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WO2007033002A1 - Conformationally constrained 3- (4-hydroxy-phenyl) - substituted-propanoic acids useful for treating metabolic disorders - Google Patents

Conformationally constrained 3- (4-hydroxy-phenyl) - substituted-propanoic acids useful for treating metabolic disorders Download PDF

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Publication number
WO2007033002A1
WO2007033002A1 PCT/US2006/034995 US2006034995W WO2007033002A1 WO 2007033002 A1 WO2007033002 A1 WO 2007033002A1 US 2006034995 W US2006034995 W US 2006034995W WO 2007033002 A1 WO2007033002 A1 WO 2007033002A1
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Prior art keywords
compound
alkyl
aryl
formula
alkylene
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PCT/US2006/034995
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French (fr)
Inventor
Michelle Akerman
Sean Brown
Jonathan B. Houze
Jinqian Liu
Zhihua Ma
Julio C. Medina
Wei Qiu
Michael J. Schmitt
Yingcai Wang
Liusheng Zhu
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Amgen Inc.
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Application filed by Amgen Inc. filed Critical Amgen Inc.
Priority to CA002621949A priority Critical patent/CA2621949A1/en
Priority to AU2006291234A priority patent/AU2006291234A1/en
Priority to EP06814336A priority patent/EP1924546A1/en
Publication of WO2007033002A1 publication Critical patent/WO2007033002A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/54—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Definitions

  • the present invention relates to compounds capable of modulating the G-protein-coupled receptor GPR40, compositions comprising the compounds, and methods for their use for controlling insulin levels in vivo and for the treatment of conditions such as type II diabetes, hypertension, ketoacidosis, obesity, glucose intolerance, and hypercholesterolemia and related disorders associated with abnormally high or low plasma lipoprotein, triglyceride or glucose levels.
  • the production of insulin is central to the regulation of carbohydrate and lipid metabolism. Insulin imbalances lead to conditions such as type II diabetes mellitus, a serious metabolic disease that afflicts around 5% of the population in Western Societies and over 150 million people worldwide. Insulin is secreted from pancreatic ⁇ cells in response to elevated plasma glucose which is augmented by the presence of fatty acids.
  • G-protein coupled receptor GPR40 The recent recognition of the function of the G-protein coupled receptor GPR40 in modulating insulin secretion has provided insight into regulation of carbohydrate and lipid metabolism in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes, cardiovascular disease and dyslipidemia.
  • GPR40 is a member of the gene superfamily of G-protein coupled receptors ("GPCRs"). GPCRs are membrane proteins characterized as having seven putative transmembrane domains that respond to a variety of molecules by activating intra-cellular signaling pathways critical to a diversity of physiological functions. GPR40 was first identified as an orphan receptor (i.e., a receptor without a known ligand) from a human genomic DNA fragment. Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun. 239: 543-547. GPR40 is highly expressed in pancreatic ⁇ cells and insulin-secreting cell lines.
  • GPCRs G-protein coupled receptors
  • GPR40 activation is linked to modulation of the G q family of intra-cellular signaling proteins and concomitant induction of elevated calcium levels. It has been recognized that fatty acids serve as ligands for GPR40, and that fatty acids regulate insulin secretion through GPR40. Itoh et al. (2003) Nature 422: 173-176; Briscoe et al. (2003) J. Biol. Chem. 278: 11303-11311; Kotarsky et al. (2003) Biochem. Biophys. Res. Commun. 301: 406-410.
  • WO 2004/041266 and EP 1559422 disclose compounds that purportedly act as GPR40 receptor function regulators.
  • WO 2004/106276 and EP 1 630 152 are directed to condensed ring compounds that purportedly possess GPR40 receptor function modulating action.
  • WO 2005/086661 and U.S. Patent Publication No. 2006/0004012 disclose compounds useful for modulating insulin levels in subjects and useful for treating type II diabetes.
  • the compounds of the invention have the general formula I:
  • Q is hydrogen, aryl, heteroaryl, (CrC ⁇ alkyl, or (C 2 -C 6 )heteroalkyl
  • L 1 is a bond, (C r C 4 )alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) k , N(R a ), C(O)-(C 5 - C 7 )heterocycloalkylene, (C 1 -C 4 )alkylene-SO 2 N(R b ), (C 1 -C 4 )alkylene-N(R b )SO 2 ,
  • L 2 is a bond, (d-C ⁇ alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, S(O) k , N(R a ), C(O)N(R b ), SO 2 N(R b ), (C 1 -C 4 )alkylene-C(O)N(R b ), (C 1 -C 4 )alkylene-N(R b )C(O), (C 2 -C 4 )alkenylene-C(O)N(R b ), (C 2 -C 4 )alkenylene-N(R b ), (C 2 -C 4 )alkenylene-N(R b )C(O), (C 1 -C 4 )alkylene-SO 2 N(R b ), (C r C 4 )alkylene-
  • M is an aromatic ring, a heteroaromatic ring, (C 5 -C 8 )cycloalkylene, ary ⁇ CpC ⁇ alkylene, or heteroaryKQ-C ⁇ alkylene;
  • X is CR 1 R 1 ', N(R 1 "), O, or S(O) k ;
  • L 3 is (C 1 -C 5 )alkylene or (C 2 -C 5 )heteroalkylene;
  • A is -CO 2 H, tetrazol-5-yl, -SO 3 H, -PO 3 H 2 , -SO 2 NH 2 , -C(O)NHSO 2 CH 3 , -CHO, thiazolidinedionyl, hydroxyphenyl, or pyridyl;
  • R a is hydrogen, (C 1
  • the present invention provides a compound having the formula II:
  • Q is selected from hydrogen, aryl, or heteroaryl
  • L 2 is selected from O, or S(0) k 5
  • R 1 is selected from (C 2 -C 8 )alkynyl, aryl, heteroaryl, or -C(O)NR 2 R 3
  • R 2 and R 3 are independently selected from hydrogen or (Ci-C 4 )alkyl
  • R 5 is independently selected from (Q-C ⁇ alkyl, halogen, (C ⁇ C ⁇ alkoxy, cyano, or nitro.
  • R 4 is independently selected from cyano, or nitro.
  • the compound has the formula IV:
  • the present invention provides a compound having the formula V:
  • the present invention provides a compound having the formula VI:
  • the present invention provides a compound having the formula VII:
  • the present invention provides a compound having the formula X or XI:
  • the present invention provides a compound having the formula (I):
  • Q is hydrogen, aryl, heteroaryl, (d-C ⁇ alkyl, or (C 2 -C 6 )heteroalkyl.
  • Q is hydrogen, aryl, or heteroaryl.
  • Q is a substituted or unsubstituted phenyl.
  • L 1 is a bond, (Ci-C 4 )alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) k ,
  • L 1 is a bond.
  • [019] represents a cyclohexane ring or a benzo-fused (C 5 -
  • Cg)cycloalkane ring is a substituted cyclohexane
  • benzo-fused (C 5 -Cg)cycloalkane ring is a
  • substituted benzo-fused (C 5 -C 8 )cycloalkane ring.
  • a benzo-fused (C 5 -Cg)cycloalkane ring is selected from the group consisting of dihydroindene (i.e., indane or a benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., a benzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., a benzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., a benzo- cyclooctyl ring).
  • dihydroindene i.e., indane or a benzo-cyclopentyl ring
  • tetrahydronaphthalene i.e., a benzo-cyclohexyl ring
  • tetrahydrobenzo[7]annulene i.e., a benzo-
  • L 2 is a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )heteroalkylene 5 oxymethylene, O, S(O) k , N(R a ), C(O)N(R b ), SO 2 N(R b ), (C 1 - C 4 )alkylene-C(O)N(R b ), (CrC 4 )alkylene-N(R b )C(O), (C 2 -C 4 )alkenylene-C(O)N(R b ), (C 2 -C 4 )alkenylene-N(R b )C(O), (d-COalkylene-SO ⁇ CR ⁇ CrC ⁇ alkylene-NCR ⁇ SOa, (C 2 -C 4 )alkenylene-SO 2 N(R b ) or (C 2 -C 4 )alkenylene- N(R b )SO 2 , where the
  • L is aryl or heteroaryl, and ' is cyclohexyl.
  • L is a bond and L 2 is -O-, -S- or -S(O)-. In certain embodiments, L 2 is -O-, -S- or
  • X is CR 1 R 1 '.
  • L 3 is a bond, (d-C 5 )alkylene, or (C 2 -C 5 )heteroalkylene, provided that L 3 is not a bond when L 2 is a bond.
  • L 3 is a (C 1 - C 5 )alkylene or is a (C 2 -C 5 )heteroalkylene.
  • L 3 is (C 1 - C 3 )alkylene.
  • L is methylene.
  • L is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl.
  • A is -CO 2 H, tetrazol-5-yl, -SO 3 H, -PO 3 H 2 , -SO 2 NH 2 ,
  • A is -CO 2 H or a salt thereof.
  • A is -CO 2 H or an alkyl ester thereof.
  • A is a C 1 -C 6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
  • R a is hydrogen, (C 1 -C 6 )alkyl, aryl(Ci-C 3 ) alkyl, or (C 2 -
  • R a is (C; ⁇ -C 6 )alkyl or (C 2 -C 6 )heteroalkyl.
  • R b is hydrogen, (d-C 6 )alkyl, or (C 2 -C 6 )heteroalkyl.
  • M is a benzene ring, and R 1 is combined with M to form a 5-, 6- or
  • M is a benzene ring substituted in addition to where it is bonded to R 1 . In some embodiments, M is a benzene ring that is bonded to R 1 but is otherwise unsubstituted.
  • R 1 is combined with the adjacent benzene ring to form a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O and S.
  • the following structures of M-X-L 3 - A exemplify some embodiments where R 1 is combined with the adjacent benzene ring to form a benzo-fused cycloalkane ring:
  • the compound can be a stereoisomerically pure compound. In some embodiments, the compound can be a mixture of stereoisomers. In some embodiments, M is a benzene ring substituted in addition to where it is bonded to
  • M is a benzene ring that is bonded to R 1 but is otherwise unsubstituted.
  • R 1 is hydrogen, cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl,
  • R 1 is hydrogen or methyl.
  • R 1 is hydrogen
  • the compound of formula I comprises a stereomerically pure stereoisomer. In other embodiments, the compound of formula I
  • the present invention provides a compound having the formula (I):
  • Q is hydrogen, aryl, heteroaryl, (Ci-C 6 )alkyl, or (C 2 -C 6 )heteroalkyl.
  • Q is hydrogen, aryl, or heteroaryl.
  • Q is a substituted or unsubstituted phenyl.
  • L 1 is a bond, (C r C 4 )alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) k ,
  • L 1 is a bond
  • [038] represents an optionally substituted (C 5 -C 8 )cycloalkane ring.
  • L 2 is a bond, (Ci-C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, S(O) k , N(R a ), C(O)N(R b ), SO 2 N(R b ), (Ci-
  • L 2 is O or S(O) k , where the subscript k is
  • L 2 is -O-, -S- or -S(O)-, where Q is aryl or
  • heteroaryl and is cyclohexyl.
  • L 1 is a bond and L 2 is -O-, -S- or -S(O)-.
  • L 2 is -O-, -S- or -S(O)-, where Q is aryl or
  • heteroaryl and is cyclohexyl.
  • M is an aromatic ring, a heteroaromatic ring, (Cs-C 8 )cycloalkylene, ary ⁇ Q-C ⁇ alkylene or heteroary ⁇ CrC ⁇ alkylene.
  • M is an aromatic ring, the term aromatic includes aryl. In other embodiments where M is a heteroaromatic ring, the term heteroaromatic includes heteroaryl.
  • M is an aromatic ring or is a heteroaromatic ring.
  • M is a monocyclic aromatic, a monocyclic heteroaromatic ring, or a (C 5 -Cg)cycloalkylene.
  • M is an unsubstituted monocyclic aromatic ring or is an unsubstituted monocyclic heteroaromatic ring. [049] In certain embodiments, M is a substituted benzene ring.
  • M is an unsubstituted benzene ring.
  • X is CR 1 R 1 ', N(R 1 "), O, or S(O) k , where the subscript k is 0, 1, or 2.
  • M is a substituted or unsubstituted benzene ring and X is para to L 2 .
  • L 3 is a bond, (C 1 -C 5 )alkylene, or (C 2 -C 5 )heteroalkylene, provided that L 3 is not a bond when L 2 is a bond. In some embodiments, L 3 is a (C 1 -
  • C 5 )alkylene or is a (C 2 -C 5 )heteroalkylene.
  • L 3 is (Ci-C 3 )alkylene.
  • L 3 is methylene
  • L 3 is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl.
  • A is -CO 2 H, tetrazol-5-yl, -SO 3 H, -PO 3 H 2 , -SO 2 NH 2 ,
  • A is -CO 2 H or a salt thereof.
  • A is -CO 2 H or an alkyl ester thereof.
  • A is a C 1 -C 6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
  • R a is hydrogen, (d-C ⁇ alkyl, 3TyI(C 1 -C 3 ) alkyl, or (C 2 -
  • R a is (d-C 6 )alkyl or (C 2 -C 6 )heteroalkyl.
  • R b is hydrogen, (d-C ⁇ alkyl, or (C 2 -C 6 )heteroalkyl.
  • R 1 is cyano, aryl, heteroaryl, (C r C 8 )alkyl, (C 2 -C 8 )alkyl,
  • R 1 is cyano, aryl, heteroaryl, (C 2 -C 8 )alkenyl,
  • R 1 is (C 2 -C 8 )alkynyl, aryl, heteroaryl, or
  • R 1 is a (C 2 -Cg)alkynyl or a heteroaryl. In some such embodiments, R 1 is a (C 3 -C 8 )alkynyl. In other such embodiments, R 1 is a heteroaryl. [066] In certain embodiments, R 1 is selected from the group consisting of prop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, triazolyl, and -C(O)NR 2 R 3 .
  • R 1' is hydrogen, cyano, aryl, heteroaryl,
  • R 1 is hydrogen or methyl.
  • R 1 is hydrogen
  • R 1 is (C 2 -C 8 )alkynyl, aryl, heteroaryl or
  • R 1 is hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl,
  • R and R are independently selected from hydrogen, aryl, heteroaryl, (d-C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -
  • R 2 and R 3 are combined to form a 4-, 5-, 6- or 7- membered ring containing the nitrogen atom to which they are attached and including from 0 to 2 additional heteroatoms selected from N, O, or S.
  • the ring formed by combining R 2 and R 3 may be a saturated, unsaturated, or aromatic ring.
  • the compound of formula I comprises a stereomerically pure stereoisomer. In other embodiments, the compound of formula I comprises a mixture of stereoisomers.
  • L 1 is a bond
  • Q is H or aryl
  • L 2 is O, oxymethylene, or oxyethylene
  • M is benzene and X is para to L 2
  • X is CR 1 R 1
  • R 1 is cyano, aryl, heteroaryl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -Cs)alkynyl, (C 3 -C 8 )alkynyl, or -C(O)NR 2 R 3
  • R 1' is H
  • L 3 is methylene
  • A is CO 2 H or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
  • the compound is a pharmaceutically acceptable salt or solvate thereof.
  • the compound is a prodrug which is, in some embodiments, an ester such as a (C 1 -C 6 )alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
  • the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula I.
  • the compound of the present invention is a compound of formula II or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, where Q is selected from hydrogen, aryl, or
  • heteroaryl represents an optionally substituted cycloalkane ring
  • L 2 is selected from O or S(O) k
  • R 1 is selected from (C 2 -C 8 )alkynyl, aryl, heteroaryl, or -C(O)NR 2 R 3 ; optionally, R 1 is combined with the adjacent benzene ring to form a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O and S
  • R 2 and R 3 are independently selected from hydrogen or (C 1 -C 4 )alkyl
  • the compounds of the invention include pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof.
  • the compounds are pharmaceutically acceptable salts.
  • the compounds are prodrugs such as esters of a carboxylic acid.
  • the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent, or excipient, and a compound of formula I-XI.
  • the invention provides methods for treating or preventing a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, hypertension, cancer, and edema.
  • a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thro
  • Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of formula I-XI.
  • the disease or condition is type II diabetes.
  • a compound of formula I-XI is administered with combination with a second therapeutic agent.
  • the second therapeutic agent is metformin or is a thiazolidinedione. The second therapeutic agent may be administered before, during, or after administration of the compound of formula I- XI.
  • the invention provides methods for treating or preventing a disease or condition responsive to the modulation of GPR40. Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of formula I-XI.
  • the invention provides methods for treating or preventing a disease or condition mediated, regulated, or influenced by pancreatic ⁇ cells. Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of formula I-XI. [083] In another aspect, the invention provides methods for modulating
  • GPR40 function in a cell Such methods include contacting a cell with a compound of formula I-XI.
  • the invention provides methods for modulating
  • GPR40 function Such methods include contacting GPR40 with a compound of formula I-XI.
  • the invention provides methods for modulating circulating insulin concentration in a subject. Such methods include administering a compound of formula I-XI to the subject. In some such embodiments, the circulating insulin concentration is increased in the subject after administration whereas in other such embodiments, the circulating insulin concentration is decreased in the subject after administration.
  • the invention provides the use of a compound of formula I-XI for treating a disease or condition or for preparing a medicament for treating a disease or condition where the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.
  • the disease or condition is type II diabetes.
  • the compounds of the invention may also be used to prepare medicaments that include a second therapeutic agent such as metformin or a thiazolidinedione.
  • the invention provides the use of a compound of formula I-XI for modulating GPR40 or for use in the preparation of a medicament for modulating GPR40.
  • the invention provides a therapeutic composition that includes a compound of formula I-XI and a second therapeutic agent such as those described herein, for example, metformin or a thiazolidinedione, as a combined preparation for simultaneous, separate, or sequential use in the treatment of a disease or condition mediated by GPR40.
  • a disease or condition is type II diabetes.
  • the compound of formula I-XI and the second therapeutic agent are provided as a single composition, whereas in other embodiments they are provided separately as parts of a kit.
  • the invention provides a method of synthesizing a compound of formula XXIV.
  • the method includes: reacting a compound of formula XXII with a compound of formula XXIII to produce the compound of formula XXIV, wherein the compounds of formula XXII and XXIII have the following structures:
  • AIk is a straight or branched chain alkyl group having from 1 to 8 carbon atoms
  • R 1 is selected from cyano, aryl, heteroaryl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )alkynyl, or C(O)NR 2 R 3
  • R 2 and R 3 are independently selected from hydrogen, aryl, heteroaryl, (C 1 -Cg)alkyl, (C 2 -C 8 )heteroalkyl, (C 3 - Cg)cycloalkyl, or (C 3 -C 8 )heterocycloalkyl; or optionally, R 2 and R 3 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N
  • W is selected from OH or a halogen.
  • W is OH and a phosphine selected from a trialkylphosphine, a dialkylarylphosphine, a alkyldiarylphosphine, or a triarylphosphine and an azodicarboxylate are used to react the compound of formula XXII with the compound of formula XXIII.
  • W is a halogen selected from Br or Cl, and a base is used to react the compound of formula XXII with the compound of formula XXIII.
  • W is selected from OH, halogen, OTs, OMs, or OTf, where Ts is p-toluenesulfonyl, Ms is methanesulfonryl, and Tf is trifiuoromethanesulfonryl.
  • AIk is selected from methyl or ethyl.
  • n is 0.
  • p 0.
  • Y is a halogen
  • the method further comprises reacting the compound of formula XXIV with a boronic acid compound.
  • the boronic acid compound has the formula aryl-B(OH) 2 or alkyl-B(OH) 2 .
  • the method further includes removing the
  • Y, R 4 , n, m, R 5 , p, and R 1 have the definitions provided with respect to the compounds of any of the embodiments of formula XXII, XXIII, and XXIV.
  • the compound of formula XXIV is reacted in the presence of a hydroxide base to produce the compound of formula XXV.
  • the hydroxide base is selected from LiOH, NaOH, KOH, or Ca(OH) 2 .
  • treat are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms.
  • prevent refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a subject from acquiring a condition or disease, or reducing a subject's risk of acquiring a condition or disease.
  • terapéuticaally effective amount refers to that amount of the compound that will elicit the biological or medical response of a tissue, system, or subject that is being sought.
  • therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated in a subject.
  • the therapeutically effective amount in a subject will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • subject is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
  • modulate refers to the ability of a compound to increase or decrease the function or activity of GPR40 either directly or indirectly.
  • Inhibitors are compounds that, for example, bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction, such as, for instance, antagonists.
  • Activators are compounds that, for example, bind to, stimulate, increase, activate, facilitate, enhance activation, sensitize or up regulate signal transduction, such as agonists for instance. Modulation may occur in vitro or in vivo.
  • GPR40-mediated condition or disorder refers to a condition or disorder characterized by inappropriate, for example, less than or greater than normal, GPR40 activity.
  • a GPR40-mediated condition or disorder may be completely or partially mediated by inappropriate GPR40 activity.
  • a GPR40-mediated condition or disorder is one in which modulation of GPR40 results in some effect on the underlying condition or disease (e.g., a GPR40 modulator results in some improvement in patient well-being in at least some patients).
  • Exemplary GPR40-mediated conditions and disorders include cancer and metabolic disorders, e.g., diabetes, type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, thrombotic disorders, metabolic syndrome, syndrome X and related disorders, e.g., cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, and edema.
  • cancer and metabolic disorders e.g., diabetes, type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, thrombotic disorders, metabolic
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (e.g., C 1- C 10 means one to ten carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • alkenyl by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C 2- C 8 means two to eight carbons) and one or more double bonds.
  • alkenyl groups include vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), and higher homologs and isomers thereof.
  • alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C 2 -C 8 means two to eight carbons) and one or more triple bonds.
  • alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers thereof.
  • alkylene by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 12 or fewer carbon atoms being preferred in the present invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
  • dialkylamino refers to an amino group having two attached alkyl groups.
  • the alkyl groups of a dialkylamino may be the same or different.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, and S may be placed at any position of the heteroalkyl group.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 .
  • a prefix such as (C 2 -C 8 ) is used to refer to a heteroalkyl group
  • the number of carbons (2 to 8, in this example) is meant to include the heteroatoms as well.
  • a C 2 -heteroalkyl group is meant to include, for example, -CH 2 OH (one carbon atom and one heteroatom replacing a carbon atom) and -CH 2 SH.
  • a heteroalkyl group is a, oxyalkyl group.
  • (C 2- C 5 )oxyalkyl is meant to include, for example -CH 2 -O-CH 3 (a C 3 -oxyalkyl group with two carbon atoms and one oxygen replacing a carbon atom), -CH 2 CH 2 CH 2 CH 2 OH, and the like.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
  • cycloalkyl and heterocycloalkyl represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively.
  • cycloalkyl and heterocycloalkyl are meant to be included in the terms “alkyl” and “heteroalkyl,” respectively.
  • a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1- cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • Examples of heterocycloalkyl include l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2- piperazinyl, and the like.
  • cycloalkylene and heterocycloalkylene represent, unless otherwise stated, cyclic versions of “alkylene” and “heteroalkylene,” respectively.
  • cycloalkylene and heterocycloalkylene are meant to be included in the terms “alkylene” and “heteroalkylene,” respectively.
  • heterocycloalkylene one or more heteroatoms can occupy positions at which the heterocycle is attached to the remainder of the molecule.
  • a cycloalkylene or heterocycloalkylene will have from 3 to 9 atoms forming the ring, more typically, 4 to 7 atoms forming the ring, and even more typically, 5 or 6 atoms will form the cycloalkylene or hetercycloalkylene ring.
  • halo or halogen
  • a fluorine, chlorine, bromine, or iodine atom mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • haloalkyl are meant to include alkyl substituted with halogen atoms which can be the same or different, in a number ranging from one to (2m' + 1), where m' is the total number of carbon atoms in the alkyl group.
  • halo(C 1- C 4 )alkyl is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • haloalkyl includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m' + 1) halogen atoms).
  • perhaloalkyl means, unless otherwise stated, alkyl substituted with (2m' + 1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group.
  • perhalo(C 1 -C 4 )alkyl is meant to include trifluoromethyl, pentachloroethyl, l,l,l-trifluoro-2-bromo-2-chloroethyl, and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, dibenzofuryl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 2-pyrimidinyl, 4-pyrimidinyl,
  • aryl refers to a phenyl or naphthyl group which is unsubstituted or substituted.
  • heteroaryl refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, triazolyl, tetrazolyl, quinoxalinyl, or quinolyl group which is unsubstituted or substituted.
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g.
  • benzyl, phenethyl, pyridylmethyl and the like including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
  • a carbon atom e.g., a methylene group
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like.
  • heteroaryl is meant to include both substituted and unsubstituted forms of the indicated radical, unless otherwise indicated. Preferred substituents for each type of radical are provided below.
  • R', R" and R'" each independently refer to hydrogen, unsubstituted (C 1 -C 8 )alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(Cj-C 4 )alkyl, or aryl-(Ci- C 4 )alkyl groups.
  • R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring.
  • -NR'R is meant to include 1-pyrrolidinyl and 4-morpholinyl.
  • an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl” is meant to include groups such as trihaloalkyl (e.g., -CF 3 and -CH 2 CF 3 ).
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH 2 ) q - U-, wherein T and U are independently -NH-, -O-, -CH 2 -, or a single bond, and q is an integer of from 0 to 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 VB-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'-, or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) s -X-(CH 2 ) r , where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • the substituent R' in -NR'- and -S(O) 2 NR'- is selected from hydrogen or unsubstituted (d-C ⁇ alkyl. Otherwise, R' is as defined above.
  • benzo-fused cycloalkane ring is meant to include bicyclic structures in which benzene is fused with a cycloalkane (or cycloheteroalkane).
  • cycloalkane or cycloheteroalkane.
  • benzo-fused cycloalkane ring includes the following structures:
  • heteroatom is meant to include oxygen
  • pharmaceutically acceptable salt is meant to include a salt of the active compound which is prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compound described herein.
  • a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginine and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al. (1977) J. Pharm. ScI 66:1-19).
  • Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.
  • the invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • solvate refers to a compound of the present invention or a salt thereof, that further includes a stoichiometric or non- stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention.
  • stereoisomer or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
  • a bond drawn with a wavy line indicates that both stereoisomers are encompassed.
  • Various compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms.
  • mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention.
  • These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
  • the compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine- 125 ( 125 I) or carbon- 14 (' C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., GPR40 assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
  • a class of compounds that modulates GPR40 is described herein. Depending on the biological environment (e.g., cell type, pathological condition of the subject, etc.), these compounds can modulate, e.g., activate or inhibit, the actions of GPR40.
  • the compounds By modulating GPR40, the compounds find use as therapeutic agents capable of regulating insulin levels in a subject.
  • the compounds find use as therapeutic agents for modulating diseases and conditions responsive to modulation of GPR40 and/or mediated by GPR40 and/or mediated by pancreatic ⁇ cells.
  • diseases and conditions include diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, cancer, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, nephropathy, thrombotic disorders, diabetic neuropathy, diabetic retinopathy, dermatopathy, dyspepsia and edema. Additionally, the compounds are useful for the treatment and/or prevention of complications of these diseases and disorders (e.g., type II diabetes, sexual dysfunction, dyspepsia and so forth).
  • complications of these diseases and disorders e.g., type II diabetes, sexual dysfunction, dyspepsia and so forth.
  • Compounds contemplated by the invention include, but are not limited to, the exemplary compounds provided herein.
  • the present invention provides a compound having the formula (I):
  • Q is hydrogen, aryl, heteroaryl, (Q-C ⁇ alkyl, or (C 2 -C 6 )heteroalkyl.
  • Q is hydrogen, aryl, or heteroaryl.
  • Q is a substituted or unsubstituted phenyl.
  • L 1 is a bond, (Q-C ⁇ alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) k ,
  • L 1 is a bond
  • [0144] represents a cyclohexane ring or a benzo-fused (C 5 -
  • (C 5 -C 8 )cycloalkane ring is an unsubstituted benzo-fused (C 5 -C 8 )cycloalkane ring.
  • the benzo-fused cycloalkane ring comprises 0-3 heteroatom ring members selected from O, N, or S.
  • the benzo-fused (C 5 -C 8 )cycloalkane ring comprises 1 or 2 heteroatom ring members selected from O or N, and in some embodiments 1 heteroatom ring member, selected from O or N.
  • the benzo-fused (C 5 -C 8 )cycloalkane comprises 0 heteroatom ring atoms, does not include any heteroatoms in the ring, such that each of the ring members of the benzo-fused
  • (C 5 -C 8 )cycloalkane is a carbon atom. In some embodiments where is a
  • benzo-fused (C 5 -C 8 )cycloalkane ring is selected from the group consisting of dihydroindene (i.e., indane or a benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., a benzo-cyclohexyl ring), tetrahydrobenzo[7]annulene
  • hexahydrobenzo[8]annulene i.e., a benzo- cyclooctyl ring
  • L 2 is a bond, (Q-C ⁇ alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, S(O) k , N(R a ), C(O)N(R b ), SO 2 N(R b ), (C 1 -
  • L 2 is O or S(O) k , where the subscript k is
  • L 2 is -O-, -S- or -S(O)-, where Q is aryl or
  • heteroaryl and is cyclohexyl.
  • L 1 is a bond and L 2 is -O-, -S- or -S(O)-.
  • L 2 is -O-, -S- or -S(O)-, where Q is aryl or
  • heteroaryl and is cyclohexyl.
  • M is an aromatic ring, a heteroaromatic ring, (C 5 -C 8 )cycloalkylene, ary ⁇ CrC ⁇ alkylene or heteroary ⁇ Q-C ⁇ alkylene.
  • M is an aromatic ring, the term aromatic includes aryl. In other embodiments where M is a heteroaromatic ring, the term heteroaromatic includes heteroaryl.
  • M is an aromatic ring or is a heteroaromatic ring.
  • M is a monocyclic aromatic, a monocyclic heteroaromatic ring, or a (C 5 -C 8 )cycloalkylene.
  • M is an unsubstituted monocyclic aromatic ring or is an unsubstituted monocyclic heteroaromatic ring.
  • M is a substituted benzene ring.
  • M is an unsubstituted benzene ring.
  • X is CR 1 R 1 ', N(R 1 " ), O, or S(O) k , where the subscript k is 0, 1, or 2.
  • M is a substituted or unsubstituted benzene ring and X is para to L 2 .
  • L 3 is a bond, (C 1 -C 5 )alkylene, or (C 2 ⁇ C 5 )heteroalkylene, provided that L is not a bond when L is a bond.
  • L is a (C 1 -
  • C 5 )alkylene or is a (C 2 -C 5 )heteroalkylene.
  • L 3 is (Q-C ⁇ alkylene.
  • L 3 is methylene.
  • L 3 is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl.
  • A is -CO 2 H, tetrazol-5-yl, -SO 3 H, -PO 3 H 2 , -SO 2 NH 2 ,
  • A is -CO 2 H or a salt thereof.
  • the salt is a sodium, potassium, or calcium salt.
  • A is -CO 2 H or an alkyl ester thereof.
  • A is a C 1 -C 6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
  • R a is hydrogen, (C r C 6 )alkyl, aryl(Ci-C 3 ) alkyl, or (C 2 -
  • R a is (C 1 -C 6 )alkyl or (C 2 -C 6 )heteroalkyl.
  • R b is hydrogen, (Ci-C 6 )alkyl, or (C 2 -C 6 )heteroalkyl.
  • R 1 is cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkyl,
  • R 1 is cyano, aryl, heteroaryl, (C 2 -C 8 )alkenyl,
  • R 1 is (C 2 -C 8 )alkynyl, aryl, heteroaryl, or
  • R 1 is a (C 2 -C 8 )alkynyl or a heteroaryl. In some such embodiments, R 1 is a (C 3 -C 8 )alkynyl. In other such embodiments, R 1 is a heteroaryl.
  • R 1 is selected from the group consisting of prop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, triazolyl, and -C(O)NR 2 R 3 .
  • R 1' is hydrogen, cyano, aryl, heteroaryl, (Q-C ⁇ alkyl,
  • R 1 is hydrogen or methyl.
  • R 1 is hydrogen
  • R 1 is (C 2 -Cs)alkynyl, aryl, heteroaryl or
  • R 1 ' is hydrogen.
  • R 1 " is hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl,
  • R and R are independently selected from hydrogen, aryl, heteroaryl, (CrC 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl, or (C 3 - C 8 )heterocycloalkyl.
  • R and R are combined to form a 4-, 5-, 6- or 7- membered ring containing the nitrogen atom to which they are attached and including from 0 to 2 additional heteroatoms selected from N, O, or S.
  • the ring formed by combining R 2 and R 3 may be a saturated, unsaturated, or aromatic ring.
  • the compound of formula I comprises a stereomerically pure stereoisomer. In other embodiments, the compound of formula I comprises a mixture of stereoisomers.
  • L 1 is a bond
  • Q is H or aryl
  • L is O, oxymethylene, or oxyethylene
  • M is benzene and X is para to L 2
  • X is CR 1 R 1
  • R 1 is cyano, aryl, heteroaryl
  • R 1 is H, L 3 is methylene, and A is CO 2 H or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
  • the compound is a pharmaceutically acceptable salt or solvate thereof.
  • the compound is a prodrug which is, in some embodiments, an ester such as a (Ci-C 6 )alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
  • the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula I.
  • the present invention provides a compound having the formula II or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:
  • Q is selected from hydrogen, aryl, or heteroaryl; — represents a cyclohexane ring or a benzo-fused (C 5 -C 8 )cycloalkane ring; L 2 is selected from O or S(O) k ; R 1 is selected from (C 2 -C 8 )alkynyl, aryl, heteroaryl, or -C(O)NR 2 R 3 ; R 2 and R 3 are independently selected from hydrogen or (d-C ⁇ alkyl; and R 4 , R 5 , and the subscripts n and p are defined below. [0186] In certain embodiments, L 2 is selected from O or S(O)k. In some embodiments, L 2 is selected from O or S(O)k.
  • L 2 is -O-, -S- or -S(O)-;
  • Q is aryl or heteroaryl; and
  • — is cyclohexyl.
  • R 1 is (C 2 -C 8 )alkynyl, aryl, heteroaryl or
  • R 1 is a (C 2 -C 8 )alkynyl. In some such embodiments, R 1 is a (C 3 -C 8 )alkynyl. In other embodiments, R 1 is an aryl. In still further embodiments, R 1 is a heteroaryl. In still other embodiments, R 1 is a
  • R 1 is selected from the group consisting of prop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, triazolyl, and -C(O)NR 2 R 3 .
  • R 1 is selected from a prop-1-ynyl.
  • R 1 is selected from an imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, or triazolyl.
  • R 1 is selected from a -C(O)NR 2 R 3 .
  • R 2 and R 3 are independently selected from hydrogen or (Q-C ⁇ alkyl. [0190] In certain embodiments where is a substituted benzo-fused
  • R', R" and R'" each independently refer to hydrogen, unsubstituted (C 1 -Cg)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C 1 -C 4 )alkyl, or aryl-(C 1 -C 4 )alkyl groups.
  • (C 5 -C 8 )cycloalkane ring is selected from the group consisting of dihydroindene (i.e., indane or a benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., a benzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., a benzo- cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., a benzo-cyclooctyl ring).
  • dihydroindene i.e., indane or a benzo-cyclopentyl ring
  • tetrahydronaphthalene i.e., a benzo-cyclohexyl ring
  • tetrahydrobenzo[7]annulene i.e., a benzo- cyclohepty
  • R 1 is (C 2 -C 8 )alkynyl, aryl, heteroaryl or -C(O)NR 2 R 3 .
  • R 1 is a (C 2 -C 8 )alkynyl.
  • R 1 is a (C 3 -C 8 )alkynyl.
  • R 1 is an aryl.
  • R 1 is a heteroaryl.
  • R 1 is a -C(O)NR 2 R 3 .
  • R 4 is independently selected from (Ci-C 8 )alkynyl, aryl, heteroaryl or -C(O)NR 2 R 3 .
  • n O, 1 or 2.
  • Each R 5 is independently selected from the group consisting of
  • R 5 is independently selected from the group consisting of (C 1 -C 6 )alkyl, halogen, (d-C 6 )alkoxy, cyano, and nitro. [0196] The subscript p is 0, 1 , 2, 3, or 4.
  • the subscript p is 0.
  • Q is hydrogen, is indane, the subscript p is zero, and R 1 is (C 2 -C 3 )alkynyl.
  • Q is phenyl, is indane, and R 1 is
  • Q is a substituted phenyl, subscript p is zero, and L 2 is oxygen.
  • L 2 is oxygen
  • the subscript n is 1
  • R 4 is independently selected from methyl, halogen, or (Ci-C 6 )alkoxy
  • R 1 is
  • Q is hydrogen, is tetrahydronaphthalene, L 2 is oxygen, and R 1 is (C 2 -C 3 )alkynyl.
  • R 1 is (C 2 -C 3 )alkynyl.
  • R 1 is (C 2 -C 8 )alkynyl, aryl, heteroaryl, or -C(O)NR 2 R 3 -.
  • the compound of formula II comprises a stereomerically pure S-enantiomer.
  • the compound of formula II comprises a stereomerically pure R-enantiomer.
  • the compound of formula II comprises a mixture of S- and R- enantiomers.
  • the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug of the compound of formula II.
  • the hydrogen on the carboxylic group in formula II is replaced with an alkyl group to form an ester.
  • the compound of the present invention can be a methyl or ethyl ester of the compound of formula II.
  • the present invention provides a compound having the formula III or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:
  • the carbon with a bond to R 1 is a chiral carbon.
  • the present invention provides a compound having formula IHa or IHb or a pharmaceutically acceptable salt, solvate, or prodrug thereof:
  • R 1 is (C 2 -
  • the compound of formula III comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula III comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula III comprises a mixture of S- and R- enantiomers.
  • the compound has the formula IV:
  • the subscript m is 1 or 2.
  • Q is hydrogen
  • L 2 is oxygen
  • the subscript n is 1 or 2
  • R 4 is independently selected from methyl, halogen or (CrC 6 )alkoxy
  • R 1 is (C 2 -C 3 )alkynyl.
  • Q, L 2 and R 4 are attached to a benzo-fused cycloalkane ring. It will be understood that in various different embodiments, the attachments of Q, L 2 and R 4 can be to any carbon of the benzo-fused cycloalkyl ring, as valency permits.
  • the present invention provides a stereoisomerically pure compound of formula IV. In some embodiments, the present invention provides a stereoisomerically mixed compound of formula IV.
  • the present invention provides a compound having the formula V:
  • R 1 is (C 2 -C 8 )alkynyl, aryl, heteroaryl, or -C(O)NR 2 R 3 , and Q, L 2 , R 2 , R 3 , R 4 , and the subscript n are as defined above with respect to formula II.
  • the compound of the invention is stereoisomerically pure.
  • the compound of the invention is a mixture of two out of four stereoisomers.
  • the compound is a mixture of three out of four stereoisomers.
  • the compound is a mixture of all four stereoisomers.
  • the present invention provides a compound having the formula VI:
  • the present invention provides a stereoisomerically pure compound of formula VI. In some embodiments, the present invention provides a stereoisomerically mixed compound of formula VI. [0218] In some embodiments, the present invention provides a compound having the formula VII:
  • the present invention provides a stereoisomerically pure compound of formula VII. In some embodiments, the present invention provides a mixed stereoisomeric compound of formula VII. [0220] In some embodiments, the present invention provides a compound having the formula X or XI:
  • the present invention provides a stereoisomerically pure compound of formula X or XI. In some embodiments, the present invention provides a mixed stereoisomeric compound of formula X or XI. [0222] In another aspect, the present invention provides a compound having the formula (I):
  • Q is hydrogen, aryl, heteroaryl, (C 1 -C 6 )alkyl, or (C 2 -C 6 )heteroalkyl.
  • Q is hydrogen, aryl, or heteroaryl.
  • Q is a substituted or unsubstituted phenyl.
  • L 1 is a bond, (Q-C ⁇ alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) k ,
  • L 1 is a bond.
  • [0227] represents a cyclohexane ring or a benzo-fused (C 5 -
  • v — is a substituted cyclohexane
  • benzo-fused (C 5 -Cs)cycloalkane ring is a
  • substituted benzo-fused C 5 -C 8 )cycloalkane ring.
  • v — is selected from the group consisting of dihydroindene (i.e., indane or a benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., a benzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., a benzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., a benzo- cyclooctyl ring).
  • dihydroindene i.e., indane or a benzo-cyclopentyl ring
  • tetrahydronaphthalene i.e., a benzo-cyclohexyl ring
  • tetrahydrobenzo[7]annulene i.e., a benzo-cycloheptyl ring
  • L 2 is a bond, (C r C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, S(O) k , N(R a ), C(O)N(R b ), SO 2 N(R b ), (C 1 - C 4 )alkylene-C(O)N(R b ), (Ci-C 4 )alkylene-N(R b )C(O), (C 2 -C 4 )alkenylene-C(O)N(R b ), (C 2 -C 4 )alkenylene-N(R b )C(O), (Ci-C 4 )alkylene-SO 2 N(R b ), (C r C 4 )alkylene-N(R b )SO 2 , (C 2 -C 4 )alkenylene-SO 2 N(R b ) or (C 2 -C 4 )
  • L 1 is a bond and L 2 is -O-, -S- or -S(O)-. In certain embodiments, L 2 is -O-, -S- or
  • X is CR 1 R 1 '.
  • L 3 is a bond, (C 1 -C 5 )alkylene, or (C 2 -C 5 )heteroalkylene, provided that L 3 is not a bond when L 2 is a bond.
  • L 3 is a (C]- C 5 )alkylene or is a (C 2 -C 5 )heteroalkylene.
  • L 3 is (C 1 - C 3 )alkylene.
  • L 3 is methylene.
  • L 3 is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl.
  • A is -CO 2 H, tetrazol-5-yl, -SO 3 H 5 -PO 3 H 2 , -SO 2 NH 2 ,
  • A is -CO 2 H or a salt thereof.
  • A is -CO 2 H or an alkyl ester thereof.
  • A is a Ci-C 6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
  • R a is hydrogen, (d-C 6 )alkyl, 3TyI(C 1 -C 3 ) alkyl, or (C 2 -
  • R a is (Q-C ⁇ alkyl or (C2-C 6 )heteroalkyl.
  • R b is hydrogen, (Ci-C 6 )alkyl, or (C 2 -C 6 )heteroalkyl.
  • M is a benzene ring, and R 1 is combined with M to form a 5-, 6- or
  • M is a benzene ring substituted in addition to where it is bonded to R 1 . In some embodiments, M is a benzene ring that is bonded to R 1 but is otherwise unsubstituted.
  • R 1 is combined with the adjacent benzene ring to form a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O and S.
  • the following structures of M-X-L 3 - A exemplify some embodiments where R 1 is combined with the adjacent benzene ring to form a benzo-fused cycloalkane ring:
  • the compound can be a stereoisomerically pure compound. In some embodiments, the compound can be a mixture of stereoisomers.
  • M is a benzene ring substituted in addition to where it is bonded to R 1 . In other embodiments, M is a benzene ring that is bonded to R 1 but is otherwise unsubstituted.
  • R 1 ' is hydrogen, cyano, aryl, heteroaryl, (C t -C ⁇ alkyl,
  • R 1 is hydrogen or methyl.
  • R 1 is hydrogen
  • the compound of formula I comprises a stereomerically pure stereoisomer. In other embodiments, the compound of formula I comprises a mixture of stereoisomers.
  • the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula I.
  • the present invention provides a stereoisomerically pure compound of formula VIII or IX. In some embodiments, the present invention provides a mixed stereoisomeric compound of formula VIII or IX.
  • the present invention provides a compound having the formula (I):
  • Q is hydrogen, aryl, heteroaryl, (Q-C ⁇ alkyl, or (C 2 -C 6 )heteroalkyl.
  • Q is hydrogen, aryl, or heteroaryl.
  • Q is a substituted or unsubstituted phenyl.
  • L 1 is a bond, (d-C 4 )alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) k ,
  • L 1 is a bond
  • [0249] represents an optionally substituted (C 5 -C 8 )cycloalkane ring.
  • L 2 is a bond, (d-C 6 )alkylene 5 (C 2 -C 6 )heteroalkylene, oxymethylene, O, S(O) k , N(R a ), C(O)N(R b ), SO 2 N(R b ), (C 1 -
  • L is O or S(O) k , where the subscript k is
  • L 2 is -O-, -S- or -S(O)-, where Q is aryl or
  • heteroaryl and is cyclohexyl.
  • L 1 is a bond and L 2 is -O-, -S- or -S(O)-.
  • L 2 is -O-, -S- or -S(O)-, where Q is aryl or
  • heteroaryl and is cyclohexyl.
  • M is an aromatic ring, a heteroaromatic ring, (C 5 -C 8 )cycloalkylene, aryl(Ci-C 4 )alkylene or heteroaryl(Ci-C 4 )alkylene.
  • M is an aromatic ring, the term aromatic includes aryl. In other embodiments where M is a heteroaromatic ring, the term heteroaromatic includes heteroaryl.
  • M is an aromatic ring or is a heteroaromatic ring.
  • M is a monocyclic aromatic, a monocyclic heteroaromatic ring, or a (C 5 -Cs)cycloalkylene.
  • M is an unsubstituted monocyclic aromatic ring or is an unsubstituted monocyclic heteroaromatic ring.
  • M is a substituted benzene ring.
  • M is an unsubstituted benzene ring.
  • X is CR 1 R 1' , N(R 1 "), O, or S(O) k , where the subscript k is 0, 1 , or 2.
  • M is a substituted or unsubstituted benzene ring and X is para to L .
  • L 3 is a bond, (C 1 -Cs)alkylene, or (C 2 -Cs)heteroalkylene, provided that L 3 is not a bond when L 2 is a bond. In some embodiments, L 3 is a (C 1 -
  • C 5 )alkylene or is a (C 2 -C 5 )heteroalkylene.
  • L 3 is (C 1 -C 3 )alkylene.
  • L 3 is methylene.
  • L 3 is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl.
  • A is -CO 2 H 5 tetrazol-5-yl, -SO 3 H, -PO 3 H 2 , -SO 2 NH 2 ,
  • A is -CO 2 H or a salt thereof.
  • A is -CO 2 H or an alkyl ester thereof.
  • A is a C 1 -C 6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
  • R a is hydrogen, (d-C 6 )alkyl, 8TyI(C 1 -C 3 ) alkyl, or (C 2 -
  • R a is (CrC 6 )alkyl or (C 2 -C 6 )heteroalkyl.
  • R b is hydrogen, (d-C ⁇ alkyl, or (C 2 -C 6 )heteroalkyl.
  • R 1 is cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkyl,
  • R 1 is cyano, aryl, heteroaryl, (C 2 -C 8 )alkenyl,
  • R 1 is (C 2 -C 8 )alkynyl, aryl, heteroaryl, or
  • R 1 is a (C 2 -C 8 )alkynyl or a heteroaryl. In some such embodiments, R 1 is a (C 3 -C 8 )alkynyl. In other such embodiments, R 1 is a heteroaryl.
  • R 1 is selected from the group consisting of prop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, triazolyl, and -C(O)NR 2 R 3 .
  • R 1' is hydrogen, cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl,
  • R 1 ' is hydrogen or methyl.
  • R 1 is hydrogen
  • R 1 is (C 2 -C 8 )alkynyl, aryl, heteroaryl or
  • R 1" is hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl,
  • R 2 and R 3 are independently selected from hydrogen, aryl, heteroaryl, (d-C ⁇ alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl 5 or (C 3 - C 8 )heterocycloalkyl.
  • R 2 and R 3 are combined to form a A-, 5-, 6- or 7- membered ring containing the nitrogen atom to which they are attached and including from 0 to 2 additional heteroatoms selected from N, O, or S.
  • the ring formed by combining R 2 and R 3 may be a saturated, unsaturated, or aromatic ring.
  • the compound of formula I comprises a stereomerically pure stereoisomer. In other embodiments, the compound of formula I comprises a mixture of stereoisomers.
  • L 1 is a bond
  • Q is H or aryl
  • L 2 is O
  • M is benzene and X is para to L
  • X is CR R
  • R is cyano, aryl, heteroaryl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )alkynyl, or -C(O)NR 2 R 3
  • R 1' is H
  • L 3 is methylene
  • A is CO 2 H or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
  • the compound is a pharmaceutically acceptable salt or solvate thereof.
  • the compound is a prodrug which is, in some embodiments, an ester such as a ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
  • an ester such as a ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
  • the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula I.
  • the compound of the present invention is a compound of formula II or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, where Q is selected from hydrogen, aryl, or
  • heteroaryl represents an optionally substituted cycloalkane ring
  • L 2 is selected from O or S(O) k
  • R 1 is selected from (C 2 -C 8 )alkynyl, aryl, heteroaryl, or -C(O)NR 2 R 3 ; optionally, R 1 is combined with the adjacent benzene ring to form a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O and S
  • R and R are independently selected from hydrogen or (Q-C ⁇ alkyl
  • the present invention provides a compound having the formula XII or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof:
  • Q is hydrogen, aryl, heteroaryl, (Ci-C 6 )alkyl, or (C 2 -C 6 )heteroalkyl.
  • Q is hydrogen, aryl, or heteroaryl.
  • Q is a substituted or unsubstituted phenyl.
  • L 1 is a bond, (Ci-C 4 )alkylene, (C 2 -C 4 )heteroalkylene, O 3 S(O) k ,
  • L 1 is a bond.
  • [0295] represents a benzo-fused (C 5 -C 8 )cycloalkane ring comprising a benzene ring fused to a (C 5 -C 8 ) cycloalkane ring, wherein the benzene ring of the benzo-fused (C 5 -C 8 )cycloalkane ring is bonded to L 2 or M, if
  • L is a bond.
  • fused (C 5 -C 8 )cycloalkane ring is selected from the group consisting of dihydroindene (i.e., indane or a benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., a benzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., a benzo- cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., a benzo-cyclooctyl ring).
  • dihydroindene i.e., indane or a benzo-cyclopentyl ring
  • tetrahydronaphthalene i.e., a benzo-cyclohexyl ring
  • tetrahydrobenzo[7]annulene i.e., a benzo- cycloh
  • L 2 is a bond, (C r C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, S(O) k , N(R a ), C(0)N(R b ), SO 2 N(R b ), (Ci- C 4 )alkylene-C(O)N(R b ), (C 1 -C 4 )alkylene-N(R b )C(O), (C 2 -C 4 )alkenylene-C(O)N(R b ), (C 2 -C 4 )alkenylene-N(R b )C(O), (C r C 4 )alkylene-SO 2 N(R b ), (C r C 4 )alkylene-N(R b )SO 2 , (C 2 -C 4 )alkenylene-SO 2 N(R b ), or (C 2 -C 4 )alkenylene-
  • L is selected from (CrC ⁇ alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, or S(O) k .
  • L 2 is selected from -CH 2 -O-, substituted oxymethylene, or O.
  • L 2 is selected from -CH 2 -O- or -CH(CH 3 )-O.
  • L 2 is selected from -CH 2 -O- or an alkyl-substituted oxymethylene.
  • L 2 is O or S(O) k .
  • M is an aromatic ring, a heteroaromatic ring, (C 5 -C 8 )cycloalkylene,
  • M is an aromatic ring, the term aromatic includes aryl. In other embodiments where M is a heteroaromatic ring, the term heteroaromatic includes heteroaryl. In some embodiments, M is an aromatic ring or is a heteroaromatic ring. In certain embodiments, M is a monocyclic aromatic or is a monocyclic heteroaromatic ring.
  • M is an unsubstituted monocyclic aromatic ring or is an unsubstituted monocyclic heteroaromatic ring. In certain embodiments, M is a substituted benzene ring. In other embodiments, M is an unsubstituted benzene ring.
  • X is CR 1 R 1' , N(R 1 "), O, or S(O) k , where the subscript k is 0, 1 , or 2.
  • X is a CR 1 R 1 .
  • M is a substituted or unsubstituted benzene ring and X is para to L 2 .
  • L 3 is a (C 1 -C 5 )alkylene, or (C 2 -C 5 )heteroalkylene. In some embodiments, L 3 is a (CrC 5 )alkylene or is a (C 2 -C 5 )heteroalkylene. In certain embodiments, L 3 is (C 1 -C 3 )alkylene. In some embodiments, L 3 is methylene. In certain embodiments, L 3 is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl.
  • A is -CO 2 H, tetrazol-5-yl, -SO 3 H, -PO 3 H 2 , -SO 2 NH 2 ,
  • A is -CO 2 H, tetrazol-5-yl, -SO 3 H, -PO 3 H 2 , -SO 2 NH 2 ,
  • A is -CO 2 H or a salt thereof.
  • A is -CO 2 H or an alkyl ester thereof.
  • A is a C 1 -C 6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
  • R a is hydrogen, (d-C 6 )alkyl, aryl(d-C 3 ) alkyl, or (C 2 -
  • R a is (d-C 6 )alkyl or (C 2 -C 6 )heteroalkyl.
  • R b is hydrogen, (d-C 6 )alkyl, or (C 2 -C 6 )heteroalkyl.
  • R 1 is cyano, aryl, heteroaryl, a heterocycloalkyl, (C 2 -C 8 )alkenyl,
  • the heterocycle of the heterocycloalkyl group of the R 1 group may be a saturated or unsaturated heterocycloalkyl comprising from 5-7 ring members of which from 1-4 are heteroatoms selected from O, S, or N with the balance of the ring members being C.
  • R 1 is selected from (C 2 -C 8 )alkynyl, aryl, heteroaryl, heterocycloalkyl, or -C(O)NR R .
  • R 1 is selected from aryl, heteroaryl, heterocycloalkyl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )alkynyl. In other embodiments, R 1 is selected from R 1 is selected from heteroaryl or heterocycloalkyl.
  • R 1 is selected from a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl.
  • R 1 is selected from a substituted or unsubstituted imidazol-2-yl; l,2,4-triazol-3-yl; l,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2- yl; or dihydroisoxazol-3-yl.
  • R 1 is selected from a substituted or unsubstituted 1 -methyl- lH-imidazol-2-yl; 2-methyl-2H- 1,2,4- triazol-3-yl; 4-methyl-4H-l ,2,4-triazol-3-yl;3-methyl-3H-l ,2,3-triazol-4-yl; 1 - methyl- lH-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; 1-methyl- lH-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl.
  • R 1 is selected from the group consisting of prop-1-ynyl, phenyl, or a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl.
  • R 1 is hydrogen, cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl,
  • R 1 is hydrogen or methyl. In some such embodiments, R 1 is hydrogen.
  • R 1 " is hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl,
  • R 2 and R 3 are independently selected from hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl, or (C 3 - C 8 )heterocycloalkyl.
  • R and R are combined to form a 4-, 5-, 6- or 7- membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N, O, or S.
  • the ring formed by combining R 2 and R 3 may be a saturated, unsaturated, or aromatic ring.
  • R 2 and R 3 are independently selected from hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl, or (C 3 - C 8 )heterocycloalkyl.
  • R 2 and R 3 are combined to form a 4-, 5-, 6- or 7- membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N, O, or S.
  • the ring formed by combining R 2 and R 3 may be a saturated, unsaturated, or aromatic ring.
  • the subscript k is, in each instance, independently selected from 0,
  • k 0.
  • the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula I; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the tautomer; or a mixture thereof.
  • the present invention provides a compound having the formula XIII or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof:
  • Q is selected from hydrogen, aryl, or heteroaryl
  • L 2 is selected from (C 1 - C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, or S(O)k
  • R 1 is selected from (C 2 -C 8 )alkynyl, aryl, heteroaryl, heterocycloalkyl, or -C(O)NR 2 R 3
  • R 2 and R 3 are independently selected from hydrogen or (Ci-C 4 )alkyl
  • R 1 is selected from 1-propynyl, substituted or unsubstituted phenyl, heteroaryl, or heterocycloalkyl. In some such embodiments, R 1 is selected from substituted or unsubstituted heteroaryl, or heterocycloalkyl.
  • R 1 is selected from a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl.
  • R 1 is selected from a substituted or unsubstituted imidazol-2-yl; l,2,4-triazol-3-yl; l,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; or dihydroisoxazol-3-yl.
  • R 1 is selected from a substituted or unsubstituted 1 -methyl- IH- imidazol-2-yl; 2-methyl-2H-l,2,4-triazol-3-yl; 4-methyl-4H-l,2,4-triazol-3-yl;3- methyl-3H-l,2,3-triazol-4-yl; l-methyl-lH-imidazol-5-yl; oxazol-5-yl; isoxazol- 3-yl; pyrimidin-5-yl; 1 -methyl- lH-tetrazol- 5 -yl; oxazol-2-yl; or 4,5- dihydroisoxazol-3-yl.
  • the subscript p is 0.
  • the carbon with a bond to R 1 is a chiral carbon.
  • the present invention provides a compound having formula XIVA or XIVB or a pharmaceutically acceptable salt, solvate, or prodrug thereof or a tautomer, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof:
  • the compound of formula XIII comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula XIII comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula XIII comprises a mixture of S- and R- enantiomers.
  • the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula XIII; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof.
  • the hydrogen on the carboxylic group in formula XIII is replaced with an alkyl group to form an ester.
  • the compound of the present invention can be a methyl or ethyl ester of the compound of formula XIII.
  • the compound has the formula XV or is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof:
  • the compound of formula XV comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula XV comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula XV comprises a mixture of S- and R- enantiomers.
  • the compound of formula XV has the formula XVI:
  • XVI or is a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof.
  • the compound of formula XV or XVI the compound has the formula XVII:
  • XVII is a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof.
  • the carbon with a bond to R 1 is a chiral carbon.
  • the present invention provides a compound having formula XVIIA or XVIIB or a pharmaceutically acceptable salt, solvate, or prodrug thereof or a tautomer, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof:
  • the compound of formula XVII comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula XVII comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula XVII comprises a mixture of S- and R- enantiomers.
  • the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula II; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof.
  • XVIIB A is -CO 2 H or is a salt thereof.
  • the hydrogen on the carboxylic group of A is replaced with an alkyl group to form an ester.
  • the compound of the present invention can be a methyl or ethyl ester of the compound of formula XV, XVI, XVII, XVIIA, or XVIIB. [0324] In some embodiments of the compounds of formula XV, XVI,
  • XVII 5 XVIIA, and XVIIB the subscript m is 1 or 2; the subscript n' is 0; L 1 is a bond; L 2 is selected from -CH 2 -O-, substituted oxymethylene, or O; R 1 is selected from aryl, heteroaryl, heterocycloalkyl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )alkynyl; R 1' is H; and A is -CO 2 H. [0326] In some embodiments of the compounds of formula XV, XVI,
  • XVII, XVIIA, and XVIIB Q is H; L 3 is CH 2 ; and L 2 is -CH 2 -O- or -CH(CH 3 )-O-. [0327] In some embodiments of the compounds of formula XV, XVI,
  • R 6 and R 6' are independently selected from H and (Ci- C 6 )alkyl and at least two of R 6 and R 6 are (C 1 -C 6 )alkyl.
  • R 6 and R 6 are independently selected from H and methyl and at least two of R 6 and R 6 are methyl groups. In some such embodiments, two of R 6 and R 6 are methyl groups.
  • R 6 and R 6 are independently selected from H and methyl and at least four of R 6 and R 6 are methyl groups. In some such embodiments, R 6 and R 6 are independently selected from H and methyl and four of R 6 and R 6 are methyl groups.
  • R 1 is selected from heteroaryl or heterocycloalkyl.
  • R 1 is selected from a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl.
  • R 1 is selected from a substituted or unsubstituted imidazol-2-yl; l,2,4-triazol-3-yl; l,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2- yl; or dihydroisoxazol-3-yl.
  • R 1 is selected from a substituted or unsubstituted 1 -methyl- lH-imidazol-2-yl; 2-methyl-2H- 1,2,4- triazol-3-yl; 4-methyl-4H-l,2,4-triazol-3-yl;3-methyl-3H-l,2,3-triazol-4-yl; 1- methyl-lH-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; 1-methyl- lH-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl.
  • the compound has the formula XVIIIA,
  • XVIIIC XVIIIID or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof.
  • XVIIIB 5 XVIIIC, or XVIIID has the formula XIXA 5 XIXB 5 XIXC 5 or XIXD:
  • XIXC has the formula XXA 5 XXB 5 XXC 5 or XXD:
  • XXC XXD or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof.
  • L 2 is -CH 2 -O- or an alkyl-substituted oxymethylene; the subscript n' is 0; R 1 is (C 2 -C 3 )alkynyl, heteroaryl, or heterocycloalkyl; R 1 is H; and A is -CO 2 H.
  • R is selected from a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl.
  • R 1 is selected from a substituted or unsubstituted imidazol-2-yl; l,2,4-triazol-3-yl; l,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; or dihydroisoxazol-3-yl.
  • R 1 is selected from a substituted or unsubstituted 1 -methyl- lH-imidazol-2-yl; 2-methyl-2H- 1,2,4- triazol-3-yl; 4-methyl-4H-l,2,4-triazol-3-yl;3-methyl-3H-l,2,3-triazol-4-yl; 1- methyl-lH-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; 1-methyl- lH-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl.
  • the compound is a compound of formula XVIIIA. In some embodiments, the compound is a compound of formula XVIIIB. In some embodiments, the compound is a compound of formula XVIIIC. In some embodiments, the compound is a compound of formula XVIIID. In some embodiments, the compound is a compound of formula XIXA. In some embodiments, the compound is a compound of formula XIXB. In some embodiments, the compound is a compound of formula XIXC. In some embodiments, the compound is a compound of formula XIXD. In some embodiments, the compound is a compound of formula XXA. In some embodiments, the compound is a compound of formula XXB. In some embodiments, the compound is a compound of formula XXC. In some embodiments, the compound is a compound of formula XXD.
  • XXC, or XXD 5 has the formula XXIA, XXIB, XXIC, or XXID:
  • XXIC XXID or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof.
  • L 2 is -CH 2 -O- or an alkyl-substituted oxymethylene; the subscript n' is 0; and R 1 is (C 2 -C 3 )alkynyl, heteroaryl, or heterocycloalkyl; R 1 is H.
  • R 1 is selected from a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl.
  • R 1 is selected from a substituted or unsubstituted imidazol-2-yl; l,2,4-triazol-3-yl; l,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; or dihydroisoxazol-3-yl.
  • R 1 is selected from a substituted or unsubstituted 1 -methyl- lH-imidazol-2-yl; 2-methyl-2H- 1,2,4- triazol-3-yl; 4-methyl-4H-l,2,4-triazol-3-yl;3-methyl-3H-l,2,3-triazol-4-yl; 1- methyl-lH-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; 1-methyl- lH-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl.
  • the compound is a compound of formula XXIA. In some embodiments, the compound is a. compound of formula XXIB. In some embodiments, the compound is a compound of formula XXIC. In some embodiments, the compound is a compound of formula XXID.
  • the compounds of the invention can be prepared by a variety of synthetic or semisynthetic techniques.
  • Scheme 1 provides a general synthetic scheme for exemplary compounds of the invention utilizing ester A in which the benzene ring may be substituted or unsubstituted with R 5 groups as defined herein.
  • Methods 1-14 below provide syntheses of A bearing different exemplary R 1 groups. Additional examples for the synthesis of esters of formula A are provided below and describe synthetic routes to exemplary compounds provided herein. Further relevant synthetic routes for related compounds are described in WO 2005/086661 and US 2006/0004012 which are both hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein.
  • AIk is a straight or branched chain alkyl group having from 1 to 8 carbon atoms. Examples of such groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, i-propyl, s-butyl, t-butyl groups, and the like. In some embodiments, AIk is a methyl or ethyl group.
  • R 1 is any of the R 1 groups described herein.
  • R 1 may be selected from cyano, aryl, heteroaryl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )alkynyl, or C(O)NR 2 R 3 where R 2 and R have the same values as set forth with respect to any of the compounds of any of the embodiments set forth herein.
  • W represents a leaving group such as a halogen like Br or Cl, an OH, a tosylate, mesylate, or the like.
  • Coupling of a compound of formula XXII with a compound of formula XXIII may be accomplished using different procedures. For example, when W is a halogen such as Br, Cl, or I (conveniently synthesized from the other two using the Finkelstein reaction as known to those skilled in the art), then a compound of formula XXII may be coupled with a compound of formula XXIII by reacting the two in the presence of any appropriate base such as, but not limited to, Cs 2 CO 3 in an appropriate solvent such as, but not limited to DMF.
  • any appropriate base such as, but not limited to, Cs 2 CO 3 in an appropriate solvent such as, but not limited to DMF.
  • a compound of formula XXII may be coupled with a compound of formula XXIII using an azodicarboxylate such as DEAD, TMAD, or DIAD in combination with a suitable phosphine such as a trialkylphosphine, a triarylphosphine, an alkyldiarylphosphine, or a dialkylarylphosphine.
  • a suitable phosphine such as a trialkylphosphine, a triarylphosphine, an alkyldiarylphosphine, or a dialkylarylphosphine.
  • Conversion of a compound of formula XXIV to a compound of formula XXV may be accomplished by reacting the compound of formula XXIV with a metal hydroxide base such as, but not limited to, LiOH, NaOH, KOH, Ca(OH) 2 , or the like.
  • a metal hydroxide base such as, but not limited to, LiOH, NaOH, KOH, Ca(OH) 2 , or the like.
  • XXII, XXIV, and XXV may be a mixture of the R and S enantiomers, may be the R enantiomer, or may be the S enantiomer. Therefore, in some embodiments each of the compounds of formula XXII, XXIV 5 and XXV are a mixture of the R and S enantiomers. In other embodiments, each of the compounds of formula XXII 5 XXIV, and XXV are the R enantiomer. In other embodiments, each of the compounds of formula XII, XXIV, and XXV are the R enantiomer. Scheme 2
  • the invention provides a method of synthesizing a compound of formula XXIV.
  • the method includes: reacting a compound of formula XXII with a compound of formula XXIII to produce the compound of formula XXIV, wherein the compounds of formula XXII and XXIII have the following structures:
  • AIk is a straight or branched chain alkyl group having from 1 to 8 carbon atoms
  • R 1 is selected from cyano, aryl, heteroaryl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )alkynyl, or C(O)NR 2 R 3
  • R 2 and R 3 are independently selected from hydrogen, aryl, heteroaryl, (d-C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 - C 8 )cycloalkyl, or (C 3 -C 8 )heterocycloalkyl; or optionally, R 2 and R 3 are combined to form a A-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from
  • n 0, 1, or 2;
  • W is selected from OH, a halogen, a group of formula OTs, OMs, or OTf where Ts is p-toluenesulfonyl, Ms is Methanesulfonyl, and Tf is trifluoromethanesulfonryl (OTs is tosylate, OMs is mesylate, and OTf is triflate).
  • W is OH and a phosphine selected from a trialkylphosphine, a dialkylarylphosphine, a alkyldiarylphosphine, or a triarylphosphine and an azodicarboxylate are used to react the compound of formula XXII with the compound of formula XXIII.
  • W is a halogen selected from Br or Cl, and a base is used to react the compound of formula XXII with the compound of formula XXIII.
  • AIk is selected from methyl or ethyl.
  • m is 1 or 2.
  • n 0.
  • p is 0.
  • Y is a halogen
  • the method further comprises reacting the compound of formula XXIV with a boronic acid compound.
  • the boronic acid compound has the formula aryl-B(OH) 2 or alkyl-B(OH) 2 .
  • the method further includes removing the
  • Y, R , n, m, R 5 , p, and R 1 have the definitions provided with respect to the compounds of any of the embodiments of formula XXII, XXIII, and XXIV.
  • the compound of formula XXIV is reacted in the presence of a hydroxide base to produce the compound of formula XXV.
  • the hydroxide base is selected from LiOH, NaOH, KOH, or Ca(OH) 2 .
  • compositions suitable for pharmaceutical use comprising one or more compounds of the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • composition as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant that the carrier, excipient, or diluent is compatible with the other ingredients of the formulation and is not deleterious to the recipient thereof.
  • composition formulation may improve one or more pharmacokinetic properties (e.g., oral bioavailability, membrane permeability) of a compound of the invention (herein referred to as the active ingredient).
  • the pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108, 4,160,452, and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate, or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or
  • the aqueous 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.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, 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, for example beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, 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 sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butane diol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3 -butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions 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-irritating 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-irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • suitable non-irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • suitable non-irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions, or suspensions, etc. containing the compounds of the invention are employed.
  • topical application is also meant to include the use of mouthwashes and gargles.
  • compositions and methods of the invention may further comprise other therapeutically active compounds, as noted herein, useful in the treatment of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
  • other therapeutically active compounds as noted herein, useful in the treatment of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidos
  • the invention provides methods of treating or preventing a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
  • the disease or condition is type II diabetes.
  • the present invention provides a method for treating a disease or condition responsive to the modulation of GPR40 comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
  • the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
  • the disease or condition is type II diabetes.
  • the disease or condition is obesity.
  • the disease or condition is hypertension.
  • the compound or composition is administered orally.
  • the compound or composition is administered parenterally.
  • the compound or composition is administered in combination with a second therapeutic agent.
  • the second therapeutic agent is an insulin sensitizing agent, such as metformin or a thiazolidinedione, for example.
  • the invention provides methods of treating or preventing a disease or disorder responsive to modulation of GPR40 comprising administering to a subject having such a disease or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions.
  • the invention provides methods of treating or preventing a GPR40-mediated condition, disease or disorder comprising administering to a subject having such a condition, disease or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions.
  • the invention provides methods of modulating GPR40 comprising contacting a cell with one or more of the subject compounds or compositions.
  • a cell that constitutively expresses GPR40 is contacted with one or more of the subject compounds or compositions.
  • a cell to be contacted can be made to express or overexpress GPR40, for example, by expressing GPR40 from heterologous nucleic acid introduced into the cell or, as another example, by upregulating the expression of GPR40 from nucleic acid endogenous to the cell.
  • the compounds of the invention may be administered by oral, parenteral ⁇ e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical ⁇ e.g., transdermal, local) routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the invention also contemplates administration of the compounds of the invention in a depot formulation, in which the active ingredient is released over a defined time period.
  • an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range, the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.
  • the compositions are preferably provided in the form of tablets containing from 1.0 to 1000 milligrams of the active ingredient, particularly 1.0,3.0, 5.0, 10.0, 15.0.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the compounds of the invention can be combined or used in combination with other agents useful in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds of the invention are useful, including type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
  • agents useful in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds of the invention are useful including type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,
  • Such other agents, or drugs may be administered, by a route and in an amount commonly used therefore, simultaneously or sequentially with a compound of the invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred.
  • the pharmaceutical compositions of the invention include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound of the invention.
  • therapeutic compositions that include a compound of the invention and a second therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of a subject with a disease or condition mediated by GPR40.
  • therapeutic compositions are provided that include a compound of the invention and a second therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the prophylactic treatment of a subject at risk for a disease or condition mediated by GPR40.
  • the components are provided as a single composition.
  • the compound and the second therapeutic agent are provided separately as parts of a kit.
  • Examples of other therapeutic agents that may be combined with a compound of the invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) cholesterol lowering agents such as HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and other statins), bile acid sequestrants (e.g., cholestyramine and colestipol), vitamin B 3 (also known as nicotinic acid, or niacin), vitamin B 6 (pyridoxine), vitamin B 12 (cyanocobalamin), fibric acid derivatives (e.g., gemfibrozil, clof ⁇ brate, fenofibrate and benzafibrate), probucol, nitroglycerin, and inhibitors of cholesterol absorption (e.g., beta- sitosterol and acylCoA-cholesterol acyltransferase (
  • a compound of the invention may be administered along with a DPP-IV inhibitor or a GLP-I analog.
  • the weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Combinations of a compound of the invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the present invention provides a method for modulating circulating insulin concentration in a subject, comprising administering a compound or composition of the invention. [0384] In some embodiments, the insulin concentration is increased.
  • the insulin concentration is decreased.
  • [l,3]dioxane-4,6-dione (M1.2).
  • An oven-dried 3L 3-neck flask was equipped with a mechanical stirrer, a nitrogen inlet, and a nitrogen outlet and placed in a room-temperature water bath. After purging with nitrogen for 20 minutes, a solution of 1-propynylmagnesium bromide in THF (0.5 N, 600 mL) was added by cannula.
  • compound Ml.l 35 g, 142 mmol
  • anhydrous THF 350 mL
  • reaction mixture changed to a thick, yellow suspension.
  • reaction mixture was stirred for 15 minutes, quenched with aqueous NH 4 Cl (0.6 N, 750 mL), and diluted with hexanes (800 mL). The layers were separated, and the organic layer was discarded. The aqueous layer was acidified to pH ⁇ 2 with saturated aqueous KHSO 4 and extracted with EtOAc (2 x 400 mL). The combined extracts were washed with saturated brine, dried over MgSO 4 , filtered, and concentrated to a light yellow solid. MS ESI (pos.) m/e: 599.0 (2M + Na).
  • (+/-)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid (Ml .3).
  • a IL round-bottom flask was charged with compound M1.2 (37 g), diethyl ketone (160 mL), and water (80 mL). The suspension was heated at reflux for 48 hours. After cooling, the aqueous layer was saturated with NaCl(s) and separated. The organic layer was dried over MgSO 4 , filtered, and concentrated to a light brown oil, which was crystallized from hot EtOAc:hexanes (1 :2). After collecting and drying, the product was obtained as an off-white powder.
  • the salt was re-suspended in 2 L of i-PrOH and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16 hours. A small sample of the salt was decomposed with aqueous acid and the free carboxylic acid was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1% TFA in 90:10 hexanes:i-PrOH) and was found to have 75% ee. The salt was re-suspended in 1.5 L of i-PrOH and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16 hours. This material was found to have 96% ee by chiral HPLC.
  • Phenol M1.4 (23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treated with KHCO 3 (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80 mmol) was added, and the reaction was stirred at 40 °C for 14 hours. An additional portion of methyl iodide (3 mL, 48 mmol) was added and heating was continued for 24 hours. Potassium salts were removed by filtration and thoroughly rinsed with acetone. The filtrate was concentrated to an oil, which was filtered through a 1 cm plug of silica gel. Elution with 2.5% MeOH in DCM followed by concentration provided phenol 1 as a light yellow oil.
  • reaction mixture was quenched with saturated ammonium chloride solution, extracted into EtOAc and washed with dilute ammonium chloride solution.
  • the organic layer was dried over magnesium sulfate.
  • the solvent was removed under vacuum, and the resulting product was flash chromatographed on silica gel, giving Ml.l as an oil.
  • (+/-)-3-(4-Fluoro-phenyl)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (M2).
  • the reaction mixture was filtered and concentrated to provide M2. 6.3 Method 3
  • M3 was prepared according to methods analogous to those described in Method 2.
  • the aqueous layer was acidified to pH ⁇ 2 with concentrated HCl and extracted with EtOAc (150 mL x 2). The extract was washed with brine and concentrated. The residue was dissolved in 100 mL of 10:1 DMF:water and heated to 100°C for 8 hours. The reaction was cooled, diluted with 500 mL water, and extracted with EtOAc (150 mL x 3). The organic layer was dried with MgSO 4 , filtered, and concentrated on a rotary evaporator. The residue was dissolved in MeOH (200 mL), 5 drops of concentrated H 2 SO 4 were added, and the solution was refluxed for 24 hours.
  • (+/-)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(5-methyloxazol-2- yl)propanoate (M5.3).
  • (+/-)-Ethyl 3-(4-hydroxyphenyl)-3-(5-methyloxazol-2- yl)propanoate M5.
  • a mixture of ethyl 3-(4-(benzyloxy)phenyl)-3-(5- methyloxazol-2-yl)propanoate (M5.3) (2.47 mmol) and Pd-C (270 mg) in EtOH was stirred under hydrogen atmosphere at room temperature for 4 hours. The Pd- C was removed by filtration through silica gel eluting with EtOH. After concentration, product M5 was obtained.
  • (+ / -) (3,5-Difluorophenyl)(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)methanol M6.1.
  • 4-(2-Tetrahydro-2H- pyranoxy)phenylmagnesium bromide (0.5 M in THF, 35 mL, 17.5 mmol) was added to a solution of 3,5-difluorobenzaldehyde (1.95 g, 13.7 mmol) in THF (50 mL) slowly via syringe at -78 0 C. The reaction mixture was stirred at this temperature for 3 hours and then quenched with saturated NH 4 Cl (aqueous).
  • (+/-)-(3,5-Difluorophenyl)(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)methanone (M6.2).
  • PDC 8.5 g, 22.6 mmol
  • DCM 100 mL
  • Silica gel about 20 g was added to the reaction mixture and the resulting slurry was filtered through a pad of silica gel to remove most of the inorganic chemicals.
  • (+/-)-Ethyl 3-(3,5-difluorophenyI)-3-(4- hydroxyphenyl)propanoate M6.
  • a solution of olefin M6.3 (5.4 g, 13.5 mmol) in EtOH (80 mL) was stirred with 10% Pd-C (1.5 g, 1.4 mmol) under a hydrogen atmosphere (provided by a balloon) overnight at room temperature.
  • the reaction mixture was filtered through a short silica gel pad and stirred with AcOH (14 mL) at room temperature for 4 hours.
  • reaction mixture was concentrated under reduced pressure to provide a yellow oily residue, which was re-dissolved in DCM (150 mL) and washed with water, saturated NaHCO 3 , water, and brine, and dried over Na 2 SO 4 . After filtration, the solvent was removed under reduced pressure, and the residue was flash chromatographed (silica gel, 0-40% EtOAc in hexane as eluant). The product (+/-)ethyl ester M6. MS ESI (pos.) m/e: 307 (M+H).
  • (+/-)-Oxazol-2-yl(4-(tetrahydro-22 ⁇ -pyran-2- yloxy)phenyl)methanol (Mll.l).
  • 4-(2-Tetrahydro-3-H- pyranoxy)phenylmagnesium bromide (6.7 mmol) in THF (0.5 M) was added dropwise to a solution of oxazole-2-carbaldehyde (5.15 mmol) in THF (8 mL). After it was stirred at room temperature for 2.5 hours, the reaction was quenched with water and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • (+/-)-Oxazol-2-yl(4-(tetrahy dro-2#-pyran-2- yloxy)phenyl)methanone (M11.2).
  • PCC (14.5 mmol, 20%w/w on silica gel) was added to a solution of Mll.l (2.91 mmol) in DCM (20 mL). After it was stirred at room temperature for 1 hour, the reaction mixture was column chromatographed (silica gel, 1:2 EtOAc/hexane). Compound M11.2 was obtained.
  • MS ESI (pos.) m/e: 296.0 (M+23).
  • (+/-)-Methyl 3-(oxazoI-2-yl)-3-(4-(tetrahydro-2iy-pyran-2- yloxy)phenyl)propanoate (M11.4).
  • a mixture of M11.3 (2.55 mmol) and Pd-C (440 mg) in MeOH was stirred under hydrogen at room temperature for 30 minutes.
  • the Pd-C was removed by filtration through silica gel eluting with EtOAc. After concentration, the residue was column chromatographed (silica gel, 1:1 EtOAc/hexane) and compound M11.4 was obtained.
  • (+/-)-Ethyl 3-(l-methyl-lH-imidazol-2-yI)-3-(4-(tetrahydro-2H- pyran-2-yloxy)phenyl)propanoate (M12.4).
  • a solution of olefin M12.3 (21 g, 55.9 mmol) in EtOH (200 niL) was stirred with 10% Pd-C (2.1 g, 2 mmol) under a hydrogen atmosphere (provided by a balloon) at room temperature overnight.
  • the reaction mixture was filtered through a silica gel pad and concentrated to provide protected ester M12.4 as an off-white oil (21 g), which was used directly in the next step.
  • (+/-)-EthyI 3-(4-hydroxyphenyl)-3-(l-methyl-lH-imidazol-2- yl)propanoate (M12.5).
  • TFA 21 mL
  • a solution of protected ester M12.4 21 g
  • dry DCM 210 mL
  • the mixture was brought to room temperature over 4 hours.
  • the reaction mixture was concentrated under reduced pressure to provide a yellow oily residue, which was re-dissolved in DCM (200 mL) and washed with water, saturated NaHCO 3 , water and brine, and dried over Na 2 SO 4 .
  • Methyl ester (M13.2).
  • Compound M13.1 (5.5 g, 12.16 mmol, prepared as described in US 2006/0004012 which is hereby incorporated by reference) was dissolved in 100 niL of EtOAc and quinoline (2 mL, 1.093 g/mL, 16.93 mmol) was added. Nitrogen was bubbled through the solution for 5 minutes. 500 mg of Lindlar's catalyst was added, and a hydrogen balloon was attached. After 8 hours, the mixture was filtered through a plug of silica with EtOAc.
  • Aldehyde (M13.3). Alkene M13.2 (5.1 g, 11.22 mmol) was dissolved in 100 mL of 4:1 (1,2-dioxane/water), and 2,6-lutidine (2.61 mL, 0.920 g/mL, 22.44 mmol) was added. Next, 1.2 g of a 3.4% OsO 4 in t-BuOH (0.22 mmol) solution was added dropwise over 5 minutes. NaIO 4 (9.6 g, 44.88 mmol) in 25 mL of water was added. The internal reaction temperature did not rise above 30 °C.
  • Acid (M13.4) Aldehyde M13.3 (2.32 g, 5.25 mmol) was dissolved in 20 mL of ACN. To this was added KH 2 PO 4 (178 mg, 1.31 mmol) in 5 mL of water. The solution was cooled to -5 °C and 30% H 2 O 2 (aq) (714 mg, 6.30 mmol) was added. NaClO 2 (712 mg, 7.88 mmol) was dissolved in 5 mL of water and added via syringe pump over 3 hours while maintaining a temperature below 0 0 C. After the addition of the NaClO 2 solution, the mixture was stirred for 1 hour.
  • Methyltriazole M13.6 (2.78 g, 5.61 mmol) was dissolved in 50 mL of EtOAc, and nitrogen was bubbled through the solution for 5 minutes. 1 g of palladium on carbon (5 wt. %, wet contains 50% water) was added, and a hydrogen balloon was attached. After 8 hours, the mixture was filtered through a plug of silica with 10% MeOH in EtOAc. The organic layer was concentrated under reduced pressure and partitioned between ACN (100 mL) and hexane (50 mL). The ACN layer was washed with hexane (4 x 50 mL).
  • Methylamide (M14.1) Acid M13.4 (6.0 g, 13.1 mmol), prepared as described above, was dissolved in 100 mL of DCM. To this mixture was added 1-hydroxybenzotriazole hydrate (3.7 g, 27.5 mmol), N-(3-dimethylaminopropyl)- N'-ethylcarbondiimide hydrochloride (5.0 g, 26.2 mmol), and 2 M methylamine in THF (14 mL, 26.2 mmol).
  • Ml.l M15.1 2,2-Dimethyl-5-(3-methyl-l-(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)but-2-enyl)-l,3-dioxane-4,6-dione (M 15.1).
  • M1.1 50 g, 0.15 mol
  • 2-methyl-l- propenyl magnesium bromide 600 mL, 0.5 M in THF, 0.30 mol
  • the reaction was left at room temperature for 2 hours and then was quenched with water, extracted with ethyl acetate, and dried with MgSO 4 . The solvent was removed to afford a gel-like M 15.1, which was used as such in the next step.
  • (+/-)-5-Bromo-2, 3-dihydro-lH-inden-l-ol 1.1.
  • 5-bromo-l-indanone 1.0 g, 4.7 mmol
  • MeOH MeOH
  • NaBH 4 0.36 g, 9.5 mmol
  • the mixture was stirred at room temperature overnight.
  • the mixture was concentrated to dryness and redissolved in water/EtOAc.
  • the layers were separated and the EtOAc layer was dried with anhydrous Na 2 SO 4 and concentrated to obtain 1.1, which was used directly in the next step.
  • (+/-)-5-Bromo-l-chloro-2, 3-dihydro-lH-indene (1.2).
  • Compound 30 (0.048 g, 0.11 mmol) was added to a 1- dram vial and dissolved in a minimal amount of anhydrous THF.
  • An aqueous solution of lithium hydroxide (2 M, 0.3 mL) was added to the vial. MeOH was added dropwise until the layers were miscible.
  • the vial was sealed and placed on a rotating wheel overnight (18 hours). When the reaction was complete, the solvent was concentrated under a flow of nitrogen until only water was left. The mixture was diluted by the addition of ⁇ 1 mL of water.

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Abstract

The present invention provides compounds useful, for example, for treating metabolic disorders in a subject. Such compounds have the general formula I: (F) where the definitions of the variables Q, L1, , L2, M, X, L3, and A are provided herein. The present invention also provides compositions that include, and methods for using, the compounds in preparing medicaments and for treating metabolic disorders such as, for example, type II diabetes.

Description

CONFORMATIONALLY CONSTRAINED 3-(4-HYDROXY-PHENYL)-
SUBSTITUTED-PROPANOIC ACIDS USEFUL FOR TREATING METABOLIC DISORDERS
1. CROSS REFERENCES TO RELATED APPLICATIONS
This application claims the benefit of United States Provisional Application No. 60/717,432, filed on September 14, 2005, which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein.
2. FIELD OF THE INVENTION
[001] The present invention relates to compounds capable of modulating the G-protein-coupled receptor GPR40, compositions comprising the compounds, and methods for their use for controlling insulin levels in vivo and for the treatment of conditions such as type II diabetes, hypertension, ketoacidosis, obesity, glucose intolerance, and hypercholesterolemia and related disorders associated with abnormally high or low plasma lipoprotein, triglyceride or glucose levels.
3. BACKGROUND OF THE INVENTION
[002] The production of insulin is central to the regulation of carbohydrate and lipid metabolism. Insulin imbalances lead to conditions such as type II diabetes mellitus, a serious metabolic disease that afflicts around 5% of the population in Western Societies and over 150 million people worldwide. Insulin is secreted from pancreatic β cells in response to elevated plasma glucose which is augmented by the presence of fatty acids. The recent recognition of the function of the G-protein coupled receptor GPR40 in modulating insulin secretion has provided insight into regulation of carbohydrate and lipid metabolism in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes, cardiovascular disease and dyslipidemia. [003] GPR40 is a member of the gene superfamily of G-protein coupled receptors ("GPCRs"). GPCRs are membrane proteins characterized as having seven putative transmembrane domains that respond to a variety of molecules by activating intra-cellular signaling pathways critical to a diversity of physiological functions. GPR40 was first identified as an orphan receptor (i.e., a receptor without a known ligand) from a human genomic DNA fragment. Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun. 239: 543-547. GPR40 is highly expressed in pancreatic β cells and insulin-secreting cell lines. GPR40 activation is linked to modulation of the Gq family of intra-cellular signaling proteins and concomitant induction of elevated calcium levels. It has been recognized that fatty acids serve as ligands for GPR40, and that fatty acids regulate insulin secretion through GPR40. Itoh et al. (2003) Nature 422: 173-176; Briscoe et al. (2003) J. Biol. Chem. 278: 11303-11311; Kotarsky et al. (2003) Biochem. Biophys. Res. Commun. 301: 406-410.
[004] Various documents have disclosed compounds reportedly having activity with respect to GPR40. For example, WO 2004/041266 and EP 1559422 disclose compounds that purportedly act as GPR40 receptor function regulators. WO 2004/106276 and EP 1 630 152 are directed to condensed ring compounds that purportedly possess GPR40 receptor function modulating action. More recently, WO 2005/086661 and U.S. Patent Publication No. 2006/0004012 disclose compounds useful for modulating insulin levels in subjects and useful for treating type II diabetes.
[005] Although a number of compounds have been disclosed that reportedly modulate GPR40 activity, the prevalence of type II diabetes, obesity, hypertension, cardiovascular disease and dyslipidemia underscores the need for new therapies to effectively treat or prevent these conditions.
4. SUMMARY OF THE INVENTION
[006] Provided herein are compounds, pharmaceutical compositions and methods useful for treating or preventing a condition or disorder such as type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X3 cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer or edema. [007] In one aspect, the compounds of the invention have the general formula I:
Figure imgf000004_0001
where Q is hydrogen, aryl, heteroaryl, (CrC^alkyl, or (C2-C6)heteroalkyl; L1 is a bond, (CrC4)alkylene, (C2-C4)heteroalkylene, O, S(O)k, N(Ra), C(O)-(C5- C7)heterocycloalkylene, (C1-C4)alkylene-SO2N(Rb), (C1-C4)alkylene-N(Rb)SO2,
or C(O)N(Rb);
Figure imgf000004_0002
represents a cyclohexane ring or a benzo-fused (C5- C8)cycloalkane ring; L2 is a bond, (d-C^alkylene, (C2-C6)heteroalkylene, oxymethylene, O, S(O)k, N(Ra), C(O)N(Rb), SO2N(Rb), (C1-C4)alkylene-C(O)N(Rb), (C1-C4)alkylene-N(Rb)C(O), (C2-C4)alkenylene-C(O)N(Rb), (C2-C4)alkenylene-N(Rb)C(O), (C1-C4)alkylene-SO2N(Rb), (CrC4)alkylene-N(Rb)SO2,
(C2-C4)alkenylene-SO2N(Rb), or (C2-C4)alkenylene- N(Rb)SO2; M is an aromatic ring, a heteroaromatic ring, (C5-C8)cycloalkylene, ary^CpC^alkylene, or heteroaryKQ-C^alkylene; X is CR1R1', N(R1"), O, or S(O)k; L3 is (C1-C5)alkylene or (C2-C5)heteroalkylene; A is -CO2H, tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2, -C(O)NHSO2CH3, -CHO, thiazolidinedionyl, hydroxyphenyl, or pyridyl; Ra is hydrogen, (C1-C6)alkyl, ary\(Ci-C3) alkyl or (C2-C6)heteroalkyl; Rb is hydrogen, (C1-Cδ)alkyl or (C2-C6)heteroalkyl; R1 is cyano, aryl, heteroaryl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3; R1' is hydrogen, cyano, aryl, heteroaryl, (C1-Cs)alkyl, (C2-Cg)alkenyl, or (C2-C8)alkynyl; R1 is hydrogen, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or (C3-C8)cycloalkyl; R2 and R3 are independently selected from hydrogen, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl, or (C3- C8)heterocycloalkyl, or, optionally, R2 and R3 are combined to form a A-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached that includes from 0 to 2 additional heteroatoms selected from N5 O5 or S; and the subscript k is 0, 1 or 2.
[008] In certain embodiments, the present invention provides a compound having the formula II:
Figure imgf000005_0001
II
where Q,
Figure imgf000005_0002
, L2 and R1 are as defined above with respect to formula I5 and each R4 is independently selected from the group consisting of substituted (C1- C6)alkyl, -R', =0, -OR', =NR', =N-OR', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NRR", -NR"C(0)R, -NR'-C(0)NR"R"', -NR'-S02NR"R"', -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH- C(NH2)=NR, -SiR'R"R", -S(O)R, -SO2R, -SO2NRR", -NR"SO2R, -CN, and -NO2, where R', R" and R'" each independently refer to hydrogen, unsubstituted (C1-C8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(Ci-C4)alkyl, or aryl-(Ci-C4)alkyl groups; the subscript n is 0, 1 or 2; each R5 is independently selected from the group consisting of (Q-C^alkyl, 1IaIo(C1 -C3)alkyl, hetero(Ci-C6)alkyl, halogen, (Q-C^alkoxy, cyano, and nitro; and the subscript p is 0, 1, 2, 3 or 4. In some such embodiments, Q is selected from hydrogen, aryl, or heteroaryl; L2 is selected from O, or S(0)k5 R1 is selected from (C2-C8)alkynyl, aryl, heteroaryl, or -C(O)NR2R3, R2 and R3 are independently selected from hydrogen or (Ci-C4)alkyl; and R5 is independently selected from (Q-C^alkyl, halogen, (C^C^alkoxy, cyano, or nitro. In some embodiments, R4 is independently selected from
Figure imgf000005_0003
cyano, or nitro. [009] In certain embodiments, the present invention provides a compound having the formula III:
Figure imgf000006_0001
III
where Q,
Figure imgf000006_0002
, L2, R1, R4 and the subscripts n are as defined with respect to formula II above.
[010] In certain embodiments, the compound has the formula IV:
Figure imgf000006_0003
IV where Q, L2, R1, R4, and the subscript n are as defined above with respect to formula II, and the subscript m is 1 , 2, 3 or 4.
[Oil] In certain embodiments, the present invention provides a compound having the formula V:
Figure imgf000006_0004
where Q, L2, R1, R4, and the subscript n are as defined above with respect to formula II. [012] In some embodiments, the present invention provides a compound having the formula VI:
Figure imgf000007_0001
VI where Q, L2, R1, R4, and the subscript n are as defined above with respect to formula II.
[013] In some embodiments, the present invention provides a compound having the formula VII:
Figure imgf000007_0002
VII where Q, L2, R1, R4, and the subscript n are as defined above with respect to formula II.
[014] In some embodiments, the present invention provides a compound having the formula X or XI:
Figure imgf000007_0003
x xi where Q, R4, and the subscript n are as defined with respect to formula I or formula II above, and the subscript m is 1, 2, 3 or 4. [015] In another aspect, the present invention provides a compound having the formula (I):
Figure imgf000008_0001
I where Q5 L1, P5 L2, M, X5 L3, and A are defined below.
[016] Q is hydrogen, aryl, heteroaryl, (d-C^alkyl, or (C2-C6)heteroalkyl.
In certain embodiments, Q is hydrogen, aryl, or heteroaryl.
[017] In certain embodiments, Q is a substituted or unsubstituted phenyl.
[018] L1 is a bond, (Ci-C4)alkylene, (C2-C4)heteroalkylene, O, S(O)k,
N(Ra), C(0)-(C5-C7)heterocycloalkylene, (C1-C4)alkylene-S02N(Rb),
(CrC4)alkylene-N(Rb)SO2, or C(O)N(Rb). In certain embodiments, L1 is a bond.
[019]
Figure imgf000008_0002
represents a cyclohexane ring or a benzo-fused (C5-
Cg)cycloalkane ring. In certain embodiments,
Figure imgf000008_0003
is a substituted cyclohexane
ring or an unsubstituted cyclohexane ring. In certain embodiments,
Figure imgf000008_0004
is a
benzo-fused (C5-Cg)cycloalkane ring. In some embodiments,
Figure imgf000008_0005
is a
substituted benzo-fused (C5-C8)cycloalkane ring. In some embodiments,
Figure imgf000008_0006
is an unsubstituted benzo-fused (C5-Cg)cycloalkane ring. In some embodiments
where
Figure imgf000008_0007
is a benzo-fused (C5-Cg)cycloalkane ring, is selected from the group consisting of dihydroindene (i.e., indane or a benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., a benzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., a benzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., a benzo- cyclooctyl ring). [020] L2 is a bond, (C1-C6)alkylene, (C2-C6)heteroalkylene5 oxymethylene, O, S(O)k, N(Ra), C(O)N(Rb), SO2N(Rb), (C1- C4)alkylene-C(O)N(Rb), (CrC4)alkylene-N(Rb)C(O), (C2-C4)alkenylene-C(O)N(Rb), (C2-C4)alkenylene-N(Rb)C(O), (d-COalkylene-SO^CR^^CrC^alkylene-NCR^SOa, (C2-C4)alkenylene-SO2N(Rb) or (C2-C4)alkenylene- N(Rb)SO2, where the subscript k is 0, 1 or 2. In certain embodiments, L2 is O or S(O)k, where the subscript k is O5 1 or 2. In certain embodiments, L2 is -O-, -S- or -S(O)-, where Q
is aryl or heteroaryl, and
Figure imgf000009_0001
' is cyclohexyl. In certain embodiments, L is a bond and L2 is -O-, -S- or -S(O)-. In certain embodiments, L2 is -O-, -S- or
-S(O)-, where Q is aryl or heteroaryl, and
Figure imgf000009_0002
is cyclohexyl. [021] X is CR1R1'.
[022] L3 is a bond, (d-C5)alkylene, or (C2-C5)heteroalkylene, provided that L3 is not a bond when L2 is a bond. In some embodiments, L3 is a (C1- C5)alkylene or is a (C2-C5)heteroalkylene. In certain embodiments, L3 is (C1- C3)alkylene. In some embodiments, L is methylene. In certain embodiments, L is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl. [023] A is -CO2H, tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2,
-C(O)NHSO2CH3, -CHO, thiazolidinedion-yl, hydroxyphenyl, or pyridyl. In certain embodiments, A is -CO2H or a salt thereof. In some embodiments, A is -CO2H or an alkyl ester thereof. In some such embodiments, A is a C1-C6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester. [024] Ra is hydrogen, (C1-C6)alkyl, aryl(Ci-C3) alkyl, or (C2-
C6)heteroalkyl. In certain embodiments, Ra is (C;ι-C6)alkyl or (C2-C6)heteroalkyl. [025] Rb is hydrogen, (d-C6)alkyl, or (C2-C6)heteroalkyl.
[026] M is a benzene ring, and R1 is combined with M to form a 5-, 6- or
7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O and S. The following structures exemplify some embodiments where R1 is combined with the adjacent benzene ring, i.e., M, to form a benzo- fused cycloalkane ring:
Figure imgf000010_0001
where the dotted lines depict the sites of attachment to L2 and L3of formula I. In certain embodiments, M is a benzene ring substituted in addition to where it is bonded to R1. In some embodiments, M is a benzene ring that is bonded to R1 but is otherwise unsubstituted.
[027] In some embodiments, R1 is combined with the adjacent benzene ring to form a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O and S. The following structures of M-X-L3- A exemplify some embodiments where R1 is combined with the adjacent benzene ring to form a benzo-fused cycloalkane ring:
Figure imgf000010_0002
where the dotted lines depict the sites of attachment to L2 of formula I, and the wavy bonds indicate that a chiral carbon is present. In certain such embodiments, the compound can be a stereoisomerically pure compound. In some embodiments, the compound can be a mixture of stereoisomers. In some embodiments, M is a benzene ring substituted in addition to where it is bonded to
R1. In other embodiments, M is a benzene ring that is bonded to R1 but is otherwise unsubstituted.
[028] R1 is hydrogen, cyano, aryl, heteroaryl, (C1-C8)alkyl,
(C2-C8)alkenyl, or (C2-C8)alkynyl.
[029] In some embodiments, R1 is hydrogen or methyl.
[030] In preferred embodiments, R1 is hydrogen.
[031] In some embodiments, the compound of formula I comprises a stereomerically pure stereoisomer. In other embodiments, the compound of formula I
[032] In another aspect, the present invention provides a compound having the formula (I):
Figure imgf000011_0001
I where Q, L1, P, L2, M, X, L3, and A are defined below.
[033] Q is hydrogen, aryl, heteroaryl, (Ci-C6)alkyl, or (C2-C6)heteroalkyl.
[034] In certain embodiments, Q is hydrogen, aryl, or heteroaryl.
[035] In certain embodiments, Q is a substituted or unsubstituted phenyl.
[036] L1 is a bond, (CrC4)alkylene, (C2-C4)heteroalkylene, O, S(O)k,
N(Ra), C(O)-(C5-C7)heterocycloalkylene,
Figure imgf000011_0002
(CrC4)alkylene-N(Rb)SO2, or C(O)N(Rb).
[037] In certain embodiments, L1 is a bond.
[038]
Figure imgf000011_0003
represents an optionally substituted (C5-C8)cycloalkane ring. [039] In certain embodiments,
Figure imgf000012_0001
is a substituted cyclohexane ring, an unsubstituted cyclohexane ring, a substituted cyclopentane ring, or an unsubstituted cyclopentane ring.
[040] L2 is a bond, (Ci-C6)alkylene, (C2-C6)heteroalkylene, oxymethylene, O, S(O)k, N(Ra), C(O)N(Rb), SO2N(Rb), (Ci-
C4)alkylene-C(O)N(Rb), (C1-C4)alkylene-N(Rb)C(O),
(C2-C4)alkenylene-C(O)N(Rb), (C2-C4)alkenylene-N(Rb)C(O),
(C1-C4)alkylene-SO2N(Rb), (C1-C4)alkylene-N(Rb)SO2,
(C2-C4)alkenylene-SO2N(Rb) or (C2-C4)alkenylene- N(Rb)SO2, where the subscript k is 0, 1 or 2.
[041] In certain embodiments, L2 is O or S(O)k, where the subscript k is
0, 1 or 2.
[042] In certain embodiments, L2 is -O-, -S- or -S(O)-, where Q is aryl or
heteroaryl, and
Figure imgf000012_0002
is cyclohexyl.
[043] In certain embodiments, L1 is a bond and L2 is -O-, -S- or -S(O)-.
[044] In certain embodiments, L2 is -O-, -S- or -S(O)-, where Q is aryl or
heteroaryl, and
Figure imgf000012_0003
is cyclohexyl.
[045] M is an aromatic ring, a heteroaromatic ring, (Cs-C8)cycloalkylene, ary^Q-C^alkylene or heteroary^CrC^alkylene. In certain embodiments where
M is an aromatic ring, the term aromatic includes aryl. In other embodiments where M is a heteroaromatic ring, the term heteroaromatic includes heteroaryl.
[046] In some embodiments, M is an aromatic ring or is a heteroaromatic ring.
[047] In certain embodiments, M is a monocyclic aromatic, a monocyclic heteroaromatic ring, or a (C5-Cg)cycloalkylene.
[048] In some embodiments, M is an unsubstituted monocyclic aromatic ring or is an unsubstituted monocyclic heteroaromatic ring. [049] In certain embodiments, M is a substituted benzene ring.
[050] In some embodiments, M is an unsubstituted benzene ring.
[051] X is CR1R1', N(R1"), O, or S(O)k, where the subscript k is 0, 1, or 2.
[052] In certain embodiments, M is a substituted or unsubstituted benzene ring and X is para to L2.
[053] L3 is a bond, (C1-C5)alkylene, or (C2-C5)heteroalkylene, provided that L3 is not a bond when L2 is a bond. In some embodiments, L3 is a (C1-
C5)alkylene or is a (C2-C5)heteroalkylene.
[054] In certain embodiments, L3 is (Ci-C3)alkylene.
[055] In some embodiments, L3 is methylene.
[056] In certain embodiments, L3 is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl.
[057] A is -CO2H, tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2,
-C(O)NHSO2CH3, -CHO, thiazolidinedion-yl, hydroxyphenyl, or pyridyl.
[058] In certain embodiments, A is -CO2H or a salt thereof.
[059] In some embodiments, A is -CO2H or an alkyl ester thereof. In some such embodiments, A is a C1-C6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
[060] Ra is hydrogen, (d-C^alkyl, 3TyI(C1-C3) alkyl, or (C2-
C6)heteroalkyl.
[061] In certain embodiments, Ra is (d-C6)alkyl or (C2-C6)heteroalkyl.
[062] Rb is hydrogen, (d-C^alkyl, or (C2-C6)heteroalkyl.
[063] R1 is cyano, aryl, heteroaryl, (CrC8)alkyl, (C2-C8)alkyl,
(C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3.
In some embodiments, R1 is cyano, aryl, heteroaryl, (C2-C8)alkenyl,
(C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3.
[064] In certain embodiments, R1 is (C2-C8)alkynyl, aryl, heteroaryl, or
-C(O)NR2R3.
[065] In certain embodiments, R1 is a (C2-Cg)alkynyl or a heteroaryl. In some such embodiments, R1 is a (C3-C8)alkynyl. In other such embodiments, R1 is a heteroaryl. [066] In certain embodiments, R1 is selected from the group consisting of prop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, triazolyl, and -C(O)NR2R3.
[067] R1' is hydrogen, cyano, aryl, heteroaryl,
Figure imgf000014_0001
(C2-C8)alkenyl, or (C2-C8)alkynyl.
[068] In some embodiments, R1 is hydrogen or methyl.
[069] In some embodiments, R1 is hydrogen.
[070] In certain embodiments, R1 is (C2-C8)alkynyl, aryl, heteroaryl or
-C(O)NR2R3, and R1' is hydrogen.
[071] R1" is hydrogen, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, or (C3-C8)cycloalkyl.
[072] R and R are independently selected from hydrogen, aryl, heteroaryl, (d-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl, or (C3-
C8)heterocycloalkyl.
[073] Optionally, R2 and R3 are combined to form a 4-, 5-, 6- or 7- membered ring containing the nitrogen atom to which they are attached and including from 0 to 2 additional heteroatoms selected from N, O, or S. The ring formed by combining R2 and R3 may be a saturated, unsaturated, or aromatic ring.
[074] In some embodiments, the compound of formula I comprises a stereomerically pure stereoisomer. In other embodiments, the compound of formula I comprises a mixture of stereoisomers.
[075] In certain embodiments, L1 is a bond, Q is H or aryl,
Figure imgf000014_0002
represents an optionally substituted cylopentane or cyclohexane ring, L2 is O, oxymethylene, or oxyethylene, M is benzene and X is para to L2, X is CR1R1 , R1 is cyano, aryl, heteroaryl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-Cs)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3, R1' is H, L3 is methylene, and A is CO2H or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some such embodiments, the compound is a pharmaceutically acceptable salt or solvate thereof. In other such embodiments, the compound is a prodrug which is, in some embodiments, an ester such as a (C1-C6)alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
[076] In certain embodiments, the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula I.
[077] In certain embodiments, the compound of the present invention is a compound of formula II or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, where Q is selected from hydrogen, aryl, or
heteroaryl;
Figure imgf000015_0001
represents an optionally substituted cycloalkane ring; L2 is selected from O or S(O)k; R1 is selected from (C2-C8)alkynyl, aryl, heteroaryl, or -C(O)NR2R3; optionally, R1 is combined with the adjacent benzene ring to form a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O and S; R2 and R3 are independently selected from hydrogen or (C1-C4)alkyl; R4 is independently selected from the group consisting of substituted (Q-QOalkyl, -R1, =0, -OR', =0, =NR', =N-0R', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R'", -NR'-S02NR"R"', -NR"CO2R', -NH-C(NH2)=NH, - NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R', -SO2R', -SO2NR'R", - NR"SO2R, -CN, and -NO2, where R', R" and R'" each independently refer to hydrogen, unsubstituted (C1-C8)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or tbioalkoxy groups, halo(C1-C4)alkyl, or aryl-(C1-C4)alkyl groups; R5 is independently selected from the group consisting of (d-C6)alkyl, halogen, (Q-C^alkoxy, cyano, and nitro; the subscript k is O, 1 or 2; the subscript n is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; and the subscript p is 0, 1, 2, 3 or 4. In some such embodiments, R4 is independently selected from (Q-C^alkyl, halogen, (C1-C6MkOXy, cyano, or and nitro.
[078] The compounds of the invention include pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof. In some embodiments, the compounds are pharmaceutically acceptable salts. In other embodiments, the compounds are prodrugs such as esters of a carboxylic acid. [079] In another aspect, the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent, or excipient, and a compound of formula I-XI.
[080] In another aspect, the invention provides methods for treating or preventing a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, hypertension, cancer, and edema. Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of formula I-XI. In some such embodiments, the disease or condition is type II diabetes. In some embodiments, a compound of formula I-XI is administered with combination with a second therapeutic agent. In some such embodiments, the second therapeutic agent is metformin or is a thiazolidinedione. The second therapeutic agent may be administered before, during, or after administration of the compound of formula I- XI.
[081] In another aspect, the invention provides methods for treating or preventing a disease or condition responsive to the modulation of GPR40. Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of formula I-XI.
[082] In another aspect, the invention provides methods for treating or preventing a disease or condition mediated, regulated, or influenced by pancreatic β cells. Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of formula I-XI. [083] In another aspect, the invention provides methods for modulating
GPR40 function in a cell. Such methods include contacting a cell with a compound of formula I-XI.
[084] In another aspect, the invention provides methods for modulating
GPR40 function. Such methods include contacting GPR40 with a compound of formula I-XI.
[085] In another aspect, the invention provides methods for modulating circulating insulin concentration in a subject. Such methods include administering a compound of formula I-XI to the subject. In some such embodiments, the circulating insulin concentration is increased in the subject after administration whereas in other such embodiments, the circulating insulin concentration is decreased in the subject after administration.
[086] In another aspect, the invention provides the use of a compound of formula I-XI for treating a disease or condition or for preparing a medicament for treating a disease or condition where the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema. In some such embodiments, the disease or condition is type II diabetes. The compounds of the invention may also be used to prepare medicaments that include a second therapeutic agent such as metformin or a thiazolidinedione.
[087] In another aspect, the invention provides the use of a compound of formula I-XI for modulating GPR40 or for use in the preparation of a medicament for modulating GPR40.
[088] In another aspect, the invention provides a therapeutic composition that includes a compound of formula I-XI and a second therapeutic agent such as those described herein, for example, metformin or a thiazolidinedione, as a combined preparation for simultaneous, separate, or sequential use in the treatment of a disease or condition mediated by GPR40. In some such embodiments, the disease or condition is type II diabetes. In some embodiments, the compound of formula I-XI and the second therapeutic agent are provided as a single composition, whereas in other embodiments they are provided separately as parts of a kit.
[089] In one aspect, the invention provides a method of synthesizing a compound of formula XXIV.
Figure imgf000018_0001
XXIV
The method includes: reacting a compound of formula XXII with a compound of formula XXIII to produce the compound of formula XXIV, wherein the compounds of formula XXII and XXIII have the following structures:
Figure imgf000018_0002
XXH XXIII wherein, AIk is a straight or branched chain alkyl group having from 1 to 8 carbon atoms; R1 is selected from cyano, aryl, heteroaryl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or C(O)NR2R3; R2 and R3 are independently selected from hydrogen, aryl, heteroaryl, (C1-Cg)alkyl, (C2-C8)heteroalkyl, (C3- Cg)cycloalkyl, or (C3-C8)heterocycloalkyl; or optionally, R2 and R3 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N, O, or S; R4 is independently selected from substituted (d-C6)alkyl, -R, =0, -OR', =0, =NR', =N-0R', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(0)R', -NR'-C(0)NR"R"', -NR'-S02NR"R"', -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR1R11R'", -S(O)R', -SO2R', -SO2NR1R", -NR"SO2R, -CN, or -NO2, wherein R', R" and R'" are each independently selected from hydrogen, unsubstituted (C1- C8)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C1-C4)alkyl, or aryl-(Ci-C4)alkyl groups; R5 is independently selected from the group consisting of (Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, cyano, or nitro; p is 0, 1, 2, 3, or 4; m is 1, 2, 3, or 4; n is 0, 1, or 2; Y is selected from substituted (CrC^alkyl, -R', =0, - OR', =0, =NR', =N-0R', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR1R", -NR"C(0)R', -NR'-C(0)NR"R"', -NR'-SO2NR"R'", -NR"C02R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN, and -NO2, where R', R" and R'" each independently refer to hydrogen, unsubstituted (C1-C8)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C1-C4)alkyl, or 8TyI-(C1- C4)alkyl group; W is a leaving group; and further wherein, the compounds of formula XXII and XXIV can be a mixture of compounds having the R and S stereochemistry at the carbon bonded to R1, can have the R stereochemistry at the carbon bonded to R1, or can have the S stereochemistry at the carbon bonded to R1.
[090] In some embodiments, W is selected from OH or a halogen. In some such embodiments, W is OH and a phosphine selected from a trialkylphosphine, a dialkylarylphosphine, a alkyldiarylphosphine, or a triarylphosphine and an azodicarboxylate are used to react the compound of formula XXII with the compound of formula XXIII. In other such embodiments, W is a halogen selected from Br or Cl, and a base is used to react the compound of formula XXII with the compound of formula XXIII. In some embodiments, W is selected from OH, halogen, OTs, OMs, or OTf, where Ts is p-toluenesulfonyl, Ms is methanesulfonryl, and Tf is trifiuoromethanesulfonryl. [091] In some embodiments, AIk is selected from methyl or ethyl.
[092] In some embodiments, m is 1 or 2. [093] In some embodiments, n is 0.
[094] In some embodiments, p is 0.
[095] In some embodiments, Y is a halogen, and the method further comprises reacting the compound of formula XXIV with a boronic acid compound. In some such embodiments, the boronic acid compound has the formula aryl-B(OH)2 or alkyl-B(OH)2.
[096] In some embodiments, the method further includes removing the
AIk group of the compound of formula XXIV to form a compound of formula
XXV or a salt thereof, and the compound of formula XXV has the following structure:
Figure imgf000020_0001
XXV wherein Y, R4, n, m, R5, p, and R1 have the definitions provided with respect to the compounds of any of the embodiments of formula XXII, XXIII, and XXIV. In some such embodiments, the compound of formula XXIV is reacted in the presence of a hydroxide base to produce the compound of formula XXV. In some such embodiments, the hydroxide base is selected from LiOH, NaOH, KOH, or Ca(OH)2.
[097] Other objects, features and advantages of the invention will become apparent to those skilled in the art from the following description and claims.
5. DETAILED DESCRIPTION OF THE INVENTION 5.1 Abbreviations and Definitions
[098] The terms "treat", "treating" and "treatment", as used herein, are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms. The terms "prevent", "preventing" and "prevention", as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a subject from acquiring a condition or disease, or reducing a subject's risk of acquiring a condition or disease.
[099] The term "therapeutically effective amount" refers to that amount of the compound that will elicit the biological or medical response of a tissue, system, or subject that is being sought. The term "therapeutically effective amount" includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated in a subject. The therapeutically effective amount in a subject will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
[0100] The term "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
[0101] The terms "modulate", "modulation" and the like refer to the ability of a compound to increase or decrease the function or activity of GPR40 either directly or indirectly. Inhibitors are compounds that, for example, bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction, such as, for instance, antagonists. Activators are compounds that, for example, bind to, stimulate, increase, activate, facilitate, enhance activation, sensitize or up regulate signal transduction, such as agonists for instance. Modulation may occur in vitro or in vivo.
[0102] As used herein, the phrases "GPR40-mediated condition or disorder", "disease or condition mediated by GPR40", and the like refer to a condition or disorder characterized by inappropriate, for example, less than or greater than normal, GPR40 activity. A GPR40-mediated condition or disorder may be completely or partially mediated by inappropriate GPR40 activity. However, a GPR40-mediated condition or disorder is one in which modulation of GPR40 results in some effect on the underlying condition or disease (e.g., a GPR40 modulator results in some improvement in patient well-being in at least some patients). Exemplary GPR40-mediated conditions and disorders include cancer and metabolic disorders, e.g., diabetes, type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, thrombotic disorders, metabolic syndrome, syndrome X and related disorders, e.g., cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, and edema.
[0103] The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (e.g., C1-C10 means one to ten carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
[0104] The term "alkenyl", by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C2-C8 means two to eight carbons) and one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), and higher homologs and isomers thereof.
[0105] The term "alkynyl", by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C2-C8 means two to eight carbons) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers thereof.
[0106] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 12 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
[0107] The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Similarly, the term dialkylamino refers to an amino group having two attached alkyl groups. The alkyl groups of a dialkylamino may be the same or different.
[0108] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, and S may be placed at any position of the heteroalkyl group. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, and -CH2-CH=N-OCH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. When a prefix such as (C2-C8) is used to refer to a heteroalkyl group, the number of carbons (2 to 8, in this example) is meant to include the heteroatoms as well. For example, a C2-heteroalkyl group is meant to include, for example, -CH2OH (one carbon atom and one heteroatom replacing a carbon atom) and -CH2SH.
[0109] To further illustrate the definition of a heteroalkyl group, where the heteroatom is oxygen, a heteroalkyl group is a, oxyalkyl group. For instance, (C2-C5)oxyalkyl is meant to include, for example -CH2-O-CH3 (a C3-oxyalkyl group with two carbon atoms and one oxygen replacing a carbon atom), -CH2CH2CH2CH2OH, and the like.
[0110] The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
[0111] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Thus, the terms "cycloalkyl" and "heterocycloalkyl" are meant to be included in the terms "alkyl" and "heteroalkyl," respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1- cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2- piperazinyl, and the like.
[0112] The term "cycloalkylene" and "heterocycloalkylene," by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkylene" and "heteroalkylene," respectively. Thus, the terms "cycloalkylene" and "heterocycloalkylene" are meant to be included in the terms "alkylene" and "heteroalkylene," respectively. Additionally, for heterocycloalkylene, one or more heteroatoms can occupy positions at which the heterocycle is attached to the remainder of the molecule. Typically, a cycloalkylene or heterocycloalkylene will have from 3 to 9 atoms forming the ring, more typically, 4 to 7 atoms forming the ring, and even more typically, 5 or 6 atoms will form the cycloalkylene or hetercycloalkylene ring. [0113] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl", are meant to include alkyl substituted with halogen atoms which can be the same or different, in a number ranging from one to (2m' + 1), where m' is the total number of carbon atoms in the alkyl group. For example, the term "halo(C1-C4)alkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus, the term "haloalkyl" includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m' + 1) halogen atoms). The term "perhaloalkyl" means, unless otherwise stated, alkyl substituted with (2m' + 1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group. For example, the term "perhalo(C1-C4)alkyl", is meant to include trifluoromethyl, pentachloroethyl, l,l,l-trifluoro-2-bromo-2-chloroethyl, and the like.
[0114] The term "aryl" means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. The term "heteroaryl" refers to aryl groups (or rings) that contain from one to four heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, dibenzofuryl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4- pyridazinyl, 5-benzothiazolyl, 2-benzoxazolyl, 5-benzoxazolyl, benzo[c][l,2,5]oxadiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, lH-indazolyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, and 8-quinolyl.
[0115] Preferably, the term "aryl" refers to a phenyl or naphthyl group which is unsubstituted or substituted. Preferably, the term "heteroaryl" refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, triazolyl, tetrazolyl, quinoxalinyl, or quinolyl group which is unsubstituted or substituted.
[0116] For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g. , benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
[0117] Each of the above terms (e.g. , "alkyl," "heteroalkyl," "aryl" and
"heteroaryl") is meant to include both substituted and unsubstituted forms of the indicated radical, unless otherwise indicated. Preferred substituents for each type of radical are provided below.
[0118] Substituents for the alkyl and heteroalkyl radicals (as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) can be a variety of groups selected from: -OR', =0, =NR', =N-OR', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR1R", -NR11C(O)R', -NR'-C(0)NR"R"', -NR'-S02NR"R"', -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR1R1TR.'", -S(O)R', -SO2R', -S02NR'R", -NR"SO2R, -CN, and -NO2, in a number ranging from zero to three, with those groups having zero, one or two substituents being particularly preferred. R', R" and R'" each independently refer to hydrogen, unsubstituted (C1-C8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(Cj-C4)alkyl, or aryl-(Ci- C4)alkyl groups. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl. [0119] Typically, an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as trihaloalkyl (e.g., -CF3 and -CH2CF3).
[0120] Preferred substituents for the alkyl and heteroalkyl radicals are selected from: -OR', =O, -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -0C(0)NR'R", -NR"C(O)R', -NR"CO2R'3 -NR'-SO2NR"R'", -S(O)R', -SO2R', -SO2NR'R", -NR"S02R, -CN, and -NO2, where R' and R" are as defined above. Further preferred substituents are selected from: -OR', =0, -NR'R", halogen, -OC(O)R', -CO2R', -CONR'R", -0C(0)NR'R", -NR"C(0)R', -NR"C02R', -NR'-S02NR"R"', -SO2R', -S02NR'R", -NR"S02R, -CN, and -NO2. [0121] Similarly, substituents for the aryl and heteroaryl groups are varied and are selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NRTR.", -NR"C(0)R', -NR"C(0)2R', -NR'-C(0)NR"R'"5 -NH-C(NH2)=NH, -NR'C(NH2)-NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro^ -C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R" and R'" are independently selected from hydrogen, (Q-C^alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C1-C4)alkyl, and (unsubstituted aryl)oxy-(C]- C4)alkyl. [0122] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH2)q- U-, wherein T and U are independently -NH-, -O-, -CH2-, or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2VB-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH2)s-X-(CH2)r, where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted (d-C^alkyl. Otherwise, R' is as defined above.
[0123] As used herein, the term "benzo-fused cycloalkane ring" is meant to include bicyclic structures in which benzene is fused with a cycloalkane (or cycloheteroalkane). To illustrate, in some embodiments, "benzo-fused cycloalkane ring" includes the following structures:
Figure imgf000028_0001
Figure imgf000028_0002
[0124] As used herein, the term "heteroatom" is meant to include oxygen
(O), nitrogen (N), and sulfur (S). [0125] The term "pharmaceutically acceptable salt" is meant to include a salt of the active compound which is prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compound described herein. When a compound of the invention contains relatively acidic functionalities, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When a compound of the invention contains relatively basic functionalities, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginine and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al. (1977) J. Pharm. ScI 66:1-19). Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. [0126] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention. [0127] In addition to salt forms, the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound. [0128] As used herein, "solvate" refers to a compound of the present invention or a salt thereof, that further includes a stoichiometric or non- stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. [0129] Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention.
[0130] As known by those skilled in the art, certain compounds of the invention may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that referral to a compound of a given structural formula includes tautomers of the structure represented by the structural formula. [0131] Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention. [0132] As used herein and unless otherwise indicated, the term
"stereoisomer" or "stereomerically pure" means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. [0133] Various compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
[0134] The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine- 125 (125I) or carbon- 14 (' C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., GPR40 assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
5.2 Embodiments of the Invention
[0135] In one aspect, a class of compounds that modulates GPR40 is described herein. Depending on the biological environment (e.g., cell type, pathological condition of the subject, etc.), these compounds can modulate, e.g., activate or inhibit, the actions of GPR40. By modulating GPR40, the compounds find use as therapeutic agents capable of regulating insulin levels in a subject. The compounds find use as therapeutic agents for modulating diseases and conditions responsive to modulation of GPR40 and/or mediated by GPR40 and/or mediated by pancreatic β cells. As noted above, examples of such diseases and conditions include diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, cancer, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, nephropathy, thrombotic disorders, diabetic neuropathy, diabetic retinopathy, dermatopathy, dyspepsia and edema. Additionally, the compounds are useful for the treatment and/or prevention of complications of these diseases and disorders (e.g., type II diabetes, sexual dysfunction, dyspepsia and so forth).
[0136] While the compounds of the invention are believed to exert their effects by interacting with GPR40, the mechanism of action by which the compounds act is not a limiting embodiment of the invention.
[0137] Compounds contemplated by the invention include, but are not limited to, the exemplary compounds provided herein.
5.2.1 Compounds
[0138] In one aspect, the present invention provides a compound having the formula (I):
Figure imgf000033_0001
I where Q, V, P, L/, M, X, I/, and A are defined below.
[0139] Q is hydrogen, aryl, heteroaryl, (Q-C^alkyl, or (C2-C6)heteroalkyl.
[0140] In certain embodiments, Q is hydrogen, aryl, or heteroaryl.
[0141] In certain embodiments, Q is a substituted or unsubstituted phenyl.
[0142] L1 is a bond, (Q-C^alkylene, (C2-C4)heteroalkylene, O, S(O)k,
N(Ra), C(O)-(C5-C7)heterocycloalkylene, (Ci-C4)alkylene-SO2N(Rb),
(C1-C4)alkylene-N(Rb)SO2, or C(O)N(Rb).
[0143] In certain embodiments, L1 is a bond.
[0144]
Figure imgf000033_0002
represents a cyclohexane ring or a benzo-fused (C5-
C8)cycloalkane ring.
[0145] In certain embodiments,
Figure imgf000033_0003
is a substituted cyclohexane ring or an unsubstituted cyclohexane ring. [0146] In certain embodiments,
Figure imgf000034_0001
is a benzo-fused (C5-
C8)cycloalkane ring. In some embodiments,
Figure imgf000034_0002
is a substituted benzo-fused
(C5-C8)cycloalkane ring. In some embodiments,
Figure imgf000034_0003
is an unsubstituted benzo-fused (C5-C8)cycloalkane ring.
[0147] In some embodiments where
Figure imgf000034_0004
is a benzo-fused
(C5-C8)cycloalkane ring, the benzo-fused cycloalkane ring comprises 0-3 heteroatom ring members selected from O, N, or S. In some such embodiments, the benzo-fused (C5-C8)cycloalkane ring comprises 1 or 2 heteroatom ring members selected from O or N, and in some embodiments 1 heteroatom ring member, selected from O or N. In some embodiments, the benzo-fused (C5-C8)cycloalkane comprises 0 heteroatom ring atoms, does not include any heteroatoms in the ring, such that each of the ring members of the benzo-fused
(C5-C8)cycloalkane is a carbon atom. In some embodiments where
Figure imgf000034_0005
is a
benzo-fused (C5-C8)cycloalkane ring,
Figure imgf000034_0006
is selected from the group consisting of dihydroindene (i.e., indane or a benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., a benzo-cyclohexyl ring), tetrahydrobenzo[7]annulene
(i.e., a benzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., a benzo- cyclooctyl ring).
[0148] L2 is a bond, (Q-C^alkylene, (C2-C6)heteroalkylene, oxymethylene, O, S(O)k, N(Ra), C(O)N(Rb), SO2N(Rb), (C1-
C4)alkylene-C(O)N(Rb), (C1-C4)alkylene-N(Rb)C(O),
(C2-C4)alkenylene-C(O)N(Rb)5 (C2-C4)alkenylene-N(Rb)C(O),
(C1-C4)alkylene-SO2N(Rb), (C1-C4)alkylene-N(Rb)SO2, (C2-C4)alkenylene-SO2N(Rb) or (C2-C4)alkenylene- N(Rb)SO2, where the subscript k is 0, 1 or 2.
[0149] In certain embodiments, L2 is O or S(O)k, where the subscript k is
0, 1 or 2.
[0150] In certain embodiments, L2 is -O-, -S- or -S(O)-, where Q is aryl or
heteroaryl, and
Figure imgf000035_0001
is cyclohexyl.
[0151] In certain embodiments, L1 is a bond and L2 is -O-, -S- or -S(O)-.
[0152] In certain embodiments, L2 is -O-, -S- or -S(O)-, where Q is aryl or
heteroaryl, and
Figure imgf000035_0002
is cyclohexyl.
[0153] M is an aromatic ring, a heteroaromatic ring, (C5-C8)cycloalkylene, ary^CrC^alkylene or heteroary^Q-C^alkylene. In certain embodiments where
M is an aromatic ring, the term aromatic includes aryl. In other embodiments where M is a heteroaromatic ring, the term heteroaromatic includes heteroaryl.
[0154] In some embodiments, M is an aromatic ring or is a heteroaromatic ring.
[0155] In certain embodiments, M is a monocyclic aromatic, a monocyclic heteroaromatic ring, or a (C5-C8)cycloalkylene.
[0156] In some embodiments, M is an unsubstituted monocyclic aromatic ring or is an unsubstituted monocyclic heteroaromatic ring.
[0157] In certain embodiments, M is a substituted benzene ring.
[0158] In some embodiments, M is an unsubstituted benzene ring.
[0159] X is CR1R1', N(R1 "), O, or S(O)k, where the subscript k is 0, 1, or 2.
[0160] In certain embodiments, M is a substituted or unsubstituted benzene ring and X is para to L2.
[0161] L3 is a bond, (C1-C5)alkylene, or (C2~C5)heteroalkylene, provided that L is not a bond when L is a bond. In some embodiments, L is a (C1-
C5)alkylene or is a (C2-C5)heteroalkylene.
[0162] In certain embodiments, L3 is (Q-C^alkylene.
[0163] In some embodiments, L3 is methylene. [0164] In certain embodiments, L3 is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl.
[0165] A is -CO2H, tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2,
-C(O)NHSO2CH3, -CHO, thiazolidinedion-yl5 hydroxyphenyl, or pyridyl.
[0166] In certain embodiments, A is -CO2H or a salt thereof. In some such embodiments, the salt is a sodium, potassium, or calcium salt.
[0167] In some embodiments, A is -CO2H or an alkyl ester thereof. In some such embodiments, A is a C1-C6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
[0168] Ra is hydrogen, (CrC6)alkyl, aryl(Ci-C3) alkyl, or (C2-
C6)heteroalkyl.
[0169] In certain embodiments, Ra is (C1-C6)alkyl or (C2-C6)heteroalkyl.
[0170] Rb is hydrogen, (Ci-C6)alkyl, or (C2-C6)heteroalkyl.
[0171] R1 is cyano, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkyl,
(C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3.
In some embodiments, R1 is cyano, aryl, heteroaryl, (C2-C8)alkenyl,
(C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3.
[0172] In certain embodiments, R1 is (C2-C8)alkynyl, aryl, heteroaryl, or
-C(O)NR2R3.
[0173] In certain embodiments, R1 is a (C2-C8)alkynyl or a heteroaryl. In some such embodiments, R1 is a (C3-C8)alkynyl. In other such embodiments, R1 is a heteroaryl.
[0174] In certain embodiments, R1 is selected from the group consisting of prop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, triazolyl, and -C(O)NR2R3.
[0175] R1' is hydrogen, cyano, aryl, heteroaryl, (Q-C^alkyl,
(C2-C8)alkenyl, or (C2-C8)alkynyl.
[0176] In some embodiments, R1 is hydrogen or methyl.
[0177] In preferred embodiments, R1 is hydrogen.
[0178] In certain embodiments, R1 is (C2-Cs)alkynyl, aryl, heteroaryl or
-C(O)NR2R3, and R1' is hydrogen. [0179] R1" is hydrogen, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, or (C3-C8)cycloalkyl.
[0180] R and R are independently selected from hydrogen, aryl, heteroaryl, (CrC8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl, or (C3- C8)heterocycloalkyl.
[0181] Optionally, R and R are combined to form a 4-, 5-, 6- or 7- membered ring containing the nitrogen atom to which they are attached and including from 0 to 2 additional heteroatoms selected from N, O, or S. The ring formed by combining R2 and R3 may be a saturated, unsaturated, or aromatic ring. [0182] In some embodiments, the compound of formula I comprises a stereomerically pure stereoisomer. In other embodiments, the compound of formula I comprises a mixture of stereoisomers.
[0183] In certain embodiments, L1 is a bond, Q is H or aryl,
Figure imgf000037_0001
represents a substituted benzo-fused (C5-C8)cycloalkane ring or an unsubstituted benzo-fused (C5-C8)cycloalkane ring, L is O, oxymethylene, or oxyethylene, M is benzene and X is para to L2, X is CR1R1 , R1 is cyano, aryl, heteroaryl,
(C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3,
R1 is H, L3 is methylene, and A is CO2H or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some such embodiments, the compound is a pharmaceutically acceptable salt or solvate thereof. In other such embodiments, the compound is a prodrug which is, in some embodiments, an ester such as a (Ci-C6)alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
[0184] In certain embodiments, the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula I.
[0185] In certain embodiments, the present invention provides a compound having the formula II or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:
Figure imgf000038_0001
II
where Q,
Figure imgf000038_0002
, L2 and R1 are as defined above with respect to formula I, and where R4, R5 and the subscripts n and p are defined below. In some such
embodiments, Q is selected from hydrogen, aryl, or heteroaryl;
Figure imgf000038_0003
— represents a cyclohexane ring or a benzo-fused (C5-C8)cycloalkane ring; L2 is selected from O or S(O)k; R1 is selected from (C2-C8)alkynyl, aryl, heteroaryl, or -C(O)NR2R3; R2 and R3 are independently selected from hydrogen or (d-C^alkyl; and R4, R5, and the subscripts n and p are defined below. [0186] In certain embodiments, L2 is selected from O or S(O)k. In some
such embodiments, L2 is -O-, -S- or -S(O)-; Q is aryl or heteroaryl; and
Figure imgf000038_0004
— is cyclohexyl.
[0187] In certain embodiments, R1 is (C2-C8)alkynyl, aryl, heteroaryl or
-C(O)NR2R3. In some embodiments, R1 is a (C2-C8)alkynyl. In some such embodiments, R1 is a (C3-C8)alkynyl. In other embodiments, R1 is an aryl. In still further embodiments, R1 is a heteroaryl. In still other embodiments, R1 is a
-C(O)NR2R3.
[0188] In certain embodiments, R1 is selected from the group consisting of prop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, triazolyl, and -C(O)NR2R3. In some embodiments, R1 is selected from a prop-1-ynyl. In other embodiments, R1 is selected from an imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, or triazolyl. In other embodiments, R1 is selected from a -C(O)NR2R3.
[0189] In certain embodiments, R2 and R3 are independently selected from hydrogen or (Q-C^alkyl. [0190] In certain embodiments where
Figure imgf000039_0001
is a substituted benzo-fused
(C5-C8)cycloalkane ring, the one or more substituents, R , is/are independently selected from the group consisting of substituted (Ci-C6)alkyl, -R', -OR', =0, =NR\ =N-OR', -NR1R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR1R", -NR11C(O)R', -NR'-C(O)NR"R'", -NR'-SO2NR"R'", -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR'5 -SiR'R"R'"? -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN, and -NO2, where R', R" and R'" each independently refer to hydrogen, unsubstituted (C1-Cg)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C1-C4)alkyl, or aryl-(C1-C4)alkyl groups.
[0191] In some embodiments where
Figure imgf000039_0002
is a benzo-fused
(C5-C8)cycloalkane ring,
Figure imgf000039_0003
is selected from the group consisting of dihydroindene (i.e., indane or a benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., a benzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., a benzo- cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., a benzo-cyclooctyl ring). In some such embodiments, R1 is (C2-C8)alkynyl, aryl, heteroaryl or -C(O)NR2R3. In some embodiments, R1 is a (C2-C8)alkynyl. In some such embodiments, R1 is a (C3-C8)alkynyl. In other embodiments, R1 is an aryl. In still further embodiments, R1 is a heteroaryl. In still other embodiments, R1 is a -C(O)NR2R3. [0192] In certain embodiments, R4 is independently selected from (Ci-
C6)alkyl, halogen, (Ci-C6)alkoxy, cyano, or nitro. [0193] The subscript n is O, 1 or 2.
[0194] Each R5 is independently selected from the group consisting of
(Ci-C6)alkyl, halo(C1-C3)alkyl, heterotd-C^alkyl, halogen, (CrC6)alkoxy, cyano, and nitro.
[0195] In some embodiments, R5 is independently selected from the group consisting of (C1-C6)alkyl, halogen, (d-C6)alkoxy, cyano, and nitro. [0196] The subscript p is 0, 1 , 2, 3, or 4.
[0197] In certain embodiments, the subscript p is 0.
[0198] In some embodiments of formula II, Q is hydrogen,
Figure imgf000040_0001
is indane, the subscript p is zero, and R1 is (C2-C3)alkynyl.
[0199] In other embodiments, Q is phenyl,
Figure imgf000040_0002
is indane, and R1 is
(C2-C3)alkynyl. In certain further embodiments, Q is a substituted phenyl, subscript p is zero, and L2 is oxygen.
[0200] In some embodiments, L2 is oxygen, the subscript n is 1, R4 is independently selected from methyl, halogen, or (Ci-C6)alkoxy, and R1 is
(C2-C3)alkynyl.
[0201] In certain embodiments, Q is hydrogen,
Figure imgf000040_0003
is tetrahydronaphthalene, L2 is oxygen, and R1 is (C2-C3)alkynyl. [0202] It will be apparent that, in certain embodiments of formula II, the carbon with a bond to R1 is a chiral carbon. Thus, in certain embodiments, the present invention provides a compound having formula Ha or Hb or a pharmaceutically acceptable salt, solvate, or prodrug thereof:
Figure imgf000040_0004
where Q,
Figure imgf000040_0005
, L2, R1, R2, R3, R4, R5 and the subscripts n and p have any of the values set forth above with respect to any of the embodiments of compounds of formula II. In some such embodiments, R1 is (C2-C8)alkynyl, aryl, heteroaryl, or -C(O)NR2R3-. [0203] In some embodiments, the compound of formula II comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula II comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula II comprises a mixture of S- and R- enantiomers.
[0204] In certain embodiments, the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug of the compound of formula II.
[0205] In some embodiments of formula II, the hydrogen on the carboxylic group in formula II is replaced with an alkyl group to form an ester.
For example, the compound of the present invention can be a methyl or ethyl ester of the compound of formula II.
[0206] In certain embodiments, the present invention provides a compound having the formula III or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:
Figure imgf000041_0001
III
where Q,
Figure imgf000041_0002
, L2, R1, R and the subscript n are as defined with respect to formula II above or any embodiments of compounds of formula II. [0207] It will be apparent that, in certain embodiments of formula III, the carbon with a bond to R1 is a chiral carbon. Thus, in certain embodiments, the present invention provides a compound having formula IHa or IHb or a pharmaceutically acceptable salt, solvate, or prodrug thereof:
Figure imgf000042_0001
where Q,
Figure imgf000042_0002
, L2, R1, R2, R3, R4 and the subscript n are as defined above in formula II or in any embodiment thereof. In some such embodiments, R1 is (C2-
C8)alkynyl, aryl, heteroaryl, or -C(O)NR2R3.
[0208] In some embodiments, the compound of formula III comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula III comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula III comprises a mixture of S- and R- enantiomers.
[0209] In certain embodiments, the compound has the formula IV:
Figure imgf000042_0003
IV or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, where Q, L2, R1, R , and the subscript n are as defined above with respect to formula II, and the subscript m is 1 , 2, 3 or 4.
[0210] In some embodiments, the subscript m is 1 or 2.
[0211] In some embodiments, Q is hydrogen, L2 is oxygen, the subscript n is 1 or 2, R4 is independently selected from methyl, halogen or (CrC6)alkoxy, and
R1 is (C2-C3)alkynyl.
[0212] As shown in formula IV, Q, L2 and R4 (if one or more R4 groups are present) are attached to a benzo-fused cycloalkane ring. It will be understood that in various different embodiments, the attachments of Q, L2 and R4 can be to any carbon of the benzo-fused cycloalkyl ring, as valency permits. [0213] In certain embodiments, the present invention provides a stereoisomerically pure compound of formula IV. In some embodiments, the present invention provides a stereoisomerically mixed compound of formula IV. [0214] In certain embodiments, the present invention provides a compound having the formula V:
Figure imgf000043_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, where Q, L2, R1, R4, and subscript n are as defined above with respect to formula II.
[0215] It will be apparent that in certain embodiments of formula V, there are two chiral carbons. Thus, in some embodiments, the present invention provides a compound having formula Va, Vb, Vc, or Vd:
Figure imgf000044_0001
Va Vb
Figure imgf000044_0002
In some such embodiments, R1 is (C2-C8)alkynyl, aryl, heteroaryl, or -C(O)NR2R3, and Q, L2, R2, R3, R4, and the subscript n are as defined above with respect to formula II. In certain embodiments, the compound of the invention is stereoisomerically pure. In some embodiments, the compound of the invention is a mixture of two out of four stereoisomers. In other embodiments, the compound is a mixture of three out of four stereoisomers. In yet other embodiments, the compound is a mixture of all four stereoisomers.
[0216] In some embodiments, the present invention provides a compound having the formula VI:
Figure imgf000044_0003
VI or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, where Q, L2, R1, R4, and the subscript n are as defined above with respect to formula II. [0217] In certain embodiments, the present invention provides a stereoisomerically pure compound of formula VI. In some embodiments, the present invention provides a stereoisomerically mixed compound of formula VI. [0218] In some embodiments, the present invention provides a compound having the formula VII:
Figure imgf000045_0001
VII or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, where Q, L2, R1, R4, and the subscript n are as defined above with respect to formula II.
[0219] In certain embodiments, the present invention provides a stereoisomerically pure compound of formula VII. In some embodiments, the present invention provides a mixed stereoisomeric compound of formula VII. [0220] In some embodiments, the present invention provides a compound having the formula X or XI:
Figure imgf000045_0002
λ XI or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, where Q, R4, and subscript n are as defined with respect to formula I or formula II above, and the subscript m is 1, 2, 3 or 4.
[0221] In certain embodiments, the present invention provides a stereoisomerically pure compound of formula X or XI. In some embodiments, the present invention provides a mixed stereoisomeric compound of formula X or XI. [0222] In another aspect, the present invention provides a compound having the formula (I):
Figure imgf000046_0001
I where Q, L1, P, L2, M, X, L3, and A are defined below.
[0223] Q is hydrogen, aryl, heteroaryl, (C1-C6)alkyl, or (C2-C6)heteroalkyl.
[0224] In certain embodiments, Q is hydrogen, aryl, or heteroaryl.
[0225] In certain embodiments, Q is a substituted or unsubstituted phenyl.
[0226] L1 is a bond, (Q-C^alkylene, (C2-C4)heteroalkylene, O, S(O)k,
N(Ra), C(O)-(C5-C7)heterocycloalkylene, (C1-C4)alkylene-SO2N(Rb), (C1-C4)alkylene-N(Rb)SO2, or C(O)N(Rb). In certain embodiments, L1 is a bond.
[0227]
Figure imgf000046_0002
represents a cyclohexane ring or a benzo-fused (C5-
Cg)cycloalkane ring. In certain embodiments, v — is a substituted cyclohexane
ring or an unsubstituted cyclohexane ring. In certain embodiments,
Figure imgf000046_0003
is a
benzo-fused (C5-Cs)cycloalkane ring. In some embodiments,
Figure imgf000046_0004
is a
substituted benzo-fused (C5-C8)cycloalkane ring. In some embodiments,
Figure imgf000046_0005
is an unsubstituted benzo-fused (Cs-Cg)cycloalkane ring. In some embodiments
where
Figure imgf000046_0006
is a benzo-fused (Cs-C8)cycloalkane ring, v — is selected from the group consisting of dihydroindene (i.e., indane or a benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., a benzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., a benzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., a benzo- cyclooctyl ring). [0228] L2 is a bond, (CrC6)alkylene, (C2-C6)heteroalkylene, oxymethylene, O, S(O)k, N(Ra), C(O)N(Rb), SO2N(Rb), (C1- C4)alkylene-C(O)N(Rb), (Ci-C4)alkylene-N(Rb)C(O), (C2-C4)alkenylene-C(O)N(Rb), (C2-C4)alkenylene-N(Rb)C(O), (Ci-C4)alkylene-SO2N(Rb), (CrC4)alkylene-N(Rb)SO2, (C2-C4)alkenylene-SO2N(Rb) or (C2-C4)alkenylene- N(Rb)SO2, where the subscript k is 0, 1 or 2. In certain embodiments, L2 is O or S(O)k, where the subscript k is 0, 1 or 2. In certain embodiments, L2 is -O-, -S- or -S(O)-, where Q
is aryl or heteroaryl, and
Figure imgf000047_0001
' is cyclohexyl. In certain embodiments, L1 is a bond and L2 is -O-, -S- or -S(O)-. In certain embodiments, L2 is -O-, -S- or
-S(O)-, where Q is aryl or heteroaryl, and
Figure imgf000047_0002
is cyclohexyl. [0229] X is CR1R1'.
[0230] L3 is a bond, (C1-C5)alkylene, or (C2-C5)heteroalkylene, provided that L3 is not a bond when L2 is a bond. In some embodiments, L3 is a (C]- C5)alkylene or is a (C2-C5)heteroalkylene. In certain embodiments, L3 is (C1- C3)alkylene. In some embodiments, L3 is methylene. In certain embodiments, L3 is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl. [0231] A is -CO2H, tetrazol-5-yl, -SO3H5 -PO3H2, -SO2NH2,
-C(O)NHSO2CH3, -CHO, thiazolidinedion-yl, hydroxyphenyl, or pyridyl. In certain embodiments, A is -CO2H or a salt thereof. In some embodiments, A is -CO2H or an alkyl ester thereof. In some such embodiments, A is a Ci-C6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester. [0232] Ra is hydrogen, (d-C6)alkyl, 3TyI(C1-C3) alkyl, or (C2-
C6)heteroalkyl. In certain embodiments, Ra is (Q-C^alkyl or (C2-C6)heteroalkyl. [0233] Rb is hydrogen, (Ci-C6)alkyl, or (C2-C6)heteroalkyl.
[0234] M is a benzene ring, and R1 is combined with M to form a 5-, 6- or
7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O and S. The following structures exemplify some embodiments where R1 is combined with the adjacent benzene ring, i.e., M, to form a benzo- fused cycloalkane ring:
Figure imgf000048_0001
where the dotted lines depict the sites of attachment to L2 and L3 of formula I. In certain embodiments, M is a benzene ring substituted in addition to where it is bonded to R1. In some embodiments, M is a benzene ring that is bonded to R1 but is otherwise unsubstituted.
[0235] In some embodiments, R1 is combined with the adjacent benzene ring to form a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O and S. The following structures of M-X-L3- A exemplify some embodiments where R1 is combined with the adjacent benzene ring to form a benzo-fused cycloalkane ring:
Figure imgf000048_0002
where the dotted lines depict the sites of attachment to L2 of formula I, and the wavy bonds indicate that a chiral carbon is present. In certain such embodiments, the compound can be a stereoisomerically pure compound. In some embodiments, the compound can be a mixture of stereoisomers. In some embodiments, M is a benzene ring substituted in addition to where it is bonded to R1. In other embodiments, M is a benzene ring that is bonded to R1 but is otherwise unsubstituted.
[0236] R1' is hydrogen, cyano, aryl, heteroaryl, (Ct-C^alkyl,
(C2-C8)alkenyl, or (C2-C8)alkynyl.
[0237] In some embodiments, R1 is hydrogen or methyl.
[0238] In preferred embodiments, R1 is hydrogen.
[0239] In some embodiments, the compound of formula I comprises a stereomerically pure stereoisomer. In other embodiments, the compound of formula I comprises a mixture of stereoisomers.
[0240] In certain embodiments, the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula I.
[0241] In some embodiments where M is a benzene ring, and R1 is combined with M to form a 5-, 6- or 7-membered benzo-fused cycloalkane ring, the present invention provides a compound having the formula VIII or IX:
Figure imgf000049_0001
VIII IX or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, where Q, L2, R4, and subscript n are as defined with respect to compounds of formula II, and the subscript m is 1, 2, 3 or 4.
[0242] In certain embodiments, the present invention provides a stereoisomerically pure compound of formula VIII or IX. In some embodiments, the present invention provides a mixed stereoisomeric compound of formula VIII or IX.
[0243] In one aspect, the present invention provides a compound having the formula (I):
Figure imgf000050_0001
I where Q, L1, P, L2, M, X, L3, and A are defined below.
[0244] Q is hydrogen, aryl, heteroaryl, (Q-C^alkyl, or (C2-C6)heteroalkyl.
[0245] In certain embodiments, Q is hydrogen, aryl, or heteroaryl.
[0246] In certain embodiments, Q is a substituted or unsubstituted phenyl.
[0247] L1 is a bond, (d-C4)alkylene, (C2-C4)heteroalkylene, O, S(O)k,
N(Ra), C(O)-(C5-C7)heterocycloalkylene, (d-C4)alkylene-SO2N(Rb),
(Ci-C4)alkylene-N(Rb)SO2, or C(O)N(Rb).
[0248] In certain embodiments, L1 is a bond.
[0249]
Figure imgf000050_0002
represents an optionally substituted (C5-C8)cycloalkane ring.
[0250] In certain embodiments,
Figure imgf000050_0003
is a substituted cyclohexane ring, an unsubstituted cyclohexane ring, a substituted cyclopentane ring, or an unsubstituted cyclopentane ring.
[0251] L2 is a bond, (d-C6)alkylene5 (C2-C6)heteroalkylene, oxymethylene, O, S(O)k, N(Ra), C(O)N(Rb), SO2N(Rb), (C1-
C4)alkylene-C(O)N(Rb), (C1-C4)alkylene-N(Rb)C(O),
(C2-C4)alkenylene-C(O)N(Rb), (C2-C4)alkenylene-N(Rb)C(O),
(C1-C4)alkylene-SO2N(Rb), (C1-C4)alkylene-N(Rb)SO2, (C2-C4)alkenylene-SO2N(Rb) or (C2-C4)alkenylene- N(Rb)SO2, where the subscript k is 0, 1 or 2.
[0252] In certain embodiments, L is O or S(O)k, where the subscript k is
0, 1 or 2.
[0253] In certain embodiments, L2 is -O-, -S- or -S(O)-, where Q is aryl or
heteroaryl, and
Figure imgf000051_0001
is cyclohexyl.
[0254] In certain embodiments, L1 is a bond and L2 is -O-, -S- or -S(O)-.
[0255] In certain embodiments, L2 is -O-, -S- or -S(O)-, where Q is aryl or
heteroaryl, and
Figure imgf000051_0002
is cyclohexyl.
[0256] M is an aromatic ring, a heteroaromatic ring, (C5-C8)cycloalkylene, aryl(Ci-C4)alkylene or heteroaryl(Ci-C4)alkylene. In certain embodiments where
M is an aromatic ring, the term aromatic includes aryl. In other embodiments where M is a heteroaromatic ring, the term heteroaromatic includes heteroaryl.
[0257] In some embodiments, M is an aromatic ring or is a heteroaromatic ring.
[0258] In certain embodiments, M is a monocyclic aromatic, a monocyclic heteroaromatic ring, or a (C5-Cs)cycloalkylene.
[0259] In some embodiments, M is an unsubstituted monocyclic aromatic ring or is an unsubstituted monocyclic heteroaromatic ring.
[0260] In certain embodiments, M is a substituted benzene ring.
[0261] In some embodiments, M is an unsubstituted benzene ring.
[0262] X is CR1R1', N(R1"), O, or S(O)k, where the subscript k is 0, 1 , or 2.
[0263] In certain embodiments, M is a substituted or unsubstituted benzene ring and X is para to L .
[0264] L3 is a bond, (C1-Cs)alkylene, or (C2-Cs)heteroalkylene, provided that L3 is not a bond when L2 is a bond. In some embodiments, L3 is a (C1-
C5)alkylene or is a (C2-C5)heteroalkylene.
[0265] In certain embodiments, L3 is (C1-C3)alkylene.
[0266] In some embodiments, L3 is methylene. [0267] In certain embodiments, L3 is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl.
[0268] A is -CO2H5 tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2,
-C(O)NHSO2CH3, -CHO, thiazolidinedion-yl, hydroxyphenyl, or pyridyl.
[0269] In certain embodiments, A is -CO2H or a salt thereof.
[0270] In some embodiments, A is -CO2H or an alkyl ester thereof. In some such embodiments, A is a C1-C6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
[0271] Ra is hydrogen, (d-C6)alkyl, 8TyI(C1-C3) alkyl, or (C2-
C6)heteroalkyl.
[0272] In certain embodiments, Ra is (CrC6)alkyl or (C2-C6)heteroalkyl.
[0273] Rb is hydrogen, (d-C^alkyl, or (C2-C6)heteroalkyl.
[0274] R1 is cyano, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkyl,
(C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3.
In some embodiments, R1 is cyano, aryl, heteroaryl, (C2-C8)alkenyl,
(C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3.
[0275] In certain embodiments, R1 is (C2-C8)alkynyl, aryl, heteroaryl, or
-C(O)NR2R3.
[0276] In certain embodiments, R1 is a (C2-C8)alkynyl or a heteroaryl. In some such embodiments, R1 is a (C3-C8)alkynyl. In other such embodiments, R1 is a heteroaryl.
[0277] In certain embodiments, R1 is selected from the group consisting of prop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, triazolyl, and -C(O)NR2R3.
[0278] R1' is hydrogen, cyano, aryl, heteroaryl, (C1-C8)alkyl,
(C2-C8)alkenyl, or (C2-C8)alkynyl.
[0279] In some embodiments, R1' is hydrogen or methyl.
[0280] In preferred embodiments, R1 is hydrogen.
[0281] In certain embodiments, R1 is (C2-C8)alkynyl, aryl, heteroaryl or
-C(O)NR2R3, and R1' is hydrogen. [0282] R1" is hydrogen, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, or (C3-C8)cycloalkyl.
[0283] R2 and R3 are independently selected from hydrogen, aryl, heteroaryl, (d-C^alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl5 or (C3- C8)heterocycloalkyl.
[0284] Optionally, R2 and R3 are combined to form a A-, 5-, 6- or 7- membered ring containing the nitrogen atom to which they are attached and including from 0 to 2 additional heteroatoms selected from N, O, or S. The ring formed by combining R2 and R3 may be a saturated, unsaturated, or aromatic ring. [0285] In some embodiments, the compound of formula I comprises a stereomerically pure stereoisomer. In other embodiments, the compound of formula I comprises a mixture of stereoisomers.
[0286] In certain embodiments, L1 is a bond, Q is H or aryl,
Figure imgf000053_0001
represents an optionally substituted cylopentane or cyclohexane ring, L2 is O,
0 1 1 * 1 oxymethylene, or oxyethylene, M is benzene and X is para to L , X is CR R , R is cyano, aryl, heteroaryl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3, R1' is H, L3 is methylene, and A is CO2H or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some such embodiments, the compound is a pharmaceutically acceptable salt or solvate thereof. In other such embodiments, the compound is a prodrug which is, in some embodiments, an ester such as a
Figure imgf000053_0002
ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
[0287] In certain embodiments, the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula I.
[0288] In certain embodiments, the compound of the present invention is a compound of formula II or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, where Q is selected from hydrogen, aryl, or
heteroaryl;
Figure imgf000053_0003
represents an optionally substituted cycloalkane ring; L2 is selected from O or S(O)k; R1 is selected from (C2-C8)alkynyl, aryl, heteroaryl, or -C(O)NR2R3; optionally, R1 is combined with the adjacent benzene ring to form a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O and S; R and R are independently selected from hydrogen or (Q-C^alkyl; R is independently selected from the group consisting of substituted (d-C6)alkyl, -R1, =0, -OR', =0, =NR', =N-OR', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(0)NR"R"', -NR'-SO2NR"R'", -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R', -SO2R', -SO2NR1R", -NR"SO2R, -CN, or and -NO2, where R', R" and R'" each independently refer to hydrogen, unsubstituted (C1-C8)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C1-C4)alkyl, or 3TyI-(C1 -C4)alkyl groups; R5 is independently selected from the group
Figure imgf000054_0001
halogen, (CrC6)alkoxy, cyano, or nitro; the subscript k is 0, 1 or 2; the subscript n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; and the subscript p is 0, 1, 2, 3 or 4. In some such embodiments, R4 is independently selected from (Q-C^alkyl, halogen, (Q-C^alkoxy, cyano, or and nitro.
[0289] In one aspect, the present invention provides a compound having the formula XII or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof:
Figure imgf000054_0002
XII where Q, L1, P, Lz, M, X, LJ, and A are defined below.
[0290] Q is hydrogen, aryl, heteroaryl, (Ci-C6)alkyl, or (C2-C6)heteroalkyl.
[0291] In certain embodiments, Q is hydrogen, aryl, or heteroaryl.
[0292] In certain embodiments, Q is a substituted or unsubstituted phenyl. [0293] L1 is a bond, (Ci-C4)alkylene, (C2-C4)heteroalkylene, O3 S(O)k,
N(Ra), C^-CCs-C^heterocycloalkylene^d-C^alkylene-SO^CR15), (CrC4)alkylene-N(Rb)SO2, or C(O)N(Rb).
[0294] In certain embodiments, L1 is a bond. In some such embodiments,
Q is H.
[0295]
Figure imgf000055_0001
represents a benzo-fused (C5-C8)cycloalkane ring comprising a benzene ring fused to a (C5-C8) cycloalkane ring, wherein the benzene ring of the benzo-fused (C5-C8)cycloalkane ring is bonded to L2 or M, if
L is a bond. In some embodiments,
Figure imgf000055_0002
is a substituted benzo-fused (C5-
C8)cycloalkane ring. In some embodiments,
Figure imgf000055_0003
is an unsubstituted benzo-
fused (C5-Cg)cycloalkane ring. In some embodiments where
Figure imgf000055_0004
' is a benzo-
fused (C5-C8)cycloalkane ring,
Figure imgf000055_0005
is selected from the group consisting of dihydroindene (i.e., indane or a benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., a benzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., a benzo- cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., a benzo-cyclooctyl ring). [0296] L2 is a bond, (CrC6)alkylene, (C2-C6)heteroalkylene, oxymethylene, O, S(O)k, N(Ra), C(0)N(Rb), SO2N(Rb), (Ci- C4)alkylene-C(O)N(Rb), (C1-C4)alkylene-N(Rb)C(O), (C2-C4)alkenylene-C(O)N(Rb), (C2-C4)alkenylene-N(Rb)C(O), (CrC4)alkylene-SO2N(Rb), (CrC4)alkylene-N(Rb)SO2, (C2-C4)alkenylene-SO2N(Rb), or (C2-C4)alkenylene- N(Rb)SO2. In some embodiments, L is selected from (CrC^alkylene, (C2-C6)heteroalkylene, oxymethylene, O, or S(O)k. In some embodiments, L2 is selected from -CH2-O-, substituted oxymethylene, or O. In some embodiments, L2 is selected from -CH2-O- or -CH(CH3)-O. In some embodiments, L2 is selected from -CH2-O- or an alkyl-substituted oxymethylene. In certain embodiments, L2 is O or S(O)k.
[0297] M is an aromatic ring, a heteroaromatic ring, (C5-C8)cycloalkylene,
OTyI(C1 -C4)alkylene or heteroaryl^-C^alkylene. In certain embodiments where
M is an aromatic ring, the term aromatic includes aryl. In other embodiments where M is a heteroaromatic ring, the term heteroaromatic includes heteroaryl. In some embodiments, M is an aromatic ring or is a heteroaromatic ring. In certain embodiments, M is a monocyclic aromatic or is a monocyclic heteroaromatic ring.
In some embodiments, M is an unsubstituted monocyclic aromatic ring or is an unsubstituted monocyclic heteroaromatic ring. In certain embodiments, M is a substituted benzene ring. In other embodiments, M is an unsubstituted benzene ring.
[0298] X is CR1R1', N(R1"), O, or S(O)k, where the subscript k is 0, 1 , or 2.
In some embodiments X is a CR1R1.
[0299] In certain embodiments, M is a substituted or unsubstituted benzene ring and X is para to L2.
[0300] L3 is a (C1-C5)alkylene, or (C2-C5)heteroalkylene. In some embodiments, L3 is a (CrC5)alkylene or is a (C2-C5)heteroalkylene. In certain embodiments, L3 is (C1-C3)alkylene. In some embodiments, L3 is methylene. In certain embodiments, L3 is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl.
[0301] A is -CO2H, tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2,
-C(O)NHSO2CH3, -CHO, thiazolidinedion-yl, hydroxyphenyl, or pyridyl. In some embodiments, A is -CO2H, tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2,
-C(O)NHSO2CH3, thiazolidinedionyl, hydroxyphenyl, or pyridyl In certain embodiments, A is -CO2H or a salt thereof. In some embodiments, A is -CO2H or an alkyl ester thereof. In some such embodiments, A is a C1-C6 alkyl ester such as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.
[0302] Ra is hydrogen, (d-C6)alkyl, aryl(d-C3) alkyl, or (C2-
C6)heteroalkyl. In certain embodiments, Ra is (d-C6)alkyl or (C2-C6)heteroalkyl.
[0303] Rb is hydrogen, (d-C6)alkyl, or (C2-C6)heteroalkyl. [0304] R1 is cyano, aryl, heteroaryl, a heterocycloalkyl, (C2-C8)alkenyl,
(C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3. In any of the embodiments described herein, the heterocycle of the heterocycloalkyl group of the R1 group may be a saturated or unsaturated heterocycloalkyl comprising from 5-7 ring members of which from 1-4 are heteroatoms selected from O, S, or N with the balance of the ring members being C. In certain embodiments, R1 is selected from (C2-C8)alkynyl, aryl, heteroaryl, heterocycloalkyl, or -C(O)NR R . In some embodiments, R1 is selected from aryl, heteroaryl, heterocycloalkyl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, or (C3-C8)alkynyl. In other embodiments, R1 is selected from R1 is selected from heteroaryl or heterocycloalkyl. In some such embodiments, R1 is selected from a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R1 is selected from a substituted or unsubstituted imidazol-2-yl; l,2,4-triazol-3-yl; l,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2- yl; or dihydroisoxazol-3-yl. In some such embodiments, R1 is selected from a substituted or unsubstituted 1 -methyl- lH-imidazol-2-yl; 2-methyl-2H- 1,2,4- triazol-3-yl; 4-methyl-4H-l ,2,4-triazol-3-yl;3-methyl-3H-l ,2,3-triazol-4-yl; 1 - methyl- lH-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; 1-methyl- lH-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl. In certain embodiments, R1 is selected from the group consisting of prop-1-ynyl, phenyl, or a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl.
[0305] R1 is hydrogen, cyano, aryl, heteroaryl, (C1-C8)alkyl,
(C2-C8)alkenyl, or (C2-C8)alkynyl. In some embodiments, R1 is hydrogen or methyl. In some such embodiments, R1 is hydrogen.
[0306] R1" is hydrogen, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, or (C3-C8)cycloalkyl. [0307] R2 and R3 are independently selected from hydrogen, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl, or (C3- C8)heterocycloalkyl. Optionally, R and R are combined to form a 4-, 5-, 6- or 7- membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N, O, or S. The ring formed by combining R2 and R3 may be a saturated, unsaturated, or aromatic ring. [0308] R2 and R3 are independently selected from hydrogen, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl, or (C3- C8)heterocycloalkyl. Optionally, R2 and R3 are combined to form a 4-, 5-, 6- or 7- membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N, O, or S. The ring formed by combining R2 and R3 may be a saturated, unsaturated, or aromatic ring. [0309] The subscript k is, in each instance, independently selected from 0,
1 , or 2. In some embodiments, k is 0.
[0310] In certain embodiments, the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula I; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the tautomer; or a mixture thereof. [0311] In certain embodiments, the present invention provides a compound having the formula XIII or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof:
Figure imgf000058_0001
XIII where Q is selected from hydrogen, aryl, or heteroaryl; L2 is selected from (C1- C6)alkylene, (C2-C6)heteroalkylene, oxymethylene, O, or S(O)k; R1 is selected from (C2-C8)alkynyl, aryl, heteroaryl, heterocycloalkyl, or -C(O)NR2R3; R2 and R3 are independently selected from hydrogen or (Ci-C4)alkyl; R4 is independently selected from substituted (Ci-C6)alkyl, -R', -OR', =0, =NR', =N-OR', -NR1R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R'", -NR'-SO2NR"R'", -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)^NR', -SiR1R1TR'", -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN, or -NO2, where R', R" and R'" each independently refer to hydrogen, unsubstituted (C1-C8)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C1-C4)alkyl, or aryl-(C1-C4)alkyl groups; R5 is independently selected from (Q-C^alkyl, halogen, (C1-C6)alkoxy, cyano, or nitro; the subscript k is 0, 1, or 2; the subscript n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; and the subscript p is 0, 1, 2, 3, or 4. In some such embodiments, R4 is independently selected from (CrC^alkyl, halogen, (Q-C^alkoxy, cyano, or nitro.
In certain embodiments,
Figure imgf000059_0001
is a benzo-fused (C5-Cg)cycloalkane ring selected from substituted or unsubstituted dihydroindene, tetrahydronaphthalene, tetrahydrobenzo[7]annulene, or hexahydrobenzo[8]annulene. In certain embodiments, R1 is selected from 1-propynyl, substituted or unsubstituted phenyl, heteroaryl, or heterocycloalkyl. In some such embodiments, R1 is selected from substituted or unsubstituted heteroaryl, or heterocycloalkyl. In some such embodiments, R1 is selected from a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R1 is selected from a substituted or unsubstituted imidazol-2-yl; l,2,4-triazol-3-yl; l,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; or dihydroisoxazol-3-yl. In some such embodiments, R1 is selected from a substituted or unsubstituted 1 -methyl- IH- imidazol-2-yl; 2-methyl-2H-l,2,4-triazol-3-yl; 4-methyl-4H-l,2,4-triazol-3-yl;3- methyl-3H-l,2,3-triazol-4-yl; l-methyl-lH-imidazol-5-yl; oxazol-5-yl; isoxazol- 3-yl; pyrimidin-5-yl; 1 -methyl- lH-tetrazol- 5 -yl; oxazol-2-yl; or 4,5- dihydroisoxazol-3-yl. In certain embodiments, the subscript p is 0. [0312] It will be apparent that, in certain embodiments of formula XIII, the carbon with a bond to R1 is a chiral carbon. Thus, in certain embodiments, the present invention provides a compound having formula XIVA or XIVB or a pharmaceutically acceptable salt, solvate, or prodrug thereof or a tautomer, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof:
Figure imgf000060_0001
XIVA XIVB where the variables can have any of the values in any of the embodiments described above.
[0313] In some embodiments, the compound of formula XIII comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula XIII comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula XIII comprises a mixture of S- and R- enantiomers.
[0314] In certain embodiments, the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula XIII; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof.
[0315] In some embodiments of formula XIII, XIVA, and XIVB, the hydrogen on the carboxylic group in formula XIII is replaced with an alkyl group to form an ester. For example, the compound of the present invention can be a methyl or ethyl ester of the compound of formula XIII.
[0316] In certain embodiments of the compound of formula XII, the compound has the formula XV or is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof:
Figure imgf000061_0001
XV where R4 is independently selected from substituted (Ci-C6)alkyl, -R', -OR', =0, =NR', =N-OR', -NRR", -SR', halogen, -OC(O)R, -C(O)R', -CO2R, -CONR'R", -OC(O)NRR", -NR1C(O)R', -NR'-C(O)NR"R'", -NR'-SO2NR"R'", -NR"C02R, -NH-C(NH2)=NH, -NRC(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R', -SO2R', -SO2NR1R", -NR"SO2R, -CN, or -NO2, where R', R" and R" each independently refer to hydrogen, unsubstituted (CrC8)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(Ci-C4)alkyl, or aryl-(C1-C4)alkyl groups; one of R6 and R6' is L1 or M, if L1 is a bond, and the others of R6 and R6' are independently selected from H, (Q-C^alkyl, halogen, (Q-C^alkoxy, cyano, or nitro; the subscript n' is 0, 1, 2, or 3; and the subscript m is 1, 2, 3, or 4. [0317] In some embodiments, the compound of formula XV comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula XV comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula XV comprises a mixture of S- and R- enantiomers.
[0318] In some embodiments, the compound of formula XV has the formula XVI:
Figure imgf000061_0002
XVI or is a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof. [0319] In some embodiments, the compound of formula XV or XVI, the compound has the formula XVII:
Figure imgf000062_0001
XVII or is a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof.
[0320] It will be apparent that, in certain embodiments of formula XVII, the carbon with a bond to R1 is a chiral carbon. Thus, in certain embodiments, the present invention provides a compound having formula XVIIA or XVIIB or a pharmaceutically acceptable salt, solvate, or prodrug thereof or a tautomer, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof:
Figure imgf000062_0002
XVIIA XVIIB where the variables can have any of the values in any of the embodiments described above.
[0321] In some embodiments, the compound of formula XVII comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula XVII comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula XVII comprises a mixture of S- and R- enantiomers.
[0322] In certain embodiments, the compound of the present invention is a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug of the compound of formula II; or a tautomer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof. [0323] In some embodiments of formula XV, XVI, XVII5 XVIIA, and
XVIIB, A is -CO2H or is a salt thereof. In some embodiments, the hydrogen on the carboxylic group of A is replaced with an alkyl group to form an ester. For example, the compound of the present invention can be a methyl or ethyl ester of the compound of formula XV, XVI, XVII, XVIIA, or XVIIB. [0324] In some embodiments of the compounds of formula XV, XVI,
XVII, XVIIA, and XVIIB, the subscript m is 1 or 2.
[0325] In some embodiments of the compounds of formula XV, XVI,
XVII5 XVIIA, and XVIIB, the subscript m is 1 or 2; the subscript n' is 0; L1 is a bond; L2 is selected from -CH2-O-, substituted oxymethylene, or O; R1 is selected from aryl, heteroaryl, heterocycloalkyl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, or (C3-C8)alkynyl; R1' is H; and A is -CO2H. [0326] In some embodiments of the compounds of formula XV, XVI,
XVII, XVIIA, and XVIIB, Q is H; L3 is CH2; and L2 is -CH2-O- or -CH(CH3)-O-. [0327] In some embodiments of the compounds of formula XV, XVI,
XVII, XVIIA, and XVIIB, R6 and R6' are independently selected from H and (Ci- C6)alkyl and at least two of R6 and R6 are (C1-C6)alkyl. In some such embodiments, R6 and R6 are independently selected from H and methyl and at least two of R6 and R6 are methyl groups. In some such embodiments, two of R6 and R6 are methyl groups. In some embodiments, R6 and R6 are independently selected from H and methyl and at least four of R6 and R6 are methyl groups. In some such embodiments, R6 and R6 are independently selected from H and methyl and four of R6 and R6 are methyl groups.
[0328] In some embodiments of the compounds of formula XII, XIII,
XIV, XIVA, XIVB, XV, XVI, XVII, XVIIA, and XVIIB, R1 is selected from heteroaryl or heterocycloalkyl. In some such embodiments, R1 is selected from a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In certain such embodiments, R1 is selected from a substituted or unsubstituted imidazol-2-yl; l,2,4-triazol-3-yl; l,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2- yl; or dihydroisoxazol-3-yl. In still further such embodiments, R1 is selected from a substituted or unsubstituted 1 -methyl- lH-imidazol-2-yl; 2-methyl-2H- 1,2,4- triazol-3-yl; 4-methyl-4H-l,2,4-triazol-3-yl;3-methyl-3H-l,2,3-triazol-4-yl; 1- methyl-lH-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; 1-methyl- lH-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl. [0329] In certain embodiments, the compound has the formula XVIIIA,
XVIIIB, XVIIIC, or XVIIID:
Figure imgf000064_0001
Figure imgf000064_0002
XVIIIB
Figure imgf000064_0003
XVIIIC XVIIIID or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof.
[0330] In certain embodiments, the compound of formula XVIIIA,
XVIIIB5 XVIIIC, or XVIIID, has the formula XIXA5 XIXB5 XIXC5 or XIXD:
Figure imgf000065_0001
Figure imgf000065_0002
XIXC XIXD or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof.
[0331] In certain embodiments, the compound of formula XIXA5 XIXB,
XIXC, or XIXD, has the formula XXA5 XXB5 XXC5 or XXD:
Figure imgf000065_0003
Figure imgf000066_0001
XXC XXD or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof.
[0332] In certain embodiments of the compound of formula XVIIIA,
XVIIIB, XVIIIC, XVIIID, XIXA, XIXB, XIXC, XIXD, XXA, XXB, XXC, or XXD, L2 is -CH2-O- or an alkyl-substituted oxymethylene; the subscript n' is 0; R1 is (C2-C3)alkynyl, heteroaryl, or heterocycloalkyl; R1 is H; and A is -CO2H. In some such embodiments, R is selected from a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R1 is selected from a substituted or unsubstituted imidazol-2-yl; l,2,4-triazol-3-yl; l,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; or dihydroisoxazol-3-yl. In still further such embodiments, R1 is selected from a substituted or unsubstituted 1 -methyl- lH-imidazol-2-yl; 2-methyl-2H- 1,2,4- triazol-3-yl; 4-methyl-4H-l,2,4-triazol-3-yl;3-methyl-3H-l,2,3-triazol-4-yl; 1- methyl-lH-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; 1-methyl- lH-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl. In some embodiments, the compound is a compound of formula XVIIIA. In some embodiments, the compound is a compound of formula XVIIIB. In some embodiments, the compound is a compound of formula XVIIIC. In some embodiments, the compound is a compound of formula XVIIID. In some embodiments, the compound is a compound of formula XIXA. In some embodiments, the compound is a compound of formula XIXB. In some embodiments, the compound is a compound of formula XIXC. In some embodiments, the compound is a compound of formula XIXD. In some embodiments, the compound is a compound of formula XXA. In some embodiments, the compound is a compound of formula XXB. In some embodiments, the compound is a compound of formula XXC. In some embodiments, the compound is a compound of formula XXD.
[0333] In certain embodiments, the compound of formula XXA, XXB,
XXC, or XXD5 has the formula XXIA, XXIB, XXIC, or XXID:
Figure imgf000067_0001
Figure imgf000067_0002
XXIC XXID or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof.
[0334] In certain embodiments of the compound of formula XXIA, XXIB,
XXIC, or XXID, L2 is -CH2-O- or an alkyl-substituted oxymethylene; the subscript n' is 0; and R1 is (C2-C3)alkynyl, heteroaryl, or heterocycloalkyl; R1 is H. In some such embodiments, R1 is selected from a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R1 is selected from a substituted or unsubstituted imidazol-2-yl; l,2,4-triazol-3-yl; l,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; or dihydroisoxazol-3-yl. In still further such embodiments, R1 is selected from a substituted or unsubstituted 1 -methyl- lH-imidazol-2-yl; 2-methyl-2H- 1,2,4- triazol-3-yl; 4-methyl-4H-l,2,4-triazol-3-yl;3-methyl-3H-l,2,3-triazol-4-yl; 1- methyl-lH-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; 1-methyl- lH-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl. In some embodiments, the compound is a compound of formula XXIA. In some embodiments, the compound is a. compound of formula XXIB. In some embodiments, the compound is a compound of formula XXIC. In some embodiments, the compound is a compound of formula XXID.
5.2.2 Preparation of the Compounds
[0335] The compounds of the invention can be prepared by a variety of synthetic or semisynthetic techniques. Scheme 1 provides a general synthetic scheme for exemplary compounds of the invention utilizing ester A in which the benzene ring may be substituted or unsubstituted with R5 groups as defined herein. Methods 1-14 below provide syntheses of A bearing different exemplary R1 groups. Additional examples for the synthesis of esters of formula A are provided below and describe synthetic routes to exemplary compounds provided herein. Further relevant synthetic routes for related compounds are described in WO 2005/086661 and US 2006/0004012 which are both hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein. Appropriate starting materials can be prepared by techniques known or apparent to those of skill in the art or the starting materials may be commercially available. One of skill in the art will understand that the synthetic routes can be modified to use different starting materials or alternative reagents and that suitable adjustments in conditions (e.g., temperatures, solvents, etc.) can be made to accomplish the desired transformations. Additionally, one of skill in the art will recognize that protecting groups may be necessary for the preparation of certain compounds and will be aware of those conditions compatible with a selected protecting group. Examples of such protecting groups include, for example, those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N. Y., (3rd Edition, 1999). Accordingly, the exemplary methods and the examples described herein are illustrative of the present invention and are not to be construed as limiting the scope thereof. Scheme 1
Figure imgf000069_0001
[0336] Scheme 2 shows a general synthetic route that can be used to prepare compounds of formula XXIV and XXV, and salts thereof. In the compound of formula XXII and XXIV, AIk is a straight or branched chain alkyl group having from 1 to 8 carbon atoms. Examples of such groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, i-propyl, s-butyl, t-butyl groups, and the like. In some embodiments, AIk is a methyl or ethyl group. In the compounds of formula XXII, XXIV and XXV, R1 is any of the R1 groups described herein. For example, R1 may be selected from cyano, aryl, heteroaryl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or C(O)NR2R3 where R2 and R have the same values as set forth with respect to any of the compounds of any of the embodiments set forth herein. In the compounds of formula XXIII, XXIV, and XXV, R4 is independently selected from substituted (d-C6)alkyl, -R', -O, -OR', =0, =NR', =N-0R', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -0C(0)NR'R", -NR"C(O)R', -NR'-C(0)NR"R"', -NR'-S02NR"R"', -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R', -SO2R', -S02NR'R", -NR"S02R, -CN, or -NO2, where R', R" and R'" each independently refer to hydrogen, unsubstituted (d-C8)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(d-C4)alkyl, or 8TyI-(C1 -C4)alkyl groups; m is selected from 1, 2, 3, or 4; n is selected from 0, 1, or 2; and Y is selected from substituted (Ci-C6)alkyl, -R', =0, -OR', =0, =NR', =N-OR', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(0)R', -NR'-C(O)NR"R'", -NR'-SO2NR"R'", -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN, and -NO2, where R', R" and R'" each independently refer to hydrogen, unsubstituted (Ci-C8)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C1-C4)alkyl, or aryl-(C1-C4)alkyl group. In the compound of formula XXIII W represents a leaving group such as a halogen like Br or Cl, an OH, a tosylate, mesylate, or the like. Coupling of a compound of formula XXII with a compound of formula XXIII may be accomplished using different procedures. For example, when W is a halogen such as Br, Cl, or I (conveniently synthesized from the other two using the Finkelstein reaction as known to those skilled in the art), then a compound of formula XXII may be coupled with a compound of formula XXIII by reacting the two in the presence of any appropriate base such as, but not limited to, Cs2CO3 in an appropriate solvent such as, but not limited to DMF. When W is an OH, then a compound of formula XXII may be coupled with a compound of formula XXIII using an azodicarboxylate such as DEAD, TMAD, or DIAD in combination with a suitable phosphine such as a trialkylphosphine, a triarylphosphine, an alkyldiarylphosphine, or a dialkylarylphosphine. This highly flexible approach allows a large number of compounds of formula XXIV to be synthesized and then converted to compounds of formula XXV by removal of the ester functionality. Conversion of a compound of formula XXIV to a compound of formula XXV may be accomplished by reacting the compound of formula XXIV with a metal hydroxide base such as, but not limited to, LiOH, NaOH, KOH, Ca(OH)2, or the like. When Y is a halogen such as a bromine in compounds of formula XXIV, then reaction with a boronic acid compound such as an aryl-B(OH2) or alkyl-B(OH)2 compound using Suzuki conditions as described herein can be used to add a substituted or unsubstituted aryl group in place of Y in the compounds of formula XXIV which may then be cleaved to provide a compound of formula XXV where Y is an optionally substituted aryl group. Those skilled in the art will recognize that the carbon atom bonded to R in compounds of formula XXII, XXIV, and XXV is a chiral center. In accordance with the method described above, XXII, XXIV, and XXV may be a mixture of the R and S enantiomers, may be the R enantiomer, or may be the S enantiomer. Therefore, in some embodiments each of the compounds of formula XXII, XXIV5 and XXV are a mixture of the R and S enantiomers. In other embodiments, each of the compounds of formula XXII5 XXIV, and XXV are the R enantiomer. In other embodiments, each of the compounds of formula XXII, XXIV, and XXV are the R enantiomer. Scheme 2
Figure imgf000071_0001
XXII XXIII xxrv
Figure imgf000071_0002
[0337] In one aspect, the invention provides a method of synthesizing a compound of formula XXIV.
Figure imgf000071_0003
XXIV The method includes: reacting a compound of formula XXII with a compound of formula XXIII to produce the compound of formula XXIV, wherein the compounds of formula XXII and XXIII have the following structures:
Figure imgf000072_0001
xxπ xxiii wherein, AIk is a straight or branched chain alkyl group having from 1 to 8 carbon atoms; R1 is selected from cyano, aryl, heteroaryl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or C(O)NR2R3; R2 and R3 are independently selected from hydrogen, aryl, heteroaryl, (d-C8)alkyl, (C2-C8)heteroalkyl, (C3- C8)cycloalkyl, or (C3-C8)heterocycloalkyl; or optionally, R2 and R3 are combined to form a A-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N,
0, or S; R4 is independently selected from substituted (Ci-C6)alkyl, -R, =0, -OR', =0, =NR', =N-0R, -NRR", -SR', halogen, -OC(O)R', -C(O)R', -CO2R, -CONR'R", -OC(O)NR'R", -NR"C(0)R, -NR'-C(0)NR"R", -NR'-S02NR"R"', -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R', -SO2R5 -SO2NR'R", -NR"S02R, -CN, or -NO2, wherein R', R" and R'" are each independently selected from hydrogen, unsubstituted (C1- C8)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C1-C4)alkyl, or aryl-(C1-C4)alkyl groups; R5 is independently selected from the group consisting of (CrC^alkyl, halogen, (d-C^alkoxy, cyano, or nitro; p is O, 1, 2, 3, or 4; m is
1, 2, 3, or 4; n is 0, 1, or 2; Y is selected from substituted (d-C6)alkyl, -R, =0, -OR', =0, =NR, =N-0R', -NR'R", -SR', halogen, -OC(O)R', -C(O)R, -CO2R, -CONR'R", -OC(O)NRR", -NR"C(0)R', -NR'-C(0)NR"R"', -NR'-S02NR"R"', -NR"C02R, -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R, -SO2R5 -SO2NR1R", -NR"SO2R, -CN, and -NO2, where R', R" and R'" each independently refer to hydrogen, unsubstituted (Ci-Cg)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C1-C4)alkyl, or aryl-(C]- C4)alkyl group; W is a leaving group; and further wherein, the compounds of formula XXII and XXIV can be a mixture of compounds having the R and S stereochemistry at the carbon bonded to R1, can have the R stereochemistry at the carbon bonded to R , or can have the S stereochemistry at the carbon bonded to R1.
[0338] In some embodiments, W is selected from OH, a halogen, a group of formula OTs, OMs, or OTf where Ts is p-toluenesulfonyl, Ms is Methanesulfonyl, and Tf is trifluoromethanesulfonryl (OTs is tosylate, OMs is mesylate, and OTf is triflate). In some such embodiments, W is OH and a phosphine selected from a trialkylphosphine, a dialkylarylphosphine, a alkyldiarylphosphine, or a triarylphosphine and an azodicarboxylate are used to react the compound of formula XXII with the compound of formula XXIII. In other such embodiments, W is a halogen selected from Br or Cl, and a base is used to react the compound of formula XXII with the compound of formula XXIII. [0339] In some embodiments, AIk is selected from methyl or ethyl.
[0340] In some embodiments, m is 1 or 2.
[0341] In some embodiments, n is 0.
[0342] In some embodiments, p is 0.
[0343] In some embodiments, Y is a halogen, and the method further comprises reacting the compound of formula XXIV with a boronic acid compound. In some such embodiments, the boronic acid compound has the formula aryl-B(OH)2 or alkyl-B(OH)2.
[0344] In some embodiments, the method further includes removing the
AIk group of the compound of formula XXIV to form a compound of formula XXV or a salt thereof, and the compound of formula XXV has the following structure:
Figure imgf000074_0001
XXV wherein Y, R , n, m, R5, p, and R1 have the definitions provided with respect to the compounds of any of the embodiments of formula XXII, XXIII, and XXIV. In some such embodiments, the compound of formula XXIV is reacted in the presence of a hydroxide base to produce the compound of formula XXV. In some such embodiments, the hydroxide base is selected from LiOH, NaOH, KOH, or Ca(OH)2.
5.2.3 Compositions
[0345] In another aspect, the invention provides pharmaceutical compositions suitable for pharmaceutical use comprising one or more compounds of the invention and a pharmaceutically acceptable carrier, excipient, or diluent. [0346] The term "composition" as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant that the carrier, excipient, or diluent is compatible with the other ingredients of the formulation and is not deleterious to the recipient thereof.
[0347] Composition formulation may improve one or more pharmacokinetic properties (e.g., oral bioavailability, membrane permeability) of a compound of the invention (herein referred to as the active ingredient). [0348] The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
[0349] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108, 4,160,452, and 4,265,874 to form osmotic therapeutic tablets for control release.
[0350] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. [0351] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous 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.
[0352] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, 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, for example beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. [0353] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, 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 sweetening, flavoring and coloring agents, may also be present. [0354] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
[0355] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. [0356] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
[0357] The pharmaceutical compositions 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-irritating 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 include, for example, cocoa butter and polyethylene glycols. [0358] For topical use, creams, ointments, jellies, solutions, or suspensions, etc., containing the compounds of the invention are employed. As used herein, topical application is also meant to include the use of mouthwashes and gargles.
[0359] The pharmaceutical compositions and methods of the invention may further comprise other therapeutically active compounds, as noted herein, useful in the treatment of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
5.2.4 Methods of Use
[0360] In another aspect, the invention provides methods of treating or preventing a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention. [0361] In one embodiment, the disease or condition is type II diabetes.
[0362] In another aspect, the present invention provides a method for treating a disease or condition responsive to the modulation of GPR40 comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
[0363] In some embodiments, the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
[0364] In certain embodiments, the disease or condition is type II diabetes.
[0365] In some embodiments, the disease or condition is obesity.
[0366] In some embodiments, the disease or condition is hypertension.
[0367] In some embodiments of administering the compounds or compositions of the invention, the compound or composition is administered orally.
[0368] In other embodiments, the compound or composition is administered parenterally.
[0369] In other embodiments, the compound or composition is administered in combination with a second therapeutic agent.
[0370] In other embodiments, the second therapeutic agent is an insulin sensitizing agent, such as metformin or a thiazolidinedione, for example.
[0371] In another aspect, the invention provides methods of treating or preventing a disease or disorder responsive to modulation of GPR40 comprising administering to a subject having such a disease or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions.
[0372] In yet another aspect, the invention provides methods of treating or preventing a GPR40-mediated condition, disease or disorder comprising administering to a subject having such a condition, disease or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions.
[0373] In yet another aspect, the invention provides methods of modulating GPR40 comprising contacting a cell with one or more of the subject compounds or compositions.
[0374] For example, in some embodiments, a cell that constitutively expresses GPR40 is contacted with one or more of the subject compounds or compositions. [0375] In certain embodiments, a cell to be contacted can be made to express or overexpress GPR40, for example, by expressing GPR40 from heterologous nucleic acid introduced into the cell or, as another example, by upregulating the expression of GPR40 from nucleic acid endogenous to the cell. [0376] Depending on the disease to be treated and the subject's condition, the compounds of the invention may be administered by oral, parenteral {e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical {e.g., transdermal, local) routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. The invention also contemplates administration of the compounds of the invention in a depot formulation, in which the active ingredient is released over a defined time period. [0377] In the treatment or prevention type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, , hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema or other conditions or disorders associated with GPR40, an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range, the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from 1.0 to 1000 milligrams of the active ingredient, particularly 1.0,3.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.O5 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
[0378] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
[0379] The compounds of the invention can be combined or used in combination with other agents useful in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds of the invention are useful, including type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema. Such other agents, or drugs, may be administered, by a route and in an amount commonly used therefore, simultaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred. Accordingly, the pharmaceutical compositions of the invention include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound of the invention.
[0380] The compounds of the invention may be used in combination with a second therapeutic agent such as those described herein. Thus, in some embodiments, therapeutic compositions are provided that include a compound of the invention and a second therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of a subject with a disease or condition mediated by GPR40. In some embodiments, therapeutic compositions are provided that include a compound of the invention and a second therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the prophylactic treatment of a subject at risk for a disease or condition mediated by GPR40. In some such embodiments, the components are provided as a single composition. In other embodiments, the compound and the second therapeutic agent are provided separately as parts of a kit. [0381] Examples of other therapeutic agents that may be combined with a compound of the invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) cholesterol lowering agents such as HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and other statins), bile acid sequestrants (e.g., cholestyramine and colestipol), vitamin B3 (also known as nicotinic acid, or niacin), vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), fibric acid derivatives (e.g., gemfibrozil, clofϊbrate, fenofibrate and benzafibrate), probucol, nitroglycerin, and inhibitors of cholesterol absorption (e.g., beta- sitosterol and acylCoA-cholesterol acyltransferase (ACAT) inhibitors such as melinamide), HMG-CoA synthase inhibitors, squalene epoxidase inhibitors and squalene synthetase inhibitors; (b) antithrombotic agents, such as thrombolytic agents (e.g., streptokinase, alteplase, anistreplase and reteplase), heparin, hirudin and warfarin derivatives, β-blockers (e.g., atenolol), β-adrenergic agonists (e.g., isoproterenol), ACE inhibitors and vasodilators (e.g., sodium nitroprusside, nicardipine hydrochloride, nitroglycerin and enaloprilat); and (c) anti-diabetic agents such as insulin and insulin mimetics, sulfonylureas (e.g., glyburide, meglinatide), biguanides, e.g., metformin (GLUCOPHAGE®), α-glucosidase inhibitors (acarbose), insulin sensitizers, e.g., thiazolidinone compounds, rosiglitazone (AVANDIA®), troglitazone (REZULIN®), ciglitazone, pioglitazone (ACTOS®) and englitazone, DPP-IV inhibitors, e.g., vildagliptin (Galvus®), sitagliptin (Januvia™), and GLP-I analogs, e.g., exenatide (Byetta®). In some US2006/034995
embodiments, a compound of the invention may be administered along with a DPP-IV inhibitor or a GLP-I analog.
[0382] The weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Combinations of a compound of the invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
[0383] In another aspect, the present invention provides a method for modulating circulating insulin concentration in a subject, comprising administering a compound or composition of the invention. [0384] In some embodiments, the insulin concentration is increased.
[0385] In other embodiments, the insulin concentration is decreased.
[0386] The following examples are offered by way of illustration and are not intended to limit the scope of the invention. Those of skill in the art will readily recognize a variety of noncritical parameters that could be modified to yield essentially similar results.
6. EXAMPLES
[0387] Unless otherwise stated, all compounds were obtained from commercial sources or were prepared using the methods and experimental procedures described herein. Various procedures are also set forth in published U.S. Patent Application No. 2006/0004012 which is hereby incorporated by reference in its entirety and for all purposes as if set forth herein. The following abbreviations are used to refer to various reagents, solvents, experimental procedures, or analytical techniques that are described in the examples:
ACN Acetonitπle
AcOH Acetic Acid
DCM Dichloromethane
DEAD Diethylazodicarboxylate
DIAD Diisoprolylazodicarboxylate DMF N5N' -Dimethyl Formamide
DMSO Dimethyl Sulfoxide
ESI Electrospray Ionization
EtOAc EtOAc
EtOH Ethanol
HPLC High Performance Liquid Chromatography
HSA Human Serum Albumin i-PrOH 2-Proρanol
LDA Lithium Diisopropylamide
MeOH Methanol
MS Mass Spectrometry
NBS N-Bromosuccinimide n-BuLi n-butyllithium
NMR Nuclear Magnetic Resonance n-PrOH 1-Propanol
PCC Pyridinium Chlorochromate
PDC Pyridinium Dichromate
PPTS Pyridinium p-Toluenesulfonate
SPA Scintillation Proximity Assay t-BuOH t-Butanol
TEA Triethylamine
THF Tetrahydrofuran
TFA Trifluoroacetic Acid
TLC Thin Layer Chromatography
TMAD N,N,N',N'-Tetramethylazodicarboxamide 6.1 Method 1
Figure imgf000085_0001
Ml.l
[0388] 5-(4-Hydroxy-benzylidene)-2,2-dimethyl-[l,3]dioxane-4,6-dione
(Ml.l). Condensation with Meldrum's acid was carried out according to the method of Bigi et. at. (2001) Tetrahedron Lett. 42:5203-5205. A 2L pear-shaped flask was charged with 4-hydroxybenzaldehyde (50 g, 409 mmol) and water (400 HiL). The flask was placed in a water bath at 75 0C, and Meldrum's acid (62 g, 430 mmol) was added as a slurry in 400 mL of water. The reaction mixture was agitated for 2 hours and cooled in an ice bath for 2 hours. The product was collected by filtration and rinsed with cold water. After drying thoroughly, adduct Ml.l was obtained as a fine yellow powder. MS ESI (pos.) m/e: 519.0 (2M + Na). 1H NMR (500 MHz) (DMSO-^6) δ 9.75 (br s, IH); 8.27 (s, IH); 8.24 (d, 2H, J=IO Hz); 6.98 (d, 2H, J=IO Hz);.1.76 (s, 6H).
Figure imgf000085_0002
Ml.l M1.2
[0389] (+/-)-5-[l-(4-Hydroxy-phenyl)-but-2-ynyl]-2,2-dimethyl-
[l,3]dioxane-4,6-dione (M1.2). An oven-dried 3L 3-neck flask was equipped with a mechanical stirrer, a nitrogen inlet, and a nitrogen outlet and placed in a room-temperature water bath. After purging with nitrogen for 20 minutes, a solution of 1-propynylmagnesium bromide in THF (0.5 N, 600 mL) was added by cannula. In a separate oven-dried and nitrogen-flushed 500 mL round-bottom flask, compound Ml.l (35 g, 142 mmol) was dissolved in anhydrous THF (350 mL) with gentle warming. The solution of Ml.l was added over 15 minutes. Over the course of the addition, the reaction mixture changed to a thick, yellow suspension. After the addition was complete, the reaction mixture was stirred for 15 minutes, quenched with aqueous NH4Cl (0.6 N, 750 mL), and diluted with hexanes (800 mL). The layers were separated, and the organic layer was discarded. The aqueous layer was acidified to pH ~2 with saturated aqueous KHSO4 and extracted with EtOAc (2 x 400 mL). The combined extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow solid. MS ESI (pos.) m/e: 599.0 (2M + Na). 1H NMR (500 MHz) (acetone-d6) δ 8.26 (s, IH); 7.39 (d, 2H, J=8.5 Hz); 6.76 (d, 2H, J=8.4 Hz); 4.73 (br s, IH); 4.46 (d, IH, J=2.4 Hz); 1.82 (s, 3H); 1.81 (s, 3H); 1.64 (s, 3H).
Figure imgf000086_0001
M1.2 M1.3
[0390] (+/-)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid (Ml .3). A IL round-bottom flask was charged with compound M1.2 (37 g), diethyl ketone (160 mL), and water (80 mL). The suspension was heated at reflux for 48 hours. After cooling, the aqueous layer was saturated with NaCl(s) and separated. The organic layer was dried over MgSO4, filtered, and concentrated to a light brown oil, which was crystallized from hot EtOAc:hexanes (1 :2). After collecting and drying, the product was obtained as an off-white powder. MS ESI (pos.) m/e: 205.1 (M + H); 227.1 (M + Na). 1H NMR (500 MHz) (DMSO-J6) δ 12.2 (s, IH); 9.27 (s, IH); 7.12 (d, 2H, J=8.5 Hz); 6.67 (d, 2H, J=8.6 Hz); 3.87 (m, IH); 2.54 (m, 2H); 1.82 (d, 3H, J=2.4 Hz).
Figure imgf000086_0002
M1.3 M1.4 [0391] (3S)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid (M1.4). A 5L round-bottom flask was charged with compound M1.3 (66.4 g, 325 mmol) and i- PrOH (1 L) and heated to 70 0C. (IS, 2R)- l-Amino-2-indanol (46.1 g, 309 mmol) was dissolved in i-PrOH (1 L) with gentle warming. The solution of amine was added to the dissolved carboxylic acid and the resulting solution was allowed to cool to room temperature. After 16 hours, the crystals were collected and dried. The salt was re-suspended in 2 L of i-PrOH and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16 hours. A small sample of the salt was decomposed with aqueous acid and the free carboxylic acid was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1% TFA in 90:10 hexanes:i-PrOH) and was found to have 75% ee. The salt was re-suspended in 1.5 L of i-PrOH and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16 hours. This material was found to have 96% ee by chiral HPLC. This material was suspended in EtOAc (300 mL) and water (100 mL). Saturated aqueous KHSO4 (100 mL) was added with vigorous mixing. After two clear layers were obtained, the layers were separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow oil, which crystallized on drying in vacuo. Compound Ml.4 was obtained as an off-white solid.
Figure imgf000087_0001
M1.4 Ml
[0392] (3S>3-(4-Hydroxy-phenyl)-hex-4-ynoic acid methyl ester (Ml).
Phenol M1.4 (23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treated with KHCO3 (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80 mmol) was added, and the reaction was stirred at 40 °C for 14 hours. An additional portion of methyl iodide (3 mL, 48 mmol) was added and heating was continued for 24 hours. Potassium salts were removed by filtration and thoroughly rinsed with acetone. The filtrate was concentrated to an oil, which was filtered through a 1 cm plug of silica gel. Elution with 2.5% MeOH in DCM followed by concentration provided phenol 1 as a light yellow oil. MS ESI (pos.) m/e: 219.1 (M + H); 241.1 (M + Na). 1H NMR (500 MHz) (acetone-d6) δ 8.2 (br s, IH); 7.20 (d, 2H, J=9.5 Hz); 6.77 (d, 2H, J=9.0 Hz); 3.98 (m, IH); 3.60 (s, 3H); 2.65 (m, 2H); 1.78 (d, 3H, J=2.5 Hz). 6.2 Method 2
Figure imgf000088_0001
M2.1 M2
[0393] Ethyl 3-(4-fluoro-phenyl)-3-(4-hydroxy-phenyl)-acrylate
(M2.1). A solution of lithium hexamethyldisilazide (23.1 niL, 1 M in THF) was added to a stirred solution of ethyl (trimethylsilyl)acetate (2.53 mL, 13.9 mmol) in THF (15 mL) in 10 minutes at -78 ° C. The reaction mixture was further stirred at this temperature for 20 minutes. A solution of (4-fluoro-phenyl)-(4-hydroxy- phenyl)-methanone (2 g, 9.2 mmol) in THF (30 mL) was slowly added to the reaction mixture. The reaction mixture was brought to 0° C over 5 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted into EtOAc and washed with dilute ammonium chloride solution. The organic layer was dried over magnesium sulfate. The solvent was removed under vacuum, and the resulting product was flash chromatographed on silica gel, giving Ml.l as an oil.
[0394] (+/-)-3-(4-Fluoro-phenyl)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (M2). A solution of M2.1 (385 mg) in EtOH (12 mL) and EtOAc (10 mL) was stirred with 10% Pd-C (50 mg) under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered and concentrated to provide M2. 6.3 Method 3
[0395] Starting from (4-hydroxy-phenyl)-phenyl-methanone, compound
M3 was prepared according to methods analogous to those described in Method 2.
Figure imgf000089_0001
M3.1 M3
6.4 Method 4
Figure imgf000089_0002
M1.1 M4.1
[0396] 2,2-Dimethyl-5-[4-(tetrahydro-pyran-2-yloxy)-benzylidene]-
[l,3]dioxane-4,6-dione (M4.1). Protection of the phenol with dihydropyran was carried out based on the method described in Miyashita et al. (1977) J. Org. Chem. 42:3772. Compound Ml.l (500 g, 2 mol) was dissolved in DCM (4 L). 3,4-Dihydro-2H-pyran (250 g, 3 mol) was added to the suspension followed by PPTS (5 g, 20 mmol). The reaction mixture was then heated at a gentle reflux (3.5 hours). The reaction was concentrated under reduced pressure to ~2 L of volume. 1 L of acetone was then added, and 2 L of solvent were removed under reduced pressure. 1 L of acetone was added, and 1 L of solvent was removed under reduced pressure. 0.5 L of acetone was added, and 0.5 L of solvent was removed under reduced pressure. The resulting slurry of very fine, light yellow crystals was filtered and rinsed sequentially with two 500 mL portions of acetone. The product was dried in a vacuum oven at 50 °C until no further solvent collected in the traps. Compound M4.1 was obtained as fine, light yellow crystals. MS ESI (pos.) m/e: 355.1 (M + Na). 1H NMR (400 MHz) (DMSCW6) δ 8.29 (s, IH); 8.18 (d, 2H, J=8.9 Hz); 7.13 (d, 2H, J=8.9 Hz);. 5.67 (m, IH); 3.70 (m, IH); 3.60 (m, 1H).1.9-1.5 (m, 12H).
Figure imgf000090_0001
M4.1 M4
[0397] (+/-)-Methyl 3-(4-hydroxyphenyl)-3-(thiophen-2-yl)propanoate
(M4). A 500 niL flask was equipped with a magnetic stir bar, a nitrogen inlet, and a nitrogen outlet and placed in a room-temperature water bath. Compound M4.1 (5.00 g, 15.1 mmol) was added to the flask along with anhydrous THF (150 mL). After purging with nitrogen for 30 minutes, a solution of thiophene-2-yl- magnesium bromide in THF (1 M, 18.1 mL) was added by cannula. After the addition was complete, the reaction mixture was stirred for 1.5 hours and quenched with aqueous NH4Cl (1 M, 100 mL), and diluted with EtOAc (100 mL). The aqueous layer was acidified to pH ~2 with concentrated HCl and extracted with EtOAc (150 mL x 2). The extract was washed with brine and concentrated. The residue was dissolved in 100 mL of 10:1 DMF:water and heated to 100°C for 8 hours. The reaction was cooled, diluted with 500 mL water, and extracted with EtOAc (150 mL x 3). The organic layer was dried with MgSO4, filtered, and concentrated on a rotary evaporator. The residue was dissolved in MeOH (200 mL), 5 drops of concentrated H2SO4 were added, and the solution was refluxed for 24 hours. The solution was concentrated to a residue on a rotary evaporator and flash column chromatographed with 30% EtOAc/hexanes as the eluant. The fractions were combined and concentrated to afford M4 as a viscous oil. 6.5 Method 5
Figure imgf000090_0002
[0398] 2-(4-(Benzyloxy)phenyl)-N-(prop-2-ynyl)acetamide (M5.1). A mixture of 4-(benzyloxy)phenylacetic acid (20.7 mniol), 1-hydroxybenzotrizole hydrate (37 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (37 mmol), propargylamine (20.7 mmol) and N-methylmorpholine (62 mmol) in DMF (60 mL) were stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (400 mL), washed with IN HCl, water, saturated Na2CO3 solution, and brine, and dried over Na2SO4. After removing solvent under reduced pressure, the residue was triturated with DCM. Compound M5.1 was obtained as a white solid after filtration and drying. LC-MS ESI (pos.) m/e: 280 (M+H).
Figure imgf000091_0001
[0399] 2-(4-Benzyloxy)benzyl)-5-methyl oxazole (M5.2). A mixture of compound M5.1 (10.1 mmol) and AuCl3 (1 mmol) in DCM (100 mL) was stirred at room temperature overnight. Additional DCM (100 mL) was added, and the reaction mixture was washed with NaHCO3 solution and saturated brine. After drying over Na2SO4 and concentration under reduced pressure, the residue was column chromatographed (1 :2 EtOAc:hexanes) to obtain compound M5.2. LC- MS ESI (pos.) m/e: 280 (M+H).
Figure imgf000091_0002
M5.2 M5.3
[0400] (+/-)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(5-methyloxazol-2- yl)propanoate (M5.3). To a solution of 2~(4-(benzyloxy)benzyl)-5- methyloxazole (M5.2) (3.23 mmol) in THF (25 mL) at -78 0C, was added dropwise LDA (4.5 mmol). The mixture was stirred for 18 minutes, followed by addition of ethyl bromoacetate (4.5 mmol). It was allowed to warm to room temperature for 3 hours, followed by addition of water, which was extracted with EtOAc. The extract was washed with brine and dried over Na2SO4 using standard work up conditions. Column chromatography (1/3 EtOAc/hexane) of the residue afforded compound M5.3. MS ESI (pos.) m/e: 366 (M+H).
Figure imgf000092_0001
M5.3 M5
[0401] (+/-)-Ethyl 3-(4-hydroxyphenyl)-3-(5-methyloxazol-2- yl)propanoate (M5). A mixture of ethyl 3-(4-(benzyloxy)phenyl)-3-(5- methyloxazol-2-yl)propanoate (M5.3) (2.47 mmol) and Pd-C (270 mg) in EtOH was stirred under hydrogen atmosphere at room temperature for 4 hours. The Pd- C was removed by filtration through silica gel eluting with EtOH. After concentration, product M5 was obtained. MS ESI (pos.) m/e 276 (M+H). 6.6 Method 6
Figure imgf000092_0002
M6.1
[0402] (+ / -) (3,5-Difluorophenyl)(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)methanol (M6.1). 4-(2-Tetrahydro-2H- pyranoxy)phenylmagnesium bromide (0.5 M in THF, 35 mL, 17.5 mmol) was added to a solution of 3,5-difluorobenzaldehyde (1.95 g, 13.7 mmol) in THF (50 mL) slowly via syringe at -78 0C. The reaction mixture was stirred at this temperature for 3 hours and then quenched with saturated NH4Cl (aqueous). The mixture was extracted with EtOAc (60 mL x 2), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a colorless oil (3.9 g) as product M6.1, which was used directly in the next step.
Figure imgf000093_0001
M6.1 M6.2
[0403] (+/-)-(3,5-Difluorophenyl)(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)methanone (M6.2). PDC (8.5 g, 22.6 mmol) was added to the solution of M6.1 (3.9 g, 13.7 mmol) in DCM (100 mL) at 0 °C in several portions. The mixture was stirred at 0 0C for 1 hour and at room temperature for 6 hours. Silica gel (about 20 g) was added to the reaction mixture and the resulting slurry was filtered through a pad of silica gel to remove most of the inorganic chemicals. The solid was washed with DCM until no further product remained on the silica gel (monitored by TLC). The combined organic solvent was washed with water and saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide an oily residue, which was flash chromatographed (silica gel, 0-30% EtOAc in hexane), generating product ketone M6.2 as light yellow oil. MS ESI (pos.) m/e: 319 (M+H).
Figure imgf000093_0002
M6.2 M6.3
[0404] (Z/E)-Ethyl 3-(3,5-difluorophenyI)-3-(4-(tetrahydro-2H-pyran-
2-yloxy)phenyl) acrylate (M6.3). Ethyl (trimethylsilyl)acetate (2.63 g/3.0 mL in 20 mL THF) was added to lithium hexamethyldisilazide (1 M in THF, 17.6 mL) at -78 0C slowly via syringe. The mixture was stirred at the same temperature for 1 hour, and the solution of ketone M6.2 (4.3 g, 13.5 mmol) in anhydrous THF (25 mL) was added slowly via syringe. The reaction mixture was further stirred at this temperature for 2 hours. The reaction temperature was then allowed to rise to -20 °C in 6 hours. The reaction mixture was quenched with saturated ammonium chloride (aqueous) at this temperature, extracted with EtOAc (2 x 100 niL) and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure and M6.3 was obtained as light yellow oil (including some ethyl (trimethylsilyl)acetate), which was used directly in the next step. MS ESI (pos.) m/e: 389 (M+H).
Figure imgf000094_0001
M6.3 M6
[0405] (+/-)-Ethyl 3-(3,5-difluorophenyI)-3-(4- hydroxyphenyl)propanoate (M6). A solution of olefin M6.3 (5.4 g, 13.5 mmol) in EtOH (80 mL) was stirred with 10% Pd-C (1.5 g, 1.4 mmol) under a hydrogen atmosphere (provided by a balloon) overnight at room temperature. The reaction mixture was filtered through a short silica gel pad and stirred with AcOH (14 mL) at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to provide a yellow oily residue, which was re-dissolved in DCM (150 mL) and washed with water, saturated NaHCO3, water, and brine, and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure, and the residue was flash chromatographed (silica gel, 0-40% EtOAc in hexane as eluant). The product (+/-)ethyl ester M6. MS ESI (pos.) m/e: 307 (M+H).
6.7 Method 7
Figure imgf000094_0002
M7 [0406] (+/-)-Ethyl 3-(2,4-difluoro-phenyl)-3-(4-hydroxy-phenyl) propanoate (M7). Compound M7 was prepared by a method analogous to that for M6.
6.8 Method 8
Figure imgf000095_0001
M8
[0407] (+/-)-Ethyl 3-(2,5-difluoro-phenyl)-3-(4-hydroxy-phenyl) propanoate (M8). Compound M8 was prepared by a method analogous to that for M6.
6.9 Method 9
Figure imgf000095_0002
M9
[0408] (+/-)-Ethyl 3-(2,6-difluoro-phenyl)-3-(4-hydroxy-phenyl) propanoate (M9). Compound M9 was prepared by a method analogous to that for M6.
6.10 Method 10
Figure imgf000095_0003
MlO
[0409] (+/-)-Ethyl 3-(4-hydroxy-phenyI)-3-(5-methyl-thiophen-2-yl) propanoate (MlO). Compound MlO was prepared by a method analogous to that for M6. 6.11 Method 11
Figure imgf000096_0001
Mll.l
[0410] (+/-)-Oxazol-2-yl(4-(tetrahydro-22ϊ-pyran-2- yloxy)phenyl)methanol (Mll.l). 4-(2-Tetrahydro-3-H- pyranoxy)phenylmagnesium bromide (6.7 mmol) in THF (0.5 M) was added dropwise to a solution of oxazole-2-carbaldehyde (5.15 mmol) in THF (8 mL). After it was stirred at room temperature for 2.5 hours, the reaction was quenched with water and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed (silica gel, 1 :2 EtOAc/hexane). Compound Mll.l was obtained. MS ESI (pos.) m/e:276 (M+H). 1H NMR (400 MHz) (DMSOd6) δ 8.02 (s, IH); 7.31 (d, J=8.7 Hz, 2H); 7.14 (s, IH); 6.97-7.01 (m, 2H); 6.27 (d, J=5 Hz, IH); 5.74 (d, J=5 Hz, IH); 5.44 (s, IH); 3.74 (m, IH); 3.52 (M, IH); 1.72-1.81 (m, 3H); 1.52-1.60(m, 4H).
Figure imgf000096_0002
Mll.l M11.2
[0411] (+/-)-Oxazol-2-yl(4-(tetrahy dro-2#-pyran-2- yloxy)phenyl)methanone (M11.2). PCC (14.5 mmol, 20%w/w on silica gel) was added to a solution of Mll.l (2.91 mmol) in DCM (20 mL). After it was stirred at room temperature for 1 hour, the reaction mixture was column chromatographed (silica gel, 1:2 EtOAc/hexane). Compound M11.2 was obtained. MS ESI (pos.) m/e: 296.0 (M+23). 1H NMR (500 MHz) (DMSOd6) δ 8.52 (s, IH); 8.43 (d, J=9 Hz, 2H); 7.67 (s, IH); 7.23 (d, J=9 Hz, 2H); 5.71 (m, IH); 3.74-3.76 (m, IH); 3.62-3.65 (m, IH); 1.88-1.91 (m, 2H); 1.81-1.82 (m, IH); 1.59-1.67 (m, 3H).
Figure imgf000097_0001
M11.2 M11.3
[0412] (E/Z)-Methyl 3-(oxazol-2-yl)-3-(4-(tetrahydro-2JH-pyran-2- yloxy)phenyl)acrylate (Ml 1.3). Lithium bis(trimethylsilyl) amide (3.46 mmol, 1 M in THF) was added dropwise to a solution of methyl trimethylsilylacetate (3.46 mmol) in THF (5 mL) at -78 °C. After it was stirred at -78 °C for 20 minutes, a solution of Ml 1.2 (2.16 mmol) in THF (9 mL) was added dropwise, and the temperature was maintained at -78 0C for 1.5 hours. The reaction was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed (silica gel, 1 : 1 EtOAc/hexane) and compound M11.3 was obtained. MS ESI (pos.) m/e 330.1 (M+H).
Figure imgf000097_0002
M11.3 M11.4
[0413] (+/-)-Methyl 3-(oxazoI-2-yl)-3-(4-(tetrahydro-2iy-pyran-2- yloxy)phenyl)propanoate (M11.4). A mixture of M11.3 (2.55 mmol) and Pd-C (440 mg) in MeOH was stirred under hydrogen at room temperature for 30 minutes. The Pd-C was removed by filtration through silica gel eluting with EtOAc. After concentration, the residue was column chromatographed (silica gel, 1:1 EtOAc/hexane) and compound M11.4 was obtained. MS ESI (pos.) m/e 332.2 (M+H).
Figure imgf000098_0001
M11.4 Mil
[0414] (+/-)-Methyl 3-(4-hydroxyphenyl)-3-(oxazol-2-yl)propanoate
(Mil). A mixture of M11.4 (2.1 nimol), p-toluenesulfonic acid monohydrate (0.57 mmol) in MeOH (15 mL) was stirred at room temperature for 1.5 hours. After it was quenched with NaHCO3 (aqueous) solution, MeOH was removed by rotary evaporator. The residue was extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered through short plug of silica gel. After removing solvent, compound Mil was obtained. MS ESI (pos.) m/e 248.1 (M+H). 1H NMR (500 MHz) (DMSO-d6) δ 9.04 (s, IH); 7.99 (s, IH); 7.14 (s, IH); 7.05(m, 2H); 6.72 (m, 2H); 4.49-4.52 (m, IH); 3.57 (s, IH); 3.22-3.27(m, IH); 2.89-2.94(m, IH). 6.12 Method 12
Figure imgf000098_0002
M12.1
[0415] (l-Methyl-lH-imidazol-2-yl)(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)methanol (M12.1). 4-(2-Tetrahydro-2H- pyranoxy)phenylmagnesium bromide (0.5 M in THF, 160 mL, 80 mmol) was added slowly to a solution of l-methyl-2-imidazolecarboxaldehyde (8 g, 72.7 mmol) in THF (100 mL) via syringe at -78 0C. The reaction mixture was stirred at this temperature for 3 hours and quenched with saturated NH4Cl (aq). The mixture was extracted with EtOAc (2 x 100 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford M12.1 as a colorless oil (21 g), which was used directly in the next step.
Figure imgf000099_0001
M12.1 M12.2
[0416] (l-Methyl-lH-imidazol-2-yl)(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)methanone (M12.2). PDC (36 g, 95.7 mmol) was added to a solution of M12.1 (21 g, 72.7 mmol) in DCM (100 niL) at 0 °C in several portions. The mixture was stirred at 0 °C for 1 hour and at room temperature for 6 hours. Silica gel (75 g) was added to the reaction mixture, and the resulting slurry was filtered through a pad of silica gel. The solid was washed with DCM (200 mL). The filtrate was washed with water and saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give an oily residue, which was flash cliromatographed (silica gel, 0-30% EtOAc in hexane) to afford ketone M12.2 as yellow solid (16 g). 1H NMR (500 MHz) (CDCl3) δ 8.33-8.35 (m, 2H); 7.10-7.29 (m, 4H); 5.56 (t, J= 3.0 Hz, IH); 4.08 (s, 3H); 3.85-3.90 (m, IH); 3.61- 3.65 (m, IH); 2.03 (m, IH); 1.90-1.91 (m, 2H); 1.69-1.74 (m, 2H); 1.61-1.64 (m, IH).
Figure imgf000099_0002
M12.2 M12.3
[0417] (Z/E)-Ethyl 3-(l-methyl-lH-imidazol-2-yl)-3-(4-(tetrahydro-
2H-pyran-2-yloxy)phenyl)acrylate (M12.3). A solution of lithium hexamethyldisilazide (1 M in THF, 64 mL) was added slowly to a stirred solution of ethyl (trimethylsilyl)acetate (9.9 g, 61.5 mmol) and ketone M12.2 (16 g, 55.9 mmol) in anhydrous THF (60 mL) via syringe at -78 0C. The reaction mixture was stirred at this temperature for 2 hours. The reaction temperature was allowed to rise to -20 0C over 6 hours. The reaction mixture was quenched with saturated ammonium chloride (aq) at this temperature, extracted with EtOAc (2 x 150 mL), and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure to afford M12.3 as a colorless oil (21 g, including some ethyl (trimethylsilyl)acetate), which was used directly in the next step. LC-MS ESI (pos.) m/e: 357 (M+H).
Figure imgf000100_0001
[0418] (+/-)-Ethyl 3-(l-methyl-lH-imidazol-2-yI)-3-(4-(tetrahydro-2H- pyran-2-yloxy)phenyl)propanoate (M12.4). A solution of olefin M12.3 (21 g, 55.9 mmol) in EtOH (200 niL) was stirred with 10% Pd-C (2.1 g, 2 mmol) under a hydrogen atmosphere (provided by a balloon) at room temperature overnight. The reaction mixture was filtered through a silica gel pad and concentrated to provide protected ester M12.4 as an off-white oil (21 g), which was used directly in the next step. LC-MS ESI (pos.) m/e: 359 (M+H).
Figure imgf000100_0002
M12.4 M12.5
[0419] (+/-)-EthyI 3-(4-hydroxyphenyl)-3-(l-methyl-lH-imidazol-2- yl)propanoate (M12.5). TFA (21 mL) was added to a solution of protected ester M12.4 (21 g) in dry DCM (210 mL) with caution at 0 0C. The mixture was brought to room temperature over 4 hours. The reaction mixture was concentrated under reduced pressure to provide a yellow oily residue, which was re-dissolved in DCM (200 mL) and washed with water, saturated NaHCO3, water and brine, and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure, and the product was crystallized in EtOAc-hexane. The mother liquid was concentrated and flash chromatographed (silica gel, 50% EtOAc in hexane as eluant). The product, (±)-ethyl 3-(4-hydroxyphenyl)-3-(l-methyl-lH-imidazol-2- yl)propanoate (M12.5) was obtained as a colorless crystal (combined yield 11 g). LC-MS ESI (pos.) m/e: 275 (M+H). 1H NMR (500 MHz) (CDCl3) δ 9.28 (s, IH); 6.98-7.00 (m, 3H); 6.65-6.77(m, 3H); 4.41 (dd, J=9.0, 3.0 Hz, IH); 3.96 (q, J=7.0, 2H); 3.39 (s, 3H); 3.19 (dd, J=I 6.0, 7.0 Hz, IH); 2.78 (dd, J= 16.0, 6.5 Hz, IH); 1.80 (t, J= 7.0 Hz, 3H).
Figure imgf000101_0001
M12.5 M12
[0420] (S)-Ethyl 3-(4-hydroxyphenyl)-3-(l-methyI-lH-imidazol-2- yl)propanoate (M12). Racemic compound M12.5 was separated on a preparatory chiral HPLC with CHIRALPAK AD column, using 11% i-PrOH in hexane as eluant. Eluant containing the peak with greater retention time was concentrated and compound M12 was obtained as colorless crystals. The enantiomer of M12 was also obtained. The absolute configuration was assigned by analogy to other GPR40 agonist compounds.
Figure imgf000101_0002
M13.1 M13.2
[0421] Methyl ester (M13.2). Compound M13.1 (5.5 g, 12.16 mmol, prepared as described in US 2006/0004012 which is hereby incorporated by reference) was dissolved in 100 niL of EtOAc and quinoline (2 mL, 1.093 g/mL, 16.93 mmol) was added. Nitrogen was bubbled through the solution for 5 minutes. 500 mg of Lindlar's catalyst was added, and a hydrogen balloon was attached. After 8 hours, the mixture was filtered through a plug of silica with EtOAc. The organic layer was washed with 2 N HCl (aq) (2 x 50 mL), saturated NaHCO3 (aq) (1 x 50 mL), brine (1 x 50 mL) and dried with MgSO4. The organic layer was filtered and concentrated under reduced pressure. The material was chromatographed on silica with 10% EtOAc/hexane to afford M13.2 (5.1 g, 11.22 mmol) as a colorless oil. MS ESI (pos.) m/e: 455.0 (M+H)+.
Figure imgf000102_0001
M13.2 M13.3
[0422] Aldehyde (M13.3). Alkene M13.2 (5.1 g, 11.22 mmol) was dissolved in 100 mL of 4:1 (1,2-dioxane/water), and 2,6-lutidine (2.61 mL, 0.920 g/mL, 22.44 mmol) was added. Next, 1.2 g of a 3.4% OsO4 in t-BuOH (0.22 mmol) solution was added dropwise over 5 minutes. NaIO4 (9.6 g, 44.88 mmol) in 25 mL of water was added. The internal reaction temperature did not rise above 30 °C. After 8 hours at room temperature, the reaction mixture was diluted with 500 mL of DCM, the layers were separated, and the organic layer was washed with 0.5 M HCl(aq) (2 x 50 mL), saturated NaHCO3 (aq) (1 x 50 mL), 5% sodium sulfite (aq) (1 x 50 mL), and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was flashed on silica with 30% EtOAc/hexanes to afford M13.3 (4.0 g, 9.09 mmol) as a yellow oil. MS ESI (pos.) m/e: 443.4 (M+H)+.
Figure imgf000102_0002
M13.3 M13.4
[0423] Acid (M13.4). Aldehyde M13.3 (2.32 g, 5.25 mmol) was dissolved in 20 mL of ACN. To this was added KH2PO4 (178 mg, 1.31 mmol) in 5 mL of water. The solution was cooled to -5 °C and 30% H2O2 (aq) (714 mg, 6.30 mmol) was added. NaClO2 (712 mg, 7.88 mmol) was dissolved in 5 mL of water and added via syringe pump over 3 hours while maintaining a temperature below 0 0C. After the addition of the NaClO2 solution, the mixture was stirred for 1 hour. 300 niL of DCM was added, and the pH of the aqueous layer was adjusted to 2 with 2 N HCl(aq). The aqueous layer was extracted with DCM (2 x 100 mL), and the combined organic extracts were washed with 5% sodium sulfite (aq) (1 x 50 mL), and brine. The organic layer was dried with NaSO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica with 50% EtOAc/hexanes to afford M13.4 (2.12 g, 4.62 mmol) as a colorless oil. MS ESI (pos.) m/e: 459.3 (M+H)+.
Figure imgf000103_0001
M13.4 M13.5
[0424] Amide (M13.5). Acid M13.4 (6.0 g, 13.1 mmol) was dissolved in
100 mL of DCM. To this was added 1-hydroxybenzotriazole hydrate (3.7 g, 27.5 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbondiimide hydrochloride (5.0 g, 26.2 mmol), and 2 M ammonia in n-PrOH (14 mL, 26.2 mmol). The reaction was stirred for 8 hours and diluted with 500 mL of EtOAc. The organic layer was washed with 2N HCl (aq) (2 x 75 mL), NaHCO3 (aq) (1 x 75 mL), and brine (1 x 75 mL) and dried with MgSO4 and filtered. The organic layer was concentrated under reduced pressure, and the residue was flashed through silica with 25% EtOAc/DCM. The combined fractions were concentrated under reduced pressure to afford M13.5 (5.3 g, 11.5 mmol) as a colorless oil.
Figure imgf000103_0002
M13.5 M13.6 [0425] (S)-3-(2-Methyl-2iy-l,2,4-triazol-3-yl)-3-[4-(4'-trifluoromethyI- biphenyl-3-ylmethoxy)-phenyl]-propionic acid (M13.6). Amide M13.5 (6.48 g, 14.2 mmol) was dissolved in 7 niL of N,N-dimethylformamide dimethyl acetal (119.17 MW, 0.894 g/mL, 52.6 mmol). The solution was gradually heated to 80 0C over 30 minutes. The mixture was allowed to cool to 35 °C, and the sample was concentrated under reduced pressure. The residue was dissolved in 20 mL of AcOH followed by careful addition of methylhydrazine (5 mL, 0.866 g/mL, 94.0 mmol) over 5 minutes (the acid/base exotherm was used to run the reaction). The temperature increased to 65 0C, and an oil bath at 80 0C was used to finish the reaction. The total heating time was 45 minutes. The reaction was allowed to come to room temperature, and was diluted with 500 mL of DCM. The organic layer was washed with water (3 x 100 mL), brine (1 x 100 mL), dried with Na2SO4, filtered, and concentrated to a residue. The material was flashed on silica with 10% ACN/DCM to afford methyltriazole M13.6 (4.3 g, 8.7 mmol) as a yellow oil. MS ESI (pos.) m/e: 496.5 (M+H)+.
Figure imgf000104_0001
M13.6 M13
[0426] (S)-MethyI 3-(4-hydroxyphenyl)-3-(2-methyl-2H-l,2,4-triazol-
3-yl)propanoate (M13). Methyltriazole M13.6 (2.78 g, 5.61 mmol) was dissolved in 50 mL of EtOAc, and nitrogen was bubbled through the solution for 5 minutes. 1 g of palladium on carbon (5 wt. %, wet contains 50% water) was added, and a hydrogen balloon was attached. After 8 hours, the mixture was filtered through a plug of silica with 10% MeOH in EtOAc. The organic layer was concentrated under reduced pressure and partitioned between ACN (100 mL) and hexane (50 mL). The ACN layer was washed with hexane (4 x 50 mL). The ACN layer was concentrated under reduced pressure to afford (S)-methyl 3-(4- hydroxyphenyl)-3-(2-methyl-2H-l,2,4-triazol-3-yl)propanoate M13 (1.30 g, 4.99 mmol) as a colorless oil. MS ESI (pos.) m/e: 262.4 (M+H)+. 6.14 Method 14
Figure imgf000105_0001
M13.4 M14.1
[0427] Methylamide (M14.1). Acid M13.4 (6.0 g, 13.1 mmol), prepared as described above, was dissolved in 100 mL of DCM. To this mixture was added 1-hydroxybenzotriazole hydrate (3.7 g, 27.5 mmol), N-(3-dimethylaminopropyl)- N'-ethylcarbondiimide hydrochloride (5.0 g, 26.2 mmol), and 2 M methylamine in THF (14 mL, 26.2 mmol). The reaction was stirred for 8 hours, diluted with 500 mL of EtOAc, and the organic layer was washed with 2N HCl(aq) (2 x 75 mL), NaHCO3 (aq) (1 x 75 mL), brine (1 x 75 mL) and dried with MgSO4 and filtered. The organic layer was concentrated under reduced pressure, and the residue was flashed through silica with 15% EtOAc/DCM. The combined fractions were concentrated under reduced pressure to afford M14.1 (4.2 g, 11.5 mmol) as a colorless oil. MS ESI (pos.) m/e: 472.3 (MH-H)+.
Figure imgf000105_0002
M14.1 M14.2
[0428] (S)-3-(l-Methyl-l#-tetrazol-5-yl)-3-[4-(4Mrifluoromethyl- biphenyl-3-ylmethoxy)-phenyl]-propionic acid (M14.2). Methylamide M14.1 (2.15 g, 4.59 mmol) was dissolved in 50 mL of ACN. NaN3 (900 mg, 13.8 mmol) was added followed by the dropwise addition OfTf2O (5.2 g, 18.4 mmol). The temperature rose to 34 °C. The reaction was stirred for 12 hours and diluted with 250 niL of DCM. The organic layer was washed with NaHCO3 (aq) (2 x 50 niL), brine (1 x 50 niL) and dried with MgSO4 and filtered. The organic layer was concentrated under reduced pressure, and the residue was flashed through silica with 15% EtOAc/DCM. The combined fractions were concentrated under reduced pressure to afford methyltetrazole M14.2 (1.52 g, 3.07 mmol) as a colorless oil. MS ESI (pos.) m/e: 497.4 (M+H)+.
Figure imgf000106_0001
M14.2 M14
[0429] (S)-Methyl 3-(4-hydroxyphenyl)-3-(l-methyl-lH-tetrazol-5- yl)propanoate (M14). Methyltetrazole M14.2 (413 mg, 0.833 mmol) was dissolved in 5 mL of EtOAc and nitrogen was bubbled through the solution for 5 minutes. Palladium on carbon (200 mg, 5 wt. %, wet contains 50% water) was added, and a hydrogen balloon was attached. After 8 hours, the mixture was filtered through a plug of silica with 10% MeOH in EtOAc. The organic layer was concentrated under reduced pressure and partitioned between ACN (10 mL) and hexane (5 mL). The ACN layer was washed with hexane (4 x 5 mL). The ACN layer was concentrated under reduced pressure to afford (5)-methyl 3-(4- hydroxyphenyl)-3-(l-methyl-lH-tetrazol-5-yl)propanoate (M14) (203 mg, 0.775 mmol) as a colorless oil. 6.
Figure imgf000106_0002
Ml.l M15.1 [0430] 2,2-Dimethyl-5-(3-methyl-l-(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)but-2-enyl)-l,3-dioxane-4,6-dione (M 15.1). To a solution of M1.1 (50 g, 0.15 mol) in THF (300 niL) at 0 0C was cannulated 2-methyl-l- propenyl magnesium bromide (600 mL, 0.5 M in THF, 0.30 mol) during a 1 hour period. The reaction was left at room temperature for 2 hours and then was quenched with water, extracted with ethyl acetate, and dried with MgSO4. The solvent was removed to afford a gel-like M 15.1, which was used as such in the next step.
EtOH/Pyridine(9:1)
Figure imgf000107_0002
Figure imgf000107_0001
M15.1 M15.2
[0431] Ethyl 3-(4-hydroxyphenyl)-5-methylhex-4-enoate (M15.2). A solution of M15.1 in EtOH:pyridine (200 mL, 9:1 v/v) was heated to 120 0C overnight. After cooling, the reaction was acidified with 2 N HCl aq., and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated to afford M15.2. MS ESI (pos.) m/e: 249.1 (M + H).
Figure imgf000107_0003
M15.2 M15.3 M15.4
[0432] (S)-Ethyl 3-(4-hydroxyphenyI)-5-methylhex-4-enoate (M15.3) and (R)-ethyl 3-(4-hydroxyphenyl)-5-methylhex-4-enoate (M15.4). Racemic compound M15.2 was separated on a preparatory chiral HPLC. M15.3, and M15.4 were assigned arbitrarily. 6.16 Example 1
Figure imgf000108_0001
1.1
[0433] (+/-)-5-Bromo-2, 3-dihydro-lH-inden-l-ol (1.1). To a clear solution of 5-bromo-l-indanone (1.0 g, 4.7 mmol) in MeOH (6 mL) was added NaBH4 (0.36 g, 9.5 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and redissolved in water/EtOAc. The layers were separated and the EtOAc layer was dried with anhydrous Na2SO4 and concentrated to obtain 1.1, which was used directly in the next step. 1HNMR (DMSO-d6) δ 7.41 (s, IH), 7.36 (d, IH, J2=8.08Hz), 7.26 (d, IH, Jl=7.99Hz), 5.28 (d, IH, J=5.90Hz), 4.99 (q, IH), 2.91 (m, IH), 2.71 (m, IH), 2.33 (m, IH), 1.78 (m, IH).
Figure imgf000108_0002
1.1 1.2
[0434] (+/-)-5-Bromo-l-chloro-2, 3-dihydro-lH-indene (1.2). A solution of 1.1 (2.0 g) in DCM (10 mL) in an ice-bath, was treated with thionyl chloride (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The resulting material was chromatographed on a silica gel column, eluting with 5-10% EtOAc in hexane, to afford 1.2. 1H NMR (DMSO-d6) δ 7.54 (s, IH), 7.45 (dd, IH, Jl=LOHz, J2=8.50Hz), 7.37 (d, IH, J=8.0Hz), 3.07 (m, IH), 5.60 (q, IH), 2.93 (m, IH), 2.59(m, IH), 2.26 (m, IH).
Figure imgf000109_0001
1.2 1.3
[0435] (3S)-Methyl 3-(4-(4-bromo-2, 3-dihydro-lH-inden-l- yloxy)phenyl)hex-4-ynoate (1.3). A mixture of (S)-methyl 3-(4- hydroxyphenyl)hex-4-ynoate (1, 0.65 g, 2.9 mmol), Cs2CO3 (1.40 g, 4.3 mmol), and 1.2 (1.0 g, 4.3 mmol) in DMF (5 mL), was heated to 80 0C for 8 hours. The reaction mixture was concentrated, and the residue was chromatographed on a silica gel column, eluting with 5-10% EtOAc in hexane, providing 1.3. MS ESI (pos.) m/e: 413.0 (M+H).
Figure imgf000109_0002
1.3 1.4
6.16.1 General procedure A: Suzuki coupling
[0436] (3S)-Methyl 3-(4-(5-(3-(trifluoromethyl)phenyl)-2,3-dihydro- lH-inden-l-yloxy)phenyl)hex-4-ynoate (1.4). A mixture of 1.3 (74 mg, 0.18 mmol), 4-(trifluoromethyl)phenylboronic acid (45.8 mg, 0.22 mmol) and CsF (56 mg, 0.37 mmol) in 1 ,2-dimethoxyethane (2 mL), was degassed with N2 for 3 minutes. Pd(PPh3)4 (21 mg, 0.018 mmol) was added, and the resulting mixture was heated at 95 °C for 8 hours. After cooling, the reaction mixture was quenched with water and extracted with EtOAc providing 1.4 (20 mg), which was directly hydrolyzed in the next step. 006/034995
Figure imgf000110_0001
1.4 1
6.16.2 General Procedure B: Alkaline hydrolysis
[0437] (3S)-3-(4-(5-(3-(trifluoromethyl)phenyl)-2,3-dihydro-lH-inden- l-yloxy)phenyl)hex-4-ynoic acid (1.5). A solution of 1.4 (20 mg) in THF/MeOH (1:1, 6 niL), was treated with 30% aqueous NaOH solution (3 niL) and stirred for 2 hours at room temperature. The reaction mixture was acidified with aqueous 2N HCl and extracted with EtOAc providing 1.5, which was chromatographed on a silica gel column, eluting with 20-40% EtOAc in hexane. MS ESI (neg.) m/e: 463.1 (M-H). 1HNMR (DMSO-d6) δ 12.24 (br, IH), 7.91 (d, 2H, J=8.22Hz), 7.83 (d, 2H, J=8.35Hz), 7.70 (s, IH), 7.61 (d, IH, J=7.84Hz), 7.51 (d, IH, J=7.92Hz), 7.32 (d, 2H, J=8.67Hz), 7.02 (d, 2H, J=8.68Hz), 5.99 (m, IH), 3.99 (m, IH), 3.11 (m, IH), 3.00 (m, IH), 2.59-2.64 (m, 3H, CH2, CH), 2.09 (m, IH), 1.81 (ss, 3H), 1.80.
6.17 Example 2
Figure imgf000110_0002
1.3 2
[0438] (3S)-3-[4-(5-Bromo-indan-l-yloxy)-phenyl]-hex-4-ynoic acid
(2). Compound 2 was obtained from compound 1.3 by following general procedure B of Example 1. MS ESI (neg.) M/E: 397.0, 399.1 (M-H). 1HNMR (DMSO-d6) δ 12.25 (br, IH)3 7.55 (s, IH), 7.43 (dd, IH, Jl=I.77Hz, J2=8.05Hz), 7.20-7.38 (m, 3H), 7.00 (d, 2H, J=8.68Hz), 5.79 (m, IH), 3.96 (m, IH), 3.07 (m, IH), 2.92 (m, IH), 2.62 (d, 2H, J=7.49Hz), 2.57 (m, IH), 2.05 (m, IH), 1.81, 1.80 (ss, 3H).
6.18 Example 3
Figure imgf000111_0001
1.3 3.1 3
[0439] (3S)-3-(4-(5-(2-Butoxy-5-methylphenyl)-2,3-dihydro-lH-inden- l-yloxy)phenyl)hex-4-ynoic acid (3). This compound was obtained from compound 1.3 by following general procedures A and B of Example 1. MS ESI (neg.) ESI (neg.) m/e: 481.3 (M-H). 1HNMR (DMSO-d6), δ 12.22 (br, IH), 7.24- 7.42 (m, 6H), 7.11 (m, 2H), 6.99 (m, 3H), 5.76(m, IH), 4.03(m, IH), 3.96 (t, 2H, J=6.37Hz), 3.05 (m, IH), 2.91 (m, IH), 2.55-2.68 (m, 3H, CH2, CH), 2.34 (s, 3H), 2.06 (m, IH), 1.92 (s, 3H), 1.60 (m, 2H), 1.41 (m, 2H), 0.89 (t, 3H, J=7.32Hz).
6.19 Example 4
Figure imgf000111_0002
1.3 4.1 4
[0440] (3S)-3-[4-(5-Thiophen-2-yl-indan-l-yloxy)-phenyl]-hex-4-ynoic acid (4). Compound 4 was prepared by a method analogous to that for 1.3. MS ESI (neg.) m/e: 401.2 (M-H). 1HNMR (DMSOd6) δ 12.27 (br, IH), 7.62 (s, IH), 7.52-7.56 (m, 3H)3 7.41 (d, IH, J=7.87Hz), 7.31 (d, 2H, J=8.47Hz), 7.16 (t, IH, J=4.99Hz), 7.00 (d, 2H, J=8.49), 5.84(m, IH), 3.98 (m, IH), 3.05 (m, IH), 2.91 (m, IH), 2.64 (d, 2H, J=7.52Hz), 2.58 (m, IH), 2.07 (m, IH), 1.81, 1.80 (ss, 3H). 6.20 Example 5
Figure imgf000112_0001
1 5.1 5
[0441] (3S)-3-[4-(4-Bromo-indan-l-yloxy)-phenyl]-hex-4-ynoic acid
(5). This compound was prepared by a method analogous to that for 2. MS ESI (neg.) m/e: 399.1 (M-H). 1HNMR (DMSOd6) δ 12.23 (br, IH), 7.56 (d, IH, J=7.65Hz),,7.41 (d, IH, J=7.34Hz), 7.32 (d, 2H, J=8.41Hz), 7.07 (t, IH, J=7.63Hz), 7.00 (d, 2H, J=8.33Hz), 3.97 (m, IH), 5.92 (m, IH), 3.12 (m, IH), 2.88 (m, IH), 2.62 (m, 3H, CH2, CH), 2.06 (m, IH), 1.80 (s, 3H). 6.21 Example 6
Figure imgf000112_0002
5.1 6.2
Figure imgf000112_0003
[0442] (3S)-3-{4-[4-(4-Trifluoromethoxy-phenyl)-indan-l-yloxy]- phenyl}-hex-4-ynoic acid (6). Compound 6 was prepared by a method analogous to that for 1.5. MS ESI (neg.) m/e: 479.2 (M-H). 1HNMR (DMSO-d6) δ 12.21 (br, IH), 7.66 (d, 2H, J=8.40Hz), 7.31-7.48 (m, 7H), 7.03 (d, 2H, J=8.40Hz), 5.87 (m, IH), 3.97 (m, IH), 3.09 (m, IH), 2.95 (m, IH), 2.64 (m, 3H, CH2, CH), 2.01 (m, IH), 1.81 (s, 3H).
6.22 Example 7
Figure imgf000113_0001
5.1 7.1
Figure imgf000113_0002
[0443] (3S)-3-{4-[4-(4-Trifluoromethoxy-phenyl)-indan-l-yloxy]- phenyl}-hex-4-ynoic acid (7). Compound 7 was prepared by a method analogous to that for 1.5. MS ESI (neg.) m/e: 463.1 (M-H). 1HNMR (DMSOd6) δ 12.25 (br, IH), 7.84 (d, 2H, J=8.25Hz), 7.76 (d, 2H, J=8.16Hz), 7.41-7.49 (m, 3H), 7.32 (d, 2H, J=8.57Hz), 7.03 (d, 2H, J=8.59Hz), 5.89 (t, IH, J=4.99Hz), 3.98 (m, IH), 3.09 (m, IH), 2.96 (m, IH), 2.68 (d, 2H, J=7.60Hz), 2.60 (m, IH), 2.05 (m, IH), 1.81, 1.80, (ss, 3H). 6.23 Example 8
Figure imgf000114_0001
5.1 8.1
Figure imgf000114_0002
8
[0444] (3S)-3-{4-[4-(2-Butoxy-5-methyl-phenyl)-indan-l-yloxy]- phenyl}-hex-4-ynoic acid (8). Compound 8 was prepared by a method analogous to that for 1.5. MS ESI (neg.) M/E: 481.3 (M-H).
Figure imgf000114_0003
5.1 9.1
Figure imgf000114_0004
[0445] (3S)-3-{4-[4-(3-Ethoxy-phenyl)-indan-l-yloxy]-phenyl}-hex-4- ynoic acid (9). Compound 9 was prepared by a method analogous to that for 1.5. MS ESI (neg.) m/e: 439.1 (M-H). 6.25 Example 10
Figure imgf000115_0001
Ml 10.1
Figure imgf000115_0002
10
[0446] (3S)-3-[4-(4-Bromo-indan-l-yloxy)-phenyl]-hex-4-ynoic acid
(10). Compound 10 was prepared by a method analogous to that for 2. MS ESI (neg.) m/e: 399.1 (M-H). 1HNMR (DMSOd6) δ 12.25 (br, IH), 7.49-7.54 (m, 2H), 7.30 (m, 3H), 7.00 (d, 2H, J=8.60Hz), 5.82 (t, IH, J=5.84Hz), 3.96 (m, IH), 3.00 (m, IH), 2.86 (m, IH), 2.63 (d, 2H, J=7.56Hz), 2.57 (m, IH), 2.05 (m, IH), 1.81,1.80 (ss, 3H).
6.26 Example 11
Figure imgf000116_0001
10.1 11.1 11
[0447] (3S)-3-(4-(6-(4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-inden- l-yloxy)phenyl)hex-4-ynoic acid (11). Compound 11 was prepared by a procedure analogous to that described for 1.5. MS ESI (neg.) m/e: 463.1 (M-H). 1HNMR (DMSOd6) δ 12.21 (br, IH), 7.87 (d, 2H, J=8.18Hz), 7.80 (d, 2H, J=8.37Hz), 7.69-7.72 (m, 2H), 7.48 (d, IH, J=7.84Hz), 7.32 (d, 2H, J=8.65Hz), 7.03 (d, 2H, J=8.62Hz), 5.89 (m, IH), 3.99 (m, IH), 3.10 (m, IH), 2.96 (m, IH), 2.60-2.65 (m, 3H, CH2, CH), 2.09 (m, IH), 1.81, 1.80 (ss, 3H). 6.27 Example 12
Figure imgf000116_0002
10.1 12.1
Figure imgf000117_0001
12
[0448] (3S)-3-{4-[6-(2-Butoxy-5-methyl-phenyl)-indan-l-yloxy]- phenyl}-hex-4-ynoic acid (12). Compound 12 was prepared by a procedure analogous to that described for 1.5. MS ESI (neg.) m/e: 481.3 (M-H). 1HNMR (DMSOd6) δ 12.20 (br, IH), 7.50 (s, IH)5 7.41 (d, IH, J=7.60Hz), 7.33 (d, IH, J-ό.OOHz), 7.29 (d, 2H, J=6.80Hz), 7.08 (m, 2H), 6.98 (m, 3H), 5.83 (t, IH, J=5.20Hz), 3.96 (m, IH), 3.90 (t, 2H, J=5.20Hz), 3.40 (m, IH), 2.92 (m, IH), 2.61 (d, 2H, J=8.50Hz), 2.26(s, 3H), 2.05 (m, IH), 1.79, 1.78 (ss, 3H), 1.57 (m, 2H), 1.36 (m, 2H), 0.85 (t, 3H, J=5.60Hz). 6.28 Example 13
Figure imgf000117_0002
10.1 13.1 13
[0449] (3S)-3-{4-[6-(4-Trifluoromethoxy-phenyl)-indan-l-yloxy]- phenyI}-hex-4-ynoic acid (13). Compound 13 was prepared by a procedure analogous to that described for 1.5. MS ESI (neg.) m/e: 479.2 (M-H). 1HNMR (DMSO-d6) δ 12.21 (br, IH), 7.77 (m, 2H), 7.63 (s, IH), 7.45-7.56 (m, 4H), 7.32 (d, 2H, J=8.69Hz), 7.02 (d, 2H, J=8.69Hz), 5.88 (m, IH)5 3.98 (m, IH), 3.12 (m, IH), 2.94 (m, IH), 2.63 (d, 2H, J=7.69Hz), 2.57 (m, IH), 2.09 (m, IH), 1.81, 1.80 (ss, 3H).
6.29 Example 14
Figure imgf000118_0001
Ml 14.1 14
[0450] (3S)-3-(4-(5-Fluoro-2,3-dihydro-lH-inden-l-yloxy)phenyl)hex-
4-ynoic acid (14). To a mixture of compound 1 (100 mg, 0.46 mmol), 4- fluoroindan-1-ol (65 mg, 0.42 mmol), and tributylphosphine (0.17 mL, 0.84 mmol) in THF (3 mL) was added N,N,N',N'- tetramethylazodicarboxamide(TMAD) (0.15 g, 0.87 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saline, extracted with EtOAc, and chromatographed on a silica gel column to afford the ester. The ester was hydrolyzed to provide compound 14 using general procedure B (see Conversion of 1.4 to 1.5). MS ESI (neg.) m/e: 337.1 (M-H). 1HNMR (DMSO-d6) δ 12.25 (br, IH), 7.41 (m IH), 7.30 (d, 2H, J=8.40Hz), 7.17 (dd, IH, Jl=9.20Hz, J2=1.6Hz), 7.07 (td, IH, Jl=9.2Hz5 J2=2.40Hz), 6.98 (d, 2H, J=8.40Hz), 5.78 (m, IH), 3.99 (m, IH), 3.05 (m, IH), 2.88 (m, IH), 2.62 (d, 2H, J=7.60Hz), 2.55 (m, IH), 2.04 (m, IH), 1.81,1.80 (ss, 3H). 6.30 Example 15
Figure imgf000119_0001
(15). Compound 15 was prepared by a procedure analogous to that described for 14. MS ESI (neg.) m/e: 353.2 (M-H). 1HNMR (DMSO-d6) δ 12.25 (br, IH), 7.41 (m, 2H), 7.29 (m, 3H), 6.99 (d, 2H, J=8.63Hz), 5.81 (m, IH), 3.98 (m, IH), 3.02 (m, IH), 2.90 (m, IH), 2.55-2.64 (m, 3H), 2.06 (m, IH), 1.81, 1.80 (s, 3H). 6.31 Example 16
Figure imgf000119_0002
Ml 16.1 16
[0452] (3S) 3-[4-(4-Methyl-indan-l-yloxy)-phenyl]-hex-4-ynoic acid
(16). Compound 16 was prepared by a procedure analogous to that described for 14. MS ESI (neg.) m/e: 333.3 (M-H). 1HNMR (DMSOd6) δ 12.26 (br, IH), 7.30 (d, 2H, J=8.66Hz), 7.19-7.28 (m, IH), 7.12-7.15 (m, 2H), 6.98 (d, 2H, J=8.66Hz), 5.81 (m, IH), 3.97 (m, IH), 2.94 (m, IH), 2.82 (m, IH), 2.62 (d, 2H, J=7.61Hz), 2.56 (m, IH), 2.27 (s, 3H), 2.04 (m, IH), 1.81, 1.80(ss, 3H). 6.32 Example 17
Figure imgf000120_0001
[0453] (3S)-3-[4-(6-Methoxy-indan-l-yloxy)-phenyl]-hex-4-ynoic acid
(17). Compound 17 was prepared by a procedure analogous to that described for 14. MS ESI (neg.) m/e: 349.1 (M-H). 1HNMR (DMSOd6) δ 12.25 (br, IH), 7.29 (d, 2H, J=8.50Hz), 7.21 (d, IH, J=8.50Hz), 6.98 (d, 2H, J=9.00Hz), 6.88-6.91 (m, 2H), 5.76 (m, IH), 3.97 (m, IH), 3.72 (s, 3H), 2.95 (m, IH), 2.60 (d, 2H, J=7.50Hz), 2.79 (m, IH), 2.54 (m, IH), 2.01 (m, IH), 1.80, 1.79 (ss, 3H). 6.33 Example 18
Figure imgf000120_0002
Ml 18.1 18
[0454] (3S)-3-[4-(5-Methoxy-indan-l-yloxy)-phenyl]-hex-4-ynoic acid
(18). Compound 18 was prepared by a procedure analogous to that described for 14. MS ESI (neg.) m/e: 349.1 (M-H). 1HNMR (DMSOd6) δ 12.24 (br, IH), 7.25-7.30 (m, 3H), 6.96 (d, 2H, J=8.66Hz), 6.90(m, IH), 6.80 (dd, IH, Jl=2.40Hz, J2=8.34Hz), 5.75 (m, IH), 3.97 (m, IH), 3.76 (s, 3H), 3.00 (m, IH), 2.87 (m, IH), 2.59 (d, 2H, J=7.66Hz), 2.54 (m, IH), 2.04 (m, IH), 1.80 1.79 (ss, 3H). 6.34 Example 19
Figure imgf000121_0001
Ml 19.1 19
[0455] (3S)-3-[4-(4,5-Dimethoxy-indan-l-yloxy)-phenyl]-hex-4-ynoic acid (19). Compound 19 was prepared by a procedure analogous to that described for 14. MS ESI (neg.) m/e: 379.1 (M-H). 6.35 Example 20
Figure imgf000121_0002
Ml 20.1 20
[0456] (3S)-3-[4-(4,7-Dimethoxy-indan-l-yloxy)-phenyl]-hex-4-ynoic acid (20). Compound 20 was prepared by a procedure analogous to that described for 14. MS ESI (neg.) m/e: 379.1 (M-H). 1HNMR (DMSOd6) δ 12.26 (br, IH), 7.28 (d, 2H, J=8.44Hz), 6.91 (m, 3H), 6.80 (d, IH, J=8.68Hz), 5.80 (d, IH, J=5.98Hz), 3.96 (m, IH), 3.77 (s, 3H), 3.70 (s, 3H), 2.92 (m, IH), 2.79 (m, IH), 2.62 (d, 2H, J=7.40Hz), 2.37 (m, IH), 2.08 (m, IH), 1.79 (s, 3H). 6.36 Example 21
Figure imgf000122_0001
Ml 21.1 21
[0457] (3S)- 3-[4-(2-Methyl-indan-l-yloxy)-phenyl]-hex-4-ynoic acid
(21). Compound 21 was prepared by a procedure analogous to that described for 14. MS ESI (neg.) m/e: 333.3 (M-H). 1HNMR (DMSOd6) δ 12.27 (br, IH), 7.28-7.35 (m, 5H), 7.19-7.23 (m, IH), 7.04 (d, IH, J=8.61Hz), 7.00 (d, IH, J=8.59Hz), 5.73 (ss, 0.5H), 5.41 (ss, 0.5H), 3.98 (m, IH), 3.20 (m, 0.5H), 3.06 (m, 0.5H), 2.88 (m, 0.5H), 2.70 (m, 0.5H), 2.64 (d, 2H, J=4.93Hz), 1.80 (s, 3H), 1.16 (ss l.5H), 0.96(s, 1.5H).
6.37 Example 22
Figure imgf000122_0002
Ml 22.1 22
[0458] (3S)- 3-[4-(2-Methyl-indan-l-yloxy)-phenyl]-hex-4-ynoic acid
(22). Compound 22 was prepared by a procedure analogous to that described for 14. MS ESI (neg.) m/e: 344.2 (M-H). 1HNMR (DMSOd6) δ 12.25 (br, IH), 7.81 (s, IH), 7.70 (d, IH, J=8.00Hz), 7.56 (d, IH, J=8.00Hz), 7.03 (d, 2H, J=8.50Hz), 7.00 (d, 2H, J=8.50Hz), 5.89 (t, IH, J=5.50Hz), 3.96 (m, IH), 3.07 (m, IH), 2.95 (m, IH), 2.62 (d, 2H, J=4.50Hz), 2.04 (m IH), 1.79, 1.78 (ss, 3H). 6.38 Example 23
Figure imgf000123_0001
MlO 23.1 23
[0459] (+/-)-3-(4-(5-Chloro-2,3-dihydro-lH-inden-l-yloxy)phenyl)-3-
(5-methylthiophen-2-yl)propanoic acid (23). Compound 23 was prepared from compound MlO by a procedure analogous to that described for 14. MS ESI (neg.) m/e: 411.1 (M-H). 1HNMR (DMSOd6) δ 12.19 (br, IH), 7.37-7.40 (m, 2H), 7.27-7.29 (m, IH), 7.22 (d, 2H, J=8.50Hz), 6.95(d, 2H, J=8.50Hz), 6.71 (d, IH, J=3.0Hz), 6.59 (dd, IH, Jl=LOHz, J2=3.0Hz), 5.76-5.79 (m, IH), 4.49 (t, IH, J=7.50Hz), 2.96-3.06 (m, 2H), 2.86-2.91 (m, 2H), 2.54-2.59 (m, IH), 2.34 (s, 3H), 1.99-2.04 (m, IH).
6.39 Example 24
Figure imgf000123_0002
Ml 24.1
Figure imgf000123_0003
24
[0460] (3S)-3-[4-(l,2,3,4-Tetrahydro-naphthalen-l-yloxy)-phenyl]-hex-
4-ynoic acid (24). Compound 24 was prepared from compound Ml by a procedure analogous to that described for 14, except that LiOH was used for hydrolysis, instead of NaOH. MS ESI (neg.) m/e: 333 (M-H). 1HNMR (CDCl3) δ 7.4(m, 3H), 7.2 (m, 2H), 7.0 (d, 2H), 5.4 (s, IH), 4.05(br s, IH), 3.0-2.7 ( m, 4H), 2.2-2.0 (m, 3H), 1.85 (s, 3H), 1.8 (m, IH). 6.40 Example 25
Figure imgf000124_0001
Ml 25.1
Figure imgf000124_0002
25
[0461] (3S)-3-[4-(5-Bromo-l,2,3,4-tetrahydro-naphthalen-l-yloxy)- phenyl]-hex-4-ynoic acid (25). Compound 25 was prepared from compound Ml by a procedure analogous to that described for 14, except that LiOH was used for hydrolysis, instead of NaOH. MS ESI (neg.) m/e: 413 (M-H). 1HNMR (CDCl3) δ 7.55(m, IH), 7.35 (m, 3H), 7.1 (m, IH), 6.95(d, 2H), 5.35 (s, IH), 4.05( br s, IH), 3.0-2.8 ( m, 4H), 2.1-1.95 (m, 3H), 1.85 (br s, 4H). 6.41 Example 26
Figure imgf000124_0003
Figure imgf000125_0001
26
[0462] (3S)-3-[4-(l,2,3,4-Tetrahydro-naphthalen-2-yloxy)-phenyl]-hex-
4-ynoic acid (26). A solution of compound Ml (100 mg, 0.46 mmol), 1,2,3,4- tetrahydro-naphthalen-2-ol (102 mg, 0.69 mmol) in toluene (2 niL) was treated with a solution of cyanomethylenetributylphophorane (166 mg, 0.69 mmol) in toluene (2 mL). The reaction mixture was stirred at 7O0C for 18 hours. The reaction mixture was directly chromatographed on a silica gel column eluting with 5-25% EtOAc in hexane. The ester obtained (36 mg) was hydrolyzed to give 26 using general procedure B (See conversion of 1.4 to 1.5) above except that LiOH was used for hydrolysis instead of NaOH. MS ESI (neg.) m/e: 333 (M-H). 1HNMR (CDCl3) δ 7.25(d, 2H), 7.15 (m, 4H), 6.9(d, 2H), 4.7 (s, IH), 4.1(s, IH), 3.2 ( dd, IH)5 3.05(m, 2H), 2.9-2.7 (m, 3H), 2.2 (m, IH), 2.0(m, IH), 1.85 (s, 3H). 6.42 Example 27
Figure imgf000125_0002
Ml 27.1
Figure imgf000125_0003
27
[0463] (3S)-3-[4-(Indan-2-yloxy)-phenyl]-hex-4-ynoic acid (27). A pear shaped flask was charged with a stir bar, phenol Ml (150 mg, 0.65 mmol), triphenylphosphine (204 mg, 0.78 mmol), 2-indanol (104 mg, 0.78 mmol), and DCM (5 mL). To the resulting solution, DIAD (158 mg, 154 μL, 0.78 mmol) was added drop-wise via syringe. The resulting solution was stirred at room temperature overnight. The reaction was filtered through a Hirsch funnel to remove precipitates, and radially chromatographed (4:1 hexane: EtOAc) to yield ester 27.1. MS ESI (pos.) m/e: 335.2 (M+H).
[0464] To a solution of ester (79 mg, 0.23 mmol) in EtOH (2 mL), was added 2N NaOH (2 mL, 4.0 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo, and the resulting residue was partitioned between IN HCl and EtOAc. The solution was extracted one additional time with EtOAc. The combined organic layers were concentrated, and the resulting residue was radially chromatographed (3:2 hexane:ethylacetate+0.1% AcOH) to yield 27. MS ESI (pos.) m/e: 321.1 (M+H). 1HNMR (400 MHz) (CHCl3-J3) δ 7.31-7.19 (m, 6H); 6.86 (d, 2H, J=8 Hz); 4.15- 4.06 (m, 2H); 3.36 (m, 2H); 3.17 (d, 2H, J=I 6 Hz); 2.56 (m, 2H); 1.84 (s, 3H). 6.43 Example 28
Figure imgf000126_0001
(+/-)-Ml 28
[0465] (+/-)-Methyl 3-(4-(4-phenylcyclohexyIoxy)phenyl)hex-4-ynoate
(28). A pear-shaped flask (25 mL) was equipped with a magnetic stir bar, a nitrogen inlet and a nitrogen outlet. The compound (+A)-Ml (0.05 g, 0.229 mmol) was added to the flask and dissolved in 0.6 mL of anhydrous toluene. To this solution, 4-phenylcyclohexanol (0.061 g, 0.344 mmol) and triphenylphosphine (0.078 g, 0.298 mmol) were added. DIAD (0.07 g, 0.344 mmol) was added, and the reaction was allowed to stir at room temperature. When the reaction was complete, the solution was concentrated in vacuo and the residue was dissolved in a minimal amount of DCM. The solution was flash column chromatographed with 0 to 100% EtOAc/hexanes as the eluant. The fractions were combined and concentrated to afford 28 as a viscous oil. 6.44 Example 29
Figure imgf000127_0001
28 29
[0466] (R, S)-3-(4-(4-phenylcyclohexyloxy)phenyl)hex-4-ynoic acid
(29). Compound 28 (0.05 g, 0.133 mmol) was added to a 3-dram vial and dissolved in a minimal amount of anhydrous THF. An aqueous solution of lithium hydroxide (2 M, 0.3 mL) was added to the vial. MeOH was added dropwise until the layers were miscible. The vial was sealed and placed on a rotating wheel overnight (18 hours). When the reaction was complete, the solvent was concentrated under a flow of nitrogen until only water was left. The mixture was diluted by the addition of ~1 mL of water. Hydrochloric acid (3 N aqueous solution) was added dropwise until the pH reached 2. The aqueous solution was extracted with DCM, and the organic layer was dried and concentrated. HPLC of the residue afforded 29 as a white film. MS ESI (pos.) m/e: 363.2 (M+H). 1H NMR (400 MHz) (CDCl3) δ 7.35-7.22 (m, 7H); 6.93 (m, 2H); 4.62 (m, IH); 4.08 (m, IH); 2.84 (dd, J=15.6, 8.5 Hz, IH); 2.74 (dd, J=15.6, 6.6 Hz, IH); 2.66-2.58 (m, IH); 2.21-2.18 (m, 2H); 1.99-1.91 (m, 2H); 1.86 (d, J=2.41 Hz3 3H); 1.73-1.61 (m, 4H).
6.45 Example 30
Figure imgf000127_0002
M4 30
[0467] (+/-)-Methyl 3-(4-(4-phenylcyclohexyloxy)phenyl)-3-(thiophen-
2-yl)propanoate (30). Compound M4 (0.2 g, 0.76 mmol) was added to a 3-dram vial and dissolved in 0.25 niL of anhydrous THF. To this solution, A- phenylcyclohexanol (0.148 g, 0.84 mmol) and triphenylphosphine (0.22 g, 0.84 mmol) were added. The vial was sealed and submerged in a sonicator for 3 minutes to mix the solution. DIAD (0.17 g, 0.84 mmol) was added over 2 minutes. After the addition was complete, the vial was sealed and again partially submerged in the sonicator for 15 minutes. After sonication was complete, the solution was concentrated in vacuo, and the residue was dissolved in a minimal amount of DCM. The solution was loaded onto a 12 g REDISEP® column and flash chromatographed with 0 to 100% EtOAc/hexanes as the eluant. The fractions were combined and concentrated to afford 30 as a viscous oil. 6.46 Example 31
Figure imgf000128_0001
30 31
[0468] (+/-)-3-(4-(4-Phenylcyclohexyloxy)phenyl)-3-(thiophen-2- yl)propanoic acid (31). Compound 30 (0.048 g, 0.11 mmol) was added to a 1- dram vial and dissolved in a minimal amount of anhydrous THF. An aqueous solution of lithium hydroxide (2 M, 0.3 mL) was added to the vial. MeOH was added dropwise until the layers were miscible. The vial was sealed and placed on a rotating wheel overnight (18 hours). When the reaction was complete, the solvent was concentrated under a flow of nitrogen until only water was left. The mixture was diluted by the addition of ~1 mL of water. Hydrochloric acid (3 N aqueous solution) was added dropwise until the pH reached 2. The aqueous solution was extracted with DCM, and the organic layer was dried and concentrated. Flash column chromatography with 0 to 100% EtOAc/hexanes as the eluant and HPLC of the residue afforded 31 as a white film. MS ESI (pos.) m/e: 407.2 (M+H). 1HNMR (400 MHz) (CDCl3) δ 7.35-7.2 (m, 7H); 7.17 (dd, J=5.1, 1.0 Hz, IH); 6.93-6.73 (m, 4H); 4.72 (m, IH); 4.61 (m, IH); 3.16 (dd, J=15.9, 7.6 Hz, IH); 3.07 (dd, J=15.9, 7.9); 2.61 (m, IH); 2.19 (m, 2H); 2.02-1.95 (m, 2H); 1.73-1.61 (m, 4H); 0.91-0.69 (m, 2H).
6.47 Example 32
Figure imgf000129_0001
32
[0469] (+/-)-3-(4-(2,3-Dihydro-lJΪ-inden-2-yloxy)phenyl)3-(oxazol-2- yl)propanoic acid (32). Compound 32 was made by a procedure similar to that used for the synthesis of 30 and 31 using Mil and the appropriate alcohol. MS ESI (neg.) m/e: 348 (M-H). 1HNMR (500 MHz) (CD3OD) δ 7.84 (IH, d, J=0.5 Hz ); 7.24-7.26 (4H, m); 7.18 (2H, m); 7.14 (IH, m); 6.92 (2H, m); 5.23(1H, m); 4.64 (IH, m); 3.40 (2H, m); 3.31 (IH, m); 3.13 (IH, m); 3.09 (IH, m); 2.95-2.98 (IH, m).
6.48 Example 33
Figure imgf000129_0002
33
[0470] (+/-)-3-(4-(5-Chloro-2,3-dihydro-ljFT-inden-l-yloxy)phenyl)-3-
(oxazol-2-yl)propanoic acid (33). Compound 33 was made by a procedure similar to one used for the synthesis of compounds 30 and 31 using Mil and the appropriate alcohol. MS ESI (neg.) m/e: 382 (M-H). 1H NMR (500 MHz) (CD3OD) δ 7.85 (IH, s); 7.36 (2H5 m); ); 7.25 (3H, m); 7.14 (IH, s); 7.00 (2H, m); 5.80 (IH, m); 4.65 (IH, m); 3.32 (IH, m); 3.15 (IH, m); 2.54 (IH, m); 2.62 (IH, m); 2.17 (IH, m). 6.49 Example 34
Figure imgf000130_0001
34
[0471] (+/-)-3-(4-(5-Chloro-2,3-dihydro-lJfiT-inden-l-yloxy)phenyl)-3-
(5-methyloxazol-2-yl)propanoic acid (34). Compound 45 was made by a procedure similar to one used for the synthesis of 30 and 31 using M5 and the appropriate alcohol. MS ESI (neg.) m/e: 396 (M-H). 1H NMR (SOO MHZ) (DMSO-dό) δ 12.3 (IH, s); 7.42 (2H, d, J=8 Hz); 7.31 (IH, d, J=8.5 Hz); 7.21 (2H, d, J=8.5 Hz); 7.01 (2H, d, J=8.5 Hz); 6.76 (IH, m); 4.80 (IH, s); 4.45 (IH, m); 3.13 (IH, m); 2.90 (IH, m); 2.81 (IH, m); 2.60 (IH, m); 2.53 (3H, s). 6.50 Example 35
Figure imgf000130_0002
M6 35
[0472] (+/-)Ethyl 3-(3,5-difluorophenyl)-3-(4-(2,3-dihydro-lH-inden-2- yloxy)phenyl)propanoate (35). At room temperature, 3-(4-fluoro-phenyl)~3-(4- hydroxy-phenyl)-propionic acid ethyl ester M6 (0.2 mmol ) and 2-indanyl p- toluenesulphonate (0.3 mmol) were dissolved in 2 mL dry DMF, and Cs2CO3 (0.3 mmol) was added to the above solution. The mixture was diluted with 50 mL EtOAc after being stirred at room temperature for 3 days. The mixture was washed with water twice (30 mL x 2) and dried over Na2SO4. The solid was filtered, solvent was evaporated, and the residue oil was cliromatographed on a silica gel column. (+/-)3-(4-Fluoro-phenyl)-3-[4-(indan-2-yloxy)-phenyl]- propionic acid ethyl ester 35 was obtained as colorless oil. MS ESI (pos.) m/e: 405 (M+H). 6.51 Example 36
Figure imgf000131_0001
35 36
[0473] (+/-)3-(3,5-Difluorophenyl)-3-(4-(2,3-dihydro-lH-inden-2- yloxy)phenyl) propanoic acid (36). (+/-)3-(3,5-Difluoro-phenyl)-3-[4-(indan-2- yloxy)-phenyl] -propionic acid ethyl ester 35 (25 mg) was dissolved in 3 mL THF- EtOH-H2O (1/1/1), and LiOH (20 mg) was added. The mixture was stirred at room temperature for 6 hours. IN HCl was added to acidify the mixture to pH 2- 3. The mixture was extracted with EtOAc (2 x 20 mL). The organic solution was washed with water and brine, dried over Na2SO4, concentrated, and flash chromatographed (0-60% EtOAc in hexane). (+/-)-3-(3,5-Difluorophenyl)-3-(4- (2,3-dihydro-lH-inden-2-yloxy)phenyl) propanoic acid 36 was obtained as a colorless oil. MS ESI (neg.) m/e: 393 (M-H). 1H NMR (500 MHz) (CDCl3) δ 7.25-7.31 (m, 2H); 7.20-7.22 (m, 2H); 7.14 (d, J = 8.4 Hz, 2H); 6.87 (d, J=8.4 Hz, 2H); 6.78 (d, J = 6.5 Hz, 2H); 6.67 (t, J = 8.9 Hz, IH); 5.16 (m, IH); 4.47 (t, J = 7.8 Hz, IH); 3.38 (dd, J = 16.7, 6.3 Hz, 2H); 3.19 (dd, J=16.7, 2.6 Hz, 2H); 3.06 (d, J = 7.9 Hz, 2H).
6.52 Example 37
Figure imgf000131_0002
37
[0474] (+/-)3-(2,5-Difluorophenyl)-3-(4-(2,3-dihydro-lH-inden-2- yloxy)phenyl) propanoic acid (37). Compound 37 was prepared by a procedure analogous to that described for 36 using M8. MS ESI (neg.) m/e: 393 (M-H). 1H NMR (500 MHz) (CDCl3) δ 7.20-7.30 (m, 6H); 6.86-7.01 (m, 5H); 5.15 (m, IH); 4.76 (t, J = 7.8 Hz, IH); 3.37 (dd, J = 16.7, 6.3 Hz, 2H); 3.18 (dd, J=16.7, 2.5 Hz, 2H); 3.09 (d, J = 7.9 Hz, 2H).
6.53 Example 38
Figure imgf000132_0001
38
[0475] (+/-)3-(2,4-Difluorophenyl)-3-(4-(2,3-dihydro-lH-inden-2- yloxy)phenyl) propanoic acid (38). Compound 38 was prepared by a procedure analogous to that described for 36 using M7. MS ESI (neg.) m/e: 393 (M-H). 1H NMR (500 MHz) (CDCl3) δ 7.16-7.29 (m, 7H); 6.77-6.86 (m, 4H); 5.15 (m, IH); 4.74 (t, J = 8.0 Hz, IH); 3.37 (dd, J = 16.7, 6.3 Hz, 2H); 3.18 (dd, J=16.7, 2.7 Hz, 2H); 3.09 (d, J = 8.0 Hz, 2H). 6.54 Example 39
Figure imgf000132_0002
39
[0476] (+/-)3-(2,6-Difluorophenyl)-3-(4-(2,3-dihydro-lH-inden-2- yloxy)phenyl) propanoic acid (39). Compound 39 was prepared by a procedure analogous to that described for 36 using M9. MS ESI (neg.) m/e: 393 (M-H). 1H NMR (500 MHz) (CDCl3) δ 7.01-7.30 (m, 7H); 6.84-6.89 (m, 4H); 5.14 (m, IH); 4.92 (t, J = 8.0 Hz, IH); 3.36 (dd, J = 16.7, 6.3 Hz, 2H); 3.29 (dd, J = 7.6, 5.5 Hz, 2H); 3.17 (dd, J=I 6.7, 2.6 Hz, 2H). 6.55 Example 40
Figure imgf000133_0001
40
[0477] (+/-)3-(4-Fluorophenyl)-3-(4-(2,3-dihydro-lH-inden-2- yloxy)phenyl) propanoic acid (40). Compound 40 was prepared by a procedure analogous to that described for 36. MS ESI (neg.) m/e: 375 (M-H). 1H NMR (500 MHz) (CDCl3) δ 7.02-7.27 (m, 6H); 7.14 (d, J = 8.5 Hz, 2H); 7.00 (t, J = 8.6 Hz, 2H); 6.85 (d, J = 8.6 Hz, 2H); 5.15 (m, IH); 4.49 (t, J = 7.9 Hz, IH); 3.37 (dd, J = 16.7, 6.3 Hz, 2H); 3.19 (dd, J=16.7, 2.7 Hz, 2H); 3.06 (d, J = 7.7 Hz, 2H). 6.56 Example 41
Figure imgf000133_0002
M3 41.1 41
[0478] (+/-)-3-[4-(5-Bromo-indan-l-yloxy)-phenyl]-3-phenyl-propionic acid (41). Compound 41 was prepared by a procedure analogous to that described for 1.3 using M3. MS ESI (neg.) m/e: 437.0 (M-H). 1HNMR (DMSOd6) δ 12.10 (br, IH), 7.54 (s, IH), 7.43-7.41 (dd, IH, Jl=1.72Hz, J2=8.07Hz), 7.34-7.16 (m, 8H), 6.94 (d, 2H, J=8.69Hz), 5.76-5.73 (m, IH), 4.39 (t, IH, J=8.03Hz), 3.07-3.03 (m, IH), 3.00 (d, 2H, J=7.96Hz), 2.91-2.84 (m, IH), 2.57-2.55 (m, IH), 2.04-1.97 (m, IH). 6.57 Example 42
Figure imgf000134_0001
2 42.1 42 [0479] (+/-)-3-[4-(5-Bromo-indan-l-yloxy)-phenyl]-3-(4-fluoro- phenyl)-propionic acid (42). Compound 42 was prepared by a procedure analogous to that described for 1.3 using M2. MS ESI (neg.) m/e: 455.0 (M-H). 1HNMR (DMSOd6) δ 12.09 (br, IH), 7.53 (s, IH), 7.42-7.40 (m, IH), 7.36-7.29 (m, 3H), 7.24 (d, 2H, J=8.50Hz), 7.11 (t, 2H, J=9.00Hz), 6.93 (d, 2H, J=8.50Hz), 5.74-5.73 (m, IH), 4.39 (t, IH, J=8.00Hz), 3.05-3.02 (m, IH), 2.99 (d, 2H, J=8.00Hz), 2.91-2.84 (m, IH), (IH overlaps with DMSO), 2.01-1.91 (m, IH). 6.58 Examples 43-45
Figure imgf000134_0002
43 44 45
[0480] (S)-3-(4-((S)-5-Bromo-2,3-dihydro-lH-inden-l- yloxy)phenyl)hex-4-ynoic acid (44) and (S)-3-(4-((S)-5-bromo-2,3-dihydro-lH- inden-l-yloxy)phenyl)hex-4-ynoic acid (45). Racemic compound 43 was obtained as described in Example 2. Racemic 43 was separated on a preparatory chiral HPLC with CHIRALPAK AD-H column, using 50% i-PrOH in hexane as eluant. Eluant containing the peak with greater retention time was concentrated and assigned as 44 arbitrarily. MS ESI (neg.) M/E: 397.0, 399.1 (M-H). 1HNMR (CDCl3) δ 7.47 (s, IH), 7.39-7.32 (m, 3H), 7.29(m, IH), 6.95 (d, 2H, J=8.50Hz), 5.69 (t, IH, J=4.50Hz), 4.09 (m, IH), 3.13 (m, IH), 2.94 (m, IH), 2.87 (m, IH), 2.76 (m, IH), 2.59 (m, IH), 2.23 (m, IH), 1.87, 1.86 (ss, 3H). The peak with shorter retention time was concentrated and assigned as 46. M/E: 397.0, 399.1 (M-H). 1HNMR (CDCl3) δ 7.48 (s, IH), 7.39-7.33 (m, 3H), 7.3 l(m, IH), 6.96 (d, 2H, J=9.00Hz), 5.69 (m, IH), 4.09 (m, IH), 3.13 (m, IH)3 2.94 (m, IH), 2.87 (m, IH)5 2.76 (m, IH), 2.59 (m, IH), 2.23 (m, IH), 1.87, 1.86 (ss, 3H). 6.59 Example 46
Figure imgf000135_0001
Ml 46.1 46
[0481] (3S)-3-(4-(2,3-Dihydro-lH-inden-l-yloxy)phenyl)hex-4-ynoic acid (46). Compound 46 was prepared by a procedure analogous to that described for 14. MS ESI (neg.) m/e: 319.1 (M-H).
6.60 Example 47 H
Figure imgf000135_0002
47.1 47.2
[0482] 5-Bromo-2,3-dihydro-lH-inden-l-ol (47.2). A mixture of 5- bromo-2,3-dihydroinden-l-one (47.1) (23.7 mmol) and NaBH4 (47.4 mmol) in EtOH (50 mL) was stirred at 6O0C for 6 minutes. After evaporation of the solvent, the residue was purified by chromatography (silica gel; 1 :2 EtOAc/hexane) providing compound 47.2 in 100% yield. MS ESI (pos.) M/E: 195.0, 197.1 (MH-H-H2O).
Figure imgf000135_0003
47.2 47.3
[0483] 5-Bromo-l-chloro-2,3-dihydro-lH-indene (47.3). A mixture of
47.2 (11.1 mmol) and thionyl chloride (44 mmol) in DCM (20 mL) was stirred at room temperature overnight. After evaporation of solvent, 47.3 was obtained and it was used without further purification.
Figure imgf000136_0001
47.3 47.4 47.5
[0484] Methyl 3-(4-(5-bromo-2,3-dihydro-lH-inden-l-yloxy)phenyl)-3-
(lH-pyrazol-l~yI)propanoate (47.5). A mixture of 47.3 (0.16 mmol) and methyl 3-(4-hydroxyphenyl)-3-(lH-pyrazol-l-yl)propanoate 47.4 (obtained by the procedure of Example 58 set forth in US 2006/0004012 which is hereby incorporated by reference) (0.11 mmol) was stirred at 40 0C for 1 hour. After work up and chromatography, 47.5 was obtained in 30% yield. MS ESI (pos.) M/E: 441, 443 (M+H).
Figure imgf000136_0002
47.5 47
[0485] 3-(4-(5-Bromo-2,3-dihydro-lH-inden-l-yloxy)phenyl)-3-(lH- pyrazol-l-yl)propanoic acid (47). Hydrolysis of 47.5 yielded 47 by the procedure of Example 18 set forth in US 2006/0004012 which is hereby incorporated by reference). MS ESI (neg.) M/E: 425, 427 (M-H). 1HNMR (DMSO-d6) δ 7.85 (s, IH), 7.56 (s, IH), 7.43 (m, 2H), 7.24-7.34 (m, 3H), 6.98 (d, 2H, J=9Hz), 6.23 (s, IH)5 5.80 (m, 2H), 3.07 (m, IH), 2.92 (m, IH). 6.61 Example 48
Figure imgf000136_0003
M4 48.1
Figure imgf000137_0001
48.1 48
[0486] (+/-)-3-(4-(2,3-Dihydro-lH-inden-2-yloxy)phenyl)-3-(thiophen-
2-yl)propanoic acid (48.1). A flask was charged with a stir bar, phenol M4 (168 mg, 0.64 mmol), tributylphosphine (0.24 mL, 0.96 mmol), 2-indanol (111 mg, 0.83 mmol), and benzene (5 mL). To the resulting solution, TMAD (165 mg, 0.96 mmol) was added drop- wise via syringe. The resulting solution was stirred at room temperature overnight. The reaction was concentrated and purified via silica chromatography (4:1 hexane:EtOAc) to provide ester 48.1 (70 mg). MS ESI (pos.) m/e: 379 (M+H).
[0487] To a solution of ester 48.1 (70 mg, 0.23 mmol) in THF/MeOH
(2/0.7 mL) was added 2 N LiOH (0.5 mL, 1 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting residue was partitioned between IN HCl and EtOAc. The solution was extracted one additional time with EtOAc. The combined organic layers were concentrated, and the resulting residue was purified via reverse phase HPLC chromatography (ACN: Water+0.1% TFA) to provide 48 (40 mg). MS ESI (pos.) m/e: 365 (M+H).
6.62 Example 49
Figure imgf000137_0002
M4 49.1
Figure imgf000138_0001
49.1 49
[0488] (+/-)3-(4-(6,7,8,9-Tetrahy dro-5H-benzo [7] annulen-5- yloxy)phenyl)-3-(thiophen-2-yl)propanoic acid (49). A flask was charged with a stir bar, phenol M4 (107 mg, 0.41 mmol), tributylphosphine (0.15 niL, 0.61 mmol), 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol (86 mg, 0.53 mmol), and benzene (5 mL). To the resulting solution, TMAD (105 mg, 0.61 mmol) was added drop-wise via syringe. The resulting solution was stirred at room temperature overnight. The reaction was concentrated and purified via silica chromatography (4:1 hexane: ethyl acetate) providing ester 49.1 (101 mg). MS ESI (pos.) m/e: 407 (M+H). To a solution of ester 49.1 (70 mg, 0.23 mmol) in THF/MeOH (2/0.7 mL) was added 2 N LiOH (0.5 mL, 1 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting residue was partitioned between 1 N HCl and EtOAc. The solution was extracted one additional time with EtOAc. The combined organic layers were concentrated, and the resulting residue was purified via reverse phase HPLC chromatography (ACN:Water+0.1% TFA) providing 49 (60 mg). MS ESI (pos.) m/e: 393 (M+H).
6.63 Example 50
Figure imgf000138_0002
1.3 50.1
Figure imgf000139_0001
50
[0489] (3S)-3-(4-(5-(3-(Trifluoromethoxy)phenyl)-2,3-dihydro-lH- inden-l-yloxy)phenyl)hex-4-ynoic acid (50) Compound 50 was prepared by a procedure analogous to that described for 3 using the boronic acid shown. MS ESI (neg.) m/e: 479.2 (M-H). 1HNMR (DMSOd6) δ 12.21 (br, IH), 7.80 (d, 2H, J=8.83Hz), 7.63 (s, IH), 7.56-7.46 (m, 4H), 7.32 (d, 2H, J=8.69Hz), 7.03 (d, 2H, J=8.69Hz), 5.88 (m, IH), 3.96 (m, IH), 3.08 (m, IH), 2.96 (m, IH), 2.62 (m, 3H), 2.10 (m, IH), 1.81, 1.80 (ss, 3H). 6.64 Example 51
Figure imgf000139_0002
M5 51.1
[0490] Ethyl 3-(4-(2,3-dihydro-lH-inden-2-yloxy)phenyl)-3-(5- methyloxazol-2-yl)propanoate (51.1). A mixture of M5 (obtained by the procedure of Example 60 set forth in US 2006/0004012 which is hereby incorporated by reference) (0.25 mmol), 2,3-dihydro-lH-inden-2-yl 4- methylbenzenesulfonate (0.38 mmol) and Cs2CO3 (0.5 mmol) in DMF (3 mL) was stirred at 130 0C for 4 hours. After work up and chromatography (silica gel; 1 :2 EtOAc / hexane), compound 51.1 was obtained in 26% yield. MS ESI (pos.) M/E: 392 (M+H).
Figure imgf000140_0001
51.1 51
[0491] 3-(4-(2,3-Dihydro-lH-inden-2-yloxy)phenyl)-3-(5- methyloxazol-2-yl)propanoic acid (51). Hydrolysis of 51.1 yielded 51 using the procedure of Example 18 set forth in US 2006/0004012 which is hereby incorporated by reference. MS ESI (neg.) M/E: 362 (M-H). 1HNMR (DMSOd6) δ 7.25 (m, 2H), 7.16 (m, 4H), 6.89 (m, 2H), 6.73 (s, IH), 5.20 (m, IH), 4.43 (m, IH), 3.07 (m, IH), 2.75 (m, IH), 2.22 (s, 3H). 6.65 Examples 52 and 53
Figure imgf000140_0002
52.1 52.2 52.3
[0492] 6-(4-Methoxy-benzyloxy)-3,4-dihydro-2H-naphthalen-l-one
(52.3). 6-Hydroxy-l-tetr alone (52.1)(3.24 g, 20 mmol) and 4-methoxybenzyl chloride (52.2) (3.13 g, 20 mmol) were dissolved in DMF (20 mL). Cs2CO3 (7.17 g, 22mmol) was added to the mixture, and the resulting mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was used without further purification for the next step. MS ESI (pos.) m/e: 283 (M+l)+.
Figure imgf000141_0001
52.3 52.4
[0493] [6-(4-Methoxy-benzyloxy)-3,4-dihydro-2H-naphthalen-(lE)- ylidene] -acetic acid (52.4). A solution of ethyl (trimethylsilyl)acetate (12.07 g, 75 mmol) in anhydrous THF (60 niL) at -780C was treated dropwise with LiHMDS (IM in THF, 66 niL). The resulting mixture was stirred at -78°C for 30 minutes. A solution of 52.3 (14.0 g, 50 mmol) in THF (10 mL) was added to the mixture over 20 minutes. The resulting mixture was stirred at -780C for 2 hours before warming to 0 0C. The reaction mixture was quenched with NH4Cl (sat. 200 mL) and extracted with ethyl acetate (70 mL x 4). The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30% ethyl acetate in Hexane). [6-(4-Methoxy- benzyloxy)-3,4-dihydro-2H-naphthalen-(lE)-ylidene] -acetic acid (52.4) was obtained as a light yellow oil (12.2 g, 69% yield). MS ESI (pos.) m/e: 353 (M+l)+.
Figure imgf000141_0002
52.4 52.5
[0494] (R/SHθ-Hydroxy-l^Λ^tetrahydro-naphthalen-l-yty-acetic acid ethyl ester (52.5). Compound 52.4 (6.2, 17.6 mmol) was dissolved in MeOH (3O mL). Pd/C (10%, 620 mg) was added to the solution carefully. A H2 balloon was connected to the reaction flask. The resulting mixture was stirred overnight at ambient temperature. The Pd/C was filtered away, and the filtrate was concentrated under reduced pressure. (R/S)-(6-Hydroxy- 1,2,3 ,4-tetrahydro- naphthalen-l-yl)-acetic acid ethyl ester (52.5) was obtained as a clear oil (3.75 g, 91%). MS ESI (pos.) m/e: 235 (M+l)+ and 257 (M+Na)+. 1H NMR (400MHz) (CDCl3) δ 7.02 (d, IH); 6.64 (d, IH); 6.56 (s, IH); 5.04 (d, IH); 4.20 (q, 2H); 3.31 (m, IH); 2.73 (m, 2H); 2.54 (m, 2H); 1.71 (m, 4H); 1.29 (t, 3H).
Figure imgf000142_0001
52.5 52
[0495] (RIS) Ethyl 2-(6-(2,3-dihydro-lH-inden-2-yloxy)-l,2,3,4- tetrahydronaphthalen-l-yl)acetate (52). Tributyl phosphine (137 mg, 0.68 mmol) and TMAD (122 mg, 0.68 mmol) were added successively to a dry benzene (10 rnL) solution of 2-indanol (92 mg, 0.68 mmol) and ethyl 2-(6- hydroxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetate 52.5 (160 mg, 0.68 mmol) with stirring under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 days. The product was isolated by silica gel column chromatography after filtration and evaporation of the solvent in vacuo. (RIS)- Ethyl 2-(6-(2,3 -dihydro- 1 H-inden-2-yloxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)acetate (52) was obtained as a colorless oil (85 mg, 35%). LC-MS ESI (pos.) m/e: 351 (M+H).
Figure imgf000142_0002
[0496] (R/S)-2-(6-(2,3-Dihydro-lH-inden-2-yloxy)-l,2,3,4- tetrahydronaphthalen-l-yl)acetic acid (53). A mixture of (R/S)-ethyl 2-(6-(2,3- dihydro-lH-inden-2-yloxy)-l,2,3,4-tetrahydronaphthalen-l-yl)acetate 52 (85 mg, 0.24 mmol) and LiOH (40 mg) in THF- H2O (1 / 1, 4 mL) was stirred at room temperature for 6 hours. 2N HC1 was added to acidify the mixture to pH 2-3. The mixture was then extracted with EtOAc (2X 20 mL). The combined organic layers were washed with water and brine, and dried over Na2SO4. The residue obtained after filtration and concentration was purified with flash chromatography (0-60% EtOAc in hexane). (R/S)-2-(6-(2,3-Dihydro-lH-inden-2-yloxy)-l,2,3,4- tetrahydronaphthalen-l-yl)acetic acid (53) was obtained as colorless oil (79 mg, 96%). MS ESI (neg.) m/e: 321 (M-H). 1H NMR (500 MHz) (CDCl3) δ 7.11-7.28 (m, 5H); 6.65-6.75 (m, 2H); 5.16 (m, IH); 3.36-3.40 (m, 3H); 3.19 (dd, J = 16.6, 3.0 Hz, 2H); 2.62-2.80 (m, 3H), 2.59 (q, J = 9.9 Hz, IH), 1.99 (m, IH)5 1.78-1.87 (m, 3H).
Figure imgf000143_0001
Ml 54.1 54
[0497] (3S)-3-(4-(5-Cyano-2,3-dihydro-lH-inden-l-yloxy)phenyl)hex-
4-ynoic acid (54). Compound 54 was prepared by a procedure analogous to that described for 14. MS: 344.2 (M-I). 1HNMR (DMSO-d6) ppm 12.25 (br, IH), 7.81 (s, IH), 7.70 (d, IH, J=8.00Hz), 7.56 (d, IH, J=8.00Hz), 7.30 (d, 2H, J=8.50Hz), 7.00 (d, 2H, J=8.50Hz), 5.89 (t, IH, J=5.50Hz), 3.96 (m, IH), 3.07 (m, IH)5 2.95 (m, IH), 2.62 (m, 3H), 2.04 (m IH), 1.78, 1.79(ss, 3H). 6.67 Example 55
Figure imgf000143_0002
Ml 55
[0498] (3S)-3-(4-(5-(2-FIuoro-5-methoxyphenyl)-2,3-dihydro-lH- inden-l-yloxy)phenyl)hex-4-ynoic acid (55). Compound 55 was made from Ml by a sequence analogous to that used for Example 59 with the appropriate boronic acid.
6.68 Example 56
Figure imgf000144_0001
M15.3 56
[0499] (S)-3-{4-[5-(2-Fluoro-5-methoxy-phenyl)-indan-l-yloxy]- phenyI}-5-methyl-hex-4-enoic acid ethyl ester (56). Compound 56 was made from M15.3 by a sequence analogous to that used for Example 59 with the appropriate boronic acid.
6.69 Example 57
Figure imgf000144_0002
M15.4 57
[0500] (R)-3-{4-[5-(2-Fluoro-5-methoxy-phenyl)-indan-l-yloxy]- phenyl}-5-methyl-hex-4-enoic acid ethyl ester (57). Compound 57 was made from M15.4 by a sequence analogous to that used for Example 59 with the appropriate boronic acid.
6.70 Example 58
Figure imgf000144_0003
M12 58.1 58
[0501] (3S)-3-(4-(5-Chloro-2,3-dihydro-lH-inden-l-yloxy)phenyl)-3-
(l-methyl-lH-imidazol-2-yl)propanoic acid (58) To a mixture of compound M12 (150 mg, 0.54 mmol), 5-chloroindan-l-ol (180 mg, 1.07 mmol), and tributylphosphine (0.40 mL, 1.62 mmol) in THF (5 mL) was added N5N5N ',N'- tetramethylazodicarboxamide(TMAD) (0.27 g, 1.56 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saline, extracted with EtOAc5 and chromatographed on a silica gel column to afford the ester 58.1. The ester was hydrolyzed to compound 58 by the general procedure B (Example 1). MS ESI (pos.) m/e: 397.1 (M+H). 1HNMR (MeOH- d4) δ 7.29 (d, IH5 J=5.0Hz)5 7.28 (br5 IH), 7.19-7.16 (m, 3H)5 7.12 (m, 2H)5 6.96 (d, 2H5 J=10.0Hz)5 5.71 (m, IH), 4.69 (m, IH), 3.61 (s, 3H)5 3.30 (m, IH)5 3.03 (m, IH)5 2.98 (m, IH)5 2.88 (m, IH)5 2.54 (m, IH)5 2.09 (m, IH). 6.71 Example 59
Figure imgf000145_0001
59.1 59.2
Figure imgf000145_0002
59.3 59
[0502] (3R)-Methyl 3-(4-(5-bromo-2,3-dihydro-lH-inden-l- yloxy)phenyl)hex-4-ynoate (59.2) Compound 59.2 was prepared from compound 59.1 by following the same procedure for Ml of Method 1 except obtaining the different enantiomer. MS ESI (neg.) M/E: 411.0 (M-H).
6.71.1 General procedure C: Suzuki coupling
[0503] (3R)-Methyl 3-(4-(5-(3-ethoxyphenyl)-2,3-dihydro-lH-inden-l- yloxy)phenyl)hex-4-ynoate (59.3). A mixture of 59.2 (30 mg5 0.073 mmol), 3-ethoxyphenylboronic acid (14.5 mg, 0.087 mmol) and CsF (55 mg, 0.36 mmol) in 1,2-dimethoxyethane (2 niL) was degassed with N2 for 3 minutes. Pd(PPh3)4 (20 mg, 0.017 mmol) was added, and the resulting mixture was heated to 95 0C for 8 hours. After cooling, the reaction mixture was quenched with water and extracted with EtOAc to obtain the ester 59.3, which was directly hydrolyzed in next step.
6.71.2 General procedure D: Alkaline hydrolysis
[0504] (3R)-3-(4-(5-(3-Ethoxyphenyl)-2,3-dihydro-lH-inden-l- yIoxy)phenyl)hex-4-ynoic acid (59). A solution of 59.3 in THF/MeOH (1 :1, 2 mL), was treated with 2N NaOH aqueous solution (1 mL) and stirred for overnight at room temperature. The reaction mixture was acidified with aqueous 4N HCl and extracted with EtOAc to obtain 59, which was purified by preparative HPLC, eluting with 5-95% ACN in water containing 0.1% TFA. MS ESI (neg.) m/e: 439.1 (M-H). 1HNMR (MeOD-d4) δ 7.65 (br, IH), 7.48 (s, IH), 7.38 (d, IH, J=7.02Hz), 7.32 (t, IH, J=7.12Hz), 7.18 (d, IH, J=6.57Hz), 7.14 (s, IH), 7.06 (m, 2H), 6.99-6.86 (m, 2H), 6.78 (m, IH), 4.79 (m, IH), 4.12(q, 2H, J=6.50Hz), 3.86 (m, IH), 3.15-3.01 (m, 2H), 2.54-2.42 (m, 2H), 2.03 (m, IH), 1.74 (ss, 3H), 1.42 (t, 3H, J=6.74Hz).
Figure imgf000146_0001
59.2 60.1
Figure imgf000146_0002
60
[0505] (3R)-3-(4-(5-(Benzo[d][l,3]dioxol-5-yl)-2,3-dihydro-lH-inden- l-yloxy)phenyl)hex-4-ynoic acid (60) Compound 60 was prepared by a procedure analogous to that described for Example 59 using the boronic acid shown MS ESI (neg.) m/e: 439.1 (M-H). 1HNMR (MeOD-d4) δ 7.66 (m, IH), 7.46 (br, IH), 7.32 (d, IH, J=6.02Hz), 7.16-7.01 (m, 4H), 6.92-6.89 (m, 2H), 6.78 (d, IH, J=6.96Hz), 5.98 (s, 2H), 4.75 (m, IH), 3.85 (m, IH), 3.06-2.97 (m, 2H), 2.72-2.54 (m, 3H), 2.19 (m, IH), 1.74 (ss, 3H). 6.73 Example 61
Figure imgf000147_0001
59.2 61.1
Figure imgf000147_0002
61
[0506] (3R)-3-(4-(5-(2,3-Dimethoxyphenyl)-2,3-dihydro-lH-inden-l- yloxy)phenyl)hex-4-ynoic acid (61) Compound 61 was prepared by a procedure analogous to that described for Example 59 using the boronic acid shown. MS ESI (neg.) m/e: 455.2 (M-H). 1HNMR (MeOD-d4) δ 7.64 (m, IH), 7.56 (m, IH), 7.42 (s, IH), 7.27 (m, IH), 7.10 (m, IH), 7.03-6.94 (m, 4H), 6.79 (dd, IH, Jl=8.21Hz, J2=2.54Hz), 4.75 (m5 IH), 3.90 (s, 3H), 3.86 (m, IH), 3.59 (s, 3H), 3.06-2.97 (m, 2H), 2.61-2.52 (m, 3H), 2.02 (m, IH), 1.75 (ss, 3H). 6.74 Example 62
Figure imgf000147_0003
59.2 62.1
Figure imgf000148_0001
62
[0507] (3R)-3-(4-(5-(3-Methoxyphenyl)-2,3-dihydro-lH-inden-l- yloxy)phenyl)hex-4-ynoic acid (62) Compound 62 was prepared by a procedure analogous to that described for 59 using the boronic acid shown. MS ESI (neg.) m/e: 425.2 (M-H). 1HNMR (MeOD-d4) δ 7.59 (s, IH), 7.40-7.31 (m, 2H), 7.21- 7.15 (m, 2H), 7.06 (m, 2H), 6.94-6.88 (m, 2H), 6.77 (d, IH, J=5.52Hz), 6.65 (m, IH), 4.78 (m, IH), 3.86 (s, 3H), 3.78 (m, IH), 3.09-2.97 (m, 2H), 2.63-2.53 (m, 3H), 2.04 (m, IH)5 1.74 (ss, 3H). 6.75 Example 63
Figure imgf000148_0002
59.2 63.1
Figure imgf000148_0003
63
[0508] (3R)-3-(4-(5-(3-(trifluoromethoxy)phenyl)-2,3-dihydro-lH- inden-l-yloxy)phenyl)hex-4-ynoic acid (63) Compound 63 was prepared by a procedure analogous to that described for 59 using the boronic acid shown. MS ESI (neg.) m/e: 479.1 (M-H). 1HNMR (MeOD-(I4) δ 7.64 (d, IH, J=7.69Hz), 7.54-7.50 (m, 3H), 7.41 (d, IH, J=7.82Hz), 7.23 (d, IH, J=8.19Hz), 7.11-7.05 (m, 2H), 6.93 (m, IH), 6.78 (dd, IH, J=8.25Hz, J2=2.48Hz), 4.78 (m, IH), 3.86 (m, IH), 3.15-2.99 (m, 2H), 2.63-2.51 (m, 3H)5 2.06 (m, IH), 1.74 (ss, 3H). 6.76 Example 64
Figure imgf000149_0001
59.2 64.1
Figure imgf000149_0002
64
[0509] (3R)-3-(4-(5-Mesityl-2,3-dihydro-lH-inden-l-yloxy)phenyl)hex-
4-ynoic acid (64) Compound 64 was prepared by a procedure analogous to that described for 59 using the boronic acid shown. MS ESI (neg.) m/e: 437.2 (M-H). 1HNMR (MeOD-d4) δ 7.07-7.02 (m, 3H), 6.96 (s, IH), 6.90-6.84 (m, 4H), 6.78 (m, IH), 4.78 (m, IH), 3.87 (m, IH), 3.03-2.96 (m, 2H), 2.59-2.53 (m, 3H), 2.30 (s, 3H), 2.03(br, 6H), 2.00 (br, IH), 1.74 (ss, 3H).
6.77 Example 65
Figure imgf000150_0001
59.2 65.1
Figure imgf000150_0002
65
[0510] (3R)-3-(4-(5-(2-Ethoxyphenyl)-2,3-dihydro-lH-inden-l- yloxy)phenyl)hex-4-ynoic acid (65) Compound 65 was prepared by a procedure analogous to that described for 59 using the boronic acid shown. MS ESI (neg.) m/e: 439.1 (M-H). 1HNMR (MeOD-d4) δ 7.71-7.54 (m, IH), 7.43 (br, IH), 7.39- 7.27 (m, 3H), 7.05-6.92 (m, 5H), 6.78 (m, IH), 4.78 (m, IH), 4.05(q, 2H, J=6.85Hz), 3.86 (m, IH), 3.18-2.99 (m, 2H), 2.63-2.53 (m, 3H), 2.05 (m, IH), 1.75 (ss, 3H), 1.34 (t, 3H, J=6.29Hz). 6.78 Example 66
Figure imgf000150_0003
59.2 66.1
Figure imgf000150_0004
66 [0511] (3R)-3-(4K5-(5-Ethoxy-2-fluorophenyl)-2,3-dihydro-lH-inden- l~yloxy)phenyl)hex-4-ynoic acid (66) Compound 66 was prepared by a procedure analogous to that described for 7 using the boronic acid shown. MS ESI (neg.) m/e: 457.1 (M-H). 1HNMR (MeOD-d4) δ 7.45 (s, IH), 7.31 (d, IH, J=7.71Hz), 7.10-6.92 (m, 5H), 6.87 (m, IH), 6.80 (m, IH), 4.78 (m, IH), 4.05 (q, 2H, J=6.85Hz), 3.87 (m, IH), 3.07-2.99 (m, 2H), 2.63-2.53 (m, 3H), 2.04 (m, IH), 1.74 (ss, 3H), 1.39 (t, 3H, J=6.72Hz). 6.79 Example 67
Figure imgf000151_0001
59.2 67.1
Figure imgf000151_0002
67
[0512] (3R)-3-(4-(5-(2-Fluoro-3-methoxyphenyl)-2,3-dihydro-lH- inden-l-yloxy)phenyl)hex-4-ynoic acid (67) Compound 67 was prepared by a procedure analogous to that described for 59 using the boronic acid shown. MS ESI (neg.) m/e: 443.2 (M-H). 1HNMR (DMSOd6) δ 12.15 (br, IH), 7.43 (s, IH)5 7.28 (d, IH, J=7.55Hz), 7.22-7.14 (m, 2H), 7.04-6.90 (m, 4H), 6.18 (m, IH), 4.65 (m, IH), 3.81 (s, 3H), 3.78 (m, 2H), 3.04-2.92 (m, 2H), 2.04 (m, IH), 1.72 (ss, 3H).
6.80 Example 68
Figure imgf000151_0003
59.1 68.1 68 [0513] (R)-3-(4-(Cyclohexylmethoxy)phenyl)hex-4-ynoic acid (68).
Compound 59.1 (30 mg, 0.14 mmol) was dissolved in DMF (1 mL), and Cs2CO3 (89 mg, 0.27 mmol), and cyclohexylmethyl bromide (29uL, 0.20 mmol) were added. The reaction was left to stir at room temperature overnight. The reaction was then blown dry and extracted with EtOAc. The compound was then purified with 5-10% EtOAc on a silica gel column to provide the ester 68.1. Ester 68.1 was hydrolyzed to provide acid 68 by general procedure D. ESI (neg.) m/e: 299.0 (M-H).
6.81 Example 69
Figure imgf000152_0001
Ml 69.1 69
[0514] (S)-3-(4-(2-cyclohexylethoxy)phenyl)hex-4-ynoic acid (69).
Compound 69 was prepared from Ml by a procedure analogous to that described for Example 14 except DEAD and triphenylphosphine were utilized instead of TMAD and tributylphosphine. MS ESI (neg.) m/e: 313.1 (M-H). 1HNMR (CDCL3) δ 7.28 (d, 2H, J=8.61), 6.85 (d, 2H, J=8.61), 4.05 (m, IH), 3.98 (t, 2H, J=6.65Hz), 2.80 (dd, IH, J=8.61, 15.65), 2.71 (dd, IH, J=6.65, 15.65), 1.83 (d, 3H, J=2.35), 1.80-1.63 (m, 7H), 1.56-1.46 (m, IH), 1.33-1.11 (m, 3H), 1.04-0.92 (m, 2H).
6.82 Example 70
Figure imgf000152_0002
Ml 70.1 70
[0515] (S)-3-(4-(2-cyclopentylethoxy)phenyl)hex-4-ynoic acid (70).
Compound 70 was prepared from Ml by a procedure analogous to that described for Example 14 except DEAD and triphenylphosphine were utilized instead of TMAD and tributylphosphine. MS ESI (neg.) m/e: 299.2 (M-H). 1HNMR (CDCL3) δ 7.28 (d, 2H, J=8.61), 6.85 (d, 2H, J=8.61), 4.05 (m, IH), 3.96 (t, 2H, J=6.65Hz), 2.80 (dd, IH, J=8.22, 15.65), 2.71 (dd, IH, J=6.65, 15.65), 2.00-1.90 (m, IH), 1.83 (d, 3H, J=2.35), 1.85-1.75 (m, 4H), 1.67-1.50 (m, 4H), 1.23-1.11 (m, 2H).
6.82.1 General Procedure E: Reaction of the various headgroups with 6-halomethyl-l,l,4,4-tetramethyl- l,2,3?4-tetrahydro-naphthalene
Figure imgf000153_0001
X = C, N
Figure imgf000153_0002
[0516] A mixture of phenol (0.18 mmol), 6-halomethyl-l,l,4,4- tetramethyl-l,2,3,4-tetrahydro-naphthalene (0.2 mmol) or another benzyl chloride or benzyl bromide compound, and cesium carbonate (0.27 mmol) in DMF (2 mL), was/is stirred at room temperature overnight. The reaction mixture was/is diluted with water and extracted into DCM. The separated DCM layer was/is washed with water. The residue obtained after concentration was/is dissolved into THF and MeOH (1 mL each) and treated with 2 M NaOH solution (0.45 niL, 0.9 mmol). The resulting solution was/is further stirred for 16-48 hours at room temperature. The reaction mixture was/is concentrated, and the residue was/is dissolved in a mixture of DMF/ACN (1:4, 5 mL) containing TFA (67 μL, 0.9 mmol). This solution was/is filtered and purified by preparatory HPLC. The solvent was/is evaporated by freeze-drying to provide the desired product generally as a white amorphous solid.
Figure imgf000154_0001
M12 71
[0517] (S)-3-(l-Methyl-lH-imidazol-2-yl)-3-[4-(5,5,8,8-tetramethyl-
5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl] -propionic acid (71).
Compound 71 was obtained from compound M12 using the general Procedure E. MS ESI (neg.) M/E: 445 (M-H). 1HNMR (DMSO-d6) δ 7.65 (s, IH), 7.6 (s, IH), 7.3 (overlapping m, 2H), 7.20 (d, 2H), 7.1 (d, IH), 7.0 (d, 2 H), 5.0 (s, 2H), 4.85 (m, IH), 3.8 (s, IH), 3.1 (dd, IH), 1.6 (s, 4H), 1.2 (s, 12H). 6.84 Example 72
Figure imgf000154_0002
72.1 72
[0518] (S)-3-(2-Methyl-2H-[l,2,4]triazoI-3-yl)-3-[4-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionic acid (72). Compound 72 was obtained from compound 72.1 (M13) by following the general Procedure E. MS ESI (neg.) MfE: 446 (M-H). 1HNMR (DMSOd6) δ 7.75 (s, IH), 7.2 (m, 2H), 7.12 (s, 2H), 7.08 (d, IH), 6.85 (d, 2H), 4.9 (s, 2H), 4.5 (m, IH), 3.6 (s, 3H), 3.1 (dd, IH), 2.7 (dd, IH), 1.55 (s, 4H), 1.15 (s, 12H).
6.85 Example 73
[0519] This example illustrates the preparation of (S)-3-(3-methyl-3H- l,2,3-triazol-4-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)methoxy)phenyl)propanoic acid (73).
Figure imgf000155_0001
73.1
[0520] l-methyl-lH-l,2,3-triazole (73.1). A mixture of 2-
(trimethylsilyl)-2H-l,2,3-triazole (179 mmol), MeI (179 mmol), and TBAF on silica gel (16.3 mmol) in ACN (200 mL), was refluxed for 4 hours. After cooling to room temperature, the mixture was concentrated with silica gel and chromatographed (silica gel, 5:95 MeOH/DCM). The fractions containing product were collected, concentrated, and distilled under vacuum to give desired product 1.1 (7.5 g, 90 mmol, b.p. = 97 °C at 3 mmHg). MS ESI (pos.) m/e 83.9 (M+H).
Figure imgf000155_0002
73.1 73.2
[0521] (4-(Benzyloxy)phenyl)(3-methyl-3H-l,2,3-triazol-4-yl)methanol
(73.2). A solution of n-BuLi (11.6 mL, 1.6 M, 18.6 mmol) in hexane was added dropwise to a solution of 73.1 (1.29 g, 15.5 mmol) in THF (75 mL) at -40 °C. After stirring at -40 0C for 2 hours, 4-(benzyloxy)benzaldehyde was added at -40 °C, and the reaction was warmed to room temperature. The reaction was quenched saturated NH4Cl (aq) after 3 hours of stirring and then extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue 73.2 was used in the next reaction without further purification. MS ESI (pos.) m/e 296.2 (M+H).
Figure imgf000156_0001
73.2 73.3
[0522] (4-(Benzyloxy)phenyl)(3-methyI-3H-l,2,3-triazol-4- yl)methanone (73.3). Dess-Martin periodinane (8 g, 19 mmol) was added to a solution of 73.2 (-15.5 mmol) in DCM (80 rnL). After 1 hour, the reaction mixture was concentrated with silica gel and chromatographed (silica gel, 1 :2 EtOAc/hexane) to obtain compound 73.3 (4.3 g, 14.7 mmol). MS ESI (pos.) m/e: 294.1 (M+H).
Figure imgf000156_0002
73.3 73.4
[0523] Ethyl 3-(4-(benzyloxy)phenyl)-3-(3-methyl-3H-l,2,3-triazol-4- yl)acrylate (73.4). To a solution of lithium bis(trimethylsilyl)amide (22 mmol, 1 M in THF) was added ethyl trimethylsilylacetate (31.5 mmol) dropwise at -78 °C. After 20 minutes at -78 0C, a solution of 73.3 (14.7 mmol) in THF (50 mL) was added dropwise, and the reaction was maintained at -78 °C for 4 hours. The reaction was quenched with saturated NH4Cl (aq) and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated with silica gel under reduced pressure. The residue was chromatographed (silica gel, 1 : 1 EtOAc/hexane) to afford compound 73.4 (5.1 g, 14 mmol). MS ESI (pos.) m/e 364.1 (M+H).
Figure imgf000157_0001
73.4 73.5
[0524] Ethyl 3-(4-hydroxyphenyl)-3-(3-methyl-3H-l,2,3-triazol-4- yl)propanoate (73.5). 73.4 was dissolved in EtOH and stirred with Pd-C (1.48 g, 0.7 mmol) under hydrogen at room temperature for 3 hours. The Pd-C was removed by filtration through celite with EtOAc as eluant. After concentration, the residue was chromatographed (silica gel, 1 : 1 EtOAc/hexane) to afford compound 3.5 (3.28 g, 12 mmol). MS ESI (pos.) m/e 276.1 (M+H).
Figure imgf000157_0002
73.5 73.6
[0525] (S)-ethyl 3-(4-hydroxyphenyl)-3-(3-methyl-3H-l,2,3-triazol-4- yl)propanoate (73.6). Racemic compound 73.5 (3.28 g, 12 mmol) was separated on a semi-preparatory chiral CHIRALCEL OJ-H column (30x250 mm), using 30% i-PrOH in hexane as eluant. Eluant containing the peak with less retention time was concentrated and compound 73.6 (1.5 g, 5.45 mmol) was obtained as off-white solid. The absolute configuration was assigned by analogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 276.1 (M+H).
Figure imgf000157_0003
73.6 73 [0526] (S)-3-(3-methyl-3H-l,2,3-triazoI-4-yl)-3-(4-((5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yI)methoxy)phenyl)propanoic acid (73). A mixture of 73.6 (0.15 mmol), 6-(bromomethyl)-l,l,4,4-tetramethyl- 1,2,3,4-tetrahydronaphthalene (0.18 mmol) and cesium carbonate (0.2 mmol) in DMF (2 mL), was stirred at room temperature for 16 hours. To the reaction mixture was added LiOH in water (1 mL, IN solution), and the resulting mixture was stirred at 50 0C for 3 hours. The mixture was filtered and purified by reverse phase HPLC to give 73 (26 mg, 0.06 mmol) after lyophilization. MS ESI (pos.) m/e 448.3 (M+H). 1H NMR (500 MHz) (CDCl3) δ 7.95 (1 H, s), 7.71 (1 H, s), 7.33 - 7.36 (2 H, m), 7.20 (1 H, dd, J=7.9, 1.5 Hz), 7.07 (2 H, d, J=8.5 Hz), 6.97 (2 H, d, J=8.9 Hz), 4.98 (2 H, s), 4.51 - 4.55 (1 H, m), 3.86 (3 H, s), 3.11 - 3.17 (1 H, m), 3.01 - 3.07 (1 H, m), 1.72 (4 H, s), 1.31 (6 H, s) 1.30 (6 H, s).
6.86 Example 74
[0527] This example illustrates the preparation of (S)-3-(l-methyl-lH- imidazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthaIen-2- yl)methoxy)phenyl)propanoic acid (74).
Figure imgf000158_0001
74.1
[0528] (l-Methyl-lH-imidazol-5-yl)(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)methanol (74.1). 4-(2-Tetrahydro-3/f-pyranoxy)phenylmagnesium bromide (110 mL, 0.5 M in THF, 55 mmol) was added dropwise to a solution of 1 -methyl- lH-imidazole-5-carbaldehyde (4.7 g, 50 mmol) in THF (790 mL) at -78 0C. After stirring -78 °C for 2 hours, the reaction was quenched with saturated NH4Cl (aq) and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 14 g of the crude product 74.1, which was used in the next reaction without further purification.
Figure imgf000159_0001
74.1 74.2
[0529] (l-Methyl-lH-imidazol-5-yl)(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)methanone (74.2). Dess-Martin periodinane (21 g, 50 mmol) was added to a solution of 74.1 (14 g crude, -50 mmol) in DCM (200 mL). After 1 hour, the reaction mixture was concentrated with silica gel and chromatographed (silica gel, 1 :2 EtOAc/hexane) to provide compound 74.2 (3.3 g, 11.5 mmol). MS ESI (pos.) m/e: 287.1 (M+H).
Figure imgf000159_0002
74.2 74.3
[0530] Ethyl 3-(l-methyl-lH-imidazol-5-yl)-3-(4-(tetrahydro-2H- pyran-2-yloxy)phenyl)acrylate (74.3). To a solution of lithium bis(trimethylsilyl)amide (6.8 mmol, 1 M in THF) was added ethyl trimethylsilylacetate (6.5 mmol) dropwise at -78 0C. After 20 minutes at -78 0C, a solution of 74.2 (5.9 mmol) in THF (20 mL) was added dropwise. The reaction was maintained at -78 °C for 3 hours and at -45 °C for 2 hours. The reaction was quenched with saturated NH4Cl (aq) at 0 °C and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude 74.3 (2.49 g). MS ESI (pos.) m/e 357.2 (M+H).
Figure imgf000159_0003
74.3 74.4 [0531] Ethyl 3-(4-hydroxyphenyl)-3-(l-methyl-lH-imidazol-5- yl)propanoate (74.4). The crade 74.3 was dissolved in EtOH (50 mL), stirred with Pd-C (1.48 g, 0.7 mmol) under hydrogen at room temperature for 60 hours. The Pd-C was removed by filtration through celite with EtOAc as eluant. After concentration, the residue was treated with TFA (2 mL) in dry DCM (20 mL) at room temperature for 2 hours. The reaction mixture was concentrated then redissolved in DCM, washed with water, washed with saturated NaHCO3, dried over Na2SO4, and concentrated under reduced pressure. The residue was chromatographed (silica gel, 1 : 1 EtOAc/hexane) to afford compound 74.4 (700 mg, 2.6 mmol). MS ESI (pos.) m/e 275.2 (M+H).
Figure imgf000160_0001
74.4 74.5
[0532] (S)-ethyl 3-(4-hydroxyphenyl)-3-(l-methyl-lH-imidazol-5- yl)propanoate (74.5). Racemic compound 74.4 (680 mg, 2.5 mmol) was separated on a semi-preparatory chiral CHIRALCEL OJ-H column (30x250 mm), using 15% i-PrOH in hexane as eluant. Eluant containing the peak with less retention time was concentrated and compound 74.5 (300 mg, 1.1 mmol) was obtained as off-white solid. The absolute configuration was assigned by analogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 275.2 (M+H).
Figure imgf000160_0002
74.5 74
[0533] (S)-3-(l-methyl-lH-imidazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-
5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (74). A mixture of 74.5 (0.15 mmol), 6-(bromomethyl)-l,l,4,4-tetramethyl-l,2,3,4- tetrahydronaphthalene (0.18 mmol) and cesium carbonate (0.2 mmol) in DMF (2 niL), was stirred at room temperature for 16 hours. To the reaction mixture was added LiOH in water (1 mL, IN solution), and the reaction was stirred at 50 0C for 3 hours. The mixture was filtered and purified by reverse phase HPLC to give 74 (35 mg, 0.08 mmol) after lyophilization. MS ESI (pos.) m/e 447.3 (M+H). 1H NMR (500 MHz) (CDCl3) δ 8.64 (1 H, s), 7.59 (1 H, s), 7.33 - 7.36 (2 H, m), 7.20 (1 H, dd, J=7.9, 1.8 Hz), 7.08 (2 H, d, J=8.5 Hz), 6.98 (2 H, d, J=8.5 Hz), 4.98 (2 H, s), 4.53 (1 H, m), 3.57 (3 H, s), 2.96 - 3.06 (2 H, m), 1.71 (4 H, s), 1.31 (6 H, S)5 1.30 (6 H, s).
6.87 Example 75
[0534] This example illustrates the preparation of (S)-3-(oxazol-5-yl)-3-
(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)methoxy)phenyl)propanoic acid (75).
Figure imgf000161_0001
75.1 [0535] Oxazol-5-yl(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol
(75.1). 4-(2-Tetrahydro-3H-pyranoxy)phenylmagnesium bromide (120 mL, 0.5 M in THF, 60 mmol) was added dropwise to a solution of oxazole-4-carbaldehyde (4.85 g, 50 mmol) in THF (90 mL) at -78 °C. After stirring at -78 °C for 21 hours, the reaction was quenched with saturated NH4Cl (aq) and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 17 g of the crude product 75.1, which was used in the next reaction without further purification.
Figure imgf000162_0001
75.1 75.2
[0536] Oxazol-5-yl(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)methanone (75.2). Dess-Martin periodinane (25 g, 60 mniol) was added to a solution of 75.1 (17 g crude, -50 mmol) in DCM (200 mL). After 1 hour, the reaction mixture was concentrated with silica gel and chromatographed (silica gel, 1 :2 EtOAc/hexane) to obtain compound 75.2 (5.74 g, 21 mmol). MS ESI (pos.) m/e: 274.1 (M+H).
Figure imgf000162_0002
75.2 75.3
[0537] Ethyl 3-(oxazol-5-yl)-3-(4-(tetrahydro-2H-pyran-2- yloxy)phenyl)acrylate (75.3). To a solution of lithium bis(trimethylsilyl)amide (31.5 mmol, 1 M in THF) was added ethyl trimethylsilylacetate (31.5 mmol) dropwise at -78 °C. After 20 minutes at -78 0C, a solution of 75.2 (21 mmol) in THF (60 mL) was added dropwise and the reaction was maintained at -78 0C for 1.5 hours. The reaction was quenched saturated NH4Cl (aq) and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated with silica gel under reduced pressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 75.3 (4.83 g, 14 mmol). MS ESI (pos.) m/e 344.2 (M+H).
Figure imgf000162_0003
75.3 75.4 [0538] Ethyl 3-(4-hydroxyphenyl)-3-(oxazol-5-yl)propanoate (75.4).
TFA (10 mL) was added to a solution of 75.3 (14 mmol) in dry DCM (100 niL) and stirred at room temperature for 2 hours. To the reaction mixture was slowly added solid NaHCO3 with stirring. The reaction was then washed with saturated NaHCO3 (2X)5 dried over Na2SO4, and concentrated under reduced pressure. The residue was then re-dissolved in EtOH, stirred with Pd-C (1.48 g, 0.7 mmol) under hydrogen at room temperature for 14 hours. The Pd-C was removed by filtration through celite with EtOAc as eluant. After concentration, the residue was chromatographed (silica gel, 1 :1 EtOAc/hexane) to afford compound 75.4 (1.3 g, 5 mmol). MS ESI (pos.) m/e 262.1 (M+H).
Figure imgf000163_0001
75.4 75.5
[0539] (S)-ethyl 3-(4-hydroxyphenyl)-3-(oxazol-5-yl)propanoate (75.5).
Racemic compound 75.4 (1.3 g, 5 mmol) was separated on a semi-preparatory chiral CHIRALCEL OJ-H column (30x250 mm), using 20% i-PrOH in hexane as eluant. Eluant containing the peak with greater retention time was concentrated and compound 75.5 (620 mg, 2.38 mmol) was obtained as off-white solid. The absolute configuration was assigned by analogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 262.1 (M+H).
Figure imgf000163_0002
75.5 75
[0540] (S)-3-(Oxazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (75). A mixture of 75.5 (0.1 mmol), 6-(bromomethyl)-l,l,4,4-tetramethyl-l,2,3,4- tetrahydronaphthalene (0.12 mmol) and cesium carbonate (0.15 mmol) in DMF (2 mL) was stirred at room temperature for 3 hours. To the reaction mixture was added LiOH in water (1 mL, IN solution), and the reaction was stirred at 50 °C for 3 hours. The mixture was filtered and purified by reverse phase HPLC to give 75 (12 mg, 0.03 mmol) after lyophilization. MS ESI (pos.) m/e 434.2 (M+H). 1H NMR (500 MHz) (CDCl3) δ 7.94 (s, IH); 7.31-7.41 (m, 3H); 7.22 (d, J=8.5Hz, 2H); 6.99 (d, J=8.5Hz, 2H); 6.87 (s, IH); 4.99 (s, 2H); 4.58 (t, J=7.9Hz, IH); 3.14 (dd, J=16.5, 7.6Hz, IH); 2.99 (dd, J=16.5, 7.6Hz, IH); 1.72 (s, 4H); 1.31 (s, 12H).
6.88 Example 76
[0541] Synthesis of (S)-3-(Isoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-
5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (76).
^ .PMB
Figure imgf000164_0001
Figure imgf000164_0002
76.1 76.2 [0542] (E)-4-Methoxybenzyl 3-(4-(4- methoxybenzyloxy)phenyl)acrylate (76.2). Potassium carbonate (21 g, 152 mmol) was added to a mixture of 4-hydroxycinnamic acid 76.1 (6.25 g, 38.1 mmol) and p-methoxy benzyl chloride (10.35 mL, 76 mmol) in DMF (100 mL). The mixture was stirred at 80 °C for five hours. After cooling, the mixture was poured into water (700 mL). The solid was collected by filtration, washed with water and dried to give 76.2 (15 g). MS ESI (pos.) m/e: 405 (M+H). 1HNMR (CDCl3) δ 7.68(d, IH), 7.47(d, 2H), 7.38(m, 4H), 6.95(m, 6H), 6.35(d, IH),
5.20(s, 2H), 5.03(s, 2H), 3.84(s, 3H), 3.83(s, 3H).
Figure imgf000164_0003
76.2 76.3 [0543] 4-Methoxybenzyl 3-(4-(4-methoxybenzyloxy)phenyI)-4- nitrobutanoate (76.3). 1,1,3,3-tetramethylguanidine (0.31 mL, 2.48 mmol) was added to 76.2 (5 g, 12.4 mmol) in nitromethane (20 mL). The mixture was stirred at room temperature for 3 hours, at 50 °C for 3 hours, and at 100 °C for 8 hours. Nitromethane was removed under vacuum and the crude product was purified by flash chromatography to give 76.3 (4.5 g). MS ESI (pos.) m/e: 466 (M+H). 1HNMR (CDCl3) δ 7.37(d, 2H), 7.19(d, 2H), 7.12(d, 2H), 6.92(m, 6H), 5.01(s, 2H), 4.97(s, 2H), 4.68(m, IH), 4.59(m, IH), 3.96(m, IH), 3.84(s, 3H), 3.82(s, 3H), 2.77(m, 2H).
Figure imgf000165_0001
76.3 76.4
[0544] 4-Methoxybenzyl 3-(4-(4-methoxybenzyloxy)phenyl)-3-
(isoxazol-3-yl)propanoate (76.4). Triethylamine (1 mL) was added to a mixture of 76.3 (1.89 g, 4.1 mmol), vinyl bromide (32.5 mL, 1.0 M solution in THF) and 1,4-phenylene diisocyanate (2.3 g, 14.35 mmol). The mixture was stirred at 80 °C for 8 hours. After cooling, the solid was removed from the mixture by filtration, and the filtrate was concentrated and purified by flash chromatography to give 76.4 (3 g). MS ESI (pos.) m/e: 474 (M+H). 1HNMR (CDCl3) δ 8.28(d, IH), 7.37(d, 2H), 7.18(m, 4H), 6.92(m, 6H), 6.07(d, IH), 5.02(s, 2H), 4.97(s, 2H), 4.59(t, IH), 3.84(s, 3H), 3.82(s, 3H), 3.33(dd, IH), 3.00(dd, IH).
Figure imgf000165_0002
76.4 76.5
[0545] Ethyl 3-(4-hydroxyphenyl)-3-(isoxazol-3-yl)propanoate (76.5).
TFA (10 mL) was added to 76.4 (940 mg) in DCM (10 mL). The mixture was stirred at room temperature for 1.5 hours. TFA and DCM were removed under vacuum, and the residue was treated with EtOH (50 mL). The insoluble solid was removed by filtration. To the filtrate was added concentrated sulfuric acid (2 drops). The mixture was stirred at 80 0C overnight. After concentration, the crude product was purified by flash chromatography to give 76.5 (410 mg). MS ESI (pos.) m/e: 262 (M+H). 1HNMR (CDCl3) δ 8.29(d, IH), 7.12(d, 2H), 6.76(d, 2H), 6.10(d, IH), 4.56(t, IH), 4.10(q, 2H), 3.27(dd, IH), 2.97(dd, IH), 1.19(t, 3H). The racemic compound 76.5 was separated into two enantiomers 76.6 and 76.7 using chiral preparative AD-H column (8% IP A/92% hexanes). The stereochemistry of 76.6 and 76.7 was assigned arbitrarily.
Figure imgf000166_0001
76.6 76
[0546] (S)-3-(Isoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (76). Cesium carbonate (14 mg, 0.042 mmol) was added into a mixture of 76.6 (10 mg, 0.038 mmol) and 6-(bromomethyl)-l,l,4,4-tetramethyl-l,2,3,4-tetrahydronaphthalene ( 11 mg, 0.038 mmol) in DMSO (0.5 mL). The mixture was stirred at room temperature for 2 hours and at 35 °C for 4 hours. After cooling, the mixture was treated with EtOAc (5 mL) and brine (5 mL). The organic layer was separated, washed with brine twice, dried and concentrated. The crude product was treated with THF (1 mL), MeOH (1 mL), water (0.5 mL) and NaOH (0.05 mL, 10N). The mixture was stirred at room temperature for 4 hours. The organic solvent was blown away by nitrogen and the aqueous was acidified by HCl (0.18 mL, 3N). The aqueous was extracted with DCM. The organic layer was dried, concentrated and purified by flash chromatography to give 76 (15 mg). MS ESI (pos.) m/e: 434 (M+H). 1HNMR (CDCl3) δ 8.30(d, IH), 7.35(m, 2H), 7.19(m, 3H), 6.96(d, 2H), 6.09(d, IH), 4.97(s, 2H), 4.57(t, IH), 3.37(dd, IH), 2.99(dd, IH), 1.71(s, 4H), 1.30(s, 12H).
Figure imgf000167_0001
76.7 77
[0547] (R)-3-(Isoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (77). Compound 7 was synthesized using the procedure above for preparing Example 76 using compound 76.7. MS ESI (pos.) m/e: 434 (M+H). 1HNMR (CDCl3) δ 8.30(d, IH), 7.35(m, 2H), 7.19(m, 3H), 6.96(d, 2H), 6.09(d, IH), 4.97(s, 2H), 4.57(t, IH), 3.37(dd5 IH), 2.99(dd, IH), 1.71(s, 4H), 1.30(s, 12H).
6.90 Example 78
[0548] Synthesis of (3S)-3-(l-Methyl-lH-imidazol-2-yl)-3-(4-(l-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoic acid (78).
Figure imgf000167_0002
78.1 78.2 78.3
[0549] (2,3-Dihydro-lH-inden-5-yl)methanol (11) To a solution of 78.1
(1.0 g, 6.17 mmol) in THF was slowly dripped BH3-THF (30 mL, 1.0 M in THF) at O0C. The reaction mixture was stirred at this temperature for 2 hours and then quenched with water. The mixture was poured into water, and extracted with EtOAc. The crude product was chromatographed on a silica gel column to afford the alcohol 78.2. 1HNMR (DMSOd6) δ 7.17-7.15 (m, 2H), 7.05 (d, IH, J-7.57Hz), 5.04 (t, IH, J=5.87Hz), 4.45 (d, 2H, J=5.63Hz), 2.84 (m, 4H), 2.01 (m5 2H).
Figure imgf000168_0001
78.4 78
[0550] (3S)-3-(l-MethyI-lH-imidazol-2-yl)-3-(4-(l-(5,5,8,8- tetramethyI-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoic acid
(78) This compound was prepared by procedure analogous to that described in Example 109 starting with intermediate 78.2 which was converted to chloride 78.3 and then reacted with the imidazole phenol M12 shown in the reaction scheme and followed be removal of the ester group. MS ESI (pos.) m/e: 377.2 (M+H). 1HNMR (MeOH-d4) δ 7.52-7.48 (d, 2H), 7.26 (s, IH), 7.23-7.15 (m, 4H), 7.02 (d, 2H, J=8.80Hz), 5.04 (s, 2H), 4.95 (m, IH), 3.84 (s, 3H), 3.37 (m, IH), 3.19 (m, IH), 2.89 (t, 4H, J=7.34Hz), 2.08 (m, 2H). 6.91 Example 79
Figure imgf000168_0002
79.1 79
[0551] (R/S)-3-Pyrimidin-5-yl-3-[4-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionic acid (79). Compound 79.1 was prepared using the procedure in Method 12 used to prepare M12.5 using pyrimidine-5-carboxaldehyde in place of l-methyl-2-imidazolecarboxaldehyde. Compound 79 was obtained from compound 79.1 by following the general Procedure E. MS ESI (neg.) M/E: 443 (M-H). 1HNMR (DMSO-d6) δ 8.9 (s, IH), 8.7 (s, 2H), 7.25 (m, 4H), 7.1 (d, IH), 6.8 (d, IH), 4.9 (s, 2H), 4.3 (m, IH), 3.1 (dd, IH), 3.0 (dd, IH), 1.55 (s, 4H), 1.15 (s, 12H). 6.92 Example 80
NaBH4 Thionyl chloride
Figure imgf000169_0001
Figure imgf000169_0002
Figure imgf000169_0003
80.1 80.2 80.3
[0552] Compound 80.1 was reduced to 80.2 using a procedure very similar to that described in JOC3 43, (1978), 2167. 80.2 was converted to 80.3 by simply treating it with thionyl chloride at room temperature.
Figure imgf000169_0004
M12 80
[0553] (S)-3-(l-Methyl-lH-imidazol-2-yl)-3-[4-(5,6,7,8-tetrahydro- naphthalen-2-ylmethoxy)-phenyI]-propionic acid (80). Compound 80 was obtained from compound M12 and 80.3 by following the general Procedure E. MS ESI (neg.) M/E: 389 (M-H). 1HNMR (DMSOd6) δ 7.6 (s, IH), 7.5 (s, IH), 7.2 (d, 2H), 7.1-6.9 (overlapping signals, 5H), 4.9 (s, 2H), 4.8 (m, IH), 3.7 (s, IH), 3.3 (dd, IH), 3.0 (dd, IH).
6.93 Example 81
Figure imgf000169_0005
5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionic acid (81).
Compound 81 was obtained from compound M14 by following the general Procedure E. MS ESI (neg.) M/E: 447 (M-H). 1HNMR (DMSOd6) δ 7.3 (2s, 2H), 7.2 (d, 2H), 7.1 (d, IH), 7.05 (d, IH), 6.85 (d, 2H), 4.9 (s, 2H), 4.6 (m, IH), 3.8 (s, 3H), 3.2 (dd, IH), 2.8 (dd, IH), 1.55 (s, 4H), 1.1 (s, 12H).
Figure imgf000170_0001
82.1 82
[0555] (S)-3-Oxazol-2-yl-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro- naphthalen-2-ylmethoxy)-phenyl]-propionic acid (82). Compound 82 was obtained from compound 82.1 (resolved compound of Method 11) by following the general Procedure E. MS ESI (neg.) M/E: 432 (M-H). 1HNMR (MeOH-d4) δ 7.8 (s, IH), 7.3 (m, 2H), 7.2 (m, 3H), 7.1 (s, 1H),6.95 (d, 2H), 5.0 (s, 2H), 4.6 (m, IH), 3.8 (s, 3H), 3.25 (dd, IH), 2.9 (dd, IH), 1.7 (s, 4H), 1.3 (s, 12H).
6.95 Examples 83 and 84 [0556] Synthesis of carboxylic acids(83) and (84).
Figure imgf000170_0002
83.1 83.2 83.3
[0557] Aldehyde (83.3). The benzyl bromide 83.1 (10.24 g, 32.5 mmol) and 4-hydroxybenzaldehyde 83.2 (3.97 g, 32.5 mmol) were dissolved in 300 mL of acetone. K2CO3 (8.9 g, 65 mmol) was then added. After 18 hours at room temperature, the reaction mixture was filtered through a plug of silica and concentrated afford 83.3 (11.4 g, 32 mmol, 98% yield). MS ESI (pos.) m/e: 357 (M+H)+.
Figure imgf000171_0001
83.3 83.4 83.5
[0558] Alcohol (83.5). 3-Mercapto-4-methyl-l,2,4-triazole (468 mg, 4.07 mmol) was dissolved in 100 mL of THF and the solution was cooled to -78°C under a nitrogen atmosphere. 2.5 M n-BuLi (4.07 mL, 10.18 mmol) was added over one minute. After 5 minutes, a solution of aldehyde 83.3 (1.45 g, 4.07 mmol) in 8 mL THF was added over 5 minutes. After 2 hours, the reaction mixture was poured onto 100 mL saturated NH4Cl(aq) solution and subsequently diluted with 100 mL EtOAc. The organic layer was washed with water (1 x 250 mL), brine (1 x 250 mL) and dried with MgSO4. The organic layer was filtered and concentrated under reduced pressure. The crude material was flashed through silica with 40% EtOAc/Hex to afford 83.5 (1.44 g, 3.06 mmol, 75% yield). MS ESI (pos.) m/e: 472 (M+H)+.
Figure imgf000171_0002
83.5 83.6
[0559] Alcohol (83.6). Alcohol 83.5 (1.44 g, 3.06 mmol) was dissolved in
50 mL of 4:1 THF/water. To this mixture was added NaNO2 (422 mg, 6.12 mmol) followed by drop wise addition of concentrated HNO3 (0.38 mL, 6.12 mmol). The reaction was stirred for 1 hour and then was diluted with 400 mL of EtOAc. The organic layer was washed with NaHCO3(aq) (2 x 150 mL), brine (1 x 150 mL), dried with MgSO4; and filtered. The organic layer was concentrated under reduced pressure to afford 83.6 (1.34 g crude material). MS ESI m/e: 440 (M+H)+.
Figure imgf000172_0001
83.6 83.7
[0560] Ketone (83.7). Alcohol 83.6 (1.34 g crude) was dissolved in 50 mL of THF and Dess-Martin (15 mL, 0.3 M5 4.5 mmol) was added. After 18 hours, the mixture was diluted with EtOAc and then washed with NaSO3(aq) (2 x 150 mL), brine (1 x 150 mL), and dried with MgSO4 and filtered. The organic layer was concentrated under reduced to afford ketone 83.7 (1.34 g crude). MS ESI (pos.) m/e: 438 (M+H)+.
Figure imgf000172_0002
83.7 83.8
[0561] Ethyl ester (83.8). LHMDS (3 mL, 1 M, 3.00 mmol) was diluted with 25 mL of THF and cooled to -78 °C. Then, ethyltrimethylsilylacetate (0.47 mL, 2.57 mmol) was added dropwise and the mixture was allowed to warm to -50 °C over 1.5 hours. The mixture was cooled to -78 °C and the ketone 83.7 (934 mg, 2.14 mmol) was added in 20 mL THF. After 1 hour, the mixture was poured onto 100 mL saturated NH4Cl(aq) solution and subsequently diluted with 250 mL of EtOAc. The organic layer was separated and washed with brine (1 x 150 mL). The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure to afford 83.8 as a crude material. MS ESI (pos.) m/e: 508 (M+H)+.
Figure imgf000172_0003
83.8 83.9 [0562] l,2,4-(4-Methyltriazole) (83.9). The ester 83.8 (-2.14 mmol) was dissolved in 50 mL of EtOAc then wet Pd/C (1.77 g) was added. The mixture was flushed with nitrogen, and a hydrogen balloon was attached. After 14 hours, the mixture was filtered through a small plug of silica, and the material was concentrated under reduced pressure. The residue was prepared by HPLC Cl 8 chromatography to afford phenol 83.9 (400 mg, 1.45 mmol) as a white solid. The material was dissolved in MeOH and the enantiomers were separated on a Chiral AD-H column. 180 mg of each enantiomer was obtained. MS ESI (pos.) m/e: 276 (M+H)+.
Figure imgf000173_0001
83.9 83.10 83 and 84
[0563] Carboxylic Acids (83 and 84). Benzyl bromide 83.10 (58 mg,
0.19 mmol) and phenol 83.9 (either of the separated enantiomers) (47 mg, 0.17 mmol) were dissolved in DMF (3 mL) and treated with Cs2CO3 (277 mg, 0.86 mmol). The reaction was stirred at room temperature for 16 hours and then diluted with EtOAc (50 mL) and washed with water (1 x 50 mL), brine (1 x 50 mL), then dried with MgSO4, filtered, and concentrated to a residue. The residue was dissolved in THF/MeOH/water, 3:1 :1, and 10 equivalents 2 N LiOH(aq) was added. The reaction was stirred for 12 hours and then concentrated to a residue. The residue was purified by HPLC Cl 8 column chromatography (ACN/Water/TFA). Eluent containing compound 83 or 84 (depending on the enantiomer of 83.9 used) was lyophilized to afford a white solid (40 mg, 52%). 1H NMR (500 mHz) (DMSOD6) δ 8.50 (s, IH); 7.35 (d, J = 1.6 Hz, IH); 7.32 (d, J = 8.8 Hz, IH); 7.16-7.19 (m, 3H); 6.96 (d, J = 9.4 Hz, 2H); 4.97 (s, 2H); 4.56 (dd, J = 6.1, 9.4 Hz, IH); 3.44 (s, 3H); 3.24 (dd, J = 9.4, 17.2 Hz, IH); 2.84 (dd, J = 6.1, 17.2 Hz, IH); 1.64 (s, 4H); 1.24 (s, 6H); 1.23 (s, 6H). MS ESI (pos.) m/e: 448.1 (MH-H)+. 6.96 Example 85
[0564] Synthesis of 3-(4,5-Dihydroisoxazol-3-yl)-3-(4-((5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (85).
Figure imgf000174_0001
76.3 85.1
[0565] 4-Methoxybenzyl 3-(4-(4-methoxybenzyloxy)phenyl)-3-(4,5- dihydroisoxazol-3-yl)propanoate (85.1). Ethylene was bubbled into a mixture of 76.3 (235 mg, 0.5 mniol, see Example 76) in benzene (2 mL) for 20 minutes. Phenyl isocyanate (0.22 mL, 2 mmol) and TEA (3 drops) were then added. The mixture was stirred at room temperature for 2 days. The solid was removed by filtration and washed by benzene. The filtrate was concentrated and purified by flash chromatography to give 85.1 (200 mg). MS ESI (pos.) m/e: 476 (M+H). 1HNMR (CDCl3) δ 7.37(d, 2H), 7.21(d, 2H), 7.16(d, 2H), 6.92(m, 6H), 5.05(dd, 2H), 4.98(s, 2H), 4.25(m, 2H), 4.10(t, IH), 3.84(s, 3H), 3.82(s, 3H), 3.24(dd, IH), 2.79(m, 3H).
Figure imgf000174_0002
85.1 85.2
[0566] 3-(4,5-Dihydroisoxazol-3-yl)-3-(4-hydroxyphenyl)propanoic acid (85.2). TFA (1 mL) was added to 85.1 (100 mg) in DCM (1 mL). The mixture was stirred at room temperature for 40 hours. TFA and DCM were removed under vacuum, and the residue was treated with EtOH (50 mL). The insoluble solid was removed by filtration. The filtrate was concentrated to give 85.2 (50 mg), which was used in the next step without further purification. MS ESI (pos.) m/e: 236 (M+H).
Figure imgf000175_0001
85.2 85
[0567] 3-(4,5-DihydroisoxazoI-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (85). Cesium carbonate (108 mg, 0.33 mmol) was added into a mixture of 85.2 (25 mg, 0.11 mmol) and 6-(bromomethyl)-l,l,4,4-tetramethyl-l,2,3,4-tetrahydronaphthalene ( 76 mg, 0.27 mmol) in DMSO (1 mL). The mixture was stirred at 45 0C for 3 hours. After cooling, the mixture was treated with EtOAc (5 mL) and brine (5 mL). The organic layer was separated, washed with brine twice, dried and concentrated. The crude product was treated with THF (1 mL), MeOH (1 mL), water (0.5 mL) and NaOH (0.05 mL, 10N). The mixture was stirred at room temperature for 4 hours. The organic solvent was blown away by nitrogen, and the aqueous layer was acidified by HCl (0.18 mL, 3N). The aqueous layer was extracted with DCM. The organic layer was dried, concentrated and purified by flash chromatography to give 85 (15 mg). MS ESI (pos.) m/e: 436 (M+H). 1HNMR (CDCl3) δ 7.35(m, 2H), 7.19(m, 3H), 6.96(d, 2H), 4.97(s, 2H), 4.28(m, 2H), 4.07(t, IH), 3.28(dd, IH), 2.79(m, 3H), 1.71(s, 4H), 1.30(s, 12H).
6.97 Example 86
[0568] Synthesis of (S)-3-(4-((8,8-Dimethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(l-methyl-lH-imidazol-2- yl)propanoic acid (86).
Figure imgf000175_0002
86.1 86.2 86.3 [0569] Starting material 86.1 was prepared according to the published procedure of Endo, Y. et al. (J Med. Chem. 1998, 41, 1476-1496). To a solution of 86.1 (150 mg, 0.78 mmol) in CHCl3 (5 niL) was added SOCl2 (3 mL). The solution was heated at reflux for 3 hours. The solvent and excess SOCl2 were removed under reduced pressure. The residue, crude 86.2 was pumped to dryness for half an hour under vacuum and redissolved in DMF (5 mL). Cs2CO3 (1.3 g, 4 mmol), and the imidazole phenol M12 shown in the reaction scheme (0.21 g, 0.77 mmol) were added as shown in the reaction scheme. The reaction mixture was left to stir at room temperature overnight, quenched with saline, extracted with EtOAc, and chromatographed on a silica gel column with 20-80% EtOAc/hexane to afford the ester 86.3.
Figure imgf000176_0001
86.3 86
[0570] (S)-3-(4-((8,8-Dimethyl-5,6,7,8-tetrahydronaphthalen-2- yl)methoxy)phenyl)-3-(l-methyl-lH-imidazol-2-yl)propanoic acid (86). The ester 86.3 was dissolved in THF (3 mL) and MeOH (3 mL). To the solution was added 2N NaOH aqueous (3 mL), and the reaction was left overnight. The mixture was neutralized with AcOH (0.5 mL), filtered, and directly purified with C18 reverse-phase HPLC eluting with 10-90% ACN/H2O containing 0.1% TFA. The product fractions were lypholized to afford 86. MS ESI (pos.) m/e: 419.2 (M+H). 1HNMR (MeOH-d4) δ 7.52 (d, 2H, J=10.76Hz), 7.37 (s, IH), 7.22 (d, 2H, J=8.80Hz), 7.09 (d, IH, J=7.83Hz), 7.03 (d, 3H, J=8.56Hz), 5.03 (s, 2H), 4.95 (m, IH)3 3.84 (s, 3H), 3.37 (m, IH), 3.19 (m, IH), 2.76 (t, 2H, J=6.36Hz), 1.82 (m, 2H), 1.69 (m, 2H), 1.27 (s, 6H).
6.98 Example 87
[0571] Synthesis of (3S)-3-(l-MethyI-lH-imidazol-2-yl)-3-(4-(l-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoic acid (87).
Figure imgf000177_0001
87.1 87.2 87.3
[0572] l-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)ethanol (87.2) To a solution of 87.1 (1.0 g, 4.34 mmol) in MeOH (20 niL) was added NaBH4 (0.41 g, 10.8 mmol) at O0C. The reaction was left at room temperature overnight. The solvent was then removed under reduced pressure. The residue was extracted with EtOAc/H2O. The crude product was chromatographed with 0-20% EtOAc/hexane to afford 87.2. 1HNMR (DMSOd6) δ 7.26 (d, IH), 7.24 (d, IH), 7.06 (dd, IH), 4.99 (d, IH), 4.64 (m, IH), 1.64 (s, 4H), 1.29 (d, 3H), 1.24 (m, 12H).
Figure imgf000177_0002
87.3 87
[0573] (3S)-3-(l-Methyl-lH-imidazol-2-yl)-3-(4-(l-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoic acid
(87) To a mixture of compound the imidazole phenol compound M12 shown in the reaction scheme (200 mg, 0.73 mmol), 87.2 (370 mg, 1.59 mmol), and tributylphosphine (0.54 mL, 2.19 mmol) in THF (8 mL) was added N,N,N',N'- tetramethylazodicarboxamide(TMAD) (0.38 g, 2.21 mmol) after bubbling with Ar for 2 minutes. The reaction mixture was stirred at room temperature overnight, quenched with saline, extracted with EtOAc, and cliromatographed on a silica gel column to afford the ester 87.3. The ester was hydrolyzed by procedure analogous to that described for Example 86. MS ESI (pos.) m/e: 461.2 (M+H). 1HNMR (MeOH-(I4) δ 7.50-7.46 (m, 2H), 7.29-7.26 (m, 2H), 7.14-7.10 (m, 3H), 6.91 (d, 2H, J=8.81Hz), 5.34 (m, IH), 4.90 (m, IH), 3.81 (ss, 3H), 3.31 (m, IH), 3.16 (m, IH), 1.69 (s, 4H), 1.58 (d, 3H, J=6.35Hz), 1.31 (m, IH), 1.27-1.16 (m, 12H).
6.99 Example 88
[0574] Synthesis of (S)-3-(4-((8,8-Diethyl-5,5-dimethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(l-methyI-lH-imidazol-2- yl)propanoic acid (88).
Figure imgf000178_0001
88.1 88.2 88.3
[0575] 6-(Bromomethyl)-4,4-diethyl-l,l-dimethyl-l,2,3,4- tetrahydronaphthalene (88.2) Starting material 88.1 was prepared according to the published procedure of Kim, C. et al. {Tetrahedron. Lett. 1994, 35 (19), 3017- 3020). A mixture of 88.1 (0.5 g, 2.17 mmol), NBS (0.58 g, 3.25 mmol), and dibenzoyl peroxide (53 mg) in CCl4 (10 mL) was heated at reflux for 5 hours. The reaction was cooled, and the precipitate was filtered out. The solvent was removed providing crude 88.2, which was used directly in the next step.
Figure imgf000178_0002
88.3 88
[0576] (S)-3-(4-((8,8-Diethyl-5,5-dimethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(l-methyl-lH-imidazoI-2- yl)propanoic acid (88) Compound 88 was prepared using a procedure analogous to that described in Example 86 starting with the imidazole phenol compound M12 shown in the reaction scheme and 88.2. MS ESI (pos.) m/e: 475.1 (M+H). 1HNMR (MeOH-d4) δ 7.47 (dd, 2H, J=I lJ, 2.2Hz), 7.32 (d, IH, J=8.1Hz), 7.09- 7.20 (m, 4H), 7.01-6.94 (m, 2H), 5.03 (s, 2H)5 4.95-4.88 (m, IH), 3.83 (s, 3H), 3.34 (m, IH), 3.14 (m, IH), 1.73-1.52 (m, 6H), 1.59-1.47 (m, 2H), 1.24 (s, 6H), 0.68 (t, 6H, J=7.3Hz).
6.100 Example 89
[0577] Synthesis of (S)-3-(4-fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-
5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (89).
Figure imgf000179_0001
89.1 89.2 89.3
[0578] Compound 89.1 was prepared using the procedure of Example 45.2 set forth in US 2006/0004012 which is hereby incorporated by reference. 89.2 and 89.3 were separated from racemic material 89.1 using a prep chiral AD column using 10% i-PrOH in hexane as eluent. Both compounds (R)-ethyl 3-(4- fluorophenyl)-3-(4-hydroxyphenyl)propanoate 89.2 (the first peak on AD column, shorter retention time) and (S)-ethyl 3-(4-fluorophenyl)-3-(4- hydroxyphenyl)propanoate 89.3 (the second peak on AD column, longer retention time) were obtained as white solid.
Figure imgf000179_0002
89.3 89
[0579] (S)-3-(4-Fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (89). Compound 89 was obtained from compound 89.3 by following the general procedure E. LC- MS ESI (neg.) M/E: 459 (M-H). 1HNMR (500 MHz, CDCl3, ppm) δ 7.35-7.37 (m, 2H), 7.19-7.23 (m, 3H), 7.16 (d, 2H, J = 10 Hz), 6.94-7.02 (m, 4H), 4.98 (s, 2H), 4.50 (t, IH J = 10 Hz), 3.06 (ddd, 2H, J = 5 Hz, 10 Hz, 10 Hz), 1.72 (s, 4H), 1.32(s, 6H), 1.31(s, 6H).
6.101 Example 90
[0580] Synthesis of (R)-3-(4-fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-
5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (90).
Figure imgf000180_0001
89.2 90
[0581] (R)-3-(4-Fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (90). Compound 90 was obtained from compound 89.2 by following the general procedure E. LC- MS ESI (neg.) M/E: 459 (M-H). 1HNMR (500 MHz, CDCl3, ppm) δ 7.35-7.37 (m, 2H), 7.19-7.23 (m, 3H), 7.16 (d, 2H, J - 10 Hz), 6.94-7.02 (m, 4H), 4.98 (s, 2H), 4.50 (t, IH J = 10 Hz), 3.06 (ddd, 2H, J = 5 Hz, 10 Hz, 10 Hz), 1.72 (s, 4H), 1.32(s, 6H), 1.31(s, 6H).
6.102 Example 91
[0582] Synthesis of (S)-3-(4-((3-bromo-5,5,8,8~tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(l-methyl-lH-imidazol-2- yl)propanoic acid (91).
Figure imgf000180_0002
91.1 91.2
[0583] 6-Bromo-7-(bromomethyl)-l,l,4,4-tetramethyl-l,2,3,4- tetrahydronaphthalene (91.2). The mixture of 6-bromo-7-methyl-l,l,4,4- tetramethyl-l,2,3,4-tetrahydronaphthalene (4.20 g, 15 mmol), NBS (3.20 g, 18 mmol), 2,2'-azobisisobutyronitrile (0.3 g, 1.8 mmol) and CCl4 (120 mL) was heated at reflux for 16 hours. The mixture was concentrated under reduced pressure to about 50 mL. The reaction was then filtered, and the solid was washed with Et2O (20 mL). The combined organic solution was then concentrated under vacuum to generate crude product. Crude 91.2 was generated as a brown oil and used directly in the next step without further purification.
Figure imgf000181_0001
M12 91.2 91.3
Figure imgf000181_0002
91
[0584] (S)-3-(4-((3-Bromo-5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(l-methyl-lH-imidazol-2- yl)propanoic acid (91). Compound 91.3 was obtained from compound M12 and 91.2 following the general procedure E and isolated as a general intermediate. Compound 91 was obtained from compound 91.3 by following the general procedure E. LC-MS ESI (neg.) M/E: 523 (M-H). 1HNMR (500 MHz, MeOH- d4, ppm) δ 7.52 (s, IH), 7.43 (s, IH), 7.18-7.21 (m, 4H), 6.96-7.20 (m, 2H), 5.07 (s, 2H), 4.73 (dd, IH J = 5 Hz, 10 Hz), 3.65 (s, 3H), 3.27 (dd, IH, J = 5 Hz, 10 Hz), 2.98 (dd, IH, J = 5 Hz, 10 Hz), 1.70 (s, 4H), 1.28(s, 6H), 1.22(s, 6H). 6.103 Example 92
[0585] Synthesis of (S)-3-(4-((3-cyclopropyl-5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(l-methyl-lH-imidazoI-2- yl)propanoic acid (92).
Figure imgf000182_0001
91 92.1
[0586] (S)-Ethyl 3-(l-methyl-lH-imidazol-2-yl)-3-(4-((3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydronaphthaIen-2-yl)methoxy)phenyI)propanoate
(92.1). The mixture of compound 91 (166 nig, 0.3 mmol), cyclopropyl boronic acid (129 mg, 1.5 mmol), K3PO4 (212 mg, 1 mmol), Pd(OAc)2 (26 mg, 0.12 mmol), Sphos (100 mg, 0.24 mmol) and dioxane (3 mL) was purged with nitrogen, and then heated at 100 0C overnight. The reaction mixture was directly purified by CombiFlash. The compound 92.1 was generated as a colorless oil. LC-MS ESI (pos.) M/E: 515 (M+H).
Figure imgf000182_0002
92.1 92
[0587] (S)-3-(4-((3-Cyclopopyl-5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(l-methyl-lH-imidazol-2- yl)propanoic acid (92). Compound 92 was obtained from compound 92.1 by following the general procedure E. LC-MS ESI (neg.) M/E: 485 (M-H). 1HNMR (500 MHz, MeOH-d4, ppm) δ 7.53 (s, IH), 7.51 (s, IH), 7.29 (s, IH), 7.23-7.25 (m, 2H), 7.05-7.07 (m, 2H), 7.01 (s, IH), 5.22 (s, 2H), 4.97 (dd, IH J = 5 Hz, 10 Hz), 3.85 (s, 3H), 3.26 (dd, IH, J = 10 Hz, 15 Hz), 3.19 (dd, IH, J = 10 Hz, 20 Hz), 1.96 (m, IH), 1.69 (s, 4H), 1.26(s, 6H), 1.23(s, 6H), 0.87-0.90 (m, 2H), 0.62-0.65 (m, 2H).
6.104 Example 93
[0588] Synthesis of (S)-3-(4-((3-methyl-5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(l-methyl-lH-imidazol-2- yl)propanoic acid (93).
Figure imgf000183_0001
91 93
[0589] (S)-3-(4-((3-Methyl-5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(l-methyl-lH-imidazol-2- yl)propanoic acid (93). Compound 93 was obtained from compound 91 and methyl boronic acid by following the same procedure used for compound 92. LC- MS ESI (neg.) M/E: 459 (M-H). 1HNMR (500 MHz, MeOH-d4, ppm) δ 7.53 (s, IH), 7.51 (s, IH), 7.27 (s, IH), 7.22-7.24 (m, 2H), 7.15 (s, IH), 7.04-7.07 (m, 2H), 5.03 (s, 2H), 4.97 (dd, IH J = 5 Hz, 10 Hz), 3.85 (s, 3H), 3.36 (dd, IH, J = IO Hz, 20 Hz), 3.19 (dd, IH, J = 10 Hz, 20 Hz), 2.30 (s, 3H), 1.70 (s, 4H), 1.28(s, 6H), 1.24(s, 6H).
6.105 Example 94
[0590] Synthesis of (S)-3-(4-((3-ethyl-5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(l-methyl~lH-imidazol-2- yl)propanoic acid (94).
Figure imgf000183_0002
91 94 [0591] (S)-3-(4-((3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(l-methyl-lH-imidazol-2- yl)propanoic acid (94). Compound 94 was obtained from compound 91 and ethyl boronic acid by following the same procedure as used for compound 92. LC-MS ESI (neg.) M/E: 473 (M-H). 1HNMR (500 MHz, MeOH-d4, ppm) δ 7.53 (s, IH), 7.51 (s, IH), 7.29 (s, IH), 7.22-7.26 (m, 2H), 7.19 (s, IH), 7.03-7.07 (m, 2H), 5.05 (s, 2H), 4.97 (dd, IH J = 5 Hz, 10 Hz), 3.86 (s, 3H), 3.36 (dd, IH, J = 10 Hz, 15 Hz), 3.20 (dd, IH, J = 10 Hz, 20 Hz)5 2.66 (q, 2H, J = 10 Hz), 1.71 (s, 4H), 1.29 (s, 6H), 1.25 (s, 6H), 1.22 (t, 3H, J = 10 Hz).
6.106 Cell-based Aequorin Assay
[0592] Cell-based aequorin assays were employed to characterize the modulatory activity of compounds on the GPR40 signaling pathway. In an exemplary assay, CHO cells were stably transfected with both GPR40 and Aequorin (Euroscreen). Cells were detached from the tissue culture dish with 2 mL of trypsin (0.25%(w/v)). Trypsinization was halted with 28 mL of Hanks Buffered Salt Solution containing 20 mM Hepes (H/HBSS) and 0.01% fatty acid- free human serum albumin (HSA). Coelantrazine is added to 1 ug/mL, and the cells were incubated for 2 hours at room temperature. Compounds were dissolved in DMSO for preparation of 10 mM stock solutions. Compounds were diluted in H/HBSS containing 0.01% HSA. Serial dilutions of the test compounds were prepared to determine dose response.
[0593] Aequorin luminescence measurements were made using an EG&G
Berthold 96-well luminometer, and the response was measured over a 20 second interval after cells and compounds were mixed. The maximum relative light units was plotted to determine dose response. The EC50 (effective concentration to reach 50% maximal response) was determined from the dose response plot. [0594] Table 1 presents representative data (EC50 values) obtained for exemplary compounds of the invention for the relative activation of human GPR40.
[0595] The stereoisomers in Table 1 are as specified, i.e., iS-enantiomers or i?-enantiomers, and if not specified, or if shown with wavy bonds, are mixtures of S-enantiomers and i?-enantiomers. In addition, the present invention provides the S-enantiomers, the i?-enantiomers, and mixtures of both S-enantiomers and R- enantiomers including racemates of each compound prepared according to the synthetic methods described herein or adapted with the necessary minor modifications from these methods.
6.107 Insulin Secretion Assay
[0596] Human islets were isolated from cadaveric donors. Islets were treated with trypsin (0.25%(w/v) and cells were seeded in 96-well plates containing 3,000 cells per well. Cells were cultured in Roswell Park Memorial Institute (RMPI) media containing 10% fetal bovine serum. [0597] For determination of insulin secretion, media was removed from islet cells and replaced with Krebs-Ringer bicarbonate buffer containing 10 mM HEPES (KRBH) and 2 mM glucose. After one hour incubation, media was replaced with KRBH containing 11.2 mM glucose and test compounds. Insulin released into the medium from the islet cells was measured using scintillation proximity assay (SPA). The compounds of Examples 4 and 9 stimulated insulin secretion from islet cells with EC50 values of less than 1 uM. [0598] For determination of insulin secretion from rodent islets, C57/B16 mice are euthanized with carbon dioxide gas. The pancreatic bile duct is clamped proximal to the duodenum and then cannulated. H/HBSS containing 0.75 mg/mL collagenase XI (Sigma) is then infused into the pancreas through the cannula. The pancreas is excised and then incubated at 37° C for 13 minutes to complete enzymatic digestion. The collagenase digestion is quenched in H/HBSS containing 1% BSA and washed once in the same buffer. Islets can be purified using density gradient centrifugation using Histopaque (Sigma) and are hand- picked under a stereomicroscope.
[0599] Islets are cultured overnight in Roswell Park Memorial Institute
(RMPI) media containing 10% fetal bovine serum and 50 uM beta- mercaptoethanol. Following overnight culture, islets are incubated in KRBH containing 2.8 mM glucose for one hour. [0600] For determination of insulin secretion, islets are incubated in
DMEM containing 12.5 niM glucose and test compounds for one hour. Insulin released into the culture medium from the islets is measured using an insulin ELISA.
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
2006/034995
Figure imgf000198_0001
95
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
[0601] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Each publication and patent application cited herein is incorporated in its entirety as if fully set forth herein. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

WHAT IS CLAIMED:
1. A compound having the formula (I):
Figure imgf000207_0001
I or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
Q is hydrogen, aryl, heteroaryl, (C1-C6)alkyl, or (C2-C6)heteroalkyl;
L1 is a bond, (Ci-C4)alkylene, (C2-C4)heteroalkylene, O, S(O)k, N(Ra), C(0)-(C5-C7)heterocycloalkylene, (CrC^alkylene-SO^R15), (CrC4)alkylene-N(Rb)SO2, or C(O)N(Rb);
Figure imgf000207_0002
represents a cyclohexane ring or a benzo-fused (C5-C8)cycloalkane ring;
L is a bond, (Q-C^alkylene, (C2-C6)heteroalkylene, oxymethylene, O, S(O)k, N(Ra), C(0)N(Rb), SO2N(Rb), (C1-C4)alkylene-C(O)N(Rb), (C1-C4)alkylene-N(Rb)C(O), (C2-C4)alkenylene-C(O)N(Rb), (C2-C4)alkenylene-N(Rb)C(O), (C1-C4)alkylene-SO2N(Rb), (C1-C4)alkylene-N(Rb)SO2, (C2-C4)alkenylene-SO2N(Rb), or (C2-C4)alkenylene- N(Rb)SO2;
M is an aromatic ring, a heteroaromatic ring, (C5-C8)cycloalkylene, ary^Ci-C^alkylene, or heteroaryl(d-C4)alkylene;
X is CR1R1', N(R1"), O, or S(O)k;
L3 is a (Cj-C5)alkylene or (C2-C5)heteroalkylene;
A is -CO2H, tetrazol-5-yl, -SO3H3 -PO3H2, -SO2NH2, -C(O)NHSO2CH3, -CHO, thiazolidinedionyl, hydroxyphenyl, or pyridyl;
Ra is hydrogen, (Q-C^alkyl, aryl(CrC3) alkyl, or (C2-C6)heteroalkyl;
Rb is hydrogen, (Ci-C6)alkyl, or (C2-C6)heteroalkyl;
R1 is cyano, aryl, heteroaryl, (C2-C8)alkenyl, (C3-Cg)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3; R1 is hydrogen, cyano, aryl, heteroaryl, (C!-C8)alkyl, (C2-C8)alkenyl, or (C2-C8)alkynyl;
R1 is hydrogen, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or (C3-C8)cycloalkyl;
R2 and R are independently selected from hydrogen, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl, or (C3-C8)heterocycloalkyl; optionally, R2 and R3 are combined to form a A-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N, O, or S; and the subscript k is 0, 1, or 2
2. The compound of Claim 1, wherein L1 is a bond, Q is H or aryl,
Figure imgf000208_0001
represents a substituted benzo-fused (C5-C8)cycloalkane ring or an unsubstituted benzo-fused (C5-Cg)cycloalkane ring, L2 is O, oxymethylene, or oxyethylene, M is benzene and X is para to L2, X is CR1R1 , R1 is cyano, aryl, heteroaryl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3, R1 is H, L3 is methylene, and A is CO2H, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
3. The compound of Claim 2, wherein the compound is a pharmaceutically acceptable salt or solvate.
4. The compound of Claim 2, wherein the compound is a prodrug.
5. The compound of Claim 4, wherein the prodrug is an ester.
6. The compound of Claim 1 , wherein the compound has the formula (II):
Figure imgf000208_0002
II or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein
Q is selected from hydrogen, aryl, or heteroaryl;
Figure imgf000209_0001
represents a cyclohexane ring or a benzo-fused (C5-C8)cycloalkane ring;
L is selected from O or S(O)k;
R1 is selected from (C2-C8)alkynyl, aryl, heteroaryl, or -C(O)NR2R3;
R2 and R3 are independently selected from hydrogen or (Ci-C4)alkyl;
R4 is independently selected from substituted (C1-C6)alkyl, -R', -OR', =0, =NR', =N-0R', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -0C(0)NR'R", -NR"C(O)R', -NR'-C(0)NR"R"', -NR'-SO2NR"R'", -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)^NR', -SiR'R"R'", -S(O)R', -SO2R', -SO2NR1R", -NR"S02R, -CN, or -NO2, wherein R', R" and R'" are each independently selected from hydrogen, unsubstituted (C]-Cs)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C1-C4)alkyl, or aryl-(d-C4)alkyl groups;
R5 is independently selected from
Figure imgf000209_0002
cyano, or nitro; the subscript k is O, 1 or 2; the subscript n is O, 1 or 2; and the subscript p is O, 1, 2, 3 or 4.
7. The compound of Claim 6, wherein R4 is independently selected from (C1- C6)alkyl, halogen,
Figure imgf000209_0003
cyano, or nitro.
8. The compound of Claim 6, wherein the compound has the formula (Ilia) or (HIb):
Figure imgf000210_0001
Ilia HIb
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
9. The compound of Claim 6, wherein
Figure imgf000210_0002
is a benzo-fused (C5- C8)cycloalkane ring selected from dihydroindene, tetrahydronaphthalene, tetrahydrobenzo[7]annulene, or hexahydrobenzo[8]annulene.
10. The compound of Claim 6, wherein the compound has the formula (IV):
Figure imgf000210_0003
IV or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein the subscript m is 1, 2, 3 or 4.
11. The compound of Claim 10, wherein the subscript m is 1 or 2.
12. The compound of Claim 10, wherein Q is hydrogen; L2 is oxygen; the subscript n is 1 or 2; R4 is independently selected from methyl, halogen, or (Q-CfOalkoxy; and R1 is (C2-C3)alkynyl.
13. The compound of Claim 6, wherein the compound has the formula (VII):
Figure imgf000211_0001
VII or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
14. The compound of any one of Claims 2-6, 10, 12, or 13, wherein R1 is selected from prop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, triazolyl, or -C(O)NR2R3.
15. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier, diluent, or excipient, and the compound of any one of Claims 1-14.
16. A method for treating a disease or condition, comprising: administering to a subject in need thereof, a therapeutically effective amount of the compound of any one of Claims 1-14, wherein the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.
17. The method of Claim 16, wherein the disease or condition is type II diabetes.
18. A method for treating a disease or condition, comprising: administering to a subject in need thereof, a therapeutically effective amount of the compound of any one of Claims 1-14, wherein the disease or condition is a disease or condition responsive to the modulation of GPR40.
19. The method of Claim 18, wherein the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.
20. The method of Claim 16 or Claim 18, wherein the compound is administered orally, parenterally, or topically.
21. The method of Claim 20, wherein the compound is administered in combination with a second therapeutic agent.
22. The method of Claim 21 , wherein the second therapeutic agent is metformin or is a thiazolidinedione.
23. A method for modulating GPR40 function in a cell, comprising: contacting the cell with the compound of any one of Claims 1-14.
24. A method for modulating GPR40 function, comprising: contacting GPR40 with the compound of any one of Claims 1-14.
25. A method for modulating circulating insulin concentration in a subject, comprising: administering the compound of any one of Claims 1-14 to the subject.
26. The method of Claim 25, wherein the circulating insulin concentration is increased in the subject after the compound is administered to the subject.
27. The method of Claim 25, wherein the circulating insulin concentration is decreased in the subject after the compound is administered to the subject.
28. The use of the compound of any one of Claims 1 - 14 for treating a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.
29. The use of Claim 28, wherein the disease or condition is type II diabetes.
30. The use of the compound of any one of Claims 1-14 for modulating GPR40.
31. The use of the compound of any one of Claims 1 - 14 in the preparation of a medicament for treating a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
32. The use of Claim 31 , wherein the disease or condition is type II diabetes.
33. The use of the compound of any one of Claims 1 - 14 in the preparation of a medicament for modulating GPR40.
34. A therapeutic composition, comprising; the compound of any one of Claims 1-14 and a second therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in the treatment of a disease or condition mediated by GPR40.
35. The therapeutic composition of Claim 34, wherein the disease or condition is type II diabetes.
36. The therapeutic composition of Claim 34, wherein the second therapeutic agent is selected from metformin or a thiazolidinedione.
37. The therapeutic composition of Claim 34, wherein the compound of any one of claims 1-14 and the second therapeutic agent are provided as a single composition.
38. The therapeutic composition of Claim 34, wherein the compound of any one of claims 1-14 and the second therapeutic agent are provided separately as parts of a kit.
39. A compound having the formula (I):
Figure imgf000214_0001
I or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
Q is hydrogen, aryl, heteroaryl, (Ci-C6)alkyl, or (C2-C6)heteroalkyl;
L1 is a bond, (d-C4)alkylene, (C2-C4)heteroalkylene, O, S(O)k, N(Ra), C(O)-(C5-C7)heterocycloalkylene, (Ci-C4)alkylene-SO2N(Rb), (d-C4)alkylene-N(Rb)SO2, or C(0)N(Rb);
Figure imgf000214_0002
represents a cyclohexane ring or a benzo-fused (C5-C8)cycloalkane ring;
L2 is a bond, (d-C6)alkylene, (C2-C6)heteroalkylene, oxymethylene, O, S(O)k, N(Ra), C(O)N(Rb), SO2N(Rb), (Ci-C4)alkylene-C(O)N(Rb), (Ci-C4)alkylene-N(Rb)C(O), (C2-C4)alkenylene-C(O)N(Rb), (C2-C4)alkenylene-N(Rb)C(O), (C1-C4)alkylene-SO2N(Rb), (C1-C4)alkylene-N(Rb)SO2, (C2-C4)alkenylene-SO2N(Rb), or (C2-C4)alkenylene- N(Rb)SO2;
M is a benzene ring, and R1 is combined with M to form a 5-, 6-, or 7- membered benzo-fused cycloalkane ring comprising 0, 1, or 2 heteroatoms selected from N, O, and S;
X is CR1R1';
L3 is a bond, (C1-Cs)alkylene or (C2-C5)heteroalkylene;
A is -CO2H, tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2, -C(O)NHSO2CH3, -CHO, thiazolidinedion-yl, hydroxyphenyl, or pyridyl;
Ra is hydrogen, (CrC6)alkyl, 8TyI(C1-C3) alkyl, or (C2-C6)heteroalkyl;
Rb is hydrogen, (CrC6)alkyl, or (C2-C6)heteroalkyl;
R1 is hydrogen, cyano, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkenyl, or (C2-C8)alkynyl;
R1 is hydrogen, aryl, heteroaryl, (C].-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or (C3-C8)cycloalkyl; and the subscript k is 0, 1 or 2.
40. The compound of Claim 39, wherein Q is hydrogen, aryl, or heteroaryl; L1 is a bond; L2 is O or S(O)k; L3 is a (C1-C3)alkylene; and A is -CO2H.
41. The compound of Claim 39 or Claim 40, wherein M is combined with R1 to form a benzo-fused cycloalkane ring having a formula selected from the group consisting of:
Figure imgf000215_0001
wherein, the dotted lines indicate sites of attachment to L2 and L3
42. The compound of Claim 39 or Claim 40, wherein M-X-L -A is selected from the group consisting of:
Figure imgf000216_0001
wherein the dotted line indicates the site of attachment to L2.
43. The compound of claim 39, wherein the compound has the formula (VIII) or (IX)
Figure imgf000216_0002
VIII IX or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein:
Q is selected from hydrogen, aryl, or heteroaryl;
L2 is selected from O or S(O)k;
R4 is independently selected from (CrC6)alkyl, halogen,
Figure imgf000216_0003
cyano, or nitro; the subscript m is 1, 2, 3 or 4; and the subscript n is 0, 1 or 2.
44. A compound having the formula (I):
Figure imgf000216_0004
or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
Q is hydrogen, aryl, heteroaryl, (Q-C^alkyl, or (C2-C6)heteroalkyl;
L1 is a bond, (Ci-C4)alkylene, (C2-C4)heteroalkylene, O, S(O)k, N(Ra), C^-CCs-C^heterocycloalkylene^Cϊ-C^alkylene-SO^CR13), (C1-C4)alkylene-N(Rb)SO2, or C(O)N(Rb);
Figure imgf000217_0001
represents an optionally substituted (C5-C8)cycloalkane ring;
L2 is a bond, (C^C^alkylene, (C2-C6)heteroalkylene, oxymethylene, O, S(O)k, N(Ra), C(0)N(Rb), SO2N(Rb), (Ci-C4)alkylene-C(O)N(Rb), (C1-C4)alkylene-N(Rb)C(O), (C2-C4)alkenylene-C(O)N(Rb), (C2-C4)alkenylene-N(Rb)C(O), (C1-C4)alkylene-SO2N(Rb), (C1-C4)alkylene-N(Rb)SO2, (C2-C4)alkenylene-SO2N(Rb), or (C2-C4)alkenylene-N(Rb)SO2;
M is an aromatic ring, a heteroaromatic ring, (C5-C8)cycloalkylene, aryl(C1-C4)alkylene, or heteroaryl(Ci-C4)alkylene;
X is CR1R1', N(R1"), O, or S(O)k;
L3 is a bond, (CrC5)alkylene, or (C2-Cs)heteroalkylene;
A is -CO2H, tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2, -C(O)NHSO2CH3, -CHO, thiazolidinedion-yl, hydroxyphenyl, or pyridyl;
Ra is hydrogen, (Q-C^alkyl, 8TyI(C1-C3) alkyl, or (C2-C6)heteroalkyl;
Rb is hydrogen, (d-C6)alkyl, or (C2-C6)heteroalkyl;
R1 is cyano, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkyl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3;
R1' is hydrogen, cyano, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkenyl, or (C2-C8)alkynyl;
R1 is hydrogen, aryl, heteroaryl, (d-C^alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or (C3-C8)cycloalkyl;
R2 and R3 are independently selected from hydrogen, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl, or (C3-C8)heterocycloalkyl; optionally, R2 and R3 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N, O, or S; and the subscript k is 0, 1, or 2
45. The compound of Claim 44, wherein L1 is a bond, Q is H or aryl,
Figure imgf000218_0001
represents an optionally substituted cyclopentane or cyclohexane ring, L2 is O, oxymethylene, or oxyethylene, M is benzene and X is para to L2, X is CR1R1 , R1 is cyano, aryl, heteroaryl, (C2-Cs)alkenyl, (C3-C8)alkenyl, (C2-Cg)alkynyl, (C3-C8)alkynyl, or -C(O)NR2R3, R1' is H, L3 is methylene, and A is CO2H or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
46. The compound of Claim45, wherein the compound is a pharmaceutically acceptable salt or solvate.
47. The compound of Claim 44, wherein the compound has the formula (II):
Figure imgf000218_0002
II or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein
Q is selected from hydrogen, aryl, or heteroaryl;
Figure imgf000218_0003
^- S represents a cycloalkane ring;
L2 is selected from O or S(O)k;
R1 is selected from (C2-C8)alkynyl, aryl, heteroaryl, or -C(O)NR2R3; optionally, R1 is combined with the adjacent benzene ring to form a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O or S; R2 and R3 are independently selected from hydrogen or (d-C4)alkyl;
R4 is independently selected from the group consisting of substituted (C1- C6)alkyl, -R', =0, -OR', =0, =NR', =N-OR'. -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R'", -NR'-SO2NR"R'", -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN, and -NO2, where R', R" and R'" are each independently selected from hydrogen, unsubstituted (Ci-C8)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C1-C4)alkyl, or 8TyI-(C1 -C4)alkyl groups;
R5 is independently selected from the group consisting of (Ci-C6)alkyl, halogen, (CrC6)alkoxy, cyano, or nitro; the subscript k is 0, 1 or 2; the subscript n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; and the subscript p is 0, 1, 2, 3 or 4.
48. The compound of Claim 47, wherein R4 is independently selected from (Q-C^alkyl, halogen, (Q-C^alkoxy, cyano, or nitro.
49. The compound of Claim 47, wherein the compound has having the formula (Ilia) or (HIb):
Figure imgf000219_0001
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R1 is (C2-C8)alkynyl, aryl, heteroaryl, or -C(O)NR2R.
50. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier, diluent, or excipient, and the compound of any one of Claims 39-49.
51. A method for treating a disease or condition, comprising: administering to a subject in need thereof, a therapeutically effective amount of the compound of any one of Claims 39-49, wherein the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.
52. The method of Claim 51 , wherein the disease or condition is type II diabetes.
53. The method of Claim 51 , wherein the compound is administered in combination with a second therapeutic agent.
54. The method of Claim 53, wherein the second therapeutic agent is metformin or is a thiazolidinedione.
55. A method for modulating circulating insulin concentration in a subject, comprising: administering the compound of any one of Claims 39-49 to the subject.
56. The use of the compound of any one of Claims 39-49 for treating a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.
57. The use of Claim 56, wherein the disease or condition is type II diabetes.
58. The use of the compound of any one of Claims 39-49 in the preparation of a medicament for treating a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
59. The use of Claim 58, wherein the disease or condition is type II diabetes.
60. A therapeutic composition, comprising; the compound of any one of Claims 39-49 and a second therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in the treatment of a disease or condition mediated by GPR40.
61. The therapeutic composition of Claim 60, wherein the second therapeutic agent is selected from metformin or a thiazolidinedione.
62. A method of synthesizing a compound of formula XXIV, the compound of formula XXIV having the following structure:
Figure imgf000221_0001
the method comprising: (a) reacting a compound of formula XXII with a compound of formula XXIII to produce the compound of formula XXIV, wherein the compounds of formula XXII and XXIII have the following structures:
Figure imgf000222_0001
XXH XXIII wherein,
AIk is a straight or branched chain alkyl group having from 1 to 8 carbon atoms;
R1 is selected from cyano, aryl, heteroaryl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, or C(O)NR2R3;
R and R are independently selected from hydrogen, aryl, heteroaryl, (Ci-Cg)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl, or (C3-C8)heterocycloalkyl; or optionally, R2 and R3 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N, O, or S;
R4 is independently selected from substituted
Figure imgf000222_0002
=0, -OR', =0, =NR', =N-0R', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -0C(0)NR'R", -NR"C(O)R', -NR'-C(0)NR"R"', -NR'-SO2NR"R"', -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN, or -NO2, wherein R', R" and R'" are each independently selected from hydrogen, unsubstituted (Cj- C8)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C]-C4)alkyl, or aryl-(Ci-C4)alkyl groups;
R5 is independently selected from the group consisting of (d-C6)alkyl, halogen, (Ci-C6)alkoxy, cyano, or nitro; m is 1, 2, 3, or 4; n is O, 1, or 2; p is 0, 1, 2, 3, or 4;
Y is selected from substituted (d-C6)alkyl, -R1, =0, -OR', =0, =NR', =N-OR', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(0)NR"R"', -NR'-SO2NR"R'"5 -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN, and -NO2, where R', R" and R'" each independently refer to hydrogen, unsubstituted
Figure imgf000223_0001
or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(Cj-C4)alkyl, or aryl-(C1-C4)alkyl group;
W is a leaving group; and further wherein, the compounds of formula XXII and XXIV can be a mixture of compounds having the R and S stereochemistry at the carbon bonded to R1, can have the R stereochemistry at the carbon bonded to R1, or can have the S stereochemistry at the carbon bonded to R1.
63. The method of Claim 62, wherein W is selected from OH, a halogen, a group of formula OTs, OMs, or OTf, wherein Ts is p-toluenesulfonyl, Ms is methanesulfonyl, and Tf is trifluoromethanesulfonyl.
64. The method of Claim 62 or Claim 63, wherein AIk is methyl or ethyl.
65. The method of Claim 64, wherein m is 1 or 2.
66. The method of Claim 62, wherein W is OH, and a phosphine selected from a trialkylphosphine, a dialkylarylphosphine, a alkyldiarylphosphine, or a triarylphosphine and an azodicarboxylate are used to react the compound of formula XXII with the compound of formula XXIII.
67. The method of Claim 62, wherein W is a halogen selected from Br or Cl, and a base is used to react the compound of formula XXII with the compound of formula XXIII.
68. The method of any one of Claims 62-67, wherein n is O.
69. The method of any one of Claims 62-68, wherein p is 0.
70. The method of any one of Claims 62-69, wherein Y is a halogen, and the method further comprises reacting the compound of formula XXIV with a boronic acid compound.
71. The method of Claim 70, wherein the boronic acid comprises a compound of formula aryl-B(OH)2 or alkyl-B(OH)2.
72. The method of any one of Claims 62-71 , further comprising removing the AIk group of the compound of formula XXIV to form a compound of formula XXV or a salt thereof, the compound of formula XXV having the structure:
Figure imgf000224_0001
XXV wherein Y, R4, n, m, R5, p, and R1 have the definitions provided with respect to the compounds of formula XXII, XXIII, and XXIV.
73. The method of claim 71 , wherein the compound of formula XXIV is reacted in the presence of a hydroxide base to produce the compound of formula XXV.
74. The method of claim 71, wherein the hydroxide base is selected from LiOH, NaOH, KOH, or Ca(OH)2.
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