Polycyclic compounds as lysophosphatidic acid receptor antagonists

专利摘要:
Described herein are compounds that are antagonists of lysophosphatidic receptor(s). Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such antagonists, alone and in combination with other compounds, for treating LPA-dependent or LPA-mediated conditions or diseases.
公开号:AU2010300594A1
申请号:U2010300594
申请日:2010-09-29
公开日:2012-05-17
发明作者:Jeannie M. Arruda；Ryan Clark；Thomas Jon Seiders；Brian Andrew Stearns；Deborah Volkots；David Nathan Zalatan；Lucy Zhao
申请人:Amira Pharmaceuticals Inc；
IPC主号:C07D261-14

专利说明:
WO 2011/041461 PCT/US2010/050786 POLYCYCLIC COMPOUNDS AS LYSOPHOSPHATIDIC ACID RECEPTOR ANTAGONISTS RELATED APPLICATIONS [0001] This application claims benefit of U.S. Provisional Application No. 61/247,877, 5 entitled "POLYCYCLIC COMPOUNDS AS LYSOPHOSPHATIDIC ACID RECEPTOR ANTAGONISTS" filed on October 1, 2009, which is herein incorporated by reference. FIELD OF THE INVENTION [0002] Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods 10 of using such compounds to treat, prevent or diagnose diseases, disorders or conditions associated with one or more of the lysophosphatidic acid (LPA) receptors. BACKGROUND OF THE INVENTION [00031 Lysophospholipids are membrane-derived bioactive lipid mediators. Lysophospholipids affect fundamental cellular functions that include proliferation, 15 differentiation, survival, migration, adhesion, invasion, and morphogensis. These functions influence many biological processes that include, but are not limited to, neurogensis, angiogenesis, wound healing, fibrosis, immunity, and carcinogenesis. [00041 Lysophosphatidic acid (LPA) is a lysophospholipid that has been shown to act through sets of specific G protein-coupled receptors (GPCRs) in an autocrine and paracrine 20 fashion. LPA binding to its cognate GPCRs (LPA 1 , LPA 2 , LPA 3 , LPA 4 , LPA 5 , LPA 6 ) activates intracellular signaling pathways to produce a variety of biological responses. Antagonists of the LPA receptors find use in the treatment of diseases, disorders or conditions in which LPA plays a role. SUMMARY OF THE INVENTION 25 [0005] In one aspect, presented herein are compounds of Formula (I) that inhibit the physiological activity of lysophosphatidic acid (LPA), and therefore, are useful as agents for the treatment or prevention of diseases in which inhibition of the physiological activity of LPA is useful, such as diseases in which an LPA receptor participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of 30 the disease. - 1- WO 2011/041461 PCT/US2010/050786 [0006] In one aspect, the compounds of Formula (I) are useful for the treatment of fibrosis of organs (liver, kidney, lung, heart and the like), liver diseases (acute hepatatis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non alcoholic steatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and the 5 like), cell proliferative disease (cancer (solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL) and the like) and invasive metastasis of cancer cell, and the like), inflammatory disease (psoriasis, nephropathy, pneumonia and the like), gastrointestinal tract disease (irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), abnormal 10 pancreatic secretion, and the like), renal disease, urinary tract-associated disease (benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, symptoms derived from diabetes, lower urinary tract disease (obstruction of lower urinary tract, and the like), inflammatory disease of lower urinary tract, dysuria, frequent urination, and the like), pancreas disease, 15 abnormal angiogenesis-associated disease (arterial obstruction and the like), scleroderma, brain-associated disease (cerebral infarction, cerebral hemorrhage, and the like), neuropathic pain, peripheral neuropathy, and the like, ocular disease (age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery scarring, and the like). In one aspect, the 20 compounds of Formula (I) are used in the treatment of fibrotic diseases or conditions. [0007] In one aspect, described herein are compounds of Formula (I), pharmaceutically acceptable salts, solvates, and prodrugs thereof. Compounds of Formula (I) are antagonists of at least one of the LPA receptors selected from LPA 1 , LPA 2 , LPA 3 , LPA 4 , LPA 5 and
LPA
6 . In one embodiment, compounds of Formula (I) are antagonists of LPA 1 . In one 25 embodiment, compounds of Formula (I) are antagonists of LPA 1 and/or LPA 3 . In some embodiments, compounds of Formula (I) are antagonists of LPA 1 and/or LPA 2 . In some embodiments, compounds of Formula (I) are selective antagonists for one of the LPA receptors relative to the other LPA receptors. In some embodiments, such a selective antagonist is selective for the LPA 1 receptor. In some embodiments, such a selective 30 antagonist is selective for the LPA 2 receptor. In some embodiments, such a selective antagonist is selective for the LPA 3 receptor. [0008] Compounds of Formula (I) are used in the treatment of diseases, disorders, or conditions in which activation of at least one LPA receptor by LPA contributes to the -2- WO 2011/041461 PCT/US2010/050786 symptomology or progression of the disease, disorder or condition. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein comprise antagonists of LPA receptor(s). In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein comprise antagonists of 5 LPA 1 , LPA 2 , or LPA 3 , or combinations thereof. [0009] In one aspect, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof: (R r (R A)m R1 N /
R
5 L2 L4 (Rc Formula (I) 10 wherein, RI is -CO 2 RD, -C(=O)NHSO 2 RE, -C(=O)N(RD) 2 , -CN, or tetrazolyl; R is H or C 1
-C
6 alkyl; RE is Cl-C 6 alkyl or a substituted or unsubstituted phenyl;
L
2 is absent, -C(=O)-, -N(RD)-, substituted or unsubstituted Ci-C 4 alkylene, or 15 substituted or unsubstituted CI-C 4 heteroalkylene, where if L 2 is substituted, then L 2 is substituted with R 12 , where R 12 is F, CI-C 4 alkyl, -OH, or -ORD; ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic CI-C 5 heteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 , each R 14 is independently selected from halogen, 20 CN, -OH, CI-C 4 alkyl, C1-C 4 fluoroalkyl, C1-C 4 fluoroalkoxy, CI-C 4 alkoxy, and C1-C 4 heteroalkyl;
L
4 is absent, or a substituted or unsubstituted C 1
-C
4 alkylene, where if L 4 is substituted then L 4 is substituted with R 13 , where R 13 is F, CI-C 4 alkyl, -OH, or -ORD; 25 R 5 is H or C 1
-C
4 alkyl; each RA is independently selected from halogen, -CN, -OH, CI-C 4 alkyl, C 1 C 4 fluoroalkyl, C 1
-C
4 fluoroalkoxy, C 1
-C
4 alkoxy, and C 1
-C
4 heteroalkyl; -3 - WO 2011/041461 PCT/US2010/050786 each RB is independently selected from halogen, -CN, -OH, CI-C 4 alkyl, C1
C
4 fluoroalkyl, C 1
-C
4 fluoroalkoxy, CI-C 4 alkoxy, and C1-C 4 heteroalkyl; each RC is independently selected from halogen, -CN, -OH, CI-C 4 alkyl, C 1 C 4 fluoroalkyl, C1-C 4 fluoroalkoxy, CI-C 4 alkoxy, and C 1
-C
4 heteroalkyl; 5 m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; r is 1, 2, 3, or 4. [0010] For any and all of the embodiments, substituents are selected from among from a DD subset of the listed alternatives. For example, in some embodiments, R 1 is -CO 2 RD or C(=O)NHSO 2 RE. In some embodiments, R 1 is -CO 2 RD. In some embodiments, R 1 is CO 2 H. In some embodiments, R 1 is -C(=O)NHSO 2 RE. In some embodiments, RE is C 1
-C
6 10 alkyl. In some embodiments, RE is -CH 3 or -CH 2
CH
3 . In some embodiments, RD is -CH 3 or -CH 2
CH
3 . [0011] In some embodiments, R 1 is -CO 2 RD, or -C(=O)NHSO 2 RE ; L 2 is absent, -C(=O)-, NH-, -N(CH 3 )-, -CH 2 -, -CH 2
CH
2 -, -CH(CH 3 )-, -CH 2
CH(CH
3 )-, -CH(CH 3
)CH
2 -, -CH(OH)-, -CH(ORD)-, -CH 2 CH(OH)-, -CH 2 CH(ORD)-, -CH(OH)CH 2 -, -CH(ORD)CH 2 -, -CH 2 NH-, 15 CH(CH 3 )NH-, -NHCH 2 - or -NHCH(CH 3 )-; L 4 is absent, -CH 2 -, -CH(CH 3 )-, -CH(OH)-, CH 2
CH
2 -, -CH 2
CH(CH
3 )-, -CH(CH 3
)CH
2 -, -CH 2 CH(OH)-, or -CH(OH)CH 2 -; R 5 is -H, CH 3 or -CH 2
CH
3 ; m is 0 or 1; n is 0 or 1; r is 1, 2, or 3. [0012] In some embodiments, L 2 is -NH-, -CH 2 -, -CH 2
CH
2 -, -CH(CH 3 )-, -CH 2
CH(CH
3 )-, CH(CH 3
)CH
2 -, -CH(OH)-, -CH 2 CH(OH)-, -CH(OH)CH 2 -, -CH 2 NH-, -CH(CH 3 )NH-, 20 NHCH 2 - or -NHCH(CH 3 )-; ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic C 1
-C
5 heteroarylene containing 1-4 N atoms, 0 or 1 0 atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 ;
L
4 is absent, -CH 2 -, or -CH(CH 3 )-; R 5 is -CH 3 ; r is 1. [0013] In some embodiments, ring A is a substituted or unsubstituted phenyl, where if ring 25 A is substituted, then ring A is substituted with 1 or 2 R 4 . [0014] In some embodiments, ring A is a substituted or unsubstituted monocyclic C 1 C 5 heteroarylene containing 1-4 N atoms, 0 or 1 0 atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 4 . [0015] In some embodiments, ring A is a substituted or unsubstituted 5-membered 30 monocyclic C1-C 4 heteroarylene containing 1-4 N atoms, 0 or 1 0 atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 4 . [0016] In some embodiments, ring A is a substituted or unsubstituted furanyl, a substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted -4- WO 2011/041461 PCT/US2010/050786 oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted 5 thiadiazolyl, where if ring A is substituted, then ring A is substituted with 1 or 2 R 4 . /0 S~ / o -, 0 / I I0" l [0017] In some embodiments, ring A is , 0<~ 0o N ~ S N N N N N- N N N N 10 N:/ N N 0 N N N N N N N N- ~ , N , 'N , N-z/ , N , N' , ' , NN--1 100181 In some embodiments, ring A is a substituted or unsubstituted 6-membered monocyclic C 3 -Csheteroarylene containing 1-3 N atoms, where if ring A is substituted, then 15 ring A is substituted with 1 or 2 R 14 . 100191 In some embodiments, ring A is NN - 5 10 N // N N N N S N -N-N N N I' N N / N-5- WO 2011/041461 PCT/US2010/050786 NN 'Y. N, N N C1 I NNA N.. N N ,or N [0020] In some embodiments, the compound of Formula (I) has the structure of Formula (II): /R1 N 5 NA LL2- (L4 c Formula (II). [0021] In some embodiments, R 1 is -CO 2 RD, or -C(=O)NHSO 2 R ; RD is H or C 1
-C
4 alkyl; RE is C 1
-C
4 alkyl; L2 is -CH 2 -, -CH(CH 3 )-, or -CH(OH)-; ring A is a substituted or unsubstituted 5-membered monocyclic CI-C 4 heteroarylene containing 1-4 N atoms and 0 or 10 1 0 atoms, where if ring A is substituted, then ring A is substituted with R 1 4 ; L 4 is -CH 2 - or
-CH(CH
3 )-; p is 0 or 1. [0022] In some embodiments, R 1 is -C0 2 RD, or -C(=O)NHSO 2 RE; RD is H or C1-C 4 alkyl; RE is C1-C 4 alkyl; L2 is -NH-, -CH 2 -, -CH(CH 3 )-, -CH(OH)-, -NHCH 2 - or -NHCH(CH 3 )-; ring A is a substituted or unsubstituted pyridinylene, where if ring A is substituted, then ring 15 A is substituted with R 14 ; L 4 is absent, -CH 2 -, or -CH(CH 3 )-; p is 0 or 1. [0023] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [0024] In one aspect, provided are compounds presented in Tables 1 to 3 and Figures 1 to 20 11. [0025] Compounds of Formula (I) are antagonists of at least one LPA receptor. In some embodiments, the compound of Formula (I) is an antagonist of LPA 1 . In some embodiments, the compound of Formula (I) is an antagonist of LPA 2 . In some embodiments, the compound of Formula (I) is an antagonist of LPA 3 . -6- WO 2011/041461 PCT/US2010/050786 [0026] In some embodiments, presented herein are compounds selected from active metabolites, tautomers, solvates, pharmaceutically acceptable salts or prodrugs of a compound of Formula (I). [0027] In some embodiments, provided is a pharmaceutical composition comprising a 5 therapeutically effective amount of a compound of Formula (I). In some embodiments, the pharmaceutical composition also contains at least one pharmaceutically acceptable inactive ingredient. [0028] In some embodiments, provided is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically 10 acceptable salt thereof, and at least one pharmaceutically acceptable inactive ingredient. In one aspect, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, inhalation, nasal administration, topical administration, ophthalmic administration or otic administration. In some embodiments, the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray 15 solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop or an ear drop. [0029] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutically active agents other than a compound of Formula (I). [0030] In some embodiments, provided is a method comprising administering a compound 20 of Formula (I) to a human with a LPA-dependent or LPA-mediated disease or condition. In some embodiments, the human is already being administered one or more additional therapeutically active agents other than a compound of Formula (I). In some embodiments, the method further comprises administering one or more additional therapeutically active agents other than a compound of Formula (I). 25 [0031] In some embodiments, the one or more additional therapeutically active agents other than a compound of Formula (I) are selected from: corticosteroids, immunosuppresants, analgesics, anti-cancer agent, anti-inflammatories, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A 1 inhibitors, phospholipase A 2 30 inhibitors, and lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, decongestants, antihistamines, mucolytics, anticholinergics, antitussives, expectorants, and J-2 agonists. -7- WO 2011/041461 PCT/US2010/050786 [0032] In another aspect is the use of a compound of Formula (I) in the treatment of a disease, disorder or condition in which the activity of at least one LPA receptor contributes to the pathology and/or symptoms of the disease or condition. In one embodiment of this aspect, the LPA receptor is selected from LPA 1 , LPA 2 , LPA 3 , LPA 4 , LPA 5 and LPA 6 . In 5 some embodiments, the LPA receptor is LPA 1 or LPA 2 or LPA 3 . In some embodiments, the disease or condition is any of the diseases or conditions specified herein. [0033] Also provided is a method of inhibiting the physiological activity of LPA in a mammal comprising administering a therapuetically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the mammal in need thereof. 10 [0034] In one aspect, is a method for treating or preventing a LPA-dependent or LPA mediated disease or condition in a mammal comprising administering a therapuetically effective amount of a compound of Formula (I). [0035] In one aspect, LPA-dependent or LPA-mediated diseases or conditions include, but are not limited to, fibrosis of organs or tissues, scarring, liver diseases, dermatological 15 conditions, cancer, cardiovascular disease, respiratory diseases or conditions, inflammatory disease, gastrointestinal tract disease, renal disease, urinary tract-associated disease, inflammatory disease of lower urinary tract, dysuria, frequent urination, pancreas disease, arterial obstruction, cerebral infarction, cerebral hemorrhage, pain, peripheral neuropathy, and fibromyalgia. 20 [0036] In some embodiments, the LPA-dependent or LPA-mediated disease or condition is selected from idiopathic pulmonary fibrosis; other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, langerhans cell granulomatosis, 25 lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease); radiation induced fibrosis; chronic obstructive pulmonary disease (COPD); scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); kidney fibrosis; 30 tubulointerstitium fibrosis; glomerular nephritis; focal segmental glomerular sclerosis; IgA nephropathy; hypertension; Alport; gut fibrosis; liver fibrosis; cirrhosis; alcohol induced liver fibrosis; toxic/drug induced liver fibrosis; hemochromatosis; nonalcoholic steatohepatitis (NASH); biliary duct injury; primary biliary cirrhosis; infection induced liver - 8- WO 2011/041461 PCT/US2010/050786 fibrosis; viral induced liver fibrosis; and autoimmune hepatitis; corneal scarring; hypertrophic scarring; Duputren disease, keloids, cutaneous fibrosis; cutaneous scleroderma; spinal cord injury/fibrosis; myelofibrosis; vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease, chronic lymphocytic 5 leukemia, tumor metastasis, transplant organ rejection, endometreosis, neonatal respiratory distress syndrome and neuropathic pain. [0037] In one aspect, is a method for treating or preventing cancer in a mammal comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the mammal in need thereof. 10 [0038] In one aspect, is a method for treating or preventing fibrosis in a mammal comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the mammal in need thereof. [0039] In one aspect, is a method for treating or preventing lung fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney 15 disease, liver fibrosis, skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, 20 atherosclerosis, Raynaud's phenomenom, or neuropathic pain in a mammal comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the mammal in need thereof. [0040] In one aspect, provided is a method for the treatment or prevention of organ fibrosis in a mammal comprising administering a therapeutically effective amount of a compound of 25 Formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need thereof. In some embodiments, the organ fibrosis comprises lung fibrosis, renal fibrosis, or hepatic fibrosis. [0041] In one aspect, provided is a method of improving lung function in a mammal comprising administering a therapeutically effective amount of a compound of Formula (I) 30 or a pharmaceutically acceptable salt thereof to the mammal in need thereof. In one aspect, the mammal has been diagnosed as having lung fibrosis. [0042] In one aspect, compounds disclosed herein are used to treat idiopathic pulmonary fibrosis (usual interstitial pneumonia) in a mammal. -9- WO 2011/041461 PCT/US2010/050786 [0043] In one aspect, compounds disclosed herein are used to treat Raynaud's phenomenon. Raynaud's phenomenon comprises both Raynaud's disease (where the phenomenon is idiopathic) and Raynaud's syndrome, where it is caused by some other instigating factor. [0044] In some embodiments, compounds disclosed herein are used to treat diffuse 5 parenchymal interstitial lung diseases in mammal: iatrogenic drug induced, occupational/environmental (Farmer lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease (scleroderma and others), alveolar proteinosis, langerhans cell granulonmatosis, lymphangioleiomyomatosis, Hermansky Pudlak Syndrome, Tuberous sclerosis, neurofibromatosis, metabolic storage disorders, 10 familial interstitial lung disease. [0045] In some embodiments, compounds disclosed herein are used to treat post-transplant fibrosis associated with chronic rejection in a mammal: Bronchiolitis obliterans for lung transplant. [0046] In some embodiments, compounds disclosed herein are used to treat cutaneous 15 fibrosis in a mammal: cutaneous scleroderma, Dupuytren disease, keloids. [0047] In one aspect, compounds disclosed herein are used to treat hepatic fibrosis with or without cirrhosis in a mammal: toxic/drug induced (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, hepatitis C virus, HCV), nonalcoholic liver disease (NASH), metabolic and auto-immune. 20 [0048] In one aspect, compounds disclosed herein are used to treat renal fibrosis in a mammal: tubulointerstitium fibrosis, glomerular sclerosis. [0049] In any of the aforementioned aspects involving the treatment of LPA dependent diseases or conditions are further embodiments comprising administering at least one additional agent in addition to the administartion of a compound having the structure of 25 Formula (I). In various embodiments, each agent is administered in any order, including simultaneously. [0050] In any of the embodiments disclosed herein, the mammal is a human. [0051] In some embodiments, compounds provided herein are administered to a human. In some embodiments, compounds provided herein are orally administered to a human. 30 [0052] In some embodiments, compounds provided herein are used as antagonists of at least one LPA receptor. In some embodiments, compounds provided herein are used for inhibiting the activity of at least one LPA receptor or for the treatment of a disease or - 10 - WO 2011/041461 PCT/US2010/050786 condition that would benefit from inhibition of the activity of at least one LPA receptor. In one aspect, the LPA receptor is LPA 1 . [0053] In other embodiments, compounds provided herein are used for the formulation of a medicament for the inhibition of LPA 1 activity. 5 [0054] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become 10 apparent to those skilled in the art from this detailed description BRIEF DESCRIPTION OF THE FIGURES [0055] Figure 1. Illustrative examples of compounds described herein. [0056] Figure 2. Illustrative examples of compounds described herein. [0057] Figure 3. Illustrative examples of compounds described herein. 15 [0058] Figure 4. Illustrative examples of compounds described herein. [0059] Figure 5. Illustrative examples of compounds described herein. [0060] Figure 6. Illustrative examples of compounds described herein. [0061] Figure 7. Illustrative examples of compounds described herein. [0062] Figure 8. Illustrative examples of compounds described herein. 20 [0063] Figure 9. Illustrative examples of compounds described herein. [0064] Figure 10. Illustrative examples of compounds described herein. [0065] Figure 11. Illustrative examples of compounds described herein. DETAILED DESCRIPTION OF THE INVENTION 25 [0066] Lysophospholipids (such as lysophosphatidic acid (LPA)) affect fundamental cellular functions that include cellular proliferation, differentiation, survival, migration, adhesion, invasion, and morphogensis. These functions influence many biological processes that include neurogensis, angiogenesis, wound healing, immunity, and carcinogenesis. [0067] LPA acts through sets of specific G protein-coupled receptors (GPCRs) in an 30 autocrine and paracrine fashion. LPA binding to its cognate GPCRs (LPA 1 , LPA 2 , LPA 3 ,
LPA
4 , LPA 5 , LPA 6 ) activates intracellular signaling pathways to produce a variety of biological responses. - 11 - WO 2011/041461 PCT/US2010/050786 [0068] LPA has a role as a biological effector molecule, and has a diverse range of physiological actions such as, but not limited to, effects on blood pressure, platelet activation, and smooth muscle contraction, and a variety of cellular effects, which include cell growth, cell rounding, neurite retraction, and actin stress fiber formation and cell 5 migration. The effects of LPA are predominantly receptor mediated. [0069] Activation of the LPA receptors with LPA mediates a range of downstream signaling cascades. The actual pathway and realized end point are dependent on a range of variables that include receptor usage, cell type, expression level of a receptor or signaling protein, and LPA concentration. Nearly all mammalian cells, tissues and organs co-express 10 several LPA-receptor subtypes, which indicates that LPA receptors signal in a cooperative manner. LPA 1 , LPA 2 , and LPA 3 share high amino acid sequence similarity. [0070] LPA regulates many important functions of fibroblasts in wound healing, including proliferation, migration, differentiation and contraction. Fibroblast proliferation is required in wound healing in order to fill an open wound. In contrast, fibrosis is characterized by 15 intense proliferation and accumulation of myofibroblasts that actively synthesize ECM and proinflammatory cytokines. LPA can either increase or suppress the proliferation of cell types important in wound healing. [0071] Tissue injury initiates a complex series of host wound-healing responses; if successful, these responses restore normal tissue structure and function. If not, these 20 responses can lead to tissue fibrosis and loss of function. [0072] A number of muscular dystrophies are characterized by a progressive weakness and wasting of musculature, and by extensive fibrosis. It has been shown that LPA treatment of cultured myoblasts induced significant expression of connective tissue growth factor (CTGF). CTGF subsequently induces collagen, fibronectin and integrin expression and 25 induces dedifferentiation of these myoblasts. Treatment of a variety of cell types with LPA induces reproducible and high level induction of CTGF. CTGF is a profibrotic cytokine, signaling down-stream and in parallel with TGF3. [0073] LPA and LPA 1 play key pathogenic roles in pulmonary fibrosis. Fibroblast chemoattractant activity plays an important role in the lungs in patients with pulmonary 30 fibrosis. Profibrotic effects of LPAi-receptor stimulation is explained by LPAI-receptor mediated vascular leakage and increased fibroblast recruitment, both profibrotic events. The
LPA-LPA
1 pathway has a role in mediating fibroblast migration and vascular leakage in IPF. The end result is the aberrant healing process that characterises this fibrotic condition. - 12 - WO 2011/041461 PCT/US2010/050786 [0074] The LPA-LPA2 pathway contributes to the activation of the TGF- pathway in pulmonary fibrosis. In some embodiments, compounds that inhibit LPA2 show efficacy in the treatment of lung fibrosis. In some embodiments, compounds that inhibit both LPA1 and LPA2 show improved efficacy in the treatment of lung fibrosis compared to compounds 5 which inhibit only LPA1 or LPA2. [0075] LPA and LPA 1 are involved in the etiology of kidney fibrosis. In mice invalidated for the LPA 1 receptor (LPA1 (-/-), the development of renal fibrosis was significantly attenuated. Unilateral ureteral obstruction (UUO; animal model of renal fibrosis) mice treated with the LPA receptor antagonist Ki16425 closely resembled the LPA 1 (-/-) mice. 10 [0076] LPA is implicated in liver disease and fibrosis. Plasma LPA levels and serum autotoxin are elevated in hepatitis patients and animal models of liver injury in correlation with increased fibrosis. LPA also regulates liver cell function. LPA 1 and LPA 2 receptors are expressed by mouse hepatic stellate cells and LPA stimulates migration of hepatic myofibroblasts. 15 [0077] LPA is in involved in wound healing in the eye. LPA 1 and LPA 3 receptors are detectable in the normal rabbit corneal epithelial cells, keratocytes and endothelial cells and
LPA
1 and LPA 3 expression are increased in corneal epithelial cells following injury. [0078] LPA is present in the aqueous humor and the lacrimal gland fluid of the rabbit eye and these levels are increased in a rabbit corneal injury model. 20 [0079] LPA induces actin stress fiber formation in rabbit corneal endothelial and epithelial cells and promotes contraction corneal fibroblasts. LPA also stimulates proliferation of human retinal pigmented epithelial cells. [0080] LPA is implicated in myocardial infarction and cardiac fibrosis. Serum LPA levels are increased in patients following mycocardial infarction (MI) and LPA stimulates 25 proliferation and collagen production (fibrosis) by rat cardiac fibroblasts. Both LPA1 and LPA3 receptors are highly expressed in human heart tissue. [0081] In one aspect, compounds of Formula (I) are used to treat or prevent fibrosis in a mammal. In one aspect, compounds of Formula (I) are used to treat or prevent fibrosis of an organ or tissue in a mammal. 30 [0082] The terms "fibrosis" or "fibrosing disorder," as used herein, refers to conditions that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of - 13 - WO 2011/041461 PCT/US2010/050786 individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract. [0083] Exemplary diseases, disorders, or conditions that involve fibrosis include, but are not limited to: Lung diseases associated with fibrosis, e.g., idiopathic pulmonary fibrosis, 5 pulmonary fibrosis secondary to systemic inflammatory disease such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury and acute respiratory distress (including bacterial pneumonia induced, trauma induced, viral pneumonia induced, 10 ventilator induced, non-pulmonary sepsis induced, and aspiration induced); Chronic nephropathies associated with injury/fibrosis (kidney fibrosis), e.g., glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, glomerular nephritis, focal segmental glomerular sclerosis, IgA nephropathy, hypertension, allograft and Alport; Gut fibrosis, e.g., scleroderma, and radiation induced gut fibrosis; 15 Liver fibrosis, e.g., cirrhosis, alcohol induced liver fibrosis, nonalcoholic steatohepatitis (NASH), biliary duct injury, primary biliary cirrhosis, infection or viral induced liver fibrosis (e.g., chronic HCV infection), and autoimmune hepatitis; Head and neck fibrosis, e.g., radiation induced; Corneal scarring, e.g., LASIK (laser-assisted in situ keratomileusis), corneal transplant, and trabeculectomy; Hypertrophic scarring and keloids, e.g., burn 20 induced or surgical; and other fibrotic diseases, e.g., sarcoidosis, scleroderma, spinal cord injury/fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease. [0084] In one aspect, a mammal suffering from one of the following non-limiting exemplary diseases, disorders, or conditions will benefit from therapy with a compound of 25 Formula (I): atherosclerosis, thrombosis, heart disease, vasculitis, formation of scar tissue, restenosis, phlobitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, bowel adhesions, bladder fibrosis and cystitis, fibrosis of the nasal passages, sinusitis, inflammation mediated by neutrophils, and fibrosis mediated by fibroblasts. 30 [0085] In one aspect, compounds of Formula (I) are used to treat a dermatological disorders in a mammal. Dermatological disorders include, but are not limited to, proliferative or inflammatory disorders of the skin such as, atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, - 14 - WO 2011/041461 PCT/US2010/050786 rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria. [0086] LPA is released following tissue injury. LPA 1 plays a role in the initiation of neuropathic pain. In one aspect, compounds of Formula (I) are used in the treatment of pain 5 in a mammal. In one aspect, the pain is acute pain or chronic pain. In another aspect, the pain is neuropathic pain. In another aspect, the pain is cancer pain. In one aspect, compounds of Formula (I) are used in the treatment of fibromylagia. [00871 Lysophospholipid receptor signaling plays a role in the etiology of cancer. Lysophosphatidic acid (LPA) and its G protein-coupled receptors (GPCRs) LPA 1 , LPA 2 , 10 and/or LPA 3 play a role in the development of several types of cancers. [0088] LPA contributes to tumorigenesis by increasing motility and invasiveness of cells. LPA has been implicated in the initiation or progression of ovarian cancer. LPA is present at significant concentrations (2-80 pM) in the ascitic fluid of ovarian cancer patients. LPA receptors (LPA2 and LPA3) are also overexpressed in ovarian cancer cells as compared to 15 normal ovarian surface epithelial cells. LPA has also been implicated in the initiation or progression of prostate cancer, breast cancer, melanoma, head and neck cancer, bowel cancer (colorectal cancer), thyroid cancer, glioblastoma, and other cancers. [0089] LPA receptors mediate both migration of and invasion by pancreatic cancer cell lines: Ki16425 and LPAI-specific siRNA effectively blocked in vitro migration in response 20 to LPA and peritoneal fluid (ascites) from pancreatic cancer patients; in addition, Ki16425 blocked the LPA-induced and ascites-induced invasion activity of a highly peritoneal metastatic pancreatic cancer cell line (Yamada et al, J. Biol. Chem., 279, 6595-6605, 2004). [00901 Colorectal carcinoma cell lines show significant expression of LPA 1 mRNA and respond to LPA by cell migration and production of angiogenic factors. Overexpression of 25 LPA receptors has a role in the pathogenesis of thyroid cancer. LPA 3 was originally cloned from prostate cancer cells, concordant with the ability of LPA to induce autocrine proliferation of prostate cancer cells. [0091] LPA has stimulatory roles in cancer progression in many types of cancer. LPA is produced from and induces proliferation of prostate cancer cell lines. LPA induces human 30 colon carcinoma DLD1 cell proliferation, migration, adhesion, and secretion of angiogenic factors through LPA 1 signalling. In other human colon carcinoma cells lines (HT29 and WiDR), LPA enhances cell proliferation and secretion of angiogenic factors. In other colon cancer cell lines, LPA 2 and LPA 3 receptor activation results in proliferation of the cells. - 15 - WO 2011/041461 PCT/US2010/050786
LPA
1 is implicated in bone metastasis (Boucharaba et al., Proc. Natl. Acad. Sci USA, 103, 9643-9648, 2006). [0092] In one aspect, a compound of Formula (I) is used in the treatment of cancer. In one aspect, compounds of Formula (I) are used in the treatment of malignant and benign 5 proliferative disease. In one aspect, compounds of Formula (I) are used to prevent or reduce proliferation of tumor cells, invasion and metastasis of carcinomas, pleural mesothelioma or peritoneal mesothelioma, cancer pain, bone metastases. In one aspect is a method of treating cancer in a mammal, the method comprising administering to the mammal a compound of Formula (I) and a second therapeutic agent, wherein the second therapeutic agent is an anti 10 cancer agent. In some embodiments, radiation therapy is also used. [0093] The types of cancer include, but is not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer) or hematological tumors (such as the leukemias) at any stage of the 15 disease with or without metastases. [0094] In one aspect, LPA is a contributor to the pathogenesis of respiratory diseases. Proinflammatory effects of LPA include degranulation of mast cells, contraction of smooth muscle cells and release of cytokines from dendritic cells. LPA induces the secretion of IL-8 from human bronchial epithelial cells. IL-8 is found in increased concentrations in BAL 20 fluids from patients with asthma, chronic obstructive lung disease, pulmonary sarcoidosis and acute respiratory distress syndrome and 11-8 has been shown to exacerbate airway inflammation and airway remodeling of asthmatics. LPA1, LPA2 and LPA3 receptors have all been shown to contribute to the LPA-induced IL-8 production. [0095] Administration of LPA in vivo induces airway hyper-responsiveness, itch-scratch 25 responses, infiltration and activation of eosinophils and neutrophils, vascular remodeling, and nociceptive flexor responses. LPA also induces histamine release from mouse and rat mast cells. In one aspect, the effects of LPA are mediated through LPA 1 and/or LPA 3 . In one aspect, compounds of Formula (I) are used in the treatment of various allergic disorders in a mammal. In one aspect, compounds of Formula (I) are used in the treatment of 30 respiratory diseases, disorders or conditions in a mammal. In one aspect, compounds of Formula (I) are used in the treatment of asthma in a mammal. In one aspect, compounds of Formula (I) are used in the treatment of chronic asthma in a mammal. - 16 - WO 2011/041461 PCT/US2010/050786 [0096] The term "respiratory disease," as used herein, refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphram and intercostals), and nerves. Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and 5 allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary 10 disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia. [0097] In one aspect, presented herein is the use of compounds of Formula (I) in the treatment or prevention of chronic obstructive pulmonary disease in a mammal comprising administering to the mammal at least once an effective amount of at least one compound of 15 Formula (I). In addition, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, and cystic fibrosis. [0098] The nervous system is a major locus for LPA 1 expression. In one aspect, provided is a compound of Formula (I) for use in the treatment or prevention of a nervous system 20 disorder in a mammal. The term "nervous system disorder," as used herein includes, but is not limited to, Alzheimer's Disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathies, Parkinson's Disease, multiple sclerosis, retinal ischemia, post surgical cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema and head injury. 25 [0099] Angiogenesis, the formation of new capillary networks from pre-existing vasculature, is normally invoked in wound healing, tissue growth and myocardial angiogenesis after ischemic injury. Peptide growth factors and lysophospholipids control coordinated proliferation, migration, adhesion, differentiation and assembly of vascular endothelial cells (VECs) and surrounding vascular smooth-muscle cells (VSMCs). In one 30 aspect, dysregulation of the processes mediating angiogenesis leads to atherosclerosis, hypertension, tumor growth, rheumatoid arthritis and diabetic retinopathy. [00100] In one aspect, compounds of Formula (I) are used to treat or prevent cardiovascular disease in mammal, including but not limited to: arrhythmia (atrial or ventricular or both); - 17 - WO 2011/041461 PCT/US2010/050786 atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or 5 traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue. [00101] In one aspect, provided herein are methods for preventing or treating vasoconstriction, atherosclerosis and its sequelae myocardial ischemia, myocardial 10 infarction, aortic aneurysm, vasculitis and stroke comprising administering at least once to the mammal an effective amount of at least one compound of Formula (I) or pharmaceutical composition or medicament which includes a compound of Formula (I). In some embodiments, provided herein are methods for preventing or treating Raynaud's phenomenon. 15 [00102] In one aspect, provided herein are methods for reducing cardiac reperfusion injury following myocardial ischemia and/or endotoxic shock comprising administering at least once to the mammal an effective amount of at least one compound of Formula (I). [00103] In one aspect, provided herein are methods for reducing the constriction of blood vessels in a mammal comprising administering at least once to the mammal an effective 20 amount of at least one compound of Formula (I). [00104] In one aspect, provided herein are methods for lowering or preventing an increase in blood pressure of a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formula (I). [00105] LPA is associated with various inflammatory/immune diseases. In one aspect, 25 compounds of Formula (I) are used to treat or prevent inflammation in a mammal. In one aspect, antagonists of LPA 1 and/or LPA 3 find use in the treatment or prevention of inflammatory/immune disorders in a mammal. [00106] Examples of inflammatory/immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory 30 muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, - 18- WO 2011/041461 PCT/US2010/050786 thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis. [00107] In accordance with one aspect, are methods for treating, preventing, reversing, 5 halting or slowing the progression of LPA-dependent or LPA-mediated diseases or conditions once it becomes clinically evident, or treating the symptoms associated with or related to LPA-dependent or LPA-mediated diseases or conditions, by administering to the mammal a compound of Formula (I). In certain embodiments, the subject already has a LPA-dependent or LPA-mediated disease or condition at the time of administration, or is at 10 risk of developing a LPA-dependent or LPA-mediated disease or condition. [00108] In certain aspects, are methods for preventing or treating eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte and/or T-cell recruitment comprising administering at least once to the mammal an effective amount of at least one compound of Formula (I). 15 [001091 In certain aspects, are methods for the treatment of cystitis, including, e.g.,interstitial cystitis, comprising administering at least once to the mammal a therapeutically effective amount of at least one compound of Formula (I). [001101 In accordance with one aspect, methods described herein include the diagnosis or determination of whether or not a patient is suffering from a LPA-dependent or LPA 20 mediated disease or condition by administering to the subject a therapeutically effective amount of a compound of Formula (I) and determining whether or not the patient responds to the treatment. [00111] In one aspect provided herein are compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable 25 solvates thereof, which are antagonists of at least one LPA receptor (e.g. LPA 1 , LPA 2 ,
LPA
3 ) and are used to treat patients suffering from one or more LPA-dependent or LPA mediated conditions or diseases, including, but not limited to, lung fibrosis, kindney fibrosis, liver fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis, inflammatory 30 bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative disorders and inflammatory conditions. In some embodiments, LPA-dependent conditions or diseases include those wherein an absolute or relative excess of LPA is present and/or observed. - 19 - WO 2011/041461 PCT/US2010/050786 [00112] In any of the aforementioned aspects the LPA-dependent or LPA-mediated diseases or conditions include, but are not limited to, organ fibrosis, asthma, allergic disorders, chronic obstructive pulmonary disease, pulmonary hypertension, lung or pleural fibrosis, peritoneal fibrosis, arthritis, allergy, cancer, cardiovascular disease, aldult respiratory 5 distress syndrome, myocardial infarction, aneurysm, stroke, and cancer. [00113] In one aspect, compounds of Formula (I) are used to improve the corneal sensitivity decrease caused by corneal operations such as laser-assisted in situ keratomileusis (LASIK) or cataract operation, corneal sensitivity decrease caused by corneal degeneration, and dry eye symptom caused thereby. 10 [00114] In one aspect, presented herein is the use of compounds of Formula (I) in the treatment or prevention of ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis in a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formula (I). [00115] In one aspect, presented herein is the use of compounds of Formula (I) in the 15 treatment or prevention of Sjogren disease or inflammatory disease with dry eyes in a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formula (I). [00116] In one aspect, LPA and LPA receptors (e.g. LPA 1 ) are involved in the pathogenesis of osteoarthritis. In one aspect, presented herein is the use of compounds of Formula (I) in 20 the treatment or prevention of osteoarthritis in a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formula (I). [00117] In one aspect, LPA receptors (e.g. LPA 1 , LPA 3 ) contribute to the pathogenesis of rheumatoid arthritis. In one aspect, presented herein is the use of compounds of Formula (I) in the treatment or prevention of rheumatoid arthritis in a mammal comprising 25 administering at least once to the mammal an effective amount of at least one compound of Formula (I). [00118] In one aspect, LPA receptors (e.g. LPA 1 ) contribute to adipogenesis. In one aspect, presented herein is the use of compounds of Formula (I) in the promotion of adipose tissue formation in a mammal comprising administering at least once to the mammal an effective 30 amount of at least one compound of Formula (I). Compounds [00119] In one aspect, provided herein is a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof: - 20 - WO 2011/041461 PCT/US2010/050786 (R r (R N /
R
5 L2 L4 (Rc Formula (I) wherein, RI is -CO 2 RD, -C(=O)NHSO 2 RE, -C(=O)N(RD) 2 , -CN, or tetrazolyl; 5 RD is H or CI-C 6 alkyl; RE is C 1
-C
6 alkyl or a substituted or unsubstituted phenyl;
L
2 is absent, -C(=O)-, -N(RD)-, substituted or unsubstituted Ci-C 4 alkylene, or substituted or unsubstituted C 1
-C
4 heteroalkylene, where if L 2 is substituted, then L 2 is substituted with R 12 , where R 12 is F, C 1
-C
4 alkyl, -OH, or -ORD; 10 ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic CI-C 5 heteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R 4 , each R' 4 is independently selected from halogen, CN, -OH, C 1
-C
4 alkyl, C 1
-C
4 fluoroalkyl, C 1
-C
4 fluoroalkoxy, C 1
-C
4 alkoxy, and
C
1
-C
4 heteroalkyl; 15 L 4 is absent, or a substituted or unsubstituted C 1
-C
4 alkylene, where if L 4 is substituted then L 4 is substituted with R 13 , where R 13 is F, CI-C 4 alkyl, -OH, or -ORD;
R
5 is H or C 1
-C
4 alkyl; each RA is independently selected from halogen, -CN, -OH, CI-C 4 alkyl, C 1 20 C 4 fluoroalkyl, C 1
-C
4 fluoroalkoxy, CI-C 4 alkoxy, and C1-C 4 heteroalkyl; each RB is independently selected from halogen, -CN, -OH, C 1
-C
4 alkyl, C1
C
4 fluoroalkyl, C1-C 4 fluoroalkoxy, CI-C 4 alkoxy, and C 1
-C
4 heteroalkyl; each RC is independently selected from halogen, -CN, -OH, CI-C 4 alkyl, C 1 C 4 fluoroalkyl, C 1
-C
4 fluoroalkoxy, C 1
-C
4 alkoxy, and C1-C 4 heteroalkyl; 25 m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; r is 1, 2, 3, or 4. [00120] For any and all of the embodiments, substituents are selected from among from a subset of the listed alternatives. For example, in some embodiments, R 1 is -CO 2 RD or ED
C(=O)NHSO
2 RE. In some embodiments, R 1 is -CO 2 RD. In some embodiments, R 1 is -21 - WO 2011/041461 PCT/US2010/050786 CO2H. In some embodiments, R 1 is -C(=O)NHSO 2 RE. In some embodiments, RE is C 1
-C
6 alkyl. In some embodiments, RE is -CH 3 or -CH 2
CH
3 . In some embodiments, RD is H, CH 3 or -CH 2
CH
3 . In some embodiments, RD is H. [00121] In some embodiments, R 5 is C 1
-C
4 alkyl. In some embodiments, R 5 is H, -CH 3 , or 5 CH2CH 3 . In some embodiments, R 5 is -CH 3 , or -CH 2
CH
3 . In some embodiments, R 5 is CH 3 . In some embodiments, R 5 is H. [00122] In some embodiments, L 2 is absent, -C(=O)-, -N(RD)-, substituted or unsubstituted
C
1
-C
4 alkylene, or substituted or unsubstituted C 1
-C
4 heteroalkylene, where if L2 is substituted, then L 2 is substituted with R 12 . In some embodiments, L 2 is -N(RD)-, 10 substituted or unsubstituted C 1
-C
2 alkylene, or substituted or unsubstituted C 1
-C
2 heteroalkylene, where if L 2 is substituted, then L 2 is substituted with R 2 . In some embodiments, L2 is -N(H)-, -N(CH 3 )-, substituted or unsubstituted methylene, or substituted or unsubstituted ethylene, where if L 2 is substituted, then L 2 is substituted with R 12 . In some embodiments, L2 is -N(H)-. In some embodiments, L 2 is substituted or unsubstituted 15 methylene, where if L 2 is substituted, then L 2 is substituted with R 12 . [00123] In some embodiments, L 2 is selected from a bond, C 1
-C
4 alkylene, -C(=O)-, CH(OH)-, -CH(ORD)-, -CH 2 CH(OH)-, - CH 2 CH(ORD)-, -CH 2 S-, -CH 2 S(O)-, -CH 2
S(O)
2 -, SCH 2 -, - S(O)CH 2 -, -S(O) 2
CH
2 -, -CH 2 0-, -OCH 2 -, -S(O) 2
CH
2 -, -N(H)-, -CH 2 N(H)-, or N(H)CH 2 -. 20 [00124] In some embodiments, L 2 is absent, -C(=O)-, -NH-, -N(CH 3 )-, -CH 2 -, -CH 2
CH
2 -, CH(CH 3 )-, -CH 2
CH(CH
3 )-, -CH(CH 3
)CH
2 -, -CH(OH)-, -CH(ORD)-, -CH 2 CH(OH)-, CH 2 CH(ORD)-, -CH(OH)CH 2 -, -CH(ORD)CH 2 -, -CH 2 NH-, -CH(CH 3 )NH-, -NHCH 2 - or NHCH(CH 3 )-. In some embodiments, L 2 is -NH-, -N(CH 3 )-, -CH 2 -, -CH(CH 3 )-, -CH(OH)-, -CH(ORD)-, -CH 2 NH-, -CH(CH 3 )NH-, -NHCH 2 - or -NHCH(CH 3 )-. In some embodiments, 25 L2 is -NH-, -N(CH 3 )-, -CH 2 NH-, -CH(CH 3 )NH-, -NHCH 2 - or -NHCH(CH 3 )-. In some embodiments, L2 is -NH-. In some embodiments, L 2 is -CH 2 -, -CH(CH 3 )-, -CH(OH)-, CH(OR D)-, -CH 2 NH-, -CH(CH 3 )NH-, -NHCH 2 - or -NHCH(CH 3 )-. In some embodiments, L2 is -CH 2 -, -CH(CH 3 )-, -CH(OH)-, or -CH(OR D)-. In some embodiments, L2 is -CH 2 - or CH(OH)-. In some embodiments, L2 is -CH(OH)-. In some embodiments, L2 is -CH 2 -. 30 [00125] In some embodiments, R 12 is F, -CH 3 , -CH 2
CH
3 , -OH, -OCH 3 , or -OCH 2
CH
3 . In some embodiments, R 12 is -CH 3 , or -OH. [00126] In some embodiments, R 1 is -CO 2 RD, or -C(=O)NHSO 2 RE- L 2 is absent, -C(=O)-, NH-, -N(CH 3 )-, -CH 2 -, -CH 2
CH
2 -, -CH(CH 3 )-, -CH 2
CH(CH
3 )-, -CH(CH 3
)CH
2 -, -CH(OH)-, - 22 - WO 2011/041461 PCT/US2010/050786 -CH(ORD)-, -CH 2 CH(OH)-, -CH 2 CH(ORD)-, -CH(OH)CH 2 -, -CH(ORD)CH 2 -, -CH 2 NH-, CH(CH 3 )NH-, -NHCH 2 - or -NHCH(CH 3 )-; L 4 is absent, -CH 2 -, -CH(CH 3 )-, -CH(OH)-, CH 2
CH
2 -, -CH 2
CH(CH
3 )-, -CH(CH 3
)CH
2 -, -CH 2 CH(OH)-, or -CH(OH)CH 2 -; R' is -H, CH 3 or -CH 2
CH
3 . 5 [00127] In some embodiments, each RA is independently selected from halogen, -OH, -CH 3 ,
-CH
2
CH
3 , -CF 3 , -OCF 3 , -OCH 3 and -OCH 2
CH
3 . In some embodiments, each RAis halogen, -OH, -CH 3 , -CH 2
CH
3 , -CF 3 , -OCF 3 , -OCH 3 or -OCH 2
CH
3 . [00128] In some embodiments, each RB is independently selected from halogen, -OH, -CH 3 ,
-CH
2
CH
3 , -CF 3 , -OCF 3 , -OCH 3 and -OCH 2
CH
3 . In some embodiments, each RB is halogen, 10 -OH, -CH 3 , -CH 2
CH
3 , -CF 3 , -OCF 3 , -OCH 3 or -OCH 2
CH
3 . [00129] In some embodiments, each RC is halogen, -OH, -CH 3 , -CH 2
CH
3 , -CF 3 , -OCF 3 , OCH 3 , -OCH 2
CH
3 , -CH 2 0CH 3 , -CH 2 0CH 2
CH
3 , or -CH 2 N( CH 3
)
2 . In some embodiments, each RC is independently selected from halogen, -OH, -CH 3 , -CH 2
CH
3 , -CF 3 , -OCF 3 , -OCH 3 and -OCH 2
CH
3 . 15 [00130] In some embodiments, m is 0 or 1; n is 0 or 1; r is 1, 2, or 3. [00131] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, r is 1, 2, or 3. In some embodiments, r is 1 or 2. In some embodiments, r is 1. [00132] In some embodiments, ring A is a substituted or unsubstituted phenyl, or a 20 substituted or unsubstituted monocyclic Ci-C 5 heteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 . [00133] In some embodiments, ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic C1-C 5 heteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 25 or 2 R 14 . [00134] In some embodiments, ring A is a substituted or unsubstituted monocyclic C 1 C 5 heteroarylene containing 1-4 N atoms, 0 or 1 0 atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 1 4 . [00135] In some embodiments, ring A is a substituted or unsubstituted 5-membered 30 monocyclic C1-C 4 heteroarylene containing 1-4 N atoms, 0 or 1 0 atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 . - 23 - WO 2011/041461 PCT/US2010/050786 [00136] In some embodiments, ring A is a substituted or unsubstituted 6-membered monocyclic C 3
-C
5 heteroarylene containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 1 . [00137] In some embodiments, ring A is a substituted or unsubstituted monocyclic ring 5 wherein the groups -L 2 - and -L 4 - are in a 1,2-relationship on ring A (i.e. an ortho relationship). [00138] In some embodiments, ring A is a substituted or unsubstituted monocyclic ring wherein the groups -L 2 - and -L 4 - are in a 1,3-relationship on ring A (i.e. a meta relationship). 10 [00139] In some embodiments, ring A is a substituted or unsubstituted monocyclic ring wherein the groups -L 2 - and -L 4 - are in a 1,4-relationship on ring A (i.e. a para relationship). [00140] In some embodiments, ring A is unsubstituted or monosubstituted with R 4 . In some embodiments, ring A is unsubstituted. In some embodiments, ring A is monosubstituted 15 with R 4 . [00141] In some embodiments, L 4 is absent, or a substituted or unsubstituted methylene, or substituted or unsubstituted ethylene, where if L 4 is substituted, then L 4 is substituted with 1344 R . In some embodiments, L 4 is absent. In some embodiments, L 4 is a substituted or unsubstituted methylene, where if L 4 is substituted, then L 4 is substituted with R 13 . In some 20 embodiments, L 4 is a substituted or unsubstituted ethylene, where if L 4 is substituted, then
L
4 is substituted with R 13 . [00142] In some embodiments, R 13 is F, -CH 3 , -CH 2
CH
3 , -OH, -OCH 3 , or -OCH 2
CH
3 . In some embodiments, R 13 is -CH 3 . [00143] In some embodiments, L 4 is absent, -CH 2 -, or -CH(CH 3 )-. 25 [00144] In some embodiments, L 2 is -NH-, -CH 2 -, -CH 2
CH
2 -, -CH(CH 3 )-, -CH 2
CH(CH
3 )-, CH(CH 3
)CH
2 -, -CH(OH)-, -CH 2 CH(OH)-, -CH(OH)CH 2 -, -CH 2 NH-, -CH(CH 3 )NH-, NHCH 2 - or -NHCH(CH 3 )-; ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic C1-C 5 heteroarylene containing 1-4 N atoms, 0 or 1 0 atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 ; 30 L 4 is absent, -CH 2 -, or -CH(CH 3 )-; R 5 is -CH 3 ; r is 1. [00145] In some embodiments, ring A is a substituted or unsubstituted phenyl, where if ring A is substituted, then ring A is substituted with 1 or 2 R 4 . - 24 - WO 2011/041461 PCT/US2010/050786 [00146] In some embodiments, ring A is a substituted or unsubstituted monocyclic C1
C
5 heteroarylene containing 1-4 N atoms, 0 or 1 0 atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 1 4 . [00147] In some embodiments, ring A is a substituted or unsubstituted 5-membered 5 monocyclic C1-C 4 heteroarylene containing 1-4 N atoms, 0 or 1 0 atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 . [00148] In some embodiments, ring A is a substituted or unsubstituted furanyl, a substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, 10 substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted thiadiazolyl, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 . [00149] In some embodiments, each R 1 4 is independently selected from halogen, -CN, -OH, 15 CH 3 , -CH 2
CH
3 , -CF 3 , -OCF 3 , -OCH 3 and -OCH 2
CH
3 . In some embodiments, each R 1 4 is halogen, -CN, -OH, -CH 3 , -CH 2
CH
3 , -CF 3 , -OCF 3 , -OCH 3 or -OCH 2
CH
3 . In some embodiments, each R1 4 is independently selected from halogen, -OH, and -CH 3 . . In some embodiments, R 14 is halogen, -OH, or -CH 3 . In some embodiments, each R 14 is independently selected from halogen and -CH 3 . /0 S / 20 [00150] In some embodiments, ring A is , T> /N // 0 N/J 5 S , N , NJ S NN- N NS N N N N -N N 0r 0>~ /y /NS> /NN~/f O N NNSN N /N ON , -N , - 25 - WO 2011/041461 PCT/US2010/050786 -N NN N / N N ~ N .NN NN N- N N0 , N , , N , N , ' N
NN
, N-1 or N [00151] In some embodiments, ring A is a substituted or unsubstituted 6-membered monocyclic C 3
-C
5 heteroarylene containing 1-3 N atoms, where if ring A is substituted, then 5 ring A is substituted with 1 or 2 R 1 . [00152] In some embodiments, ring A is a substituted or unsubstituted pyridinylene, a substituted or unsubstituted pyridazinylene, a substituted or unsubstituted pyrimidinylene, a substituted or unsubstituted pyrazinylene, or a substituted or unsubstituted triazinylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R 4 . 10 [00153] In some embodiments, ring A is a substituted or unsubstituted pyridinylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R 4 . N [00154] In some embodiments, ring A is N N N N1 N , N , Nor NN "Y1RN N " N N N N N - N NN N Nal N N6N 15 N N ,or N [00155] In some embodiments, the compound of Formula (I) has the structure of Formula N L2-C L4 (c Formula (II). - 26 - WO 2011/041461 PCT/US2010/050786 [00156] In some embodiments, R 1 is -CO 2 RD, or -C(=0)NHSO 2 RE; RD is H or C 1
-C
4 alkyl; RE is C 1
-C
4 alkyl; L2 is -CH 2 -, -CH(CH 3 )-, or -CH(OH)-; ring A is a substituted or unsubstituted 5-membered monocyclic C1-C 4 heteroarylene containing 1-4 N atoms and 0 or 1 0 atoms, where if ring A is substituted, then ring A is substituted with R 14 , R 14 is halogen, 5 -CN, -OH, -CH 3 , -CH 2
CH
3 , -CF 3 , -OCF 3 , -OCH 3 or -OCH 2
CH
3 ; L4 is -CH 2 - or -CH(CH 3 )-; p is 0 or 1. [00157] In some embodiments, R 1 is -CO 2 RD, or -C(=O)NHSO 2 RE; RD is H or CI-C 4 alkyl; RE is C 1
-C
4 alkyl; L2 is -NH-, -CH 2 -, -CH(CH 3 )-, -CH(OH)-, -NHCH 2 - or -NHCH(CH 3 )-; ring A is a substituted or unsubstituted pyridinylene, where if ring A is substituted, then ring 10 A is substituted with R 14 , R 14 is halogen, -CN, -OH, -CH 3 , -CH 2
CH
3 , -CF 3 , -OCF 3 , -OCH 3 or -OCH 2
CH
3 ; L 4 is absent, -CH 2 -, or -CH(CH 3 )-; p is 0 or 1. [00158] In some embodiments, p is 0, 1 or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. [00159] In some embodiments, (Rc)P is phenyl, 2-fluorophenyl, 2,3 15 difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 2,4-dichlorophenyl, 2-hydroxyphenyl, 3- hydroxyphenyl, 4- hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4 methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2 20 cyanophenyl, 3-cyanophenyl, or 4-cyanophenyl. 1001601 In some embodiments, -L 2 - is as described in Table(s) 1, 2 and/or 3. [00161] In some embodiments, -L 4 - is as described in Table(s) 1, 2 and/or 3. 1001621 In some embodiments, ring A is as described in Table(s) 1, Table 2 and/or 3. [001631] In some embodiments, (R) is R 2 as defined in Table(s) 1, 2 and/or 3. 25 [00164] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [00165] In some embodiments, compounds of Formula (I) include, but are not limited to, those described in Tables 1 to 3 and Figures 1 to 11. 30 Table 1: - 27 - WO 2011/041461 PCT/US2010/050786
H
3 C O 2 H A L4 R2 Cmpd r L2 A L 4
R
2 M+H* No 1 I -CH2- Pyrazol-1,3-diyl - Phenyl 476 2 1 -CH2- [1,2,3]Triazol-1,4- Phenyl 477 11 diyl 3 1 -CH2- [1,3,4]Oxadiazol- Phenyl 478 2,5-diyl 4 1 -CH2- [1,2,3]Tnazol-1,4- -CH2- Phenyl 491 1 diyl 5 1 -CH2- Pyrazol-1,3-diyl - 4-Bromo-phenyl 554 6 1 -CH 2 -NH- [1,3,4]Oxadiazol- - Phenyl 493 ________ 2,5-diyl ____ 7 1 -CH2- [1,2,3]Triazol-1,5- - Phenyl 477 1 diyl 8 1 -CH2- Tetrazol-2,5-diyl - Phenyl 478 9 1 -CH2- Pyrazol-1,4-diyl - Phenyl 476 10 1 - [1,3,4]Oxadiazol- -CH2- Phenyl 478 2,5-diyl 11 1 -CH(OH) 1H-[1,243iazol -CH2- Phenyl 507 12 1 -CH2- [1,3,4]Oxadiazol- -CH2- Phenyl 492 2,5-diyl 13 1 -CH(OH)- [1,3,4]Oxadiazol- -CH2- Phenyl 508 2,5-diyl 14 1 -CH2- 1H-[1,2,3]Triazol- -CH2- Phenyl 491 1,4-diyl 15 1 (S)-CH(OH)- [1,3,4]Oxadiazol- -CH2- Phenyl 508 2,5-diyl 16 1 (R)-CH(OH)- [1,3,4]Oxadiazol- - Phenyl 508 2,5-diyl 17 1 -CH(OH)- [1,3,4]Oxadiazol- Phenyl 494 2,5-diyl 18 1 (S)-CH(OH)- 1H-[1,2,3]Triazol- -CH2- Phenyl 507 1,4-diyl 19 1 (R)-CH(OH)- 1H-[ 1,2,3]Triazol- -H Phenyl 507 1,4-diyl 20 1 -CH(OH)- [1,3,4]Oxadiazol- -CH2- 4-Trifluoromethyl- 576 2,5-diyl phenyl 21 1 -CH(OH)- 1H-[1,2,3]Triazol- -CH2- 3-Trifluoromethyl- 575 1,4-diyl phenyl 22 1 -CH(OH)- Phenyl-1,3-diyl - Phenyl 502 23 1 -CH(OH)- 1H-[1,2,3]Triazol- -CH(CH 3 )- Phenyl 521 1,4-diyl ___ 24 1 -CH(OH)- 1H-[1,2,3]Triazol- -CH2- 2-Trifluoromethyl 2 11,4-diyl phenyl 25 1 -CH(OH)- 1H-[1,2,3]Triazol- -CH 2 - 3-Chloro-phenyl 541 -28- WO 2011/041461 PCT/US2010/050786 Cmpd r L2 A L4 RM2 +H* -No 1,4-diyl 26 1 -CH(OH)- Phenyl-1,3-diyl -CH 2 - Phenyl 516 27 1 -CH(OH)- Pyridine-3,5-diyl -CH 2 - Phenyl 517 28 1 -CH(OH)- 1H-[1,2,3]Triazol- -CH 2 - 2-Chloro-phenyl 541 1,4-diyl 29 1 -CH(OH)- 1H-[1,2,3]Triazol- -CH 2 - 4-Chloro-phenyl 541 1,4-diyl 30 1 (R)-CH(OH)- 1H-[1,2,3]Triazol- -CH 2 - 2-Choro-phenyl 541 1,4-diyl 31 1 -CH(OH)- 1H-[1,2,3 ]Triazol- -CH 2 - 3,4-Dichloro-phenyl 1,4-diyl 32 1 (R)-CH(OH)- 1H-[1,2,3]Triazol- -CH(CH 3 )- (R) Phenyl 521 1 ,4-diyl 33 1 -NH- Pyridine-2,6-diyl - Phenyl 488 34 1 -CHO- Pyridine-2,6-diyl -CH 2 - Phenyl 517 35 11C(O) H-[ 1,2,3]Triazol- -CH 2 - 2-Methyl-phenyl 521 0 1 -H- |P1,4-diyl S 1 -H - iH-[1,2,3]Triazol- - 2-Chloro-6-foo ro- 556 -1,4-diyl phenyl 37 1 -H - [1,2,3]Triazol- -CH 2 - 2,6-Dichloro-phenyl 575 1,4-diyl 38 1 -NH- Pyridine-2,6-diyl -CH 2 - Phenyl 502 39 1 -NH- Phenyl-1,3-diyl - Phenyl 487 40 1 -NH- Phenyl-1,4-diyl - Phenyl 487 41 1 -NH- Pyridine-2,6-diyl - 3-Trifluoromethyl- 556 phenyl 42 1 -NH- Pyrazine-2,6-diyl - Phenyl 489 43 1 -NH- [1,3,4]Oxadiazol- - Phenyl 479 1 -NH- | 2,5-diyl 44 1 -NH- [1,3,4]Oxadiazol- -CH 2 - Phenyl 493 1 -NH-2,5-diyl 45 1 -NH- Pyridine-2,6-diyl -CH 2 - 2-Fluoro-phenyl 520 46 1 -NH- Pyridine-2,6-diyl -CH 2 - 3-Fluoro-phenyl 520 47 1 -NH- Pyridine-2,6-diyl -CH 2 - 4-Fluoro-phenyl 520 48 1 -NH- Pyridine-2,6-diyl - 3-Methoxy-phenyl 518 49 1 -NH- Phenyl-1,3-diyl -CH 2 - Phenyl 501 50 1 -NH- Pyridine-2,6-diyl - 2-Cyano-phenyl 513 51 1 -NH- Pyridine-2,6-diyl - 4-Methoxy-phenyl 518 52 1 -NH- Pyridine-2,6-diyl - 3-Fluoro-phenyl 506 53 1 -NH- Pyridine-2,6-diyl - 2-Methoxy-phenyl 518 54 1 -NH- Pyridine-2,6-diyl - 2-Fluoro-phenyl 506 55 1 -NH- Pyridine-2,6-diyl - 2-Trifluoromethyl- 556 phenyl 56 1 -NHCH 2 - 1,3-Thiazole-2,5- -Phenyl 508 diyl 57 1 -NH- Phenyl-1,3-diyl - 2-Trifluoromethyl- 555~> 1 ~phenyl ___ 58 1 -NH- Pyridine-3,5-diyl - Phenyl 488 59 1 -NH- Pyridine-3,5-diyl - 3-Fluoro-phenyl 506 60 1 -NH- Pyridine-2,6-diyl - 2-Chioro-phenyl 522 - 29 - WO 2011/041461 PCT/US2010/050786 Cmpd r L A L4 RM2 +H* No 61 1 -CH(OH)- Pyridine-2,6-diyl - Phenyl 503 62 1 -NH- Pyridine-2,4-diyl - Phenyl 488 63 1 -NH- Pyridine-2,4-diyl - 3-Fluoro-phenyl 506 64 1 -NH- Pyridine-3,5-diyl - 2-Chloro-phenyl 522 65 1 -NH- Pyridine-2,4-diyl - 2-Chloro-phenyl 522 66 1 -NH- Pyrimidine-2,6-diyl - Phenyl 489 67 1 -NH- Pyridine-2,4-diyl - Phenyl 488 68 1 -NH- Pyridine-3,5-diyl - 3-Trifluoromethyl phenyl 69 1 -NH- Pyridine-3,5-diyl - 4-Trifluoromethyl- 556 phenyl 70 2 -NH- Pyridine-2,6-diyl - Phenyl 502 71 1 -CH(OH)- Pyridine-3,5-diyl - Phenyl 503 72 1 -CH(OH)- Pyridine-3,5-diyl - 3-Trifluoromethyl- 571 phenyl 73 1 -NH- Pyridine-2,6-diyl -C--C- Phenyl 512 74 1 -NH- Pyridine-2,6-diyl - 3-Cyano-phenyl 513 75 1 -NH- Pyridine-2,6-diyl - 5-Fluoro-2-methoxy- 536 phenyl 76 1 -NH- Pyridine-2,6-diyl - 3-Chloro-5-fluoro- 540 phenyl 77 1 -NH- Pyridine-2,6-diyl - 2,5-Difluoro-phenyl 524 78 1 -NH- Pyridine-2,6-diyl - 2,6-Dichloro-phenyl 556 79 1 -NH- Pyridine-2,6-diyl - 2-Chloro-5-fluoro- 540 phenyl 80 1 -NH- Pyridine-2,6-diyl - 2,3-Difluoro-phenyl 524 81 1 -NH- Pyridine-2,6-diyl - 2-Chloro-3-fluoro- 540 phenyl 82 1 -NH- Pyridine-3,5-diyl - 2-Chloro-3-fluoro- 540 phenyl 83 1 -NH- Pyridine-2,6-diyl - 3-Fluoro-2-methyl- 520 phenyl 2-Chloro-3 84 1 -NH- Pyridine-2,6-diyl - trifluoromethyl- 590 phenyl 85 1 -NH- Phenyl-1,3-diyl - 2-(Dimethylamino)- 544 methyl-phenyl 86 1 -NH- Pyridine-2,6-diyl - 2,3-Dichloro-phenyl 556 87 1 -NH- Pyridine-2,6-diyl - 3-Fluoro-2-methoxy- 536 phenyl 88 1 -NH- Pyridine-3,5-diyl - 3-Chloro-phenyl 522 89 1 -NH- Pyridine-3,5-diyl - 2,5-Difluoro-phenyl 524 90 1 -NH- Pyridine-2,6-diyl - 3-Chloro-phenyl 522 * mass spectrometric data Table 2: - 30 - WO 2011/041461 PCT/US2010/050786 H 30 NH L2 S02CH 3 A R 2 Cmpd L 2 A L4
R
2 M+H* No 91 -CH(OH)- [1,2,3]Triazol-1,4-diyl -CH 2 - Phenyl 584 92 -CH(OH)- [1,3,4]Oxadiazol-2,5-diyl -CH 2 - Phenyl 585 93 -CH(OH)- [1,2,3]Triazol-1,4-diyl -CH 2 - 3-Trifluoromethyl-phenyl 652 94 -NH- [1,3,4]Oxadiazol-2,5-diyl - Phenyl 556 95 -NH- Pyridine-2,6-diyl -CH 2 - Phenyl 579 96 -NH- Pyridine-2,6-diyl - Phenyl 565 * mass spectrometric data Table 3: 5 R 5 0 2 H /L2 A R 2 Cmpdl 2 A 4 R2 R5 MH CNo~ L 2A L 4 R 2R M V+H* No 97 -NH- Pyridine-2,6-diyl - Phenyl -CH 2
CH
3 502 98 -NH- [1,3,4]Oxadiazol-2,5-diy1 - Phenyl -CH 2
CH
3 493 * mass spectrometric data Synthesis of Compounds 10 [00166] Compounds of Formula (I) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. In additions, solvents, temperatures and other reaction conditions presented herein may vary. [00167] The starting material used for the synthesis of the compounds of Formula (I) are 15 either synthesized or obtained from commercial sources, such as, but not limited to, Sigma Aldrich, Fluka, Acros Organics, Alfa Aesar, and the like. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein or otherwise known, including those found in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED 20 ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, -31 - WO 2011/041461 PCT/US2010/050786 PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). General methods for the preparation of compounds can be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formulae as provided herein. 5 [00168] In some embodiments, the synthesis of compounds of Formula (I) begins with the synthetic steps outlined in Scheme 1. Scheme 1 Br Br Br 1-III OMeNH 2 NH 0 0 H 2 NOH-HCI 0 0 MeOH pyridine, THF 0 AcO H _ I -IV 1-V LiOH reduction MeOH,
H
2 Br Br Br Br HON HCI 1-VII I H DPPA, NEt 3 , toluene O o NH 2 N 80*C _ OH N _ OH N N o/ N_ 1 -VI 1-IX 1-VIII 1-x 10 [00169] In one aspect, the synthesis of compounds of Formula (I) described herein begins with the reaction of an alkyl acetoacetate with methylamine to provide a compound of structure 1-II. Compounds of structure 1-II are reacted with a substituted or unsubstituted 4-halo-benzoyl chloride (structure 1-111) to provide compounds of structure 1-IV. Treatment of compounds of structure 1-IV with hydroxyl amine and acetic acid provides 15 isoxazoles of structure 1-V. Hydrolysis of the ester group of isoxazoles of structure 1-V provides carboxylic acids of structure 1-VI. A Curtius rearrangement of carboxylic acids of structure 1-VI in the presence of hydroxy compounds of structure 1-VII provides carbamate compounds of structure 1-VIII. Deprotection of the tert-butoxycarbonyl group provides amines of structure 1-IX which are further functionalized into compounds of Formula (I). 20 In some embodiments, compounds of 1-V are reduced to the alcohol and then further functionalized into compounds of Formula (I). - 32 - WO 2011/041461 PCT/US2010/050786 [00170] In some embodiments, compounds are prepared as outlined in Scheme 2. R11 R1 r B(OH)2 Pd(O) catalyst R N 2-1 0 R 0 L 2
-A-L
4
--R
2 N- N { 2-Ill 2 -1I 2 -1II Br B(OH)2 R 3-1ll Pd(O) catalyst N L 2
-A-L
4
--R
2 N 2-IV [00171] In some embodiments, compounds of structure 2-1 are subjected to a palladium catalyzed coupling with boronic acid deriviatives 3-111 to provide compounds of structure 5 2-II. In some embodiments, R is -NH 2 , -NHCO 2 alkyl, -CO 2 alkyl, -CH 2 OH, -CH 2 CN, CH 2 Br, -C(=O)H, -CH 2
N
3 , -CO 2
NHNH
2 , -CH 2
CO
2
NHNH
2 or any other suitable group that can be transformed to provide L 2 as described herein. Compounds of structure 2-II are then utilized to provide compounds of structure 2-III. Alternatively, compounds of structure 2-I are derivatized to provide compounds of structure 2-IV, which are subsequently coupled 10 with compound 3-III to provide compounds of structure 2-III. R2 in scheme 2 is a substituted or unsubstituted phenyl. [00172] Suitable reactions for transforming 2-I to 2-IV or 2-II to 2-III include, but are not limited to, nucleophilic displacement reactions (where R includes a suitable leaving group), organometallic chemical reactions, reductive amination reactions, cycloaddition reactions 15 (e.g. Huisgen-Sharpless cycloaddition), and the like. [00173] In some embodiments, compounds of Formula (I) are synthesized as outlined in the Examples. [00174] Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. - 33 - WO 2011/041461 PCT/US2010/050786 [00175] A detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference 5 for such disclosure. Further Forms of Compounds [00176] In one aspect, compounds of Formula (I) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, and enantiomeric forms. Stereoisomers are 10 obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns. [00177] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of Formula (I), as well 15 as metabolites and active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In specific embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in 20 unsolvated form. [00178] In some embodiments, compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain 25 embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. [00179] In some embodiments, sites on the aromatic ring portion of compounds of Formula (I) are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway. 30 In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. - 34 - WO 2011/041461 PCT/US2010/050786 [00180] In another embodiment, the compounds described herein are labeled isotopically or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. [00181] In one aspect, substitution with isotopes such as deuterium affords certain 5 therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. [00182] "Pharmaceutically acceptable," as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without 10 causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. [00183] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) with acids. Pharmaceutically acceptable salts are also obtained by reacting a compound of Formula (I) with a base to form a salt. 15 [00184] Compounds described herein may be formed as, and/or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like); or with an organic acid (e.g. acetic acid, 20 propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2 ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, 25 phenylacetic acid, phenylbutyric acid, valproic acid, and the like); (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, 30 tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum - 35 - WO 2011/041461 PCT/US2010/050786 hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. In some embodiments, a sodium salt of the compound of Formula (I) is prepared. [00185] It should be understood that a reference to a pharmaceutically acceptable salt 5 includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the 10 compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. [00186] Compounds described herein, such as compounds of Formula (I), may be in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate 15 forms. In addition, compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Certain Terminology [00187] Unless otherwise stated, the following terms used in this application, including the 20 specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. In this application, the use 25 of "or" or "and" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [00188] An "alkyl" refers to an aliphatic hydrocarbon. The alkyl may be saturated or 30 unsaturated. The alkyl, whether saturated or unsaturated, is a branched alkyl or straight chain alkyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, hexyl, allyl, but-2-enyl, but-3-enyl, and the like. - 36 - WO 2011/041461 PCT/US2010/050786 [00189] The term "alkylene" refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In one aspect, an alkelene is a C1-C 6 alkylene. In another apsect, an alkylene is a CI-C 4 alkylene. Typical alkylene groups include, but are not limited to, methylene, 5 ethylene, propylene and butylene. Typical alkylene groups include, but are not limited to, CH 2 -, -CH(CH 3 )-, -C(CH 3
)
2 -, -CH 2
CH
2 -, -CH 2
CH(CH
3 )-, -CH 2
C(CH
3
)
2 -, -CH 2
CH
2
CH
2 -, CH 2
CH
2
CH
2
CH
2 -, and the like. [00190] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein. [001911 "Cycloalkyl" refers to cyclopropyl, cyclopropenyl, cyclobutyl, 10 cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl. [00192] The term "halo" or, alternatively, "halogen" or "halide" means fluoro, chloro, bromo or iodo. [00193] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. 15 [00194] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. NH or Nalkyl), sulfur, or combinations thereof. In some embodiments, one aspect, heteroalkyl refers to an alkyl group in which one of the skeletal atoms of the alkyl is oxygen. In some embodiments, one aspect, heteroalkyl refers to an alkyl group in which one of the skeletal 20 atoms of the alkyl is NH or Nalkyl. [00195] The term "heteroalkylene" refers to an alkylene group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. NH or Nalkyl), sulfur, or combinations thereof. In one aspect, a heteroalkylene is a C 1 C 6 heteroalkylene. In another aspect, a heteroalkylene is a C1-C 4 heteroalkylene. Examplary 25 heteroalkylenes include, but are not limited to, -OCH 2 -, -OCH(CH 3 )-, -OC(CH 3
)
2 -, OCH 2
CH
2 -, -CH 2 0-, -CH(CH 3 )O-, -C(CH 3
)
2 0-, -CH 2
CH
2 0-, -CH 2 0CH 2 -, -CH 2 0CH 2
CH
2 , -CH 2
CH
2 0CH 2 -, -SCH 2 -, -SCH(CH 3 )-, -SC(CH 3
)
2 -, -SCH 2
CH
2 -, -CH 2 S-, -CH(CH 3 )S-, C(CH 3
)
2 S-, -CH 2
CH
2 S-, -CH 2
SCH
2 -, -CH 2
SCH
2
CH
2 -, -CH 2
CH
2
SCH
2 -, -SO 2
CH
2 -, SO 2
CH(CH
3 )-, -SO 2
C(CH
3
)
2 -, -SO 2
CH
2
CH
2 -, -CH 2
SO
2 -, -CH(CH 3
)SO
2 -, -C(CH 3
)
2
SO
2 -, 30 CH 2
CH
2
SO
2 -, -CH 2
SO
2
CH
2 -, -CH 2
SO
2
CH
2
CH
2 -, -CH 2
CH
2
SO
2
CH
2 -, -NHCH 2 -, NHCH(CH 3 )-, -NHC(CH 3
)
2 -, -NHCH 2
CH
2 -, -CH 2 NH-, -CH(CH 3 )NH-, -C(CH 3
)
2 NH-, CH 2
CH
2 NH-, -CH 2
NHCH
2 -, -CH 2
NHCH
2
CH
2 -, -CH 2
CH
2
NHCH
2 -, and the like. - 37 - WO 2011/041461 PCT/US2010/050786 [00196] The terms "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Monocyclic heteroaryls include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 5 thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl. In one aspect, a heteroaryl contains 0-4 N atoms. In another aspect, a heteroaryl contains 1-3 N atoms. In another aspect, a heteroaryl contains 0-3 N atoms, 0-1 0 atoms, and 0-1 S atoms. In one aspect, monocyclic heteroaryl is a C1-C 5 heteroaryl. In one aspect, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. Depending on the structure, a heteroaryl group 10 can be a monoradical or a diradical (i.e., a heteroarylene group). [00197] The term "heteroarylene" refers to a divalent heteroaryl radical. Any of the above mentioned monovalent heteroaryl groups may be a heteroarylene by abstraction of a second hydrogen atom from the heteroaryl group. The divalent heteroaryl radical may be attached through two carbon atoms, or through one carbon atom and one heteroatom, or through two 15 heteroatoms. [00198] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3
)
2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, -S-alkyl, or -S(=O) 2 alkyl. In some 20 embodiments, an optional substituent is selected from halogen, -CN, -NH 2 , -OH, -NH(CH 3 ),
-N(CH
3
)
2 , -CH 3 , -CH 2
CH
3 , -CF 3 , -CH 2
CF
3 , -OCH 3 , -OCH 2
CH
3 , -OCF 3 and - OCH 2
CF
3 . In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups. 25 [00199] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. [00200] The term "modulate," as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to 30 enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. [00201] The term "modulator," as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the - 38 - WO 2011/041461 PCT/US2010/050786 interactions of an agonist, partial agonist, an inverse agonist and antagonist. In one embodiment, a modulator is an antagonist. [00202] The term "agonist," as used herein, refers to a molecule such as a compound, a drug, an enzyme activator or a hormone modulator that binds to a specific receptor and triggers a 5 response in the cell. An agonist mimics the action of an endogenous ligand (such as LPA, prostaglandin, hormone or neurotransmitter) that binds to the same receptor. [00203] The term "antagonist," as used herein, refers to a molecule such as a compound, which diminishes, inhibits, or prevents the action of another molecule or the activity of a receptor site. Antagonists include, but are not limited to, competitive antagonists, non 10 competitive antagonists, uncompetitive antagonists, partial agonists and inverse agonists. [00204] The term "LPA-dependent", as used herein, refers to conditions or disorders that would not occur, or would not occur to the same extent, in the absence of LPA. [00205] The term "LPA-mediated", as used herein, refers to refers to conditions or disorders that might occur in the absence of LPA but can occur in the presence of LPA. 15 [00206] The terms "co-administration" or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. [00207] The terms "effective amount" or "therapeutically effective amount," as used herein, 20 refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as 25 disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. [00208] The term "pharmaceutical combination" as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed 30 and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of Formula (I) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of Formula (I) - 39 - WO 2011/041461 PCT/US2010/050786 and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active 5 ingredients. [00209] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkey, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, and the like. In one embodiment, the mammal is a human. 10 [00210] The terms "treat," "treating" or "treatment," as used herein, include alleviating, abating or ameliorating at least one symptom of a disease disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the 15 symptoms of the disease or condition either prophylactically and/or therapeutically. Pharmaceutical Compositions/Formulations and Routes of Administration [00211] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients 20 that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack 25 Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure. [00212] A pharmaceutical composition, as used herein, refers to a mixture of a compound of 30 Formula (I) with other chemical components (i.e. pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, - 40 - WO 2011/041461 PCT/US2010/050786 penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism. [00213] Pharmaceutical formulations described herein are administerable to a subject in a 5 variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections), intranasal, buccal, topical or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, 10 self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. 15 [00214] In some embodiments, the compounds of Formula (I) are administered orally. [00215] In some embodiments, the compounds of Formula (I) are administered topically. In such embodiments, the compound of Formula (I) is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams or ointments. In 20 one aspect, the compounds of Formula (I) are administered topically to the skin. [00216] In another aspect, the compounds of Formula (I) are administered by inhalation. [00217] In another aspect, the compounds of Formula (I) are formulated for intranasal adminstration. Such formulations include nasal sprays, nasal mists, and the like. [00218] In another aspect, the compounds of Formula (I) are formulated as eye drops. 25 [00219] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound of Formula (I) is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation to the mammal; and/or (e) administered by nasal administration to the mammal; or and/or (f) administered by injection to the mammal; 30 and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) adminstered non systemically or locally to the mammal. - 41 - WO 2011/041461 PCT/US2010/050786 [00220] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously. 5 [00221] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the 10 mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 15 days to 1 year. [00222] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner. [00223] In some embodiments, the compound described herein is administered topically. In some embodiments, the compound described herein is administered systemically. 20 [00224] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, pharmaceutical formulations of the compounds of Formula (I) are in the form of a capsule. [00225] In one aspect, liquid formulation dosage forms for oral administration are in the form of aqueous suspensions or solutions selected from the group including, but not limited 25 to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. [00226] For administration by inhalation, a compound of Formula (I) is formulated for use as an aerosol, a mist or a powder. [00227] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner. 30 [00228] In some embodiments, compounds of Formula (I) are prepared as transdermal dosage forms. [00229] In one aspect, a compound of Formula (I) is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection. - 42 - WO 2011/041461 PCT/US2010/050786 [00230] In some embodiments, the compounds described herein may be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. 5 [00231] In some embodiments, the compounds of Formula (I) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas. Methods of Dosing and Treatment Regimens [00232] In one embodiment, the compounds of Formula (I) are used in the preparation of 10 medicaments for the treatment of LPA-dependent or LPA-mediated diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound of Formula (I) or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof, in therapeutically effective amounts to said 15 subject. [00233] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the 20 symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial. 25 [00234] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. [00235] In certain embodiments, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). 30 [00236] Doses employed for adult human treatment are typically in the range of 0.01mg 5000 mg per day or from about 1mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses. Patient Selection - 43 - WO 2011/041461 PCT/US2010/050786 [00237] In any of the aforementioned aspects involving the prevention or treatment of LPA mediated diseases or conditions are further embodiments comprising identifying patients by screening for LPA receptor gene SNPs. Patients can be further selected based on increased LPA receptor expression in the tissue of interest. LPA receptor expression are determined 5 by methods including, but not limited to, northern blotting, western blotting, quantitative PCR (qPCR), flow cytometry, autoradiography (using a small molecule radioligand or PET ligand). In some embodiments, patients are selected based on the concentration of serum or tissue LPA measured by mass spectrometry. In some embodiments, patients are selected based on a combination of the above markers (increased LPA concentrations and increased 10 LPA receptor expression). Combination Treatments [00238] In certain instances, it is appropriate to administer at least one compound of Formula (I) in combination with another therapeutic agent. [00239] In one specific embodiment, a compound of Formula (I) is co-administered with a 15 second therapeutic agent, wherein the compound of Formula (I) and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. [00240] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug(s) employed, on the specific drug(s) 20 employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially. [00241] If administration is simultaneous, the multiple therapeutic agents are, by way of 25 example only, provided in a single, unified form, or in multiple forms. [00242] In another embodiment described herein, methods for treatment of proliferative disorders, including cancer, comprises administration to a mammal a compound of Formula (I) in combination with one or more anti-cancer agents and/or radiation therapy. [00243] In one aspect, compounds of Formula (I) are to treat or reduce fibrosis in a mammal. 30 In one aspect, compounds of Formula (I) are administered in combination with one or more immunosuppresants. In some embodiments, a compound of Formula (I) is adminsitered with corticosteroids. - 44 - WO 2011/041461 PCT/US2010/050786 [00244] In yet another embodiment described herein, methods for treating LPA-dependent or LPA-mediated conditions or diseases, such as the therapy of respiratory disorders (e.g., pulmonary fibrosis, asthma, COPD, rhinitis), comprises administration to a patient compounds, pharmaceutical compositions, or medicaments described herein in combination 5 with at least one agent used in the treatment of respiratory conditions. [00245] In some embodiments, compounds of Formula (I) are administered to a patient in combination with anti-inflammatory agents. [00246] In one embodiment, compounds of Formula (I) are administered to a patient in combination with inhaled corticosteroids. 10 EXAMPLES [00247] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. Example 1: Synthesis of 1-[4'-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester 15 [00248] Step 1: 3-Methylamino-but-2-enoic acid methyl ester: To a solution of methyl acetoacetate (29.4 g, 253 mmol) in MeOH (30 mL) was added methylamine (33 wt% in EtOH; 48 mL, 385 mmol) dropwise at room temperature. The reaction was stirred for 1 hour, and then concentrated and dried to give the title compound as a white crystalline solid. [00249] Step 2: 2-(4-Bromo-benzoyl)-3-oxo-butyric acid methyl ester: To 3 20 methylamino-but-2-enoic acid methyl ester (5.0 g, 39.1 mmol) in THF (100 mL) was added pyridine (3.7 mL, 47 mmol). The mixture was cooled to 0 0 C, and 4-bromobenzoyl chloride (8.55 g, 39.1 mmol) in THF (30 mL) was added dropwise over 2 minutes. The reaction was warmed to room temperature over 1 hour and stirred overnight. Aqueous workup provided the title compound. 25 [00250] Step 3: 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester: To a mixture of 2-(4-bromo-benzoyl)-3-oxo-butyric acid methyl ester (11 g, 39 mmol) in acetic acid (50 mL) was added hydroxylamine hydrochloride (2.66 g, 39 mmol), and the reaction was stirred at 115 0 C for 1 hour. After cooling, aqueous workup provided the title compound, which was used directly in the hydrolysis step. 30 [00251] Step 4: 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid: 5-(4-Bromo phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (39 mmol) in MeOH (50 mL) and H 2 0 (10 mL) was treated with lithium hydroxide (2 g, 48 mmol), and the reaction was - 45 - WO 2011/041461 PCT/US2010/050786 stirred at 60 'C for 1 hour. The mixture was acidified, and standard workup provided the title compound. [00252] Step 5: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester: 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (1.6 g, 6.0 mmol), 5 diphenylphosphoryl azide (1.6 g, 6.0 mmol), and triethylamine (1.3 mL, 9.3 mmol) were combined in t-BuOH and refluxed overnight. After cooling, the mixture was concentrated, and the residue was partitioned between EtOAc and H 2 0. The organic layer was separated and concentrated, and the residue was purified by silica gel chromatography (16-18% EtOAc in hexanes) to give the title compound. 10 [00253] Step 6: 1-(4-Bromo-phenyl)-cyclopropanecarbonitrile: Potassium hydroxide (14.3 g, 255 mmol) was dissolved in H 2 0 (5 mL) and toluene (40 mL). 4 Bromophenylacetonitrile (5.0 g, 25.5 mmol) and tetrabutylammonium bromide (0.41 g, 1.3 mmol) was added, followed by 1,2-dibromoethane (3.25 mL, 38 mmol) dropwise over 10 minutes. The reaction was stirred at room temperature for 2 hours and then worked-up to 15 give the title compound. [00254] Step 7: 1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid: 1-(4-Bromo-phenyl) cyclopropanecarbonitrile (5 g, 22.5 mmol) and potassium hydroxide (5 g, 89.3 mmol) were combined in ethylene glycol (70 mL), and the reaction was stirred at 180 0 C for 4 hours. The mixture was poured into H 2 0, acidified, and filtered to give the title compound. 20 [00255] Step 8: 1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid ethyl ester: 1-(4 Bromo-phenyl)-cyclopropanecarboxylic acid (5 g, 20.7 mmol) in EtOH (50 mL) was treated with sulfuric acid (2 mL), and the reaction was stirred at 75 0 C for 1 hour. The mixture was worked up to give the title compound. [00256] Step 9: 1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] 25 cyclopropanecarboxylic acid ethyl ester: 1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid ethyl ester (3.6 g, 13.4 mmol), bis(pinacolato)diboron (3.37 g, 16.1 mmol), and potassium acetate (2.8 g, 29.0 mmol) were combined in 1,4-dioxane (30 mL) under N 2 atmosphere. The solution was purged with N 2 (g) for 10 minutes, and then (1,1' bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.50 g, 0.65 mmol) was added and 30 the reaction was heated to 80 0 C for 2 hours. After aqueous workup, the crude material was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound. - 46 - WO 2011/041461 PCT/US2010/050786 [00257] Step 10: 1-[4'-(4-tert-Butoxycarbonylamino-3-methyl-isoxazol-5-yl)-biphenyl-4 yl]-cyclopropanecarboxylic acid ethyl ester: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4 yl]-carbamic acid tert-butyl ester (2.0 g, 5.6 mmol), 1-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (1.78 g, 5.6 5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.56 mmol), and sodium bicarbonate (1.4 g, 16.8 mmol) were combined in DME (30 mL) and H 2 0 (10 mL), and the mixture was purged with N 2 (g). The reaction was stirred at 80 0 C overnight, and after aqueous workup, the crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound. 10 [00258] Step 11: 1-[4'-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester: 1-[4'-(4-tert-Butoxycarbonylamino-3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (1.5 g, 3.2 mmol) in
CH
2 Cl 2 (10 mL) was treated with trifluoroacetic acid (4 mL), and the reaction was stirred for 1 hour. The mixutre was neutralized and worked up to give the title compound. 15 Example 2: Reductive Amination Procedure [00259] Amine containing compound (1 equivalent) and ketone compound or aldehyde compound (1-1.5 equivalents) were combined in toluene and stirred at 110 C for 1 hour. After cooling to room temperature, THF was added, followed by excess sodium cyanoborohydride ( 2 - 3 equivalents), and the reaction was stirred at room temperature for 20 2 hours to overnight. The mixture was purified by silica gel chromatography. Example 3: Hydrolysis of Alkyl Esters [00260] To cyclopropanecarboxylic acid ethyl ester compound (1 equivalent) in ~2: 1:1
THF:H
2 0:MeOH was added lithium hydroxide (3 - 10 equivalents), and the reaction was stirred at 70 0 C for 2 hours to overnight. After acidic workup, the crude material was 25 purified by preparative HPLC. Example 4: Suzuki Coupling Raction [00261] A 4-substituted-5-(4-bromo-phenyl)-3-methyl-isoxazole (1 equivalent), 1-[4 (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (1.2-2.0 equivalents), tetrakis(triphenylphosphine)palladium(0) (-0.05 - 0.15 30 equivalents), and sodium bicarbonate (~2.5 equivalents) were combined in ~3:1 DME:H 2 0, and the mixture was purged with N 2 (g). The reaction was stirred at 60-80 0 C for at least 1 hour to overnight and then cooled and concentrated. The crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes). - 47 - WO 2011/041461 PCT/US2010/050786 Example 5: Synthesis of [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 5 (4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde [00262] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl] -methanol: 5-(4-Bromo phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (5 g, 16.8 mmol) and lithium 5 borohydride (1.85 g, 84.1 mmol) were combined in EtOH and stirred at 60 0 C. After aqueous workup, the crude material was purified by silica gel chromatography to give the title compound. [00263] Step 2: 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde: [5-(4-Bromo phenyl)-3-methyl-isoxazol-4-yl]-methanol (1.2 g, 4.5 mmol) was treated with 4 10 methylmorpholine N-oxide (0.786 g, 6.7 mmol) and tetrapropylammonium perruthenate (catalytic) in CH 2 Cl 2 . The reaction was monitored by analytical LCMS and when complete it was filtered through Celite then submitted to silica gel chromatography to give the title compound. Example 6: Synthesis of 1-{4'-[3-Methyl-4-(3-phenyl-pyrazol-1-ylmethyl)-isoxazol-5 15 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 1) [00264] Step 1: 1-[4'-(4-Hydroxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 4, using [5 -(4-bromo-phenyl)-3 -methyl-isoxazol-4-yl]-methanol and 1-[4 (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl 20 ester. [00265] Step 2: 1-[4'-(4-Bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester: Phosphorus tribromide (0.43 mL, 4.53 mmol) was added to a solution of 1-[4'-(4-hydroxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester (1.14 g, 3.02 mmol) in DME (30 mL) at 0 0 C. The 25 reaction was stirred overnight at room temperature, and then cooled to 0 0 C and neutralized with saturated aqueous NaHCO 3 to pH 7. The mixture was partitioned between CH 2 Cl 2 and
H
2 0, and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried over MgSO 4 , filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound. 30 [00266] Step 3: 1-{4'-[3-Methyl-4-(3-phenyl-pyrazol-1-ylmethyl)-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid: 1-[4'-(4-Bromomethyl-3-methyl-isoxazol-5 yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.132 g, 0.3 mmol) and 3 phenyl-1H-pyrazole (0.043 g, 0.3 mmol) were combined in DMF. Sodium hydride (60% in - 48 - WO 2011/041461 PCT/US2010/050786 mineral oil; 0.014 g, 0.35 mmol) was added, and the reaction was stirred at room temperature for 1.5 hours. Once no starting material was seen by analytical LCMS, the mixture was diluted with EtOAc and IN aqueous HCl. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with H 2 0 and brine, and then 5 dried over Na 2
SO
4 , filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound. Example 7: Synthesis of 1-{4'-[3-Methyl-4-(4-phenyl-[1,2,3]triazol-1-ylmethyl) isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 2) [00267] Step 1: 1-{4'-[3-Methyl-4-(4-phenyl-[1,2,3]triazol-1-ylmethyl)-isoxazol-5-yl] 10 biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 6, Step 3, using 1-[4'-(4-bromomethyl-3-methyl-isoxazol 5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-phenyl-1H-1,2,3 triazole. [00268] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure 15 described in Example 3. Example 8: Synthesis of 1-{4'-[3-Methyl-4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl) isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 3) [00269] Step 1: 4-Bromomethyl-5-(4-bromo-phenyl)-3-methyl-isoxazole: [5-(4-Bromo phenyl)-3-methyl-isoxazol-4-yl]-methanol (2.88 g, 10.74 mmol) in DME (23 mL) was 20 treated with phosphorus tribromide (1.5 mL, 16.11 mmol), and the reaction was stirred at room temperature for 1 hour. Aqueous workup provided the title compound. [00270] Step 2: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetonitrile: To 4 bromomethyl-5-(4-bromo-phenyl)-3-methyl-isoxazole (10.74 mmol) in DMF (30 mL) was added potassium cyanide (0.729 g, 10.74 mmol), and the reaction was stirred at 65 0 C 25 overnight. After aqueous workup, the crude material was purified by silica gel chromatography (0-70% EtOAc in hexanes) to give the title compound. [00271] Step 3: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl] -acetic acid: [5-(4-Bromo phenyl)-3-methyl-isoxazol-4-yl]-acetonitrile (1.652 g, 5.96 mmol) in EtOH (9 mL) was treated with 4N aqueous NaOH (6 mL, 23.85 mmol), and the reaction was stirred at 75 0 C 30 for 3 hours. The mixture was acidified with 2N aqueous HCl (12 mL) and a precipitate formed as the solution cooled to room temperature. The mixture was filtered, and the solid material was dried to give the title compound. - 49 - WO 2011/041461 PCT/US2010/050786 [00272] Step 4: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid ethyl ester: To [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid (0.200 g, 0.68 mmol) in EtOH (3 mL) was added thionyl chloride (0.10 mL, 1.35 mmol), and the reaction was stirred for 1 hour. The mixture was quenched with saturated aqueous NH 4 Cl and diluted with EtOAc 5 and H 2 0. After standard aqueous workup, the crude material was purified by silica gel chromatography to give the title compound. [00273] Step 5: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid hydrazide: To [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid ethyl ester (0.114 g, 0.37 mmol) in EtOH (4 mL) was added hydrazine (IM in THF; 2 mL), and the reaction was sealed and 10 stirred at 80 0 C overnight. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were washed with H 2 0 and brine, and then dried over MgSO 4 , filtered, and concentrated to give the title compound. [00274] Step 6: 2-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-5-phenyl [1,3,4]oxadiazole: To [5 -(4-bromo-phenyl)-3 -methyl-isoxazol-4-yl]-acetic acid hydrazide 15 (0.142 g, 0.46 mmol) in CH 2 Cl 2 (2.3 mL) at 0 0 C was added triethylamine (0.19 mL, 1.37 mmol) and benzoyl chloride (0.05 mL, 0.46 mmol), and the reaction was stirred at room temperature for 3 hours. Toluenesulfonyl chloride (0.088 g, 0.46 mmol) was added, and the reaction was stirred overnight. After aqueous workup, the crude material was purified by silica gel chromatography to give the title compound. 20 [00275] Step 7: Synthesis of 1-{4'-[3-Methyl-4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl) isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 4, using 2-[5-(4-bromo-phenyl)-3-methyl isoxazol-4-ylmethyl]-5-phenyl-[1,3,4]oxadiazole and 1-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. 25 [00276] Step 8: The ester from Step 7 was hydrolyzed to the acid according to the procedure described in Example 3. Example 9: Synthesis of 1-{4'-[4-(4-Benzyl-[1,2,3]triazol-1-ylmethyl)-3-methyl isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 4) [00277] Step 1: 1-[4'-(4-Azidomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] 30 cyclopropanecarboxylic acid ethyl ester: Sodium nitrile (0.060 g, 0.91 mmol) was dissolved in H 2 0 (0.5 mL). DMF (2 mL) was added, followed by 1-[4'-(4-Bromomethyl-3 methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.200 g, 0.45 mmol), and the reaction was stirred overnight. The mixture was diluted with H 2 0 and - 50 - WO 2011/041461 PCT/US2010/050786 extracted with EtOAc. The combined organic layers were dried over Na 2
SO
4 , filtered, and concentrated to give the title compound. [00278] Step 2: 1-{4'-[4-(4-Benzyl-[1,2,3]triazol-1-ylmethyl)-3-methyl-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: To a solution of 1-[4'-(4 5 azidomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.183 g, 0.45 mmol) in tBuOH (1.5 mL) and H 2 0 (1.5 mL) was added 3-phenyl-1 propyne (0.053 g, 0.45 mmol), followed by sodium ascorbate (0.009 g, 0.045 mmol) and copper(II) sulfate pentahydrate (0.00 1 g, 0.005 mmol), and the reaction was stirred overnight. After aqueous workup, the crude material was purified by silica gel 10 chromatography to give the title compound. [00279] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 10: Synthesis of 1-(4'-{4-[3-(4-Bromo-phenyl)-pyrazol-1-ylmethyl]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 5) 15 Step 1: 1-(4'-{4-[3-(4-Bromo-phenyl)-pyrazol-1-ylmethyl]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 6, Step 3, using 1-[4'-(4-bromomethyl-3-methyl-isoxazol 5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-(4-bromo-phenyl)-1H pyrazole. 20 [00280] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 11: Synthesis of 1-(4'-{3-Methyl-4-[(5-phenyl-[1,3,4]oxadiazol-2-ylamino) methyl]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 6) [00281] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-(5-phenyl 25 [1,3,4]oxadiazol-2-yl)-amine: Prepared according to the procedure described in Example 2, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 5-phenyl [1,3,4]oxadiazol-2-ylamine. [00282] Step 2: 1-(4'-{3-Methyl-4-[(5-phenyl-[1,3,4]oxadiazol-2-ylamino)-methyl] isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared 30 according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3 methyl-isoxazol-4-ylmethyl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 1-[4-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. -51 - WO 2011/041461 PCT/US2010/050786 [00283] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 12: Synthesis of 1-{4'-[3-Methyl-4-(5-phenyl-[1,2,3]triazol-1-ylmethyl) isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 7) 5 [00284] Step 1: 1-{4'-[3-Methyl-4-(5-phenyl-[1,2,3]triazol-1-ylmethyl)-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 6, Step 3, using 1-[4'-(4-bromomethyl-3-methyl-isoxazol 5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 5-phenyl-1H [1,2,3]triazole. 10 [00285] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 13: Synthesis of 1-{4'-[3-Methyl-4-(5-phenyl-tetrazol-2-ylmethyl)-isoxazol-5 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 8) [00286] Step 1: 1-{4'-[3-Methyl-4-(5-phenyl-tetrazol-2-ylmethyl)-isoxazol-5-yl] 15 biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 6, Step 3, using 1-[4'-(4-bromomethyl-3-methyl-isoxazol 5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 5-phenyl-2H-tetrazole. [00287] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. 20 Example 14: Synthesis of 1-{4'-[3-Methyl-4-(4-phenyl-pyrazol-1-ylmethyl)-isoxazol-5 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 9) [00288] Step 1: 1-{4'-[4-(4-Bromo-pyrazol-1-ylmethyl)-3-methyl-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 6, Step 3, using 1-[4'-(4-bromomethyl-3-methyl-isoxazol 25 5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-Bromo-1H-pyrazole. [00289] Step 2: 1-{4'-[3-Methyl-4-(4-phenyl-pyrazol-1-ylmethyl)-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: 1- {4'- [4-(4-Bromo-pyrazol- 1 ylmethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.062 g, 0.122 mmol), phenylboronic acid (0.0 18 g, 0.146 mmol), tri(o-tolyl)phosphine 30 (0.004 g, 0.0122 mmol) and sodium bicarbonate (0.041 g, 0.488 mmol) were dissolved in DME (1.5 mL) and H 2 0 (0.5 mL) and N 2 (g) was bubbled through the mixture for 10 minutes. Palladium(II) acetate (1 mg, 0.002 mmol) was added and the reaction was heated - 52 - WO 2011/041461 PCT/US2010/050786 to 90 'C for 1 hour. The reaction was cooled and purified via silica gel chromatography to afford the title compound. [00290] Step 3: 1-{4'-[3-Methyl-4-(4-phenyl-pyrazol-1-ylmethyl)-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid: 1-{4'-[3-Methyl-4-(4-phenyl-pyrazol-1 5 ylmethyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.051 g, 0.101 mmol) was dissolved in THF (1 mL) then MeOH (0.5 mL) and NaOH (3N aq., 0.5 mL) was added and the reaction stirred at room temperature. After 8 hours the reaction was acidified with IN aq. HCl then submitted to standard workup procedures to give the title compound. 10 Example 15: Synthesis of 1-{4'-[4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-3-methyl-isoxazol-5 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 10) [00291] Step 1: 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid hydrazide: 5 (4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (0.061 g, 2.16 mmol) was dissolved in THF (5 mL) then 1,1'-carbonyldiimidazole (0.390 g, 2.38 mmol) was added 15 and the reaction was heated to 70 'C for 40 minutes. The reaction was then cooled to 0 'C and hydrazine monohydrate (0.220 mL, 4.32 mmol) was added. The reaction was then allowed to slowly warm to room temperature and stirred overnight. Standard aqueous workup afforded the title compound, which was brought to the next step without further purification. 20 Step 2: 2-Benzyl-5-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1,3,4]oxadiazole: Prepared according to the procedure described in Example 8, Step 6, using 5-(4-bromo phenyl)-3-methyl-isoxazole-4-carboxylic acid hydrazide and phenylacetyl chloride. [00292] Step 3: 1-{4'-[4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-3-methyl-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the 25 procedure described in Example 1, Step 10, using 2-benzyl-5-[5-(4-bromo-phenyl)-3 methyl-isoxazol-4-yl]-[1,3,4]oxadiazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan 2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. [00293] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure described in Example 14, Step 3. 30 Example 16: Synthesis of 1-(4'-{4-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl] 3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 11) [00294] Step 1: 1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol: 5-(4 Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.285 g, 1.07 mmol) was dissolved in - 53 - WO 2011/041461 PCT/US2010/050786 THF (8 mL) and the solution was cooled to -78 'C. Ethynylmagnesium bromide (0.5M in THF, 2.6 mL, 1.28 mmol) was added dropwise and the reaction was allowed to warm to room temperature. After 1 hour the reaction was quenched with aqueous ammonium chloride the submitted to standard workup to yield the title compound. 5 [00295] Step 2: (1-Benzyl-1H-[1,2,3]triazol-4-yl)-[5-(4-bromo-phenyl)-3-methyl isoxazol-4-yl]-methanol: Prepared according to the procedure described in Example 9, Step 2, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol and azidomethyl benzene. [00296] Step 3: 1-(4'-{4-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl]-3-methyl 10 isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using (1-benzyl-1H [1,2,3 ]triazol-4-yl)- [5 -(4-bromo-phenyl)-3 -methyl-isoxazol-4-yl]-methanol and 1-[4 (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. 15 [00297] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure described in Example 14, Step 3. Example 17: Synthesis of 1-[4'-(4-Formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester [00298] Step 1: 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.5 g, 1.88 mmol) 20 was mixed with 1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] cyclopropanecarboxylic acid ethyl ester (0.72 g, 2.07 mmol) and sodium bicarbonate (0.553 g, 6.58 mmol) in DME (5 mL) and H 2 0 (2.5 mL). The reaction was purged with N 2 (g) then bis(triphenylphosphine)palladium(II) dichloride (0.066 g, 0.094 mmol) was added and the reaction was heated to 85 'C overnight. After cooling to room temperature the reaction 25 was submitted to standard aqueous workup the purified by silica gel chromatograph (0-20% EtOAc in hexanes) to give the title compound. Example 18: Synthesis of 1-{4'-[4-(5-Benzyl-[1,3,4]oxadiazol-2-ylmethyl)-3-methyl isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 12) [00299] Step 1: 2-Benzyl-5-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl] 30 [1,3,4]oxadiazole: Prepared according to the procedure described in Example 8, Step 6, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid hydrazide and phenylacetyl chloride. - 54 - WO 2011/041461 PCT/US2010/050786 [00300] Step 2: 1-{4'-[4-(5-Benzyl-[1,3,4]oxadiazol-2-ylmethyl)-3-methyl-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 2-benzyl-5-[5-(4-bromo-phenyl)-3 methyl-isoxazol-4-ylmethyl]-[1,3,4]oxadiazole and 1-[4-(4,4,5,5-tetramethyl 5 [1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. [00301] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 14, Step 3. Example 19: Synthesis of 1-(4'-{4-[(5-Benzyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 13) 10 [00302] Step 1: (5-Benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol 4-yl]-methanol: 2-Benzyl-[1,3,4]oxadiazole (0.500 g, 3.12 mmol) was dissolved in THF and cooled to -70 'C then n-butyllithium (1.5M in THF, 2.1 mL, 3.12 mmol) was added and the reaction stirred for 1.5 hours. Magnesium bromide ethyl etherate (0.631 g, 3.43 mmol) was added and the reaction was allowed to warm to -45 'C. After 45 minutes 5-(4-bromo 15 phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.415 g, 1.56 mmol) in THF (2 mL) was added and the reaction was allowed to stir overnight. The reaction was quenched with aqueous ammonium chloride then submitted to standard workup and purification via silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound. [00303] Step 2: 1-(4'-{4-[(5-Benzyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-3-methyl 20 isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using (5-benzyl [1,3,4]oxadiazol-2-yl)- [5 -(4-bromo-phenyl)-3 -methyl-isoxazol-4-yl] -methanol and 1-[4 (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. 25 [00304] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 14, Step 3. Example 20: Synthesis of 1-{4'-[4-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-3-methyl isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 14) [00305] Step 1: 1-{4'-[4-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-3-methyl-isoxazol-5-yl] 30 biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: 1-(4'- {4-[(1 -Benzyl- 1H [1,2,3]triazol-4-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl) cyclopropanecarboxylic acid ethyl ester (0.123 g, 0.230 mmol) and triethylsilane (0.044 mL, 0.276 mmol) were dissolved in CH 2 Cl 2 (0.5 mL) then trifluoromethanesulfonic acid - 55 - WO 2011/041461 PCT/US2010/050786 (0.5 mL) was slowly added. After stirring for 1 hour at room temperature, an additional portion of triethylsilane (0.050 mL) was added and the reaction was heated to 50 'C for 3.5 hours. An additional portion of triethylsilane (1 mL) was added and the reaction continued to stir at 50 'C for 1 hour. The reaction mixture was concentrated, dissolved in CH 2 Cl 2 , and 5 filtered through a plug of silica gel. The crude material was then purified via preparatory HPLC to afford the title compound. [00306] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 14, Step 3. Example 21: Synthesis of 1-(4'-{4-[(5-Benzyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-3 10 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Enantiomer A) (Compound 15) [00307] Step 1: (5-Benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol 4-yl]-methanol: Prepared according to the procedure described in Example 19, Step 1, using 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-benzyl 15 [1,3,4]oxadiazole. [00308] The recovered material was purified by silica gel chromatography (0-60% EtOAc in hexanes) then the by preparatory chiral HPLC (Chiralpak AD column, 95:5 hexanes:EtOH) to give enantiomer A (first to elute) and enantiomer B (second to elute) with undetermined absolute stereochemistry. 20 [00309] Step 2: 1-(4'-{4-[(5-Benzyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester (Enantiomer A): Prepared according to the procedure described in Example 1, Step 10, using (5-benzyl [1,3,4]oxadiazol-2-yl)- [5 -(4-bromo-phenyl)-3 -methyl-isoxazol-4-yl] -methanol (Enantiomer A) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic 25 acid ethyl ester. [00310] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 14, Step 3. Example 22: Synthesis of 1-(4'-{4-[(5-Benzyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Enantiomer B) 30 (Compound 16) [00311] Step 1: 1-(4'-{4-[(5-Benzyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester (Enantiomer B): Prepared according to the procedure described in Example 1, Step 10, using (5-benzyl - 56 - WO 2011/041461 PCT/US2010/050786 [1,3,4]oxadiazol-2-yl)- [5 -(4-bromo-phenyl)-3 -methyl-isoxazol-4-yl] -methanol (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. [00312] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure 5 described in Example 14, Step 3. Example 23: Synthesis of 5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylamine Step 1: 5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylamine: Prepared according to the procedure described in Example 1, Step 11, using [5-(4-bromo-phenyl)-3-methyl-isoxazol 4-yl]-carbamic acid tert-butyl ester. 10 Example 24: Synthesis of 1-(4'-{4-[Hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methyl] 3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 17) [00313] Step 1: 2-Phenyl-[1,3,4]oxadiazole: Benzoic acid methyl ester (1.01 g, 7.34 mmol) and hydrazine monohydrate (10 mL) were dissolved in EtOH (20 mL) then heated in a sealed tube to 80 'C for 23 hours. The reaction was allowed to cool and then 15 triethylorthoformate (25 mL) and p-toluenesulfonic acid (0.100 g, 0.526 mmol) were added, the tube was re-sealed, and the reaction was heated to 120 'C for 26 hours. The reaction mixture was then submitted to standard aqueous workup and purified on silica gel (0-70% EtOAc in hexanes) to afford the title compound. [00314] Step 2: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol 20 2-yl)-methanol: Prepared according to the procedure described in Example 19, Step 1, using 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-phenyl [1,3,4]oxadiazole. [00315] Step 3: 1-(4'-{4-[Hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methyl]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared 25 according to the procedure described in Example 17, Step 1, using [5-(4-bromo-phenyl)-3 methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methanol and 1-[4-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. [00316] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure described in Example 14, Step 3. 30 Example 25: Synthesis of 1-(4'-{4-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl] 3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Enantiomer A) (Compound 18) - 57 - WO 2011/041461 PCT/US2010/050786 [00317] Step 1: 1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol: Prepared according to the procedure described in Example 16, Step 1, and after the reaction the material was purified via preparatory chiral HPLC (Chiralcel AD column, 85:15 hexanes:EtOH) to give enantiomer A (first to elute) and enantiomer B (second to elute) with 5 undetermined absolute stereochemistry. [00318] Step 2: (1-Benzyl-1H-[1,2,3]triazol-4-yl)-[5-(4-bromo-phenyl)-3-methyl isoxazol-4-yl] -methanol (Enantiomer A): To a solution of 1-[5-(4-Bromo-phenyl)-3 methyl-isoxazol-4-yl]-prop-2-yn-1-ol (Enantiomer A) (0.530 g, 1.81 mmol) in DMSO (4 mL) and H 2 0 (4 mL) was added azidomethyl-benzene (0.242 g, 1.81 mmol), followed by 10 sodium ascorbate (0.036 g, 0.181 mmol) and copper(II) sulfate pentahydrate (0.005 g, 0.018 mmol), and the reaction was stirred overnight. After aqueous workup the crude material was purified by silica gel chromatography (15 -100% EtOAc in hexanes) to give the title compound. [00319] Step 3: 1-(4'-{4-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl]-3-methyl 15 isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester (Enantiomer A): Prepared according to the procedure described in Example 1, Step 10, using (1-benzyl-1H [1,2,3 ]triazol-4-yl)- [5 -(4-bromo-phenyl)-3 -methyl-isoxazol-4-yl] -methanol (Enantiomer A) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. 20 [00320] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure described in Example 14, Step 3. Example 26: Synthesis of 1-(4'-{4-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl] 3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Enantiomer B) (Compound 19) 25 [00321] Step 1: (1-Benzyl-1H-[1,2,3]triazol-4-yl)-[5-(4-bromo-phenyl)-3-methyl isoxazol-4-yl] -methanol (Enantiomer B): Prepared according to the procedure described in Example 25, Step 2, using 1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1 ol (Enantiomer B) and azidomethyl-benzene. [00322] Step 2: 1-(4'-{4-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl]-3-methyl 30 isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester (Enantiomer B): Prepared according to the procedure described in Example 1, Step 10, using (1-benzyl-1H [1,2,3 ]triazol-4-yl)- [5 -(4-bromo-phenyl)-3 -methyl-isoxazol-4-yl] -methanol (Enantiomer B) - 58 - WO 2011/041461 PCT/US2010/050786 and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. [00323] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 14, Step 3. 5 Example 27: Synthesis of [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-phenyl isoxazol-5-yl)-ethyl]-amine [00324] Step 1: Prepared according to the procedure described in Example 2, using 5-(4 bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-(3-phenyl-isoxazol-5-yl)-ethanone. Example 28: Synthesis of 1-[4'-(4-{Hydroxy-[5-(3-trifluoromethyl-benzyl) 10 [1,3,4]oxadiazol-2-yl]-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid (Compound 20) [00325] Step 1: 2-(3-Trifluoromethyl-benzyl)-[1,3,4]oxadiazole: (3-Trifluoromethyl phenyl)-acetic acid methyl ester (0.720 g, 3.30 mmol) was dissolved in hydrazine (7 mL) and EtOH (15 mL) and heated to 90 'C overnight. Analytical LCMS indicated complete 15 reaction so the mixture was concentrated and azeotroped twice with toluene. The crude material was dissolved in triethylorthoformate and heated to 135 'C for 20 hours then allowed to cool. The reaction mixture was concentrated to afford the title compound. [00326] Step 2: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[5-(3-trifluoromethyl benzyl)-[1,3,4]oxadiazol-2-yl]-methanol: Prepared according to the procedure described in 20 Example 19, Step 1, using 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2 (3-trifluoromethyl-benzyl)-[1,3,4]oxadiazole. [00327] Step 3: 1-[4'-(4-{Hydroxy-[5-(3-trifluoromethyl-benzyl)-[1,3,4]oxadiazol-2-yl] methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using [5-(4 25 bromo-phenyl)-3-methyl-isoxazol-4-yl]-[5-(3-trifluoromethyl-benzyl)-[1,3,4]oxadiazol-2 yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] cyclopropanecarboxylic acid ethyl ester. [00328] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure described in Example 14, Step 3. 30 Example 29: Synthesis of 1-[4'-(4-{Hydroxy-[1-(3-trifluoromethyl-benzyl)-1H [1,2,3]triazol-4-yl]-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid (Compound 21) - 59 - WO 2011/041461 PCT/US2010/050786 [00329] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-trifluoromethyl benzyl)-1H- [1,2,3]triazol-4-yl] -methanol: 1-Bromomethyl-3-trifluoromethyl-benzene (0.0491 g, 0.205 mmol) and sodium azide (0.0222 g, 0.342 mmol) were combined in DMSO and stirred at room temperature for 2 hours. Then, 1-[5-(4-bromo-phenyl)-3 5 methyl-isoxazol-4-yl]-prop-2-yn-1-ol (0.500 g, 0.171 mmol), copper(II)sulfate pentahydrate (0.0043 g, 0.0 17 mmol) and sodium ascorbate (0.0034 g, 0.0 17 mmol) were added and the reaction stirred at room temperature for 2 days. The reaction was submitted to standard aqueous workup and purified on silica gel to afford the title compound. [00330] Step 2: 1-[4'-(4-{Hydroxy-[1-(3-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl] 10 methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using [5-(4 bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4 yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] cyclopropanecarboxylic acid ethyl ester. 15 [00331] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 30: Synthesis of 1-{4'-[4-(Biphenyl-3-yl-hydroxy-methyl)-3-methyl-isoxazol 5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 22) [00332] Step 1: Biphenyl-3-yl- [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl] -methanol: 20 Prepared according to the procedure described in Example 16, Step 1, using 5-(4-bromo phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-(biphenyl)magnesium bromide. [00333] Step 2: 1-{4'-[4-(Biphenyl-3-yl-hydroxy-methyl)-3-methyl-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using biphenyl-3-yl-[5-(4-bromo-phenyl)-3 25 methyl-isoxazol-4-yl] -methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) phenyl]-cyclopropanecarboxylic acid ethyl ester. Additionally, (1,1' bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0) [00334] Step 3: 1-{4'-[4-(Biphenyl-3-yl-hydroxy-methyl)-3-methyl-isoxazol-5-yl] 30 biphenyl-4-yl}-cyclopropanecarboxylic acid [00335] 1-{4'-[4-(biphenyl-3-yl-hydroxy-methyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid ethyl ester (1 equivalent) was dissolved in THF then EtOH and - 60 - WO 2011/041461 PCT/US2010/050786 NaOH (3N aq., 3 equivalents) was added and the reaction stirred at 60 'C overnight. The reaction was worked up and purified via preparatory HPLC (0.1 % TFA/H 2 0/ACN). Example 31: Synthesis of 1-[4'-(4-{Hydroxy-[1-(1-phenyl-ethyl)-1H-[1,2,3]triazol-4-yl] methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid 5 (Compound 23) [00336] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(1-phenyl-ethyl)-1H [1,2,3]triazol-4-yl]-methanol: Prepared according to the procedure described in Example 29, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol and (1 bromo-ethyl)-benzene. 10 [00337] Step 2: 1-[4'-(4-{Hydroxy-[1-(1-phenyl-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl}-3 methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3 methyl-isoxazol-4-yl] -[1 -(1 -phenyl-ethyl)- 1H- [1,2,3 ]triazol-4-yl] -methanol and 1-[4 (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl 15 ester. [00338] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 32: Synthesis of 1-[4'-(4-{Hydroxy-[1-(2-trifluoromethyl-benzyl)-1H [1,2,3]triazol-4-yl]-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] 20 cyclopropanecarboxylic acid (Compound 24) [00339] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-trifluoromethyl benzyl)-1H- [1,2,3]triazol-4-yl] -methanol: Prepared according to the procedure described in Example 29, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1 ol and 1-bromomethyl-2-trifluoromethyl-benzene. 25 [00340] Step 2: 1-[4'-(4-{Hydroxy-[1-(2-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl] methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using [5-(4 bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4 yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] 30 cyclopropanecarboxylic acid ethyl ester. [00341] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. - 61 - WO 2011/041461 PCT/US2010/050786 Example 33: Synthesis of 1-[4'-(4-{[1-(3-Chloro-benzyl)-1H-[1,2,3]triazol-4-yl] hydroxy-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 25) [00342] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-chloro-benzyl)-1H 5 [1,2,3]triazol-4-yl]-methanol: Prepared according to the procedure described in Example 29, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol and 1 bromomethyl-3-chloro-benzene. [00343] Step 2: 1-[4'-(4-{[1-(3-Chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy-methyl} 3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: 10 Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo phenyl)-3-methyl-isoxazol-4-yl]- [1 -(3 -chloro-benzyl)- 1H-[ 1,2,3 ]triazol-4-yl] -methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. [00344] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure 15 described in Example 3. Example 34: Synthesis of 1-(4'-{4-[(3-Benzyl-phenyl)-hydroxy-methyl]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 26) [00345] Step 1: (3-Bromo-phenyl)-phenyl-methanol: Prepared according to the procedure described in Example 16, Step 1, using 3-bromobenzaldehyde and phenylmagnesium 20 bromide. [00346] Step 2: 1-Benzyl-3-bromo-benzene: (3-Bromo-phenyl)-phenyl-methanol (from previous step) was dissolved in diethyl ether (10 mL) and the solution was added dropwise to a suspension of lithium aluminum hydride (0.607 g, 16 mmol) and aluminum chloride (2.11 g, 16 mmol) stirring in THF (15 mL). The reaction was heated to 40 'C for 1 hour 25 then cooled to 0 'C, quenched with H 2 0, and submitted to standard aqueous workup. The crude product was purified via silica gel chromatography (0-5% EtOAc in hexanes) to afford the title compound. [00347] Step 3: (3-Benzyl-phenyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl] methanol: 1-Benzyl-3-bromo-benzene (0.811 g, 3.3 mmol) was dissolved in THF (2 mL), 30 cooled to -78 'C and then n-butyllithium (2.0 M in THF, 1.65 mL, 3.3 mmol) was added dropwise. The reaction was stirred for 15 minutes then warmed to 0 'C and 5-(4-bromo phenyl)-3-methyl-isoxazole-4-carbaldehyde (1.05 g, 3.96 mmol) was added. The reaction was allowed to warm to room temperature while stirring for 1 hour. The reaction was - 62 - WO 2011/041461 PCT/US2010/050786 quenched with aqueous ammonium chloride then submitted to standard aqueous workup and silica gel chromatography to give the title compound. [00348] Step 4: 1-(4'-{4-[(3-Benzyl-phenyl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the 5 procedure described in Example 17, Step 1, using (3-benzyl-phenyl)-[5-(4-bromo-phenyl) 3 -methyl-isoxazol-4-yl] -methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) phenyl]-cyclopropanecarboxylic acid ethyl ester. [00349] Step 5: The ester from Step 4 was hydrolyzed to the acid according to the procedure described in Example 3. 10 Example 35: Synthesis of 1-(4'-{4-[(5-Benzyl-pyridin-3-yl)-hydroxy-methyl]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 27) [00350] Step 1: 3-Benzyl-5-bromo-pyridine: Benzylmagnesium bromide (1.0 M in THF, 20 mL, 20 mmol) was added to a solution of zinc chloride (2.73 g, 20 mmol) in THF (20 mL) and the reaction was heated to 50 'C for 2.5 hours. The solution was then added by 15 canula to a solution of 3,5-dibromo-pyridine (3.07 g, 13 mmol), copper(I) iodide (0.0148 g, 0.78 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.048 g, 0.65 mmol) in THF (20 mL). The reaction was heated to 50 'C for 48 hours then quenched with H 2 0, submitted to standard aqueous workup, and purified via silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound. 20 [00351] Step 2: (5-Benzyl-pyridin-3-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl] methanol: 3-Benzyl-5-bromo-pyridine (0.474 g, 1.91 mmol) was dissolved in THF (10 mL) and cooled to 0 'C. Isopropylmagnesium chloride (2 M in THF, 0.96 mL, 1.91 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 1 hour. Analytical LCMS indicated no reaction so an additional portion of 25 isopropylmagnesium chloride (1.91 mmol) was added and the reaction stirred for 1 hour at room temperature. Analytical LCMS still indicated no progress so the reaction was cooled to -78 'C and n-butyllithium (2.5 M in hexanes, 0.764 mL, 1.91 mL) was added. The reaction was allowed to slowly warm to 0 'C then 5-(4-bromo-phenyl)-3-methyl-isoxazole 4-carbaldehyde (0.610 g, 2.29 mmol) was added and the reaction was allowed to warm to 30 room temperature. The reaction was quenched with H 2 0, submitted to standard aqueous workup and then purified via silica gel chromatography to yield the title compound. [00352] Step 3: 1-(4'-{4-[(5-Benzyl-pyridin-3-yl)-hydroxy-methyl]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the - 63 - WO 2011/041461 PCT/US2010/050786 procedure described in Example 17, Step 1, using (5-benzyl-pyridin-3-yl)-[5-(4-bromo phenyl)-3 -methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. [00353] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure 5 described in Example 3. Example 36: Synthesis of 1-[4'-(4-{[1-(2-Chloro-benzyl)-lH-[1,2,3]triazol-4-yl] hydroxy-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 28) [00354] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-chloro-benzyl)-1H 10 [1,2,3]triazol-4-yl]-methanol: Prepared according to the procedure described in Example 29, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol and 1 bromomethyl-2-chloro-benzene. [00355] Step 2: 1-[4'-(4-{[1-(2-Chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy-methyl} 3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: 15 Prepared according to the procedure described in Example 1, Step 10, using [5-(4-Bromo phenyl)-3-methyl-isoxazol-4-yl]- [1 -(2-chloro-benzyl)- 1H-[ 1,2,3 ]triazol-4-yl] -methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. [00356] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure 20 described in Example 3. Example 37: Synthesis of 1-[4'-(4-{[1-(4-Chloro-benzyl)-1H-[1,2,3]triazol-4-yl] hydroxy-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 29) [00357] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(4-chloro-benzyl)-1H 25 [1,2,3]triazol-4-yl]-methanol: Prepared according to the procedure described in Example 29, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol and 1 bromomethyl-4-chloro-benzene. [00358] Step 2: 1-[4'-(4-{[1-(4-Chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy-methyl} 3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: 30 Prepared according to the procedure described in Example 1, Step 10, using [5-(4-Bromo phenyl)-3-methyl-isoxazol-4-yl]- [1 -(4-chloro-benzyl)- 1H-[ 1,2,3 ]triazol-4-yl] -methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. - 64 - WO 2011/041461 PCT/US2010/050786 [00359] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 38: Synthesis of 1-[4'-(4-{(R)-[1-(2-Chloro-benzyl)-1H-[1,2,3]triazol-4-yl] hydroxy-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid 5 (Compound 30) [00360] Step 1: (S)-i-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol: Zinc triflate (0.75 g, 2.1 mmol), (IS, 2R)-(+)-N-methylephedrine (0.41 g, 2.3 mmol) and triethylamine (0.23 g, 2.3 mmol) were stirred in toluene (10 mL) at room temperature for 2 hours. (Trimethylsilyl)acetylene (0.32 g, 2.3 mmol) was added and the reaction stirred for 10 15 minute then 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.5 g, 1.9 mmol) was added and the reaction stirred at room temperature for 2 weeks. The reaction mixture was purified on by silica gel chromatography (0-20% EtOAc in hexanes) to afford the title product with 97.5% ee as measured by analytical chiral HPLC. [00361] Step 2: (R)-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-chloro-benzyl) 15 1H-[1,2,3]triazol-4-yl]-methanol: Prepared according to the procedure described in Example 29, Step 1, using (S)-i-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1 ol and 1-bromomethyl-2-chloro-benzene. [00362] Step 3: 1-[4'-(4-{(R)-[1-(2-Chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl 20 ester: Prepared according to the procedure described in Example 1, Step 10, using (R)-[5 (4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-chloro-benzyl)-1H-[1,2,3]triazol-4-yl] methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] cyclopropanecarboxylic acid ethyl ester. [00363] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure 25 described in Example 3. Example 39: Synthesis of 1-[4'-(4-{[1-(3,4-Dichloro-benzyl)-1H-[1,2,3]triazol-4-yl] hydroxy-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 31) [00364] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3,4-dichloro-benzyl) 30 1H-[1,2,3]triazol-4-yl]-methanol: Prepared according to the procedure described in Example 29, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol and 4-bromomethyl-1,2-dichloro-benzene. - 65 - WO 2011/041461 PCT/US2010/050786 [00365] Step 2: 1-[4'-(4-{[1-(3,4-Dichloro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using [5-(4 bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3,4-dichloro-benzyl)-1H-[1,2,3]triazol-4-yl] 5 methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] cyclopropanecarboxylic acid ethyl ester. [00366] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 40: Synthesis of 1-[4'-(4-{(R)-Hydroxy-[1-((R)-1-phenyl-ethyl)-1H 10 [1,2,3]triazol-4-yl]-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid (Compound 32) [00367] Step 1: ((S)-1-Bromo-ethyl)-benzene: Bromine (3.2 g, 20.0 mmol) was added to a suspension of triphenylphosphine (5.2 g, 19.8 mmol) stirring in ACN at -15 'C. The reaction was warmed to room temperature and stirred for 50 mintues then cooled to -35 'C 15 and (R)-(+)- 1 -phenylethanol (1.6 g, 13.1 mmol) was added. The reaction was allowed to warm to -10 'C over 70 minutes and was then quenched with H 2 0 and submitted to standard aqueous workup to afford the title compound which was used without further purification. [00368] Step 2: (R)-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-((R)-1-phenyl 20 ethyl)-1H-[1,2,3]triazol-4-yl]-methanol: Prepared according to the procedure described in Example 29, Step 1, using (S)-i-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1 ol and ((R)- 1 -bromo-ethyl)-benzene. [00369] Step 3: 1-[4'-(4-{(R)-Hydroxy-[1-((R)-1-phenyl-ethyl)-1H-[1,2,3]triazol-4-yl] methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl 25 ester: Prepared according to the procedure described in Example 1, Step 10, using (R)-[5 (4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-((R)-1-phenyl-ethyl)-1H-[1,2,3]triazol-4-yl] methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] cyclopropanecarboxylic acid ethyl ester. [00370] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure 30 described in Example 3. Example 41: Synthesis of 1-{4'-[3-Methyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol-5 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 33) - 66 - WO 2011/041461 PCT/US2010/050786 [00371] Step 1: 2-Bromo-6-phenyl-pyridine: 2,6-Dibromo-pyridine (1.2 g, 0.508 mmol), phenylboronic acid (0.620 g, 0.508 mmol) and sodium carbonate (2 M aq., 30 mL) were dissolved in MeOH (10 mL) and toluene (30 mL) and the solution was degassed with bubbling N 2 (g). Tetrakis(triphenylphosphine)palladium(0) (0.172 g, 0.149 mmol) was 5 added and the reaction was heated to 100 'C overnight. After cooling the reaction was submitted to standard aqueous workup and purified by silica gel chromatography to give the title compound. [00372] Step 2: 1-{4'-[3-Methyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol-5-yl]-biphenyl 4-yl}-cyclopropanecarboxylic acid ethyl ester: 1-[4'-(4-Amino-3-methyl-isoxazol-5-yl) 10 biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.250 g, 0.689 mmol), 2-bromo-6 phenyl-pyridine (0.1457 g, 0.62 mmol), cesium carbonate (0.2694 g, 0.826 mmol) and (+) 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.032 g, 0.052 mmol) were dissolved in toluene (3 mL) and the solution was degassed with bubbling N 2 (g). Tris(dibenzylideneacetone)dipalladium(0) (0.0158 g, 0.017 mmol) was added and the 15 reaction was heated to 110 'C for 24 hours. After cooling the reaction was submitted to standard aqueous workup and silica gel chromatography to afford the title compound. [00373] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 42: Synthesis of 1-(4'-{4-[(6-Benzyl-pyridin-2-yl)-hydroxy-methyl]-3-methyl 20 isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 34) [00374] Step 1: 2-Benzyl-6-bromo-pyridine: 2,6-Dibromopyridine (2.36 g, 1 mmol), benzylzinc bromide (0.9 M in THF, 1.05 mL, 0.95 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.01 mmol) were placed in THF (75 mL) and heated to 60 'C for 20 hours. The reaction mixture was cooled, submitted to standard 25 aqueous workup and purified on silica gel to afford the title compound. [00375] Step 2: (6-Benzyl-pyridin-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl] methanol: Prepared according to the procedure described in Example 34, Step 3, using 5 (4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-benzyl-6-bromo-pyridine. [00376] Step 3: 1-(4'-{4-[(6-Benzyl-pyridin-2-yl)-hydroxy-methyl]-3-methyl-isoxazol-5 30 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using (6-benzyl-pyridin-2-yl)-[5-(4-bromo phenyl)-3 -methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. Additionally, - 67 - WO 2011/041461 PCT/US2010/050786 (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(O). [00377] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure described in Example 3. 5 Example 43: Synthesis of 1-[4'-(4-{Hydroxy-[1-(2-methyl-benzyl)-1H-[1,2,3]triazol-4 yl]-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 35) [00378] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-methyl-benzyl)-1H [1,2,3]triazol-4-yl]-methanol: Prepared according to the procedure described in Example 10 29, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol and 1 bromomethyl-2-methyl-benzene. [00379] Step 2: 1-[4'-(4-{Hydroxy-[1-(2-methyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methyl} 3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo 15 phenyl)-3 -methyl-isoxazol-4-yl]- [1 -(2-methyl-benzyl)- 1H-[ 1,2,3 ]triazol-4-yl] -methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. [00380] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. 20 Example 44: Synthesis of 1-[4'-(4-{[1-(2-Chloro-6-fluoro-benzyl)-1H-[1,2,3]triazol-4 yl]-hydroxy-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 36) [00381] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-chloro-6-fluoro benzyl)-1H- [1,2,3]triazol-4-yl] -methanol: Prepared according to the procedure described 25 in Example 29, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1 ol and 2-bromomethyl-1-chloro-3-fluoro-benzene. [00382] Step 2: 1-[4'-(4-{[1-(2-Chloro-6-fluoro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using [5-(4 30 bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-chloro-6-fluoro-benzyl)-1H-[1,2,3]triazol-4 yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] cyclopropanecarboxylic acid ethyl ester. - 68 - WO 2011/041461 PCT/US2010/050786 [00383] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 45: Synthesis of 1-[4'-(4-{[1-(2,6-Dichloro-benzyl)-lH-[1,2,3]triazol-4-yl] hydroxy-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid 5 (Compound 37) [00384] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2,6-dichloro-benzyl) 1H-[1,2,3]triazol-4-yl]-methanol: Prepared according to the procedure described in Example 29, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-yn-1-ol and 2-bromomethyl-1,3-dichloro-benzene. 10 [00385] Step 2: 1-[4'-(4-{[1-(2,6-Dichloro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using [5-(4 bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2,6-dichloro-benzyl)-1H-[1,2,3]triazol-4-yl] methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] 15 cyclopropanecarboxylic acid ethyl ester. [00386] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 46: Synthesis of 1-{4'-[4-(6-Benzyl-pyridin-2-ylamino)-3-methyl-isoxazol-5 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 38) 20 [00387] Step 1: 1-{4'-[4-(6-Benzyl-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl 4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4 yl]-cyclopropanecarboxylic acid ethyl ester and 2-benzyl-6-bromo-pyridine. [00388] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure 25 described in Example 3. Example 47: Synthesis of 1-{4'-[4-(Biphenyl-3-ylamino)-3-methyl-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 39) [00389] Step 1: 1-{4'-[4-(Biphenyl-3-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described 30 in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester and 3-bromo-biphenyl. [00390] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. - 69 - WO 2011/041461 PCT/US2010/050786 Example 48: Synthesis of 1-{4'-[4-(Biphenyl-4-ylamino)-3-methyl-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 40) [00391] Step 1: 1-{4'-[4-(Biphenyl-4-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described 5 in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester and 4-bromo-biphenyl. [00392] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 49: Synthesis of 1-(4'-{3-Methyl-4-[6-(3-trifluoromethyl-phenyl)-pyridin-2 10 ylamino]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 41) [00393] Step 1: 4,4,5,5-Tetramethyl-2-(3-trifluoromethyl-phenyl)-[1,3,2]dioxaborolane: Prepared according to the procedure described in Example 1, Step 9, using 1-bromo-3 trifluoromethyl-benzene and bis(pinacolato)diboron. [00394] Step 2: 2-Bromo-6-(3-trifluoromethyl-phenyl)-pyridine: Prepared according to 15 the procedure described in Example 1, Step 10, using 4,4,5,5-tetramethyl-2-(3 trifluoromethyl-phenyl)-[ 1,3,2]dioxaborolane and 2,6-dibromo-pyridine. Additionally, (1,1' bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(O). [00395] Step 3: 1-(4'-{3-Methyl-4-[6-(3-trifluoromethyl-phenyl)-pyridin-2-ylamino] 20 isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(3 trifluoromethyl-phenyl)-pyridine. [00396] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure 25 described in Example 3. Example 50: Synthesis of 1-{4'-[3-Methyl-4-(6-phenyl-pyrazin-2-ylamino)-isoxazol-5 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 42) [00397] Step 1: 2-Bromo-6-phenyl-pyrazine: Prepared according to the procedure described in Example 1, Step 10, using 2,6-dibromo-pyrazine and phenylboronic acid. 30 Additionally, (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(O). [00398] Step 2: 1-{4'-[3-Methyl-4-(6-phenyl-pyrazin-2-ylamino)-isoxazol-5-yl]-biphenyl 4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure - 70 - WO 2011/041461 PCT/US2010/050786 described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4 yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyrazine. [00399] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. 5 Example 51: Synthesis of 1-{4'-[3-Methyl-4-(5-phenyl-[1,3,4]oxadiazol-2-ylamino) isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 43) [00400] Step 1: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol 2-yl)-amine: 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (1 g, 3.6 mmol), triethylamine (1 mL, 7.2 mmol) and diphenylphosphoryl azide (1.98 g, 7.2 mmol) were 10 placed in toluene (20 mL) and heated to 60 'C for 20 minutes. Benzoic acid hydrazide (0.98 g, 7.2 mmol) was added in a single portion and the reaction was heated and stirred for 2 hours. The reaction was cooled and submitted to aqueous workup. The crude material was dissolved in dioxane (100 mL), phosphorous(V) oxychloride was added and the reaction was heated to 100 'C overnight. The reaction was cooled and worked up and the 15 residue was purified on silica gel (0-80% EtOAc in hexanes ) to yield the title compound. [00401] Step 2: 1-{4'-[3-Methyl-4-(5-phenyl-[1,3,4]oxadiazol-2-ylamino)-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol 4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl 20 [1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. Additionally, (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0). [00402] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. 25 Example 52: Synthesis of 1-{4'-[4-(5-Benzyl-[1,3,4]oxadiazol-2-ylamino)-3-methyl isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 44) [00403] Step 1: Phenyl-acetic acid hydrazide: Phenyl-acetic acid methyl ester (5 g, 33.3 mmol) was dissolved in hydrazine hydrate (25 mL) and EtOH (50 mL) and the reaction was heated in a sealed tube to 80 'C overnight. After cooling the reaction was concentrated to 30 afford the title compound. [00404] Step 2: (5-Benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol 4-yl]-amine: Prepared according to the procedure described in Example 51, Step 1, using 5 (4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid and phenyl-acetic acid hydrazide. - 71 - WO 2011/041461 PCT/US2010/050786 [00405] Step 3: 1-{4'-[4-(5-Benzyl-[1,3,4]oxadiazol-2-ylamino)-3-methyl-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using (5-benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4 bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and 1-[4-(4,4,5,5-tetramethyl 5 [1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. Additionally, (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(O). [00406] Step 4: The ester from Step 4 was hydrolyzed to the acid according to the procedure described in Example 3. 10 Example 53: Synthesis of 1-(4'-{4-[6-(2-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 45) [00407] Step 1: 2-Fluoro-benzylzinc bromide: 2-Fluoro-benzyl bromide (1 g, 5.29 mmol), zinc (0.380 g, 5.82 mmol) and 1,2-dibromoethane (0.050 mL, 0.58 mmol) were mixed in THF (10 ML) and heated to reflux overnight. After cooling a solution of the title compound 15 was obtained that was used directly and immediately in the next step. [00408] Step 2: 2-Bromo-6-(2-fluoro-benzyl)-pyridine: A solution of 2-fluoro-benzylzinc bromide was added to 2,6-dibromo-pyridine (1.25 g, 5.27 mmol) then tetrakis(triphenylphosphine)palladium(0) (0.122 g, 0.106 mmol) was added and the reaction was heated to 68 'C for 4 hours. After cooling, silica gel was added to the reaction and it 20 was concentrated to near-dryness. The silica gel was loaded onto a column of silica gel for purification to afford thet title compound. [00409] Step 3: 1-(4'-{4-[6-(2-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) 25 biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(2-fluoro-benzyl) pyridine. [00410] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure described in Example 3. Example 54: Synthesis of 1-(4'-{4-[6-(3-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl 30 isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 46) [00411] Step 1: 3-Fluoro-benzylzinc bromide: Prepared according to the procedure described in Example 53, Step 1, using 3-fluoro-benzyl bromide. - 72 - WO 2011/041461 PCT/US2010/050786 [00412] Step 2: 2-Bromo-6-(3-fluoro-benzyl)-pyridine: Prepared according to the procedure described in Example 53, Step 2, using 2,6-dibromo-pyridine and 3-fluoro benzylzinc bromide. [00413] Step 3: 1-(4'-{4-[6-(3-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5 5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(3-fluoro-benzyl) pyridine. [00414] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure 10 described in Example 3. Example 55: Synthesis of 1-(4'-{4-[6-(4-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 47) [00415] Step 1: 4-Fluoro-benzylzinc bromide: Prepared according to the procedure described in Example 53, Step 1, using 4-fluoro-benzyl bromide. 15 [00416] Step 2: 2-Bromo-6-(4-fluoro-benzyl)-pyridine: Prepared according to the procedure described in Example 53, Step 2, using 2,6-dibromo-pyridine and 4-fluoro benzylzinc bromide. [00417] Step 3: 1-(4'-{4-[6-(4-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the 20 procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(4-fluoro-benzyl) pyridine. [00418] Step 4: The ester from Step 3 was hydrolyzed to the acid according to the procedure described in Example 3. 25 Example 56: Synthesis of 1-(4'-{4-[6-(3-Methoxy-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 48) Step 1: 1-(4'-{4-[6-(3-Methoxy-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo-pyridin-2-ylamino)-3 30 methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3 methoxyphenylboronic acid. [00419] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. - 73 - WO 2011/041461 PCT/US2010/050786 Example 57: Synthesis of 1-{4'-[4-(3-Benzyl-phenylamino)-3-methyl-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 49) [00420] Step 1: 1-{4'-[4-(3-Benzyl-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described 5 in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester and 1-benzyl-3-bromo-benzene. [00421] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 58: Synthesis of 1-(4'-{4-[6-(2-Cyano-phenyl)-pyridin-2-ylamino]-3-methyl 10 isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 50) [00422] Step 1: 1-(4'-{4-[6-(2-Cyano-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1- {4'- [4-(6-bromo-pyridin-2-ylamino)-3 methyl-isoxazol-5-yl]-biphenyl-4-yl} -cyclopropanecarboxylic acid ethyl ester and 2 15 cyanophenylboronic acid. [00423] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 59: Synthesis of 1-(4'-{4-[6-(4-Methoxy-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 51) 20 Step 1: 1-(4'-{4-[6-(4-Methoxy-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1- {4'- [4-(6-bromo-pyridin-2-ylamino)-3 methyl-isoxazol-5-yl]-biphenyl-4-yl} -cyclopropanecarboxylic acid ethyl ester and 4 methoxyphenylboronic acid. 25 [00424] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 60: Synthesis of 1-(4'-{4-[6-(3-Fluoro-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 52) [00425] Step 1: 1-(4'-{4-[6-(3-Fluoro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5 30 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1- {4'- [4-(6-bromo-pyridin-2-ylamino)-3 methyl-isoxazol-5-yl]-biphenyl-4-yl} -cyclopropanecarboxylic acid ethyl ester and 3 fluorophenylboronic acid. - 74 - WO 2011/041461 PCT/US2010/050786 [00426] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 61: Synthesis of 1-(4'-{4-[6-(2-Methoxy-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 53) 5 [00427] Step 1: 1-(4'-{4-[6-(2-Methoxy-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-(3-bromo-phenyl)-2-methoxy pyridine. 10 [00428] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 62: Synthesis of 1-(4'-{4-[6-(2-Fluoro-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 54) [00429] Step 1: 1-(4'-{4-[6-(2-Fluoro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5 15 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1- {4'- [4-(6-bromo-pyridin-2-ylamino)-3 methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-(2 fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. [00430] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure 20 described in Example 3. Example 63: Synthesis of 1-(4'-{3-methyl-4-[6-(2-trifluoromethyl-phenyl)-pyridin-2 ylamino]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 55) Step 1: 1-(4'-{3-Methyl-4-[6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamino]-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the 25 procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo-pyridin-2-ylamino)-3 methyl-isoxazol-5 -yl] -biphenyl-4-yl} -cyclopropanecarboxylic acid ethyl ester and 4,4,5,5 tetramethyl-2-(2-trifluoromethyl-phenyl)- [1,3,2] dioxaborolane. [00431] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. 30 Example 64: Synthesis of 1-(4'-{3-Methyl-4-[(2-phenyl-thiazol-5-ylmethyl)-amino] isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 56) [00432] Step 1: 1-(4'-{3-Methyl-4-[(2-phenyl-thiazol-5-ylmethyl)-amino]-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the - 75 - WO 2011/041461 PCT/US2010/050786 procedure described in Example 1, Step 12, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenyl-thiazole-5 carbaldehyde. [00433] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure 5 described in Example 3. Example 65: Synthesis of 1-{4'-[3-Methyl-4-(2'-trifluoromethyl-biphenyl-3-ylamino) isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 57) [00434] Step 1: 1-{4'-[4-(3-Bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described 10 in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester and 1,3-dibromo-benzene. [00435] Step 2: 1-{4'-[3-Methyl-4-(2'-trifluoromethyl-biphenyl-3-ylamino)-isoxazol-5 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(3-bromo-phenylamino)-3 15 methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2 (trifluoromethyl)phenylboronic acid. [00436] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 66: Synthesis of 1-{4'-[3-Methyl-4-(5-phenyl-pyridin-3-ylamino)-isoxazol-5 20 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 58) [00437] Step 1: 3-Bromo-5-phenyl-pyridine: Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and phenylboronic acid. [00438] Step 2: 1-{4'-[3-Methyl-4-(5-phenyl-pyridin-3-ylamino)-isoxazol-5-yl]-biphenyl 4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure 25 described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4 yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-phenyl-pyridine. [00439] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 67: Synthesis of 1-(4'-{4-[5-(3-Fluoro-phenyl)-pyridin-3-ylamino]-3-methyl 30 isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 59) [00440] Step 1: 3-Bromo-5-(3-fluoro-phenyl)-pyridine: Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 3 flurophenylboronic acid. - 76 - WO 2011/041461 PCT/US2010/050786 [00441] Step 2: 1-(4'-{4-[5-(3-Fluoro-phenyl)-pyridin-3-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3-fluoro-phenyl) 5 pyridine. [00442] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 68: Synthesis of 1-(4'-{4-[6-(2-Chloro-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 60) 10 [00443] Step 1: 1-(4'-{4-[6-(2-Chloro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1- {4'- [4-(6-bromo-pyridin-2-ylamino)-3 methyl-isoxazol-5-yl]-biphenyl-4-yl} -cyclopropanecarboxylic acid ethyl ester and 2 chlorophenylboronic acid. 15 [00444] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 69: Synthesis of 1-(4'-{4-[Hydroxy-(6-phenyl-pyridin-2-yl)-methyl]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 61) [00445] Step 1: 1-(4'-{4-[Hydroxy-(6-phenyl-pyridin-2-yl)-methyl]-3-methyl-isoxazol-5 20 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 34, Step 3, using 1-[4'-(4-formyl-3-methyl-isoxazol-5-yl) biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyridine. [00446] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. 25 Example 70: Synthesis of 1-{4'-[3-Methyl-4-(2-phenyl-pyridin-4-ylamino)-isoxazol-5 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 62) [00447] Step 1: 1-{4'-[3-Methyl-4-(2-phenyl-pyridin-4-ylamino)-isoxazol-5-yl]-biphenyl 4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4 30 yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-2-phenyl-pyridine. [00448] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. - 77 - WO 2011/041461 PCT/US2010/050786 Example 71: Synthesis of 1-(4'-{4-[2-(3-Fluoro-phenyl)-pyridin-4-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 63) [00449] Step 1: 1-(4'-{4-[2-(3-Fluoro-phenyl)-pyridin-4-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the 5 procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-2-(3-fluoro-phenyl) pyridine. [00450] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. 10 Example 72: Synthesis of 1-(4'-{4-[5-(2-Chloro-phenyl)-pyridin-3-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 64) [00451] Step 1: 3-Bromo-5-(2-chloro-phenyl)-pyridine: Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 2 chlorophenylboronic acid. 15 [00452] Step 2: 1-(4'-{4-[5-(2-Chloro-phenyl)-pyridin-3-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(2-chloro-phenyl) pyridine. 20 [00453] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 73: Synthesis of 1-(4'-{4-[2-(2-Chloro-phenyl)-pyridin-4-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 65) [00454] Step 1: 4-Bromo-2-(2-chloro-phenyl)-pyridine: Prepared according to the 25 procedure described in Example 1, Step 10, using 2,4-dibromo-pyridine and 2 chlorophenylboronic acid. [00455] Step 2: 1-(4'-{4-[2-(2-Chloro-phenyl)-pyridin-4-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) 30 biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-2-(2-chloro-phenyl) pyridine. [00456] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. - 78 - WO 2011/041461 PCT/US2010/050786 Example 74: Synthesis of 1-{4'-[3-Methyl-4-(4-phenyl-pyrimidin-2-ylamino)-isoxazol 5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 66) [00457] Step 1: 1-{4'-[3-Methyl-4-(4-phenyl-pyrimidin-2-ylamino)-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the 5 procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-4-phenyl-pyrimidine. [00458] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 75: Synthesis of 1-{4'-[3-Methyl-4-(4-phenyl-pyridin-2-ylamino)-isoxazol-5 10 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 67) [00459] Step 1: 1-{4'-[3-Methyl-4-(4-phenyl-pyridin-2-ylamino)-isoxazol-5-yl]-biphenyl 4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4 yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-4-phenyl-pyridine. 15 [00460] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 76: Synthesis of 1-(4'-{3-Methyl-4-[5-(3-trifluoromethyl-phenyl)-pyridin-3 ylamino]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 68) [00461] Step 1: 3-Bromo-5-(3-trifluoromethyl-phenyl)-pyridine: Prepared according to 20 the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 3 (trifluoromethyl)-phenylboronic acid. [00462] Step 2: 1-(4'-{3-Methyl-4-[5-(3-trifluoromethyl-phenyl)-pyridin-3-ylamino] isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl 25 isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3 trifluoromethyl-phenyl)-pyridine. [00463] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 77: Synthesis of 1-(4'-{3-Methyl-4-[5-(4-trifluoromethyl-phenyl)-pyridin-3 30 ylamino]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 69) [00464] Step 1: 3-Bromo-5-(4-trifluoromethyl-phenyl)-pyridine: Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 4 (trifluoromethyl)-phenylboronic acid. - 79 - WO 2011/041461 PCT/US2010/050786 [00465] Step 2: 1-(4'-{3-Methyl-4-[5-(4-trifluoromethyl-phenyl)-pyridin-3-ylamino] isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(4 5 trifluoromethyl-phenyl)-pyridine. [00466] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 78: Synthesis of 1-{4'-[3-Methyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol-5 yl]-biphenyl-4-yl}-cyclobutanecarboxylic acid (Compound 70) 10 [00467] Step 1: 1-(4-Bromo-phenyl)-cyclobutanecarboxylic acid ethyl ester: Ethyl 4 bromophenyl acetate (2 g, 8.2 mmol) was dissolved in DMF (20 mL) and cooled to 0 'C under N 2 atmosphere. Sodium hydride (60% in mineral oil, 0.72 g, 18.1 mmol) was added and the reaction was allowed to warm to room temperature. After 10 minutes the ice bath was replaced and 1,3-dibromopropane (0.92 mL, 9.0 mmol) was added, and the reaction 15 was again allowed to warm to room temperature. After 30 minutes the reaction was submitted to aqueous workup and purified on silica gel to give the title compound. [00468] Step 2: 1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] cyclobutanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 9, using 1-(4-bromo-phenyl)-cyclobutanecarboxylic acid ethyl ester and 20 bis(pinacolato)diboron. [00469] Step 3: 1-[4'-(4-tert-Butoxycarbonylamino-3-methyl-isoxazol-5-yl)-biphenyl-4 yl]-cyclobutanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] 25 cyclobutanecarboxylic acid ethyl ester. Additionally, (1,1' bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0). [00470] Step 4: 1-[4'-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclobutanecarboxylic acid ethyl ester: Prepared according to the procedure described in 30 Example 1, Step 9, using 1-[4'-(4-tert-butoxycarbonylamino-3-methyl-isoxazol-5-yl) biphenyl-4-yl]-cyclobutanecarboxylic acid ethyl ester. [00471] Step 5: 1-{4'-[3-Methyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol-5-yl]-biphenyl 4-yl}-cyclobutanecarboxylic acid ethyl ester: Prepared according to the procedure - 80 - WO 2011/041461 PCT/US2010/050786 described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4 yl]-cyclobutanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyridine. [00472] Step 6: The ester from Step 5 was hydrolyzed to the acid according to the procedure described in Example 3. 5 Example 79: Synthesis of 1-(4'-{4-[Hydroxy-(5-phenyl-pyridin-3-yl)-methyl]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 71) [00473] Step 1: 1-(4'-{4-[Hydroxy-(5-phenyl-pyridin-3-yl)-methyl]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 19, Step 1, using 1-[4'-(4-formyl-3-methyl-isoxazol-5-yl) 10 biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-phenyl-pyridine. [00474] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 80: Synthesis of 1-[4'-(4-{Hydroxy-[5-(3-trifluoromethyl-phenyl)-pyridin-3 yl]-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid 15 (Compound 72) [00475] Step 1: 1-[4'-(4-{Hydroxy-[5-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-methyl} 3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 19, Step 1, using 1-[4'-(4-formyl 3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3 20 bromo-5-(3-trifluoromethyl-phenyl)-pyridine. [00476] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 81: Synthesis of 1-{4'-[3-Methyl-4-(6-phenylethynyl-pyridin-2-ylamino) isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 73) 25 [00477] Step 1: 1-{4'-[3-Methyl-4-(6-phenylethynyl-pyridin-2-ylamino)-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: 1- {4'-[4-(6-Bromo-pyridin-2 ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.200 g, 0.386 mmol) was dissolved in toluene along with phenylacetylene (0.051 mL, 0.46 mmol), copper(I) iodide (0.367 g, 1.93 mmol), triethylamine (0.269 mL, 1.93 mmol) 30 and bis(triphenylphosphine)palladium(II) dichloride (0.032 g, 0.039 mmol). The reaction was heated to 40 'C for 3 days then cooled, diluted with EtOAc and filtered through a plug of silica gel. The crude material was purified on silica gel to yield the title compound. - 81 - WO 2011/041461 PCT/US2010/050786 [00478] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 82: Synthesis of 1-(4'-{4-[6-(3-Cyano-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 74) 5 [00479] Step 1: 1-(4'-{4-[6-(3-Cyano-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1- {4'- [4-(6-bromo-pyridin-2-ylamino)-3 methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-cyano phenylboronic acid. 10 [00480] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 83: Synthesis of 1-(4'-{4-[6-(5-Fluoro-2-methoxy-phenyl)-pyridin-2-ylamino] 3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 75) [00481] Step 1: 1-(4'-{4-[6-(5-Fluoro-2-methoxy-phenyl)-pyridin-2-ylamino]-3-methyl 15 isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 5-fluoro-2-methoxy-phenylboronic acid. [00482] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure 20 described in Example 3. Example 84: Synthesis of 1-(4'-{4-[6-(3-Chloro-5-fluoro-phenyl)-pyridin-2-ylamino]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 76) [00483] Step 1: 1-(4'-{4-[6-(3-Chloro-5-fluoro-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared 25 according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-chloro-5-fluorophenylboronic acid. [00484] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. 30 Example 85: Synthesis of 1-(4'-{4-[6-(2,5-Difluoro-phenyl)-pyridin-2-ylamino]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 77) [00485] Step 1: 1-(4'-{4-[6-(2,5-Difluoro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol 5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the - 82 - WO 2011/041461 PCT/US2010/050786 procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo-pyridin-2-ylamino)-3 methyl-isoxazol-5-yl]-biphenyl-4-yl} -cyclopropanecarboxylic acid ethyl ester and 2,5 difluoro-phenylboronic acid. [00486] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure 5 described in Example 3. Example 86: Synthesis of 1-(4'-{4-[6-(2,6-Dichloro-phenyl)-pyridin-2-ylamino]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 78) [00487] Step 1: 1-(4'-{4-[6-(2,6-Dichloro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol 5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the 10 procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo-pyridin-2-ylamino)-3 methyl-isoxazol-5-yl]-biphenyl-4-yl} -cyclopropanecarboxylic acid ethyl ester and 2,6 dichloro-phenylboronic acid. Additionally, (1,1 '-bis(diphenylphosphino)ferrocene) dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0). 15 [00488] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 87: Synthesis of 1-(4'-{4-[6-(2-Chloro-5-fluoro-phenyl)-pyridin-2-ylamino]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 79) [00489] Step 1: 1-(4'-{4-[6-(2-Chloro-5-fluoro-phenyl)-pyridin-2-ylamino]-3-methyl 20 isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-chloro-5-fluoro-phenylboronic acid. Additionally, (1,1' bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of 25 tetrakis(triphenylphosphine)palladium(0). [00490] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 88: Synthesis of 1-(4'-{4-[6-(2,3-Difluoro-phenyl)-pyridin-2-ylamino]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 80) 30 [00491] Step 1: 1-(4'-{4-[6-(2,3-Difluoro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol 5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo-pyridin-2-ylamino)-3 methyl-isoxazol-5-yl]-biphenyl-4-yl} -cyclopropanecarboxylic acid ethyl ester and 2,3 - 83 - WO 2011/041461 PCT/US2010/050786 difluoro-phenylboronic acid. Additionally, (1,1 '-bis(diphenylphosphino)ferrocene) dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(O). [00492] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure 5 described in Example 3. Example 89: Synthesis of 1-(4'-{4-[6-(2-Chloro-3-fluoro-phenyl)-pyridin-2-ylamino]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 81) [00493] Step 1: 1-(4'-{4-[6-(2-Chloro-3-fluoro-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared 10 according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-chloro-3-fluoro-phenylboronic acid. (1,1' Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(O). 15 [00494] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 90: Synthesis of 1-(4'-{4-[5-(2-Chloro-3-fluoro-phenyl)-pyridin-3-ylamino]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 82) [00495] Step 1: 3-Bromo-5-(2-chloro-3-fluoro-phenyl)-pyridine: Prepared according to 20 the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 2-chloro-3 fluoro-phenylboronic acid. (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0). [00496] Step 2: 1-(4'-{4-[5-(2-Chloro-3-fluoro-phenyl)-pyridin-3-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared 25 according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(2 chloro-3-fluoro-phenyl)-pyridine. [00497] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. 30 Example 91: Synthesis of 1-(4'-{4-[6-(3-Fluoro-2-methyl-phenyl)-pyridin-2-ylamino]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 83) [00498] Step 1: 1-(4'-{4-[6-(3-Fluoro-2-methyl-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared - 84 - WO 2011/041461 PCT/US2010/050786 according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-fluoro-2-metheyl-phenylboronic acid. Additionally, (1,1' bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of 5 tetrakis(triphenylphosphine)palladium(O). [00499] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. Example 92: Synthesis of 1-(4'-{4-[6-(2-Chloro-3-trifluoromethyl-phenyl)-pyridin-2 ylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid 10 (Compound 84) [00500] Step 1: 1-(4'-{4-[6-(2-Chloro-3-trifluoromethyl-phenyl)-pyridin-2-ylamino]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid 15 ethyl ester and 2-chloro-3-(trifluoromethyel)phenylboronic acid. Additionally, (1,1' bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(O). [00501] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. 20 Example 93: Synthesis of Synthesis of N-[1-(4'-{4-[(1-Benzyl-1H-[1,2,3]triazol-4-yl) hydroxy-methyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarbonyl] methanesulfonamide (Enantiomer B) (Compound 91) [00502] A solution of 1-(4'-{4-[(1-benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl]-3-methyl isoxazol-5-yl} -biphenyl-4-yl)-cyclopropanecarboxylic acid (Enantiomer B) (0.100 g, 0.197 25 mmol), carbonyldiimidazole (0.080 g, 0.5 mmol), NN-dimethylamino pyridine (0.002 g, 0.02 mmol) in THF (2 mL) was stirred at room temperature overnight. Added MeSO 2
NH
2 (0.050 g, 0.5 mmol) and DBU (0.100 mL, 0.65 mmol) and the mixture heated to 100 C in a capped vial for 4.5 hours. The solution was poured into sat. aqueous NH 4 Cl, then water and EtOAc was added. The organic layer was separated, dried (Na 2
SO
4 ), concentrated and the 30 resulting reside purified by preparative HPLC to yield the title compound. Example 94: Synthesis of N-[1-(4'-{4-[(5-Benzyl-[1,3,4]oxadiazol-2-yl)-hydroxy methyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarbonyl] methanesulfonamide (Enantiomer A) (Compound 92) - 85 - WO 2011/041461 PCT/US2010/050786 [00503] Step 1: N-[1-(4-Bromo-phenyl)-cyclopropanecarbonyl]-methanesulfonamide: 1 (4-Bromo-phenyl)-cyclopropanecarboxylic acid (22 g, 91.3 mmol) and SOCl 2 (13.6 mL, 183 mmol) in CH 2 Cl 2 were heated together for 1.5 hours then evaporated to afford a dark oil. This oil was added via syringe over 30 minutes to a mixture of MeSO 2
NH
2 (19 g, 200 5 mmol) in THF (250 mL) that was pre-treated at room temperature with NaH (60% in oil; 8.0 g, 200 mmol) for 1.5 hours. After a further 20 minutes, the mixture was poured into water, acidified and extracted with CH 2 Cl 2 , washed with water (2x) and evaporated to ~100 mL. Hexane (300 mL) was added and the product collected by filtration to yield the title compound (25 g). 10 [00504] Step 2: N-{1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] cyclopropanecarbonyl}-methanesulfonamide: N-[1-(4-Bromo-phenyl) cyclopropanecarbonyl]-methanesulfonamide (22 g, 69 mmol), bis(pinacolato)diborane (21.1 g, 83 mmol), KOAc (21.6 g, 220 mmol) in dioxane (300 mL) were degassed with N 2 for 30 minutes and then (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (1.0 g, 1.4 15 mmol) was added. The mixture was heated at reflux for 2 hours then at 70 0 C for 16 hours. Then solution was poured into EtOAc/H 2 0, acidified and the organic layer concentrated to give the boronate which was used in the next step without further purification. [00505] Step 3: N-[1-(4'-{4-[(5-Benzyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarbonyl]-methanesulfonamide 20 (Enantiomer A): A solution of N- {1 -[4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl) phenyl]-cyclopropanecarbonyl}-methanesulfonamide (0.045 g, 0.124 mmol), 5-benzyl [1,3,4]oxadiazol-2-yl)- [5 -(4-bromo-phenyl)-3 -methyl-isoxazol-4-yl] -methanol (Enantiomer A) (0.053 g, 0.124 mmol), NaHCO 3 (0.031 g, 0.372 mmol), DME (1.5 mL) and H 2 0 (1 mL) was degassed by bubbling with N 2 for 10 minutes. 25 Tetrakis(triphenylphosphine)palladium(0) (0.007g, 0.006 mmol) was added and the sealed reaction vial was stirred at 80 0 C for 16 hours. The mixture was poured into EtOAc/H 2 0, washed with IN HCl then aqueous Na 2
SO
4 and concentrated. The resulting reside purified by preparative HPLC to yield the title compound. Example 95: Synthesis of N-{1-[4'-(4-{Hydroxy-[1-(3-trifluoromethyl-benzyl)-1H 30 [1,2,3]triazol-4-yl]-methyl}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarbonyl}-methanesulfonamide (Compound 93) [00506] Step 1: Prepared according to the procedure described in Example 94, Step 3, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-trifluoromethyl-benzyl)-1H - 86 - WO 2011/041461 PCT/US2010/050786 [1,2,3 ]triazol-4-yl] -methanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) phenyl]-cyclopropanecarbonyl} -methanesulfonamide. Example 96: Synthesis of N-(1-{4'-[3-Methyl-4-(5-phenyl-[1,3,4]oxadiazol-2-ylamino) isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarbonyl)-methanesulfonamide (Compound 5 94) [00507] Step 1: Prepared according to the procedure described in Example 94, Step 3, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and N-{ 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl} methanesulfonamide. 10 Example 97: Synthesis of N-(1-{4'-[4-(6-Benzyl-pyridin-2-ylamino)-3-methyl-isoxazol 5 -yl]-biphenyl-4-yl}-cyclopropanecarbonyl)-methanesulfonamide (Compound 95) [00508] Step 1: N-(1-{4'-[4-(6-Benzyl-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarbonyl)-methanesulfonamide: 1-{4'-[4-(6-benzyl-pyridin 2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (sodium 15 salt; 0.050 g, 0.083 mmol), carbonyldiimidazole (0.0676 g, 0.417 mmol), MeSO 2
NH
2 (0.0789 g, 0.83 mmol) and DBU (0.0248 mL, 0.166 mmol) were combined in THF (1 mL) and the mixture was heated to 70 0 C in a capped vial for 25 hours. The mixture was purified by preparative HPLC to yield the title compound. Example 98: Synthesis of N-(1-{4'-[3-Methyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol 20 5-yl]-biphenyl-4-yl}-cyclopropanecarbonyl)-methanesulfonamide (Compound 96) [00509] Step 1: {5-[4'-(1-Methanesulfonylaminocarbonyl-cyclopropyl)-biphenyl-4-y]-3 methyl-isoxazol-4-yl}-carbamic acid tert-butyl ester: Prepared according to the procedure described in Example 94, Step 3, using [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl] carbamic acid tert-butyl ester and N-{ 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) 25 phenyl]-cyclopropanecarbonyl}-methanesulfonamide. [00510] Step 2: N-{1-[4'-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarbonyl}-methanesulfonamide: {5-[4'-(1-Methanesulfonylaminocarbonyl cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazol-4-yl}-carbamic acid tert-butyl ester (0.25 g, 0.49 mmol)) in CH 2 Cl 2 (2 mL) and TFA (2 mL) was stirred overnight then poured into 30 EtOAc/NaHCO 3 (aq). The organic layer was concentrated to yield the title compound that was used directly in the next step. [00511] Step 3: N-(1-{4'-[3-Methyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarbonyl)-methanesulfonamide: N- {1 -[4'-(4-Amino-3 - 87 - WO 2011/041461 PCT/US2010/050786 methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarbonyl}-methanesulfonamide (0.103 g, 0.25 mmol), 2-bromo-6-phenylpyridine (0.059 g, 0.25 mmol), potassium carbonate (0.243 g, 0.75 mmol), and BINAP (15 mg, 0.025 mmol) were combined in THF (10 mL) and the solution was degassed with N 2 for 10 minutes. Palladium(II)acetate (0.003 g, 5 0.0125 mmol) was added and degassing was continued for 10 minutes. The reaction mixture was sealed and heated at 65 0 C overnight then poured into EtOAc/water. The organic layer was concentrated and purified by silica gel chromatography to give the title compound. Example 99: 1-{4'-[4-(2'-Dimethylaminomethyl-biphenyl-3-ylamino)-3-methyl 10 isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 85) [00512] Step 1: 1-{4'-[4-(2'-Dimethylaminomethyl-biphenyl-3-ylamino)-3-methyl isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(3-bromo phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl 15 ester and 2-(NN-dimethylaminomethyl)-phenylboronic acid. (1,1' Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(O). [00513] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. 20 Example 100: Synthesis of 1-(4'-{4-[6-(2,3-Dichloro-phenyl)-pyridin-2-ylamino]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 86) [00514] Step 1: 1-(4'-{4-[6-(2,3-Dichloro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol 5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo-pyridin-2-ylamino)-3 25 methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,3 dichlorophenylboronic acid. (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0). [00515] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. 30 Example 101: Synthesis of 1-(4'-{4-[6-(3-Fluoro-2-methoxy-phenyl)-pyridin-2 ylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 87) - 88 - WO 2011/041461 PCT/US2010/050786 [00516] Step 1: 1-(4'-{4-[6-(3-Fluoro-2-methoxy-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid 5 ethyl ester and 3-fluoro-2-methoxyphenylboronic acid. (1,1' Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(O). [00517] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure described in Example 3. 10 Example 102: Synthesis of 1-(4'-{4-[5-(3-Chloro-phenyl)-pyridin-3-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 88) [00518] Step 1: 3-Bromo-5-(3-chloro-phenyl)-pyridine: Prepared according to the procedure described in Example 1, Step 10, using the following starting materials: 3,5 dibromo-pyridine and 3-chlorophenylboronic acid. 15 [00519] Step 2: 1-(4'-{4-[5-(3-Chloro-phenyl)-pyridin-3-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3-chloro-phenyl) pyridine. 20 [00520] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. Example 103: Synthesis of 1-(4'-{4-[5-(2,5-Difluoro-phenyl)-pyridin-3-ylamino]-3 methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 89) [00521] Step 1: 3-Bromo-5-(2,5-difluoro-phenyl)-pyridine: Prepared according to the 25 procedure described in Example 41, Step 1, using 3,5-dibromo-pyridine and 2,5 difluorophenylboronic acid. [00522] Step 2: 1-(4'-{4-[5-(2,5-Difluoro-phenyl)-pyridin-3-ylamino]-3-methyl-isoxazol 5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-methyl-isoxazol-5-yl) 30 biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(2,5-difluoro phenyl)-pyridine. [00523] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. - 89 - WO 2011/041461 PCT/US2010/050786 Example 104: Synthesis of 1-(4'-{4-[6-(3-Chloro-phenyl)-pyridin-2-ylamino]-3-methyl isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 90) [00524] Step 1: 1-(4'-{4-[6-(3-Chloro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5 yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the 5 procedure described in Example 1, Step 10, using 1-{4'-[4-(6-bromo-pyridin-2-ylamino)-3 methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3 chlorophenylboronic acid. (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(O). [00525] Step 2: The ester from Step 1 was hydrolyzed to the acid according to the procedure 10 described in Example 3. Example 105: Synthesis of 1-{4'-[3-Ethyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol-5 yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 97) [00526] Step 1: 3-Methylamino-pent-2-enoic acid methyl ester: Prepared according to the procedure described in Example 1, Step 1, using the following starting materials: 3-oxo 15 pentanoic acid methyl ester and methylamine. [00527] Step 2: 2-(4-Bromo-benzoyl)-3-oxo-pentanoic acid methyl ester: Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 3-methylamino-pent-2-enoic acid methyl ester and 4-bromobenzoyl chloride. [00528] Step 3: 5-(4-Bromo-phenyl)-3-ethyl-isoxazole-4-carboxylic acid methyl ester: 20 Prepared according to the procedure described in Example 1, Step 3, using the following starting material: 2-(4-bromo-benzoyl)-3-oxo-pentanoic acid methyl ester. [00529] Step 4: 5-(4-Bromo-phenyl)-3-ethyl-isoxazole-4-carboxylic acid: Prepared according to the procedure described in Example 1, Step 4, using the following starting material: 5-(4-bromo-phenyl)-3-ethyl-isoxazole-4-carboxylic acid methyl ester. 25 [00530] Step 5: [5-(4-Bromo-phenyl)-3-ethyl-isoxazol-4-yl]-carbamic acid tert-butyl ester: Prepared according to the procedure described in Example 1, Step 5, using the following starting material: 5-(4-bromo-phenyl)-3-ethyl-isoxazole-4-carboxylic acid. [00531] Step 6: 1-[4'-(4-tert-Butoxycarbonylamino-3-ethyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described 30 in Example 1, Step 10, using the following starting materials: [5-(4-bromo-phenyl)-3-ethyl isoxazol-4-yl]-carbamic acid tert-butyl ester and 1-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. (1,1' - 90 - WO 2011/041461 PCT/US2010/050786 bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(O). [00532] Step 7: 1-[4'-(4-Amino-3-ethyl-isoxazol-5-yl)-biphenyl-4-yl] cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described 5 in Example 1, Step 11, using 1-[4'-(4-tert-butoxycarbonylamino-3-ethyl-isoxazol-5-yl) biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester. [00533] Step 8: 1-{4'-[3-Ethyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol-5-yl]-biphenyl-4 yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using 1-[4'-(4-amino-3-ethyl-isoxazol-5-yl)-biphenyl-4 10 yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyridine. [00534] Step 9: The ester from Step 8 was hydrolyzed to the acid according to the procedure described in Example 3. Example 106: Synthesis of 1-{4'-[3-Ethyl-4-(5-phenyl-[1,3,4]oxadiazol-2-ylamino) isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 98) 15 [00535] Step 1: [5-(4-Bromo-phenyl)-3-ethyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2 yl)-amine: Prepared according to the procedure described in Example 51, Step 1, using 5 (4-bromo-phenyl)-3-ethyl-isoxazole-4-carboxylic acid and benzoic acid hydrazide. [00536] Step 2: 1-{4'-[3-Ethyl-4-(5-phenyl-[1,3,4]oxadiazol-2-ylamino)-isoxazol-5-yl] biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester: Prepared according to the 20 procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-ethyl-isoxazol-4 yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. (1,1' bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(O). 25 [00537] Step 3: The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3. [00538] In some embodiments, mass spectrometric data (mass spec. data) is obtained with a Shimadzu LCMS 2010A. Example 107: Establishment of a CHO Cell Line Stably Expressing Human LPA 1 30 [00539] A 1.1 kb cDNA encoding the human LPA 1 receptor was cloned from human lung. Human lung RNA (Clontech Laboratories, Inc. USA) was reverse transcribed using the RETROscript kit (Ambion, Inc.) and the full-length cDNA for human LPA 1 was obtained by PCR of the reverse transcription reaction. The nucleotide sequence of the cloned human - 91 - WO 2011/041461 PCT/US2010/050786
LPA
1 was determined by sequencing and confirmed to be identical to the published human
LPA
1 sequence (An et al. Biochem. Biophys. Res. Commun. 231:619 (1997). The cDNA was cloned into the pCDNA5/FRT expression plasmid and transfected in CHO cells using lipofectamine 2000 (Invitrogen Corp., USA). Clones stably expressing human LPA 1 were 5 selected using hygromycin and identified as cells that show Ca-influx in response to LPA. Example 108: Generation of Cells Transiently Expressing Human LPA 2 [00540] A vector containing the human LPA 2 receptor cDNA was obtained from the Missouri S&T cDNA Resource Center (www.cdna.org). The full-length cDNA fragment for human LPA 2 was obtained by PCR from the vector. The nucleotide sequence of the cloned 10 human LPA 2 was determined by sequencing and confirmed to be identical to the published human LPA 2 sequence (NCBI accession number NM_004720). The cDNA was cloned into the pCDNA3.1 expression plasmid and transfected into B103 cells (Invitrogen Corp., USA) by seeding cells in a 96-well poly-D-lysine coated plate at 30,000-35,000 cells per well together with 0.2 gl lipofectamine 2000 and 0.2 gg of the LPA 2 expression vector. Cells 15 were cultured overnight in complete media before being assayed for LPA-induced Ca influx. Example 109: Establishment of a CHO Cell Line Stably Expressing Human LPA 3 [00541] A vector containing the human LPA 3 receptor cDNA was obtained from the Missouri S&T cDNA Resource Center (www.cdna.org). The full-length cDNA fragment for 20 human LPA 3 was obtained by PCR from the vector. The nucleotide sequence of the cloned human LPA 3 was determined by sequencing and confirmed to be identical to the published human LPA 3 sequence (NCBI accession number NM_012152). The cDNA was cloned into the pCDNA5/FRT expression plasmid and transfected in CHO cells using lipofectamine 2000 (Invitrogen Corp., USA). Clones stably expressing human LPA 3 were selected using 25 hygromycin and identified as cells that show Ca-influx in response to LPA. Example 110: LPA1 and LPA3 Calcium Flux Assays. [00542] Human LPA 1 or LPA 3 expressing CHO cells are seeded at 20,000-45,000 cells per well in a 96-well poly-D-lysine coated plate one or two days before the assay. Prior to the assay, the cells are washed once with PBS and then cultured in serum-free media overnight. 30 On the day of the assay, a calcium indicator dye (Calcium 4, Molecular Devices) in assay buffer (HBSS with Ca 2 and Mg 2 " and containing 20 mM Hepes and 0.3% fatty-acid free human serum albumin) is added to each well and incubation continued for 1 hour at 37'C. 10 gl of test compounds in 2.5% DMSO are added to the cells and incubation continued at - 92 - WO 2011/041461 PCT/US2010/050786 room temperature for 30 minutes. Cells are the stimulated by the addition of 10 nM LPA and intracellular Ca measured using the Flexstation 3 (Molecular Devices). IC 50 s are determined using Graphpad prism analysis of drug titration curves. Example 111: LPA2 Calcium Flux Assay. 5 [00543] Following an overnight culture with lipofectamine 2000 and the LPA 2 expression vector, the B103 cells are washed once with PBS then serum starved for 4 hours. A calcium indicator dye (Calcium 4, Molecular Devices) in assay buffer (HBSS with Ca2+ and Mg 2 + and containing 20 mM Hepes and 0.3% fatty-acid free human serum albumin) is added to each well and incubation continued for 1 hour at 37'C. 10 gl of test compounds in 2.50% 10 DMSO are added to the cells and incubation continued at room temperature for 30 minutes. Cells are the stimulated by the addition of 10 nM LPA and intracellular Ca2+ measured using the Flexstation 3 (Molecular Devices). IC 50 s are determined using Graphpad prism analysis of drug titration curves. Example 112: GTPyS Binding Assay 15 [00544] The ability of a compound to inhibit binding of GTP to LPA 1 is assessed via a membrane GTPyS assay. CHO cells stably expressing the recombinant human LPA 1 receptor are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT, lysed and centrifuged at 75,000 xg to pellet the membranes. The membranes are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT and 10% glycerol. Membranes (~25 gg per well) are 20 incubated in 96-well plates with 0.1 nM [1 5 S]-GTPyS, 900 nM LPA, 5 gM GDP, and test compound in Assay Buffer (50 mM Hepes, pH 7.4, 100 mM NaCl, 10 mM MgCl 2 , 50 gg/ml saponin and 0.2% fatty-acid free human serum albumin) for 30 minutes at 30'C. The reactions are terminated by rapid filtration through Whatman GF/B glass fibre filter plates. The filter plates are washed 3 times with 1 ml cold Wash Buffer (50 mM Hepes, 7.5, 100 25 mM NaCl and 10 mM MgCl 2 ) and dried. Scintillant is then added to the plates and the radioactivity retained on the filters is determined on a Packard TopCount (Perkin Elmer). Specific binding is determined as total radioactive binding minus non-specific binding in the absence of the ligand (900 nM LPA). IC 50 s were determined using Graphpad prism analysis of drug titration curves. 30 [00545] Illustrative in vitro biological data for representative compounds of Formula (I) is presented in the Table below. Unless otherwise noted, all the compounds in Table 4 that were tested in this assay had IC 50 values of less than 50 tM. - 93 - WO 2011/041461 PCT/US2010/050786 Table 4. Compound No. HLPA1 Ca Flux IC 50 1 A 2 A 3 A 4 A 5 C 6 A 7 B 8 A 9 A 10 C 11 A 12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 20 B 21 C 22 A 23 A 24 C 25 A 26 A 27 A 28 A 29 A 30 A 31 A 32 A 33 A 34 A 35 A 36 A 37 B 38 A 39 A 40 B 41 A 42 A 43 A 44 A 45 A - 94 - WO 2011/041461 PCT/US2010/050786 Compound No. HLPA1 Ca Flux IC 50 46 A 47 A 48 A 49 A 50 A 51 A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 A 61 A 62 B 63 C 64 A 65 A 66 A 67 A 68 A 69 A 70 A 71 A 72 A 73 A 74 A 75 A 76 A 77 A 78 A 79 A 80 A 81 A 82 A 83 A 84 B 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A - 95 - WO 2011/041461 PCT/US2010/050786 Compound No. HLPA1 Ca Flux IC 50 93 C 94 A 95 A 96 A 97 A 98 A A = less than 0.3 piM; B = greater than 0.3 piM and less than 1 jiM; C= greater than 1 [tM and less than 50 ptM. Example 113. LPA1 Chemotaxis Assay. 5 [00546] Chemotaxis of the A2058 human melanoma cells was measured using the Neuroprobe ChemoTx@ System plates (8 gm pore size, 5.7 mm diameter sites). The filter sites were coated with 0.001% fibronectin (Sigma) in 20 mM Hepes, pH 7.4 and allowed to dry. A2058 cells were serum-starved for 24 hours , then harvested with Cell Stripper and resuspended in DMEM containing 0.1% fatty-acid-free bovine serum albumin (BSA) to a 10 concentration of 1 x 10 6 /ml. Cells were mixed with an equal volume of test compound (2X) in DMEM containing 0.1% fatty-acid-free BSA and incubated at 37'C for 15 minutes. LPA (100 nM in DMEM containing 0.1% fatty-acid-free BSA) or vehicle was added to each well of the lower chamber and 50 pl of the cell suspension/test compound mix was applied to the upper portion of the ChemoTx plate. Plates were incubated at 37'C for three hours and then 15 the cells removed from the upper portion by rinsing with PBS and scraping. The filter was dried then stained with HEMA 3 Staining System (Fisher Scientific). The absorbance of the filter was read at 590 nM and IC 50 s were determined using Symyx Assay Explorer. [00547] In this experiment, compounds 11, 13, 19, 23, 26, 27, 32, 33, 38,39 41, 44, 45, 46, 47, 49, 52, 58, 59, 60, 64, 66, 67, 68, 75, 79, 81, 82, 83, 91, 92, and 95 inhibited LPA 20 driven chemotaxis (IC 50 less than 100 nM) of human A2058 melanoma cells. Example 114: Bleomycin-induced Lung fibrosis model in mice [00548] Female C57B1/6 mice (Harlan, 25-30g) are housed 4 per cage, given free access to food and water and allowed to acclimate for at least 7 days prior to test initiation. After the habituation phase, mice are lightly anesthetized with isoflurane (5% in 100% 02) and 25 administered with bleomycin sulfate (0.0 1-5 U/kg, Henry Schein) via intratracheal instillation (Cuzzocrea S et al. Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1095-104. Epub 2007 Jan 12.). Mice are returned to their cages and monitored daily for the duration of the experiment. Test compound or vehicle is delivered po, ip or sc daily. The route and frequency of dosing is based on previously determined 30 pharmacokinetic properties. All animals are sacrificed using inhaled isoflurane 3, 7, 14, 21 - 96 - WO 2011/041461 PCT/US2010/050786 or 28 days after bleomycin instillation. Following sacrifice, mice are intubated with a 20 gauge angiocatheter attached to a 1 ml syringe. Lungs are lavaged with saline to obtain bronchoalveolar lavage fluid (BALF) and then removed and fixed in 10% neutral buffered formalin for subsequent histopathological analysis. BALF is centrifuged for 10 min at 800 5 x g to pellet the cells and the cell supernatant removed and frozen at -80 0 C for subsequent protein analysis using the DC protein assay kit (Biorad, Hercules, CA.) and soluble collagen analysis using Sircol (Biocolor Ltd, UK). BALF is analyzed for concentrations of inflammatory, pro-fibrotic and tissue injury biomarkers including transforming growth factor 0 1, hyaluronic acid, tissue inhibitor of metalloproteinase- 1, matrix matelloproteinase 10 7, connective tissue growth factor and lactate dehydrogenase activity, using commercially available ELISA. The cell pellet is re-suspended in PBS. Total cell counts are then obtained using a Hemavet hematology system (Drew Scientific, Wayne, PA.) and differential cells counts are determined using Shandon cytospin (Thermo Scientific, Waltham, MA.). Lung tissue is stained using hematoxylin and eosin (H&E) and trichrome and lung fibrosis.is 15 determined by semiquantitative histopathological scoring (Ashcroft T. et al. J. Clin. Path. 1988;41;4, 467-470) using light microscopy (10x magnification) and quantitative, computer-assisted densitometry of collagen in lung tissue sections using light microscopy. The data are plotted using Graphpad prism and statistical differences between groups determined. 20 [00549] In the acute setting (3 day), Compound 19 significantly reduced total protein and collagen concentrations in broncheoalveolar lavage fluid (BALF). Example 115: Mouse carbon tetrachloride (CC1 4 )-induced liver fibrosis model [0055o] Female C57BL/6 mice (Harlan, 20-25g) housed 4/cage are given free access to food and water and allowed to acclimate for at least 7 days prior to test initiation. After the 25 habituation phase, mice receive CCl 4 (1.0 ml/kg body weight) diluted in corn oil vehicle (100 gL volume) via i.p. injection twice a week for 8 weeks. (Higazi, A. A. et al., Clin Exp Immunol. 2008 Apr;152(1):163-73. Epub 2008 Feb 14.). Control mice receive an equivalent volume of corn oil vehicle only. Test compound or vehicle is delivered po, ip or sc daily. At the end of the study (8 weeks after first i.p. injection of CCl 4 ), mice are sacrificed using 30 inhaled isoflurane and blood is drawn via cardiac puncture for subsequent analysis of ALT/AST levels. The liver is harvested, and one half of the liver is frozen at -80'C and the other half is fixed in 10% neutral buffered formalin for histological assessment of liver fibrosis using light microscopy (lOx magnification). Liver tissue homogenates are analyzed - 97 - WO 2011/041461 PCT/US2010/050786 for collagen levels using Sircol (Biocolor Ltd, UK). Fixed Liver tissue is stained using hematoxylin and eosin (H&E) and trichrome and liver fibrosis is determined by quantitative, computer-assisted densitometry of collagen in liver tissue sections using light microscopy. Plasma and liver tissue lysates are also analyzed for concentrations of 5 inflammatory, pro-fibrotic and tissue injury biomarkers including transforming growth factor 0 1, hyaluronic acid, tissue inhibitor of metalloproteinase- 1, matrix matelloproteinase 7, connective tissue growth factor and lactate dehydrogenase activity, using commercially available ELISA. The resulting data are plotted using Graphpad prism and statistical differences between groups determined. 10 Example 116: Mouse intravenous LPA-induced histamine release [00551] A mouse intravenous LPA-induced histamine release model is utilized to determine the in vivo potency of LPA 1 and LPA 3 receptor antagonists. Female CD-I mice (weighing 25 - 35 grams) are administered compound (i.p., s.c. or p.o.) in a volume of 10ml/kg 30 minutes to 24 hours prior to intravenous LPA challenge (300 gg/mouse in 0.l1% FAF BSA). 15 Immediately following LPA challenge mice are placed into an enclosed Plexiglas chamber and exposed to an isoflurane for a period of 2 minutes. They are removed, decapitated and trunk blood collected into tubes containing EDTA. Blood is then centrifuged at 10,000 X g for 10 minutes at 4'C. Histamine concentrations in the plasma are determined by EIA. Drug concentrations in plasma are determined by mass spectrometry. The dose to achieve 50% 20 inhibition of blood histamine release is calculated by nonlinear regression (Graphpad Prism) and plotted as the ED 50 . The plasma concentration associated with this dose is plotted as the
EC
50 . Example 117: Mouse unilateral ureteral obstruction kidney fibrosis model [00552] Female C57BL/6 mice (Harlan, 20-25g) housed 4/cage will be given free access to 25 food and water and allowed to acclimate for at least 7 days prior to test initiation. After the habituation phase, mice undergo unilateral ureteral obstruction (UUO) surgery or sham to left kidney. Briefly, a longitudinal, upper left incision is performed to expose the left kidney. The renal artery is located and 6/0 silk thread is passed between the artery and the ureter. The thread is looped around the ureter and knotted 3 times insuring full ligation of 30 ureter. The kidney is returned to abdomen, the abdominal muscle is sutured and the skin is stapled closed. Mice are returned to their cages and monitored daily for the duration of the experiment. Test compound or vehicle is delivered po, ip or sc daily. The route and frequency of dosing is based on previously determined pharmacokinetic properties. All - 98 - WO 2011/041461 PCT/US2010/050786 animals are sacrificed using inhaled isoflurane 4, 8 or 14 days after UUO surgery. Following sacrifice blood is drawn via cardiac puncture, the kidneys are harvested and one half of the kidney is frozen at -80 0 C and the other half is fixed in 10% neutral buffered formalin for histological assessment of kidney fibrosis using light microscopy (1Ox 5 magnification). Kidney tissue homogenates are analyzed for collagen levels using Sircol (Biocolor Ltd, UK). Fixed kidney tissue is also stained using hematoxylin and eosin (H&E) and trichrome and kidney fibrosis is determined by quantitative, computer-assisted densitometry of collagen in liver tissue sections using light microscopy and collagen content in kidney lysate. Plasma and kidney tissue lysates are also analyzed for concentrations of 10 inflammatory, pro-fibrotic and tissue injury biomarkers including transforming growth factor 0 1, hyaluronic acid, tissue inhibitor of metalloproteinase- 1, and plasminogen activator inhibitor -1, using commercially available ELISA. The resulting data are plotted using Graphpad prism and statistical differences between groups determined. Example 118: Clinical Trial in Humans with Idiopathic Pulmonary Fibrosis (IPF) 15 Purpose [00553] The purposes of this study is to assess the efficacy of treatment with a compound of Formula (I) compared with placebo in patients with idiopathic pulmonary fibrosis (IPF) and to assess the safety of treatment with a compound of Formula (I) compared with placebo in patients with IPF. 20 [00554] The primary outcome variable is the absolute change in percent predicted forced vital capacity (FVC) from baseline to Week 72. [00555] Secondary outcome measures include: composite outcomes of important IPF-related events; progression-free survival; categorical assessment of absolute change in percent predicted FVC from baseline to Week 72; change in Shortness-of-Breath from baseline to 25 Week 72; change in percent predicted hemoglobin (Hb)-corrected carbon monoxide diffusing capacity (DLco) of the lungs from baseline to Week 72; change in oxygen saturation during the 6 minute walk test (6MWT) from baseline to Week 72; change in high-resolution computed tomography (HRCT) assessment from baseline to Week 72; change in distance walked in the 6MWT from baseline to Week 72. 30 Criteria [00556] Patients eligible for this study include those patients that satisfy the following inclusion criteria: diagnosis of IPF; 40 to 80 years of age; FVC > 50% predicted value; DLco > 35% predicted value; either FVC or DLco < 90% predicted value; no improvement - 99 - WO 2011/041461 PCT/US2010/050786 in past year; able to walk 150 meters in 6 minutes and maintain saturation > 83% while on no more than 6 L/min supplemental oxygen. [00557] Patients are excluded from this study if they satisfy any of the following criteria: unable to undergo pulmonary function testing; evidence of significant obstructive lung 5 disease or airway hyper-responsiveness; in the clinical opinion of the investigator, the patient is expected to need and be eligible for a lung transplant within 72 weeks of randomization; active infection; liver disease; cancer or other medical condition likely to result in death within 2 years; diabetes; pregnancy or lactation; substance abuse; personal or family history of long QT syndrome; other IPF treatment; unable to take study medication; 10 withdrawal from other IPF trials. [00558] Patients are orally dosed with either placebo or an amount of compound of Formula (I) (1 mg/day - 1000 mg/day). The primary outcome variable will be the absolute change in percent predicted FVC from Baseline to Week 72. Patients will receive blinded study treatment from the time of randomization until the last patient randomized has been treated 15 for 72 weeks. A Data Monitoring Committee (DMC) will periodically review safety and efficacy data to ensure patient safety. [00559] After week 72, patients who meet the Progression of Disease (POD) definition, which is a > 10% absolute decrease in percent predicted FVC or a > 150% absolute decrease in percent predicted DLco, will be eligible to receive permitted IPF therapies in addition to 20 their blinded study drug. Permitted IPF therapies include corticosteroids, azathioprine, cyclophosphamide and N-acetyl-cysteine. Example 119: Parenteral Pharmaceutical Composition [00560] To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous, and the like), 100 mg of a water-soluble salt of a 25 compound of Formula (I) is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection [00561] In another embodiment, the following ingredients are mixed to form an injectable formulation: 1.2 g of a compound of Formulas (I), 2.0 mL of sodium acetate buffer solution 30 (0.4 M), HCl (1 N) or NaOH (1 M) (q.s. to suitable pH), water (distilled, sterile) (q.s.to 20 mL). All of the above ingredients, except water, are combined and stirred and if necessary, with slight heating if necessary. A sufficient quantity of water is then added. - 100 - WO 2011/041461 PCT/US2010/050786 Example 120: Oral Pharmaceutical Composition [00562] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formula (I) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration. 5 Example 121: Sublingual (Hard Lozenge) Pharmaceutical Composition [00563] To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100 mg of a compound of Formula (I) with 420 mg of powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract. The mixture is gently blended and poured into a mold to form a lozenge suitable for buccal 10 administration. Example 122: Fast-Disintegrating Sublingual Tablet [00564] A fast-disintegrating sublingual tablet is prepared by mixing 48.5% by weigh of a compound of Formula (I), 44.5% by weight of microcrystalline cellulose (KG-802), 5% by weight of low-substituted hydroxypropyl cellulose (50 pim), and 2% by weight of 15 magnesium stearate. Tablets are prepared by direct compression (AAPSPharmSciTech. 2006;7(2):E41). The total weight of the compressed tablets is maintained at 150 mg. The formulation is prepared by mixing the amount of compound of Formula (I) with the total quantity of microcrystalline cellulose (MCC) and two-thirds of the quantity of low substituted hydroxypropyl cellulose (L-HPC) by using a three dimensional manual mixer 20 (Inversina @, Bioengineering AG, Switzerland) for 4.5 minutes. All of the magnesium stearate (MS) and the remaining one-third of the quantity of L-HPC are added 30 seconds before the end of mixing. Example 123: Inhalation Pharmaceutical Composition [00565] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a 25 compound of Formula (I) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration. Example 124: Rectal Gel Pharmaceutical Composition [00566] To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound 30 of Formula (I) is mixed with 2.5 g of methylcelluose (1500 mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purified water. The resulting gel mixture is then incorporated into rectal delivery units, such as syringes, which are suitable for rectal administration. - 101 - WO 2011/041461 PCT/US2010/050786 Example 125: Topical Gel Pharmaceutical Composition [00567] To prepare a pharmaceutical topical gel composition, 100 mg of a compound of Formula (I) is mixed with 1.75 g of hydroxypropyl celluose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is 5 then incorporated into containers, such as tubes, which are suitable for topicl administration. Example 126: Ophthalmic Solution [00568] To prepare a pharmaceutical opthalmic solution composition, 100 mg of a compound of Formula (I) is mixed with 0.9 g of NaCl in 100 mL of purified water and filterd using a 0.2 micron filter. The resulting isotonic solution is then incorporated into 10 ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration. Example 127: Nasal spray solution [00569] To prepare a pharmaceutical nasal spray solution, 10 g of a compound of Formula (I) is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is 15 placed in a nasal administrator designed to deliver 100 ptl of spray for each application. [00570] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims. - 102 -

权利要求:
Claims (20)
[1] 1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof: (R r (R A)m R1 N / R 5 L2 L4 ORc 5 Formula (I) wherein, RI is -CO 2 RD, -C(=O)NHSO 2 RE, -C(=O)N(RD) 2 , -CN, or tetrazolyl; RD is H or CI-C 6 alkyl; RE is C 1 -C 6 alkyl or a substituted or unsubstituted phenyl; 10 L 2 is absent, -C(=O)-, -N(RD)-, substituted or unsubstituted CI-C 4 alkylene, or substituted or unsubstituted C1-C 4 heteroalkylene, where if L 2 is substituted, then L 2 is substituted with R1 2 , where R1 2 is F, CI-C 4 alkyl, -OH, or -ORD; ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic CI-C 5 heteroarylene, where if ring A is substituted, then ring A is 15 substituted with 1 or 2 R 14 , each R 14 is independently selected from halogen, CN, -OH, CI-C 4 alkyl, CI-C 4 fluoroalkyl, CI-C 4 fluoroalkoxy, CI-C 4 alkoxy, and C1-C 4 heteroalkyl; L 4 is absent, or a substituted or unsubstituted CI-C 4 alkylene, where if L 4 is substituted then L 4 is substituted with R 13 , where R 13 is F, CI-C 4 alkyl, -OH, or 20 -ORD. R 5 is H or C 1 -C 4 alkyl; each RA is independently selected from halogen, -CN, -OH, C 1 -C 4 alkyl, C1 C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 alkoxy, and C 1 -C 4 heteroalkyl; each RB is independently selected from halogen, -CN, -OH, CI-C 4 alkyl, C 1 25 C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 alkoxy, and C1-C 4 heteroalkyl; each RC is independently selected from halogen, -CN, -OH, CI-C 4 alkyl, C1 C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 alkoxy, and C1-C 4 heteroalkyl; m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; r is 1, 2, 3, or 4. - 103 - WO 2011/041461 PCT/US2010/050786
[2] 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: RI is -CO 2 RD, or -C(=O)NHSO 2 RE; L 2 is absent, -C(=O)-, -NH-, -N(CH 3 )-, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH(OH)-, -CH(ORD)-, -CH 2 CH(OH)-, 5 CH 2 CH(ORD)-, -CH(OH)CH 2 -, -CH(ORD)CH 2 -, -CH 2 NH-, -CH(CH 3 )NH-, NHCH 2 - or -NHCH(CH 3 )-; L 4 is absent, -CH 2 -, -CH(CH 3 )-, -CH(OH)-, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, CH(CH 3 )CH 2 -, -CH 2 CH(OH)-, or -CH(OH)CH 2 -; R 5 is -H, -CH 3 or -CH 2 CH 3 ; 10 m is 0 or 1; n is 0 or 1; r is 1, 2, or 3.
[3] 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: L2 is -NH-, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, 15 CH(OH)-, -CH 2 CH(OH)-, -CH(OH)CH 2 -, -CH 2 NH-, -CH(CH 3 )NH-, -NHCH 2 or -NHCH(CH 3 )-; ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic CI-C 5 heteroarylene containing 1-4 N atoms, 0 or 1 0 atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 20 R4; L 4 is absent, -CH 2 -, or -CH(CH 3 )-; R 5 is -CH 3 ; r is 1.
[4] 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: 25 ring A is a substituted or unsubstituted phenyl, where if ring A is substituted, then ring A is substituted with 1 or 2 R 1 .
[5] 5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: ring A is a substituted or unsubstituted monocyclic CI-C 5 heteroarylene containing 1 4 N atoms, 0 or 1 0 atoms and 0 or 1 S atoms, where if ring A is substituted, 30 then ring A is substituted with 1 or 2 R 4 .
[6] 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein: - 104 - WO 2011/041461 PCT/US2010/050786 ring A is a substituted or unsubstituted 5-membered monocyclic C1-C 4 heteroarylene containing 1-4 N atoms, 0 or 1 0 atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R.
[7] 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein: 5 ring A is a substituted or unsubstituted furanyl, a substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted 10 isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted thiadiazolyl, where if ring A is substituted, then ring A is substituted with 1 or 2 R 1 .
[8] 8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein: /0 S~ ring A is 0 15 ~N ~'CN- NI I r/ I 1Y,> 15 N N N N S N o O S S N N - N N S N N N N N - N-N N N N0 -N r/N -N N N 20 N/ , N , 'N , N ,or N
[9] 9. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: ring A is a substituted or unsubstituted 6-membered monocyclic C 3 -Csheteroarylene containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 . - 105 - WO 2011/041461 PCT/US2010/050786
[10] 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein: NN NAr SN ring Ais NIo / N~ N N N , N , N N,.N NN 4VVV 5 N Nd- ,o N N N 5 N N ,or N
[11] 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure of Formula (II): I R1 N / 2- 4-(R Formula (II). 10
[12] 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: RI is -CO 2 RD, or -C(=O)NHSO 2 RE; RD is H or C 1 -C 4 alkyl; RE RE is C 1 -C 4 alkyl; L2 is -CH 2 -, -CH(CH 3 )-, or -CH(OH)-; 15 ring A is a substituted or unsubstituted 5-membered monocyclic C 1 -C 4 heteroarylene containing 1-4 N atoms and 0 or 1 0 atoms, where if ring A is substituted, then ring A is substituted with R 14 ; L 4 is -CH 2 - or -CH(CH 3 )-; p is 0 or 1. 20
[13] 13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: RI is -CO 2 RD, or -C(=0)NHSO 2 RE; - 106 - WO 2011/041461 PCT/US2010/050786 RD is H or CI-C 4 alkyl; RE RE is CI-C 4 alkyl; L2 is -NH-, -CH 2 -, -CH(CH 3 )-, -CH(OH)-, -NHCH 2 - or -NHCH(CH 3 )-; ring A is a substituted or unsubstituted pyridinylene, where if ring A is substituted, 5 then ring A is substituted with R 14 ; L 4 is absent, -CH 2 -, or -CH(CH 3 )-; p is 0 or 1.
[14] 14. The compound of claim 1, wherein the compound is: 1- {4'-[3-Methyl-4-(3-phenyl-pyrazol- 1 -ylmethyl)-isoxazol-5-yl]-biphenyl-4-yl} 10 cyclopropanecarboxylic acid (Compound 1); 1- {4'-[3-Methyl-4-(4-phenyl-[1,2,3]triazol- 1 -ylmethyl)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 2); 1- {4'-[3-Methyl-4-(5-phenyl-[ 1,3,4]oxadiazol-2-ylmethyl)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 3); 15 1- {4'-[4-(4-Benzyl-[ 1,2,3]triazol-1 -ylmethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 4); 1-(4'- {4-[3-(4-Bromo-phenyl)-pyrazol- 1 -ylmethyl]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 5); 1-(4'- {3-Methyl-4-[(5-phenyl-[ 1,3,4]oxadiazol-2-ylamino)-methyl]-isoxazol-5-yl} 20 biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 6); 1- {4'-[3-Methyl-4-(5-phenyl-[1,2,3]triazol- 1 -ylmethyl)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 7); 1- {4'-[3-Methyl-4-(5-phenyl-tetrazol-2-ylmethyl)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 8); 25 1- {4'-[3-Methyl-4-(4-phenyl-pyrazol- 1 -ylmethyl)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 9); 1- {4'- [4-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 10); 1-(4'- {4-[(1 -Benzyl- 1H-[1,2,3]triazol-4-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl} 30 biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 11); 1- {4'- [4-(5-Benzyl-[ 1,3,4]oxadiazol-2-ylmethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 12); - 107 - WO 2011/041461 PCT/US2010/050786 1-(4'- {4-[(5-Benzyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 13); 1- {4'-[4-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 14); 5 1-(4'- {4-[(S)-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 15); 1-(4'- {4-[(R)-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 16); 1-(4'- {4-[Hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methyl]-3-methyl-isoxazol-5-yl} 10 biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 17); 1-(4'- {4-[(S)-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 18); 1-(4'- {4-[(R)-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 19); 15 1-[4'-(4- {Hydroxy-[5-(3-trifluoromethyl-benzyl)-[1,3,4]oxadiazol-2-yl]-methyl} -3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 20); 1-[4'-(4- {Hydroxy-[1-(3-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methyl} -3 methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 21); 1- {4'-[4-(Biphenyl-3-yl-hydroxy-methyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} 20 cyclopropanecarboxylic acid (Compound 22); 1-[4'-(4- {Hydroxy-[1-(1-phenyl-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl} -3-methyl-isoxazol 5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 23); 1-[4'-(4- {Hydroxy-[1-(2-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methyl} -3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 24); 25 1-[4'-(4- { [1-(3-Chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy-methyl} -3-methyl-isoxazol 5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 25); 1-(4'- {4-[(3-Benzyl-phenyl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 26); 1-(4'- {4-[(5-Benzyl-pyridin-3-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl) 30 cyclopropanecarboxylic acid (Compound 27); 1-[4'-(4- { [1-(2-Chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy-methyl} -3-methyl-isoxazol 5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 28); - 108 - WO 2011/041461 PCT/US2010/050786 1-[4'-(4- { [1 -(4-Chloro-benzyl)- 1H-[1,2,3]triazol-4-yl]-hydroxy-methyl} -3-methyl-isoxazol 5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 29); 1-[4'-(4- {(R)-[1-(2-Chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy-methyl}-3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 30); 5 1-[4'-(4- {[1-(3,4-Dichloro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy-methyl}-3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 31); 1-[4'-(4- {(R)-Hydroxy-[1-((R)-1-phenyl-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl}-3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 32); 1- {4'-[3-Methyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} 10 cyclopropanecarboxylic acid (Compound 33); 1-(4'- {4-[(6-Benzyl-pyridin-2-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 34); 1-[4'-(4- {Hydroxy-[1-(2-methyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methyl}-3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 35); 15 1-[4'-(4- {[1-(2-Chloro-6-fluoro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy-methyl}-3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 36); 1-[4'-(4- {[1-(2,6-Dichloro-benzyl)-1H-[1,2,3]triazol-4-yl]-hydroxy-methyl}-3-methyl isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 37); 1- {4'-[4-(6-Benzyl-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} 20 cyclopropanecarboxylic acid (Compound 38); 1- {4'-[4-(Biphenyl-3-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 39); 1- {4'-[4-(Biphenyl-4-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 40); 25 1-(4'- {3-Methyl-4-[6-(3-trifluoromethyl-phenyl)-pyridin-2-ylamino]-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 41); 1- {4'-[3-Methyl-4-(6-phenyl-pyrazin-2-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 42); 1- {4'-[3-Methyl-4-(5-phenyl-[1,3,4]oxadiazol-2-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} 30 cyclopropanecarboxylic acid (Compound 43); 1- {4'-[4-(5-Benzyl-[1,3,4]oxadiazol-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 44); - 109 - WO 2011/041461 PCT/US2010/050786 1-(4'- {4-[6-(2-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 45); 1-(4'- {4-[6-(3-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 46); 5 1-(4'- {4-[6-(4-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 47); 1-(4'- {4-[6-(3-Methoxy-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4 yl)-cyclopropanecarboxylic acid (Compound 48); 1- {4'-[4-(3-Benzyl-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} 10 cyclopropanecarboxylic acid (Compound 49); 1-(4'- {4-[6-(2-Cyano-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 50); 1-(4'- {4-[6-(4-Methoxy-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4 yl)-cyclopropanecarboxylic acid (Compound 51); 15 1-(4'- {4-[6-(3-Fluoro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 52); 1-(4'- {4-[6-(2-Methoxy-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4 yl)-cyclopropanecarboxylic acid (Compound 53); 1-(4'- {4-[6-(2-Fluoro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) 20 cyclopropanecarboxylic acid (Compound 54); 1-(4'- {3-Methyl-4-[6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamino]-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 55); 1-(4'- {3-Methyl-4-[(2-phenyl-thiazol-5-ylmethyl)-amino]-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 56); 25 1- {4'-[3-Methyl-4-(2'-trifluoromethyl-biphenyl-3-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 57); 1- {4'-[3-Methyl-4-(5-phenyl-pyridin-3-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 58); 1-(4'- {4-[5-(3-Fluoro-phenyl)-pyridin-3-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) 30 cyclopropanecarboxylic acid (Compound 59); 1-(4'- {4-[6-(2-Chloro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 60); -110- WO 2011/041461 PCT/US2010/050786 1-(4'- {4-[Hydroxy-(6-phenyl-pyridin-2-yl)-methyl]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 61); 1- {4'-[3-Methyl-4-(2-phenyl-pyridin-4-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 62); 5 1-(4'- {4-[2-(3-Fluoro-phenyl)-pyridin-4-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 63); 1-(4'- {4-[5-(2-Chloro-phenyl)-pyridin-3-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 64); 1-(4'- {4-[2-(2-Chloro-phenyl)-pyridin-4-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) 10 cyclopropanecarboxylic acid (Compound 65); 1- {4'-[3-Methyl-4-(4-phenyl-pyrimidin-2-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 66); 1- {4'-[3-Methyl-4-(4-phenyl-pyridin-2-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 67); 15 1-(4'- {3-Methyl-4-[5-(3-trifluoromethyl-phenyl)-pyridin-3-ylamino]-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 68); 1-(4'- {3-Methyl-4-[5-(4-trifluoromethyl-phenyl)-pyridin-3-ylamino]-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 69); 1- {4'-[3-Methyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} 20 cyclobutanecarboxylic acid (Compound 70); 1-(4'- {4-[Hydroxy-(5-phenyl-pyridin-3-yl)-methyl]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 71); 1-[4'-(4- {Hydroxy-[5-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-methyl} -3-methyl-isoxazol 5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (Compound 72); 25 1- {4'-[3-Methyl-4-(6-phenylethynyl-pyridin-2-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 73); 1-(4'- {4-[6-(3-Cyano-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 74); 1-(4'- {4-[6-(5-Fluoro-2-methoxy-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} 30 biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 75); 1-(4'- {4-[6-(3-Chloro-5-fluoro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 76); - 111 - WO 2011/041461 PCT/US2010/050786 1-(4'- {4-[6-(2,5-Difluoro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} -biphenyl-4 yl)-cyclopropanecarboxylic acid (Compound 77); 1-(4'- {4-[6-(2,6-Dichloro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4 yl)-cyclopropanecarboxylic acid (Compound 78); 5 1-(4'- {4-[6-(2-Chloro-5-fluoro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 79); 1-(4'- {4-[6-(2,3-Difluoro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4 yl)-cyclopropanecarboxylic acid (Compound 80); 1-(4'- {4-[6-(2-Chloro-3-fluoro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} 10 biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 81); 1-(4'- {4-[5-(2-Chloro-3-fluoro-phenyl)-pyridin-3-ylamino]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 82); 1-(4'- {4-[6-(3-Fluoro-2-methyl-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 83); 15 1-(4'- {4- [6-(2-Chloro-3 -trifluoromethyl-phenyl)-pyridin-2-ylamino] -3 -methyl-isoxazol-5 yl} -biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 84); 1- {4'- [4-(2'-Dimethylaminomethyl-biphenyl-3 -ylamino)-3 -methyl-isoxazol-5 -yl] -biphenyl 4-yl} -cyclopropanecarboxylic acid (Compound 85); 1-(4'- {4- [6-(2,3 -Dichloro-phenyl)-pyridin-2-ylamino] -3 -methyl-isoxazol-5 -yl} -biphenyl-4 20 yl)-cyclopropanecarboxylic acid (Compound 86); 1-(4'- {4-[6-(3-Fluoro-2-methoxy-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 87); 1-(4'- {4-[5-(3-Chloro-phenyl)-pyridin-3-ylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 88); 25 1-(4'- {4-[5-(2,5-Difluoro-phenyl)-pyridin-3-ylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4 yl)-cyclopropanecarboxylic acid (Compound 89); 1-(4'- {4-[6-(3-Chloro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl) cyclopropanecarboxylic acid (Compound 90); N-[1-(4'-{4-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl} 30 biphenyl-4-yl)-cyclopropanecarbonyl]-methanesulfonamide (Enantiomer B) (Compound 91); -112 - WO 2011/041461 PCT/US2010/050786 N-[1 -(4'- {4-[(5-Benzyl-[ 1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl} biphenyl-4-yl)-cyclopropanecarbonyl]-methanesulfonamide (Enantiomer A) (Compound 92); N- { 1-[4'-(4- {Hydroxy-[1-(3-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methyl} -3 5 methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarbonyl}-methanesulfonamide (Compound 93); N-(1-{4'-[3-Methyl-4-(5-phenyl-[1,3,4]oxadiazol-2-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarbonyl)-methanesulfonamide (Compound 94); N-(1-{4'-[4-(6-Benzyl-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl} 10 cyclopropanecarbonyl)-methanesulfonamide (Compound 95); N-(1-{4'-[3-Methyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarbonyl)-methanesulfonamide (Compound 96); 1- {4'-[3-Ethyl-4-(6-phenyl-pyridin-2-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 97); 15 1- {4'-[3-Ethyl-4-(5-phenyl-[1,3,4]oxadiazol-2-ylamino)-isoxazol-5-yl]-biphenyl-4-yl} cyclopropanecarboxylic acid (Compound 98); or a pharmaceutically acceptable salt thereof.
[15] 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof. 20
[16] 16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, inhalation, nasal administration, topical administration, ophthalmic administration or otic administration.
[17] 17. The pharmaceutical composition of claim 15, wherein the pharmaceutical 25 composition is a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop or an ear drop.
[18] 18. A method of treating cancer in a mammal comprising administering a therapeutically effective amount of a compound according to any one of claims 1-14 30 or a pharmaceutically acceptable salt thereof to the mammal in need thereof.
[19] 19. A method of treating or preventing fibrosis in a mammal comprising administering a therapeutically effective amount of a compound according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof to the mammal in need thereof. -113 - WO 2011/041461 PCT/US2010/050786
[20] 20. A method of treating or preventing lung fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis, skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, 5 bowel cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenom, or neuropathic pain in a mammal comprising administering a therapeutically effective 10 amount of a compound according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof to the mammal in need thereof. -114-

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IN2012DN02702A|2015-09-04|

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法律状态:
2015-03-05| MK1| Application lapsed section 142(2)(a) - no request for examination in relevant period|

优先权:

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申请号 | 申请日 | 专利标题

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US24787709P| true| 2009-10-01|2009-10-01||

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US61/247,877||2009-10-01||

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PCT/US2010/050786|WO2011041461A2|2009-10-01|2010-09-29|Polycyclic compounds as lysophosphatidic acid receptor antagonists|

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