleotide reverse transcriptase inhibitors
US20030013705A1 (en) Novel carboxyl substituted chroman derivatives useful as beta 3 adrenoreceptor agonists
CZ20002257A3 (en) Carboxy-substituted chroman derivatives that can be used as beta-3-adrenoreceptor agonists

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION