Isoxazole N-linked carbamoylcyclohexyl acids as LPA antagonists

Abstract

The present invention provides compounds of formula (Ia) and (Ib): (Ia) or (Ib), or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all variables are as defined herein. These compounds are selective LPA receptor inhibitors.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 607,407, filed December 19, 2017; the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to novel substituted isoxazole compounds, compositions containing the same, and methods of using the same, such as methods of using the same to treat disorders associated with one or more lysophosphatidic acid (LPA) receptors. Background Art

[0004] Lysophospholipids are membrane-derived bioactive lipid mediators, of which one of the most important in medicine is lysophosphatidic acid (LPA). LPA is not a single molecular entity, but a group of endogenous structural variants of fatty acids with different lengths and degrees of saturation (Fujiwara et al., J Biol. Chem., 2005, 280, 35038-35050). The structural backbone of LPA is derived from glycerol-based phospholipids, such as phosphatidylcholine (PC) or phosphatidic acid (PA).

[0005] LPA is a bioactive lipid (signaling lipid) that regulates various cellular signaling pathways by binding to cognate 7-transmembrane domain G protein-coupled (GPCR) receptors (Chun, J., Hla, T., Spiegel, S., Moolenaar, W., eds., Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley; ISBN: 978-0-470-56905-4 and Zhao, Y. et al., Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Of Lipids, 2013, 1831, 86-92). Currently known LPA receptors are named LPA1, LPA2, LPA3, LPA4, LPA5 and LPA6 (Choi, JW, Annu. Rev. Pharmacol. Toxicol., 2010, 50, 157-186; Kihara, Y. et al., Br. J. Pharmacol., 2014, 171, 3575-3594).

[0006] LPA has long been known as a precursor for phospholipid biosynthesis in eukaryotic and prokaryotic cells, but LPA has only recently emerged as a signaling molecule that is rapidly produced and released by activated cells, especially platelets, to affect target cells by acting on specific cell surface receptors (see, e.g., Moolenaar et al., BioEssays, 2004, 26, 870-881, and van Leewen et al., Biochem. Soc. Trans., 2003, 31, 1209-1212). In addition to being synthesized and processed into more complex phospholipids in the endoplasmic reticulum, LPA can be produced after cell activation by hydrolysis of pre-existing phospholipids; for example, the sn-2 position is usually missing fatty acid residues due to deacylation, leaving only the sn-1 hydroxyl group esterified to fatty acids. In addition, the key enzyme in the production of LPA, autotaxin (lysoPLD / NPP2), may be the product of an oncogene, as many tumor types upregulate autotaxin (Brindley, D., J. Cell Biochem. 2004, 92, 900-12). LPA concentrations in human plasma and serum and in human bronchoalveolar lavage fluid (BALF) have been reported, including using sensitive and specific LC / MS and LC / MS / MS procedures (Baker et al., Anal. Biochem., 2001, 292, 287-295; Onorato et al., J. Lipid Res., 2014, 55, 1784-1796).

[0007] LPA affects a wide variety of biological responses, ranging from inducing cell proliferation, stimulating cell migration and neurite retraction, gap junction closure, and even slime mold chemotaxis (Goetzl et al., Scientific World J., 2002, 2, 324-338; Chun, J., Hla, T., Spiegel, S., Moolenaar, W., Editors, Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley; ISBN: 978-0-470-56905-4). The body of knowledge about LPA biology continues to grow as LPA responses are tested in more and more cell systems. For example, it is now known that in addition to stimulating cell growth and proliferation, LPA also promotes cell tension and cell surface fibronectin binding, which is an important event in wound repair and regeneration (Moolenaar et al., BioEssays, 2004, 26, 870-881). Recently, anti-apoptotic activity has also been attributed to LPA, and PPARγ has recently been reported as a receptor / target of LPA (Simon et al., J. Biol. Chem., 2005, 280, 14656-14662).

[0008] Fibrosis is the result of an uncontrollable tissue healing process, which causes excessive accumulation and insufficient reabsorption of extracellular matrix (ECM), ultimately leading to end-organ failure (Rockey, DC et al., New Engl. J. Med., 2015, 372, 1138-1149). LPA1 receptors have been reported to be overexpressed in patients with idiopathic pulmonary fibrosis (IPF). LPA1 receptor knockout mice are free from bleomycin-induced pulmonary fibrosis (Tager et al., Nature Med., 2008, 14, 45-54). LPA1 antagonist BMS-986020 was shown to significantly reduce the rate of FVC (forced vital capacity) decay in a 26-week clinical trial in IPF patients (Palmer et al., Chest, 2018, 154, 1061-1069). LPA pathway inhibitors (eg, LPA1 antagonists) have been shown to be chemopreventive antifibrotic agents for the treatment of hepatocellular carcinoma in a rat model (Nakagawa et al., Cancer Cell, 2016, 30, 879-890).

[0009] Therefore, antagonizing the LPA1 receptor may be useful in treating fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, arterial fibrosis and systemic sclerosis, and thereby treating diseases caused by fibrosis (pulmonary fibrosis - idiopathic pulmonary fibrosis [IPF], liver fibrosis - non-alcoholic steatohepatitis [NASH], kidney fibrosis - diabetic nephropathy, systemic sclerosis - scleroderma, etc.). Summary of the invention

[0010] The present invention provides novel substituted isoxazole compounds, including stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, which are useful as antagonists against one or more lysophosphatidic acid (LPA) receptors, especially LPA1 receptors.

[0011] The present invention also provides methods and intermediates for making the compounds of the present invention.

[0012] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof.

[0013] The compounds of the invention may be used to treat conditions in which LPA plays a role.

[0014] The compounds of the invention may be used in therapy.

[0015] The compounds of the invention can be used in the preparation of medicaments for treating conditions where inhibition of the physiological activity of LPA is useful, such as diseases in which the LPA receptor is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease.

[0016] In another aspect, the present invention relates to a method for treating organ fibrosis (liver, kidney, lung, heart and the like and skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver dysfunction, liver blood flow disorders and the like), cell proliferation diseases [cancer (solid tumors, solid tumor metastasis, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL) and the like) and invasive metastasis of cancer cells, and the like], inflammation (psoriasis, nephropathy, pneumonia and the like), gastrointestinal diseases (irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) D), abnormal pancreatic secretion, and the like), kidney disease, urinary tract related diseases (benign prostatic hyperplasia or symptoms related to neuropathy bladder disease, spinal cord tumors, intervertebral disc herniation, spinal stenosis, symptoms derived from polyuria, lower urinary tract diseases (lower urinary tract obstruction, and the like), inflammation of the lower urinary tract, urinary pain, frequent urination, and the like), pancreatic diseases, abnormal angiogenesis related diseases (arterial obstruction and the like), scleroderma, brain related diseases (cerebral infarction, cerebral hemorrhage and the like), neuralgia, peripheral neuropathy and the like, eye diseases (age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), scar pemphigoid, glaucoma filtering surgery scarring, and the like).

[0017] In another aspect, the invention relates to a method of treating a disease, disorder or condition in which LPA activates at least one LPA receptor resulting in symptoms or progression of the disease, disorder or condition. These diseases, disorders or conditions may be derived from one or more of genetic, iatrogenic, immune, infectious, metabolic, neoplastic, toxic, surgical and / or traumatic etiologies.

[0018] In another aspect, the present invention relates to a method for treating renal fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis and systemic sclerosis, comprising administering to a patient in need of such treatment a compound of the present invention as described above.

[0019] In one aspect, the present invention provides methods, compounds, pharmaceutical compositions and medicaments described herein, which comprise an LPA receptor antagonist, in particular, an LPA1 antagonist.

[0020] The compounds of the present invention may be used alone, in combination with other compounds of the present invention or in combination with one or more (preferably one to two) other pharmaceutical agents.

[0021] These and other features of the present invention will be set forth in expanded form as the disclosure proceeds. DETAILED DESCRIPTION

[0022] I. Compounds of the Invention

[0023] In one aspect, the present invention provides, inter alia, compounds of formula (Ia) or (Ib):

[0024]

[0025] or a stereoisomer, tautomer, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0026] X 1 , X 2 , X 3 and X 4 Each independently is CR 6 or N; its condition is X 1 , X 2 , X 3 or X 4 No more than two of them are N;

[0027] Y 1 O or NR 3 ;

[0028] Y 2 for

[0029] Y 3 O or NR 4a ; The conditions are (1) Y 1 and Y 3 are not all O, and (2) when Y 2 When C(O), Y 1 Not for O;

[0030] L is a covalent bond or is bound by 0 to 4 R 7 Substituted C 1-4 Alkylene;

[0031] R 1 (-CH2) a R 9 ;

[0032] a is an integer 0 or 1;

[0033] R 2 are independently halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl or haloalkoxy;

[0034] n is an integer 0, 1 or 2;

[0035] R 3 and R 4a are independently hydrogen, C 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

[0036] R 4 C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Haloalkyl, C 1-10 Alkenyl, C 3-8 Cycloalkyl, 6- to 10-membered aryl, 3- to 8-membered heterocyclic group, -(C 1-6 Alkylene)-(C 3-8 Cycloalkyl), -(C 1-6 alkylene)-(6- to 10-membered aryl), -(C 1-6 alkylene)-(3 to 8 membered heterocyclic group) or -(C 1-6 wherein the alkyl, alkylene, alkenyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, by themselves or as part of other moieties, are each independently substituted by 0 to 3 R 8 Replace; or alternatively, R 3 and R 4 Together with the N and O to which they are connected, they form 0 to 3 R 8 a substituted 4- to 9-membered heterocyclic moiety;

[0037] R 5 and R 6 are independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; or alternatively, R 3 and R 5 Together with the atoms to which they are attached, they form a 5- to 8-membered heterocyclic ring;

[0038] R 7 is halogen, oxo, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

[0039] R 8 are independently deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C2-6 alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5- to 6-membered heteroaryl; or alternatively, two R 8 Together with the one or more atoms to which they are attached, they form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, each of which is independently represented by 0 to 3 R 12 replace;

[0040] R 9 Selected from -CN, -C(O)OR 10 、-C(O)NR 11a R 11b ,

[0041]

[0042] R e C 1-6 Alkyl, C 3-6 Cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl or haloalkoxyalkyl;

[0043] R 10 is hydrogen or C 1-10 Alkyl; and

[0044] R 11a and R 11b are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; and

[0045] R 12 For halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl or 5- to 6-membered heteroaryl.

[0046] In one embodiment of formula (Ia) or (Ib), Partially selected

[0047] and

[0048] Y 4 is O or NH.

[0049] In any of the foregoing embodiments of formula (Ia) or (Ib), the compound is represented by formula (I'a) or (I'b):

[0050]

[0051] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a) or (I'b), L is methylene.

[0052] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a) or (I'b), X 1 CR 6 , where R 6 is hydrogen or C 1-4 An alkyl group, such as a methyl group.

[0053] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a) or (I'b), n is 0.

[0054] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a) or (I'b), a is 0.

[0055] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a) or (I'b), R 1 is CO2H.

[0056] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a) or (I'b), R 5 C 1-4 alkyl; or alternatively, R 3 and R 5 Together with the atoms to which they are attached, they form a 5- to 8-membered heterocyclic ring. 5 It is methyl.

[0057] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a) or (I'b), R 4 C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-6 Cycloalkyl, -(C 1-4 Alkylene)-(C 3-6 wherein the alkyl, alkylene, cycloalkyl and benzyl are each independently substituted by 0 to 3 R 8 Replace; and R 8 are independently halogen, hydroxy, amino, cyano, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; or alternatively, two R 8 Together with the atoms to which they are attached, they form a 3- to 6-membered carbon ring. The alkyl and alkylene groups are each independently straight chain or branched; and the methylene and phenyl portions of the benzyl group are each independently substituted by 0 to 3 R 8 replace.

[0058] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a) or (I'b), the compound is represented by Formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf):

[0059]

[0060] Each R 7a are independently hydrogen, halogen, oxo, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

[0061] f is an integer 0, 1 or 2;

[0062] n is 0 or 1;

[0063] R 3 and R 4a are independently hydrogen or C 1-4 alkyl;

[0064] R 5 It is C 1-4 alkyl; or alternatively, R 3 and R 5 Together with the atoms to which they are attached, they form a 5- to 8-membered heterocyclic ring; and

[0065] R 1 , R 2 ,n,R 4 , X 1 , X 2 , X 3 , X 4 and Z are the same as defined above.

[0066] In one embodiment of Formula (Ia), (Ib), (I'a), (I'b), (IIa) or (IIb), R 1 is CO2H.

[0067] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a), (I'b), (IIa) or (IIb), X 1 CR 6 , where R 6 is hydrogen or C 1-4 In one embodiment, X 1 It is CH or CCH3.

[0068] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a), (I'b), (IIa) or (IIb), X 3 is N.

[0069] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a), (I'b), (IIa) or (IIb), X 1 , X 2 , X 3 and X 4 CR 6 , where each R 6 are independently hydrogen or C 1-4 In one embodiment, X 1 , X 2 , X 3 and X 4 For CH.

[0070] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a), (I'b), (IIa) or (IIb), Partially selected

[0071]

[0072] R 6a are independently halogen, cyano, hydroxyl, amino, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; and

[0073] d is an integer of 0, 1 or 2.

[0074] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a), (I'b), (IIa) or (IIb), Partially selected

[0075] and

[0076] R 6 are independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy.

[0077] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a), (I'b), (IIa) or (IIb), L is methylene, or f is 1. In one embodiment, R 7a For hydrogen.

[0078] In any of the foregoing embodiments of Formula (Ia), (Ib), (I'a), (I'b), (IIa) or (IIb), the compound is represented by Formula (IIIa) or Formula (IIIb):

[0079]

[0080] R 3 is hydrogen or CH3; and

[0081] R 1 , R 4 , X 1 , X 2 , X 3 and X 4 Same as defined above.

[0082] In one embodiment of formula (IIIa) or (IIIb), Partially selected

[0083]

[0084] In any of the foregoing embodiments of Formula (IIIa) or (IIIb), R 1 is CO2H.

[0085] In any of the foregoing embodiments of Formula (IIIa) or (IIIb),

[0086] Said Partially selected

[0087]

[0088] In any of the foregoing embodiments of Formula (IIIa) or (IIIb),

[0089] R 4 C 3-10 Alkyl, C 3-10 Haloalkyl, C 3-6 Cycloalkyl, -(C 1-4 Alkylene)-(C 1-3 Alkoxy), -(C 1-4 Alkylene)-(C 3-6 Cycloalkyl) or -(C 1-4 wherein the alkyl, alkylene, cycloalkyl and phenyl are each independently substituted by 0 to 3 R 8 replace; and

[0090] R 8 are independently halogen, C 1-6alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy. The alkyl and alkylene groups are each independently linear or branched; and the methylene and phenyl portions of the benzyl group are each independently substituted by 0 to 3 R 8 replace.

[0091] In any of the foregoing embodiments of Formula (IIIa) or (IIIb), R 4 C 3-10 Alkyl, C 3-10 Haloalkyl, cyclobutyl, cyclopentyl, -(CH2) 1-2 -(C 1-3 Alkoxy), -(CHR 8a ) 1-2 -cyclopropyl, -(CHR 8a )-cyclobutyl or -(CHR 8a )-phenyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl and phenyl are each independently substituted by 0 to 3 R 8 Replacement; R 8a are each independently hydrogen or methyl; and R 8 are each independently halogen or C 1-4 alkyl.

[0092] In one embodiment of the present invention, the compound is selected from any one of the examples described in the specification, or a stereoisomer, tautomer or a pharmaceutically acceptable salt or solvate thereof.

[0093] In another embodiment of the present invention, the compound is selected from Examples 1 to 65 as described in the specification, or a stereoisomer, tautomer or a pharmaceutically acceptable salt or solvate thereof.

[0094] In another embodiment of the present invention, the compound is selected from Examples 1 to 35 as described in the specification, or a stereoisomer, tautomer or a pharmaceutically acceptable salt or solvate thereof.

[0095] In one embodiment, using the LPA1 functional antagonist assay, the compounds of the invention have hLPA1 IC 50 Value ≤5000nM; In another embodiment, the compounds of the present invention have hLPA1 IC 50 Value ≤ 1000 nM; In another embodiment, the compounds of the present invention have hLPA1 IC 50 Value ≤500nM; In another embodiment, the compounds of the present invention have hLPA1 IC 50 Value ≤ 200 nM; In another embodiment, the compounds of the present invention have hLPA1 IC 50Value ≤ 100 nM; In another embodiment, the compounds of the present invention have hLPA1 IC 50 Value ≤50nM.

[0096] II. Other Embodiments of the Invention

[0097] In some embodiments, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt or solvate thereof is an antagonist of at least one LPA receptor. In some embodiments, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt or solvate thereof is an LPA1 antagonist. In some embodiments, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt or solvate thereof is an LPA2 antagonist. In some embodiments, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt or solvate thereof is an LPA3 antagonist.

[0098] In some embodiments, provided herein is a compound selected from an active metabolite, a tautomer, a pharmaceutically acceptable salt, or a solvate of a compound of Formula (Ia) or (Ib).

[0099] In another embodiment, the present invention provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0100] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or at least one of its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0101] In another embodiment, the present invention provides a process for preparing a compound of the present invention.

[0102] In another embodiment, the present invention provides an intermediate for preparing a compound of the present invention.

[0103] In another embodiment, the present invention provides a pharmaceutical composition further comprising an additional therapeutic agent.

[0104] In another embodiment, the present invention provides a method of treating a disease, disorder or condition associated with LPA receptor-mediated fibrosis, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention or at least one of its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates. As used herein, the term "patient" encompasses all mammalian species.

[0105] In another embodiment, the present invention provides a method for treating a disease, disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof. In one embodiment of the method, the disease, disorder or condition is associated with pathological fibrosis, transplant rejection, cancer, osteoporosis or inflammation. In one embodiment of the method, the pathological fibrosis is pulmonary, liver, kidney, heart, dermis, eye or pancreatic fibrosis. In one embodiment of the method, the disease, disorder or condition is idiopathic pulmonary fibrosis (IPF), non-alcoholic fatty hepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy and systemic sclerosis. In one embodiment of the method, the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitals, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicles, or thyroid.

[0106] In another embodiment, the present invention provides a method for treating fibrosis in a mammal, comprising administering a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof to a mammal in need thereof. In one embodiment of the method, fibrosis is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), chronic kidney disease, diabetic nephropathy and systemic sclerosis.

[0107] In another embodiment, the present invention provides a method of treating pulmonary fibrosis (idiopathic pulmonary fibrosis), asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis (non-alcoholic steatohepatitis), skin fibrosis, intestinal fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, intestinal cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant rejection, scleroderma, ocular fibrosis, age-related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenon, or neuropathic pain in a mammal, the method comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0108] As used herein, "treating" or "treatment" encompasses treating a disease state in a mammal (particularly, a human) and includes: (a) inhibiting the disease state, i.e., curbing its development; and / or (b) alleviating the disease state, i.e., causing the disease state to regress. As used herein, "treating" or "treatment" also includes preventive treatment of a disease state to reduce and / or minimize the risk of a disease state and / or reduce the risk of recurrence of a disease state, which is achieved by administering to the patient a therapeutically effective amount of a compound of the present invention or at least one of its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates. Such preventive therapies can be selected for a patient based on factors known to increase the risk of developing a clinical disease state compared to the general population. For preventive treatment, the condition of a clinical disease state may or may not yet exist. Preventive therapy can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as a therapy that reduces or minimizes the risk of a disease state in a patient who has not yet presented a clinical disease state, while secondary prevention is defined as minimizing or reducing the risk of recurrence or secondary occurrence of the same or similar clinical disease state.

[0109] The present invention can be implemented in other specific forms without departing from its spirit or essential characteristics. The present invention encompasses all combinations of the preferred aspects of the present invention mentioned herein. It should be understood that any and all embodiments of the present invention can be combined with any other embodiment to describe other embodiments. It should also be understood that each individual element in the embodiment is its own independent embodiment. In addition, any element of an embodiment is intended to be combined with any and all other elements of any embodiment to describe another embodiment.

[0110] III. Chemistry

[0111] Throughout the specification and the appended claims, the designated chemical formula or name shall encompass all stereoisomers and optical isomers and racemates thereof (if such isomers exist). Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms belong to the scope of the present invention. Compounds may also exist in many geometric isomers of C=N double bonds, C=N double bonds, ring systems and the like, and all such stable isomers are encompassed in the present invention. Cis and trans (or E and Z) geometric isomers of the compounds of the present invention have been described and may be separated in the form of isomer mixtures or in separated isomeric forms. The compounds of the present invention may be separated in optically active or racemic form. Optically active forms may be prepared by resolving racemic forms or by synthesis from optically active starting materials. All methods for preparing the compounds of the present invention and the intermediates prepared therein are considered part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, such as by chromatography or fractional crystallization. Depending on the processing conditions, the final product of the present invention is obtained in free (neutral) form or in salt form. Both the free form and the salt of these final products belong to the scope of the present invention. When so desired, one form of the compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into a free compound or another salt; a mixture of isomeric compounds of the present invention can be separated into individual isomers. The compounds of the present invention, free forms and salts thereof can exist in a variety of tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms in the molecule are rearranged accordingly. It should be understood that all tautomeric forms, as long as they can exist, are included in the present invention.

[0112] The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable. The term "diastereomer" refers to stereoisomers that are not mirror images. The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomeric species, wherein the composition lacks optical activity.

[0113] The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. The isomeric descriptors "R" and "S" are used as described herein to indicate the atomic configuration relative to the core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68: 2193-2222 (1996)).

[0114] The term "chirality" refers to the structural feature of a molecule that makes superimposition of it on its mirror image impossible. The term "homochirality" refers to the state of enantiomeric purity. The term "optically active" refers to the degree to which a homochiral molecule or a non-racemic mixture of chiral molecules rotates the plane of polarized light.

[0115] As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. While "alkyl" refers to a monovalent saturated aliphatic group (such as ethyl), "alkylene" refers to a divalent saturated aliphatic group (such as ethylene). For example, "C1 to C 10 Alkyl" or "C 1-10 "Alkyl" is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Alkyl. "C1 to C 10 "Alkylene" or "C 1-10 The term "alkylene" is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 In addition, for example, "C1 to C6 alkyl" or "C 1-6 "C1 to C6 alkylene" or "C 1-6 "C1 to C4 alkyl" or "C 1-4 "C1 to C4 alkylene" or "C 1-4 "C0 alkyl" or "C0 alkylene" refers to an alkylene group having 1 to 4 carbon atoms. The alkyl group may be unsubstituted or substituted, wherein at least one hydrogen is replaced by another chemical group. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C0 alkyl" or "C0 alkylene" is used, it is intended to represent a direct bond. In addition, the term "alkyl" by itself or as part of another group, such as alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, and haloalkoxy, may be an alkyl group having 1 to 4 carbon atoms, or 1 to 6 carbon atoms, or 1 to 10 carbon atoms.

[0116] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms have been replaced by a heteroatom (such as O, N or S). For example, if the carbon atom of the alkyl group connected to the parent molecule is replaced by a heteroatom (such as O, N or S), the resulting heteroalkyl group is an alkoxy group (such as -OCH3, etc.), an alkylamino group (such as -NHCH3, -N(CH3)2, etc.), or a sulfanyl group (such as -SCH3). If the non-terminal carbon atom of the alkyl group not connected to the parent molecule is replaced by a heteroatom (such as O, N or S), the resulting heteroalkyl group is an alkyl ether (such as -CH2CH2-O-CH3, etc.), an alkylaminoalkyl group (such as -CH2NHCH3, -CH2N(CH3)2, etc.) or a sulfanyl ether (such as -CH2-S-CH3). If the terminal carbon atom of the alkyl group is replaced by a heteroatom (such as O, N or S), the resulting heteroalkyl group is a hydroxyalkyl group (such as -CH2CH2-OH), an aminoalkyl group (such as -CH2NH2) or an alkylthiol group (such as -CH2CH2-SH). The heteroalkyl group may have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. The C1-C6 heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.

[0117] "Alkenyl" or "alkenylene" is intended to include hydrocarbon chains in a straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may be present at any stable point along the chain. For example, "C2 to C6 alkenyl" or "C 2-6 "Alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.

[0118] "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains in a straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds that may exist at any stable point along the chain. For example, "C2 to C6 alkynyl" or "C 2-6 "Alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5 and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0119] As used herein, "arylalkyl" (also known as aralkyl), "heteroarylalkyl", "carbocyclylalkyl" or "heterocyclylalkyl" refers to a non-cyclic alkyl group in which the carbon atom (typically terminal or sp 3In some embodiments, one of the hydrogen atoms of the alkyl radical (carbon atom) is replaced by an aryl, heteroaryl, carbocyclyl or heterocyclyl radical. Typical arylalkyl radicals include, but are not limited to, benzyl, 2-phenylethyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, naphthobenzyl, 2-naphthophenylethyl-1-yl and the like. Arylalkyl, heteroarylalkyl, carbocyclylalkyl or heterocyclylalkyl radicals may contain 4 to 20 carbon atoms and 0 to 5 heteroatoms, for example, the alkyl moiety may contain 1 to 6 carbon atoms.

[0120] As used herein, the term "benzyl" refers to a methyl group in which one hydrogen atom is replaced by a phenyl group, wherein the phenyl group may be optionally substituted by 1 to 5 groups, preferably 1 to 3 groups, of OH, OCH3, Cl, F, Br, I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(=O)CH3, SCH3, S(=O)CH3, S(=O)2CH3, CH3, CH2CH3, CO2H and CO2CH3. "Benzyl" may also be represented by the formula "Bn".

[0121] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. "C1 to C6 alkoxy" or "C 16 "Alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5 and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above having the specified number of carbon atoms attached through a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0122] As used herein by itself or as part of another group, the term "alkanoyl" or "alkylcarbonyl" refers to an alkyl group attached to a carbonyl group. For example, an alkylcarbonyl group can be represented by alkyl-C(O)-. "C1 to C6 alkylcarbonyl" (or alkylcarbonyl) is intended to include C1, C2, C3, C4, C5, and C6 alkyl-C(O)- groups.

[0123] As used herein by itself or as part of another group, the term "alkylsulfonyl" or "sulfonamide" refers to an alkyl or amino group attached to a sulfonyl group. For example, an alkylsulfonyl group can be represented by -S(O)2R', while a sulfonamide group can be represented by -S(O)2NR c R d R' is a C1 to C6 alkyl group; and R c and R d Same as defined below for "amino group".

[0124] As used herein by itself or as part of another group, the term "carbamate" refers to an oxygen attached to an amide group. For example, a carbamate can be made of N(R c R d )-C(O)-O-, and R c and R d Same as defined below for "amino group".

[0125] As used herein by itself or as part of another group, the term "amide" refers to an amine group attached to a carbonyl group. For example, an amide group can be N(R c R d )-C(O)-, and R c and R d Same as defined below for "amino group".

[0126] The term "amino" is defined as -NR c1 R c2 , where R c1 and R c2 independently H or C 1-6 alkyl; or alternatively, R c1 and R c2 Together with the atoms to which they are attached, they form a 3- to 8-membered heterocyclic ring, which is optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxy, amino, oxo, C 1-6 Alkyl, alkoxy and aminoalkyl. c1 or R c2 (or both) is C 1-6 When the amino group is an alkyl group, the amino group may also be referred to as an alkylamino group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, and the like. In one embodiment, the amino group is -NH2.

[0127] The term "aminoalkyl" refers to an alkyl group in which one hydrogen atom is replaced by an amino group. For example, an aminoalkyl group can be N(R c1 R c2 )-alkylene-. "C1 to C6" or "C 1-6 "Aminoalkyl" (or aminoalkyl) is intended to include C1, C2, C3, C4, C5 and C6 aminoalkyl groups.

[0128]

[0046] The term "halogen" or "halo" as used herein by itself or as part of another group refers to chlorine, bromine, fluorine and iodine, with chlorine or fluorine being preferred.

[0129] "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens. "C1 to C6 haloalkyl" or "C 1-6"Haloalkyl" (or haloalkyl) is intended to include C1, C2, C3, C4, C5 and C6 haloalkyl. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl", which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, substituted with one or more fluorine atoms. As used herein, the term "polyhaloalkyl" refers to an "alkyl" as defined above including 2 to 9, preferably 2 to 5 halogen substituents (such as F or Cl, preferably F), such as a polyfluoroalkyl, for example CF3CH2, CF3 or CF3CF2CH2.

[0130] "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above having the specified number of carbon atoms attached through an oxygen bridge. For example, "C1 to C6 haloalkoxy" or "C 1-6 "Haloalkoxy" is intended to include C1, C2, C3, C4, C5 and C6 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above having the specified number of carbon atoms, connected by a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-. As used herein, the term "polyhaloalkoxy" refers to an "alkoxy" or "alkyloxy" as defined above including 2 to 9, preferably 2 to 5 halogen substituents (such as F or Cl, preferably F), such as a polyfluoroalkoxy group, for example CF3CH2O, CF3O or CF3CF2CH2O.

[0131] "Hydroxyalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more hydroxyl (OH) groups. "C1 to C6 hydroxyalkyl" (or hydroxyalkyl) is intended to include C1, C2, C3, C4, C5 and C6 hydroxyalkyl groups.

[0132] The term "cycloalkyl" refers to a cyclized alkyl group, including monocyclic, bicyclic or polycyclic ring systems. "C3 to C8 cycloalkyl" or "C 3-8 "Cycloalkyl" is intended to include C3, C4, C5, C6, C7 and C8 cycloalkyl groups, including monocyclic, bicyclic and polycyclic rings. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. The definition of "cycloalkyl" includes branched chain cycloalkyl groups, such as 1-methylcyclopropyl and 2-methylcyclopropyl, and spiro and bridged cycloalkyl groups.

[0133] The term "cycloheteroalkyl" refers to a cyclized heteroalkyl group, including monocyclic, bicyclic or polycyclic ring systems. "C3 to C7 cycloheteroalkyl" or "C3-7 “Cycloheteroalkyl” is intended to include C3, C4, C5, C6 and C7 cycloheteroalkyl. Examples of cycloheteroalkyl include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl. The definition of “cycloheteroalkyl” includes branched chain cycloheteroalkyl such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl and pyrazinylmethyl.

[0134] As used herein, "carbocycle", "carbocyclyl" or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12- or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decahydronaphthalene), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As indicated above, the definition of carbocycle also includes bridged rings (e.g., [2.2.2]bicyclooctane). Unless otherwise specified, preferred carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term "carbocyclyl" is used, it is intended to include "aryl". When one or more carbon atoms connect two non-adjacent carbon atoms, a bridged ring is created. Preferably the bridge is one or two carbon atoms. It should be noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents described for the ring may also be present on the bridge.

[0135] In addition, as used herein by itself or as part of another group, the term "carbocyclyl" (including "cycloalkyl" and "cycloalkenyl") includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocycloalkyl, bicycloalkyl and tricycloalkyl, which contain a total of 3 to 20 carbon atoms forming the ring, preferably 3 to 10 carbon atoms or 3 to 6 carbon atoms forming the ring, and which may be fused with 1 or 2 aromatic rings as described for aryl, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

[0136]

[0137] Any of the groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol and / or alkylthio and / or any alkyl substituent.

[0138] As used herein, the term "bicyclic carbocyclyl" is intended to mean a stable 9- or 10-membered carbocyclic ring system containing two fused rings and consisting of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered saturated, partially unsaturated, or unsaturated carbocyclic ring. The bicyclic carbocyclyl may be attached to its side group at any carbon atom that results in a stable structure. If the resulting compound is stable, the bicyclic carbocyclyl described herein may be substituted on any carbon. Examples of bicyclic carbocyclyls are, but are not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

[0139] As used herein, the term "aryl" as used herein by itself or as part of another group refers to monocyclic or polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons, including, for example, phenyl, naphthyl, anthracenyl and phenanthrenyl. Aryl moieties are well known and described in, for example, Lewis, RJ, ed., Hawley's Condensed Chemical Dictionary, 13th edition, John Wiley & Sons, Inc., New York (1997). In one embodiment, the term "aryl" refers to monocyclic and bicyclic aromatic groups (such as phenyl or naphthyl, including 1-naphthyl and 2-naphthyl) containing 6 to 10 carbons in the ring portion. For example, "C6 or C 10 Aryl" or "C 6-10 "Aryl" refers to phenyl and naphthyl. Unless otherwise specified, "aryl", "C6 or C 10 Aryl", "C 6-10 The "aryl" or "aromatic residue" may be unsubstituted or substituted by 1 to 5 groups, preferably 1 to 3 groups, selected from -OH, -OCH3, -Cl, -F, -Br, -I, -CN, -NO2, -NH2, -N(CH3)H, -N(CH3)2, -CF3, -OCF3, -C(O)CH3, -SCH3, -S(O)CH3, -S(O)2CH3, -CH3, -CH2CH3, -CO2H and -CO2CH3.

[0140] As used herein, the term "benzyl" refers to a methyl group in which one hydrogen atom is replaced by a phenyl group, wherein the phenyl group may be optionally substituted by 1 to 5 of the following groups, preferably 1 to 3 of the following groups: OH, OCH3, Cl, F, Br, I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(=O)CH3, SCH3, S(=O)CH3, S(=O)2CH3, CH3, CH2CH3, CO2H and CO2CH3.

[0141] As used herein, the term "heterocycle", "heterocyclyl" or "heterocyclic group" is intended to mean a stable 3-, 4-, 5-, 6- or 7-membered monocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered polycyclic (including bicyclic and tricyclic) heterocyclic ring that is saturated or partially unsaturated and contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; and includes any polycyclic group in which any of the heterocycles defined above is fused to a carbocyclic or aryl (e.g., benzene) ring. That is, the term "heterocycle", "heterocyclyl" or "heterocyclic group" includes non-aromatic ring systems such as heterocycloalkyl and heterocycloalkenyl. The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N→O and S(O) p , wherein p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or another substituent (if defined)). The heterocyclic ring may be attached to its side group at any heteroatom or carbon atom that produces a stable structure. If the resulting compound is stable, the heterocyclic ring described herein may be substituted on a carbon atom or a nitrogen atom. The nitrogen in the heterocyclic ring may be optionally quaternized. Preferably, if the total number of S and O atoms in the heterocyclic ring exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocyclic ring does not exceed 1. Examples of heterocyclic groups include, but are not limited to, azetidinyl, piperazinyl, piperidinyl, piperidonyl, piperonyl, pyranyl, morpholinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, morpholinyl, dihydrofurano[2,3-b]tetrahydrofuran.

[0142] As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclyl" is intended to mean a stable 9-membered or 10-membered heterocyclic ring system containing two fused rings and consisting of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring, including a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to the second ring. The second ring is a 5- or 6-membered monocyclic ring, which is saturated, partially unsaturated or unsaturated and includes a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (with the proviso that if the second ring is a carbocycle, the first ring is not a benzo ring).

[0143] The bicyclic heterocyclic group may be attached to its side group at any heteroatom or carbon atom that produces a stable structure. If the resulting compound is stable, the bicyclic heterocyclic group described herein may be substituted on a carbon atom or a nitrogen atom. Preferably, if the total number of S and O atoms in the heterocyclic ring exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocyclic ring does not exceed 1. Examples of bicyclic heterocyclic groups are (but are not limited to) 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.

[0144] Also included in the definition of heterocycle are bridged rings. When one or more atoms (i.e., C, O, N, or S) connect two non-adjacent carbon or nitrogen atoms, a bridged ring is created. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It should be noted that the bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, substituents described in the ring may also be present on the bridge.

[0145] As used herein, the term "heteroaryl" is intended to mean stable monocyclic and polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen or nitrogen. Heteroaryl includes, but is not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolyl, benzodioxolyl and benzodioxane. Heteroaryl is substituted or unsubstituted. Nitrogen atom is substituted or unsubstituted (i.e., N or NR, wherein R is H or another substituent (if defined)). The nitrogen and sulfur heteroatoms may optionally be oxidized (ie, N→O and S(O) p , where p is 0, 1 or 2).

[0146] Examples of heteroaryl groups include, but are not limited to, acridinyl, azinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolinyl, oxazolopyridinyl, indolene, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazole alkyl pteridinyl (oxazolidinylperimidinyl), oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, Quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

[0147] Examples of 5- to 10-membered heteroaryl groups include, but are not limited to, pyridyl, furanyl, thienyl, pyrazolyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benzotetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzothiazolyl, benzisothiazolyl, isatoyl, isoquinolinyl, octahydroisoquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazopyridinyl, and pyrazolopyridinyl. Examples of 5- to 6-membered heteroaryl groups include, but are not limited to, pyridyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. In some embodiments, the heteroaryl group is selected from benzothiazolyl, imidazopyridinyl, pyrrolopyridinyl, quinolinyl, and indolyl.

[0148] Unless otherwise indicated, "carbocyclyl" or "heterocyclyl" includes one to three additional rings fused to a carbocyclic or heterocyclic ring (such as an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring), for example

[0149]

[0150] and optionally substituted through available carbon or nitrogen atoms (where applicable) with 1, 2 or 3 groups selected from the group consisting of hydrogen, halogen, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl The invention can be substituted with any of the alkyl substituents described herein, such as alkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino, and arylsulfonylaminocarbonyl, and / or any of the alkyl substituents described herein.

[0151] When any of the terms alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are used as part of another group, the number of carbon atoms and ring members are the same as defined in the term itself. For example, alkoxy, haloalkoxy, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, alkylthio, and the like each independently contain the same number of carbon atoms as defined for the term "alkyl", such as 1 to 4 carbon atoms, 1 to 6 carbon atoms, 1 to 10 carbon atoms, etc. Similarly, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, aralkylamino, arylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkoxy and the like each independently contain the same ring members as defined for the terms "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl", such as 3-6, 4-7, 6-10, 5-10, 5 or 6 members, etc.

[0152] According to the conventions used in the art, as used in the structural formulas herein, bonds pointing to bold lines, such as Depicts bonds that are points of attachment of a moiety or substituent to the core or backbone structure.

[0153] According to the conventions used in the art, waves or wavy bonds in structural formulas, such as The stereocenters are used to depict the carbon atoms to which X', Y', and Z' are attached, and are intended to represent both enantiomers in a single figure. That is, a structural formula having a wavy bond, such as When a wavy or wavy bond is attached to a double bond (such as C=C or C=N) moiety, it includes cis or trans (or E- and Z-) geometric isomers or mixtures thereof.

[0154] It should be understood that, herein, if a carbocyclic or heterocyclic moiety can be bonded or otherwise attached to a specified substrate through different ring atoms without indicating a specific point of attachment, all possible points are contemplated, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" means 2-pyridyl, 3-pyridyl, or 4-pyridyl, the term "thienyl" means 2-thienyl or 3-thienyl, and so forth.

[0155] If a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. If a substituent is listed without indicating that such substituent is bonded to an atom in the remainder of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0156] Those skilled in the art will recognize that substituents and other moieties of the compounds of the invention should be selected to provide sufficiently stable compounds, thereby providing pharmaceutically useful compounds that can be formulated into acceptable stable pharmaceutical compositions. Compounds of the invention having such stability are contemplated to be within the scope of the invention.

[0157] The term "counter ion" is used to refer to negatively charged species such as chloride, bromide, hydroxide, acetate and sulfate. The term "metal ion" refers to alkali metal ions such as sodium, potassium or lithium; and alkaline earth metal ions such as magnesium and calcium; as well as zinc and aluminum.

[0158] As referred to herein, the term "substituted" means that at least one hydrogen atom (attached to a carbon atom or a heteroatom) is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound. When the substituent is oxo (i.e., =O), then 2 hydrogens on the atom are replaced. Oxo substituents are not present on aromatic moieties. When a ring system (e.g., a carbocycle or heterocycle) is said to be substituted with a carbonyl or double bond, it is intended that the carbonyl or double bond is part of the ring (i.e., within it). As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). The term "substituted" with respect to alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl and heterocyclyl means alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl and heterocyclyl, respectively, in which one or more hydrogen atoms attached to a carbon atom or heteroatom are each independently replaced with one or more non-hydrogen substituents.

[0159] Where nitrogen atoms (e.g., amines) are present on the compounds of the invention, these can be converted to N-oxides by treatment with oxidizing agents (e.g., mCPBA and / or hydrogen peroxide) to afford other compounds of the invention. Thus, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxide (N→O) derivative.

[0160] When any variable occurs more than one time in any constituent or formula, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0, 1, 2, or 3 R groups, then the group is unsubstituted or substituted with up to three R groups when it is substituted with 0 R groups, and R is selected independently at each occurrence according to its definition of R.

[0161] Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0162] As used herein, the term "tautomer" refers to each of two or more isomers of a compound that coexist in equilibrium and are readily interchangeable by migration of atoms or groups within the molecule. For example, one skilled in the art will readily appreciate that, as defined above, 1,2,3-triazole exists in two tautomeric forms:

[0163]

[0164] Therefore, the present invention is intended to encompass all possible tautomers, even when a structure depicts only one of them.

[0165] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0166] The compounds of the present invention may exist in the form of salts, which are also within the scope of the present invention. Pharmaceutically acceptable salts are preferred. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds of the present invention, wherein the parent compound is modified by preparing its acid salt or base salt. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing basic or acidic parts. In general, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of the two; in general, non-aqueous media (such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile) are preferred. A list of suitable salts is found in Remington's Pharmaceutical Sciences 18th edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference.

[0167] If the compounds of the invention have, for example, at least one basic center, they can form acid addition salts. These acid addition salts are formed by the following acids, for example: strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or hydrohalic acids; organic carboxylic acids, such as alkanecarboxylic acids with 1 to 4 carbon atoms (e.g. acetic acid), which are unsubstituted or substituted, for example, with halogen (e.g. chloroacetic acid), such as saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid, such as amino acids (e.g. aspartic acid or glutamic acid or lysine or arginine) or benzoic acid; or organic sulfonic acids, such as (C1-C4) alkyl or arylsulfonic acids, which are unsubstituted or substituted, for example, with halogen, for example methanesulfonic acid or p-toluenesulfonic acid. If necessary, the corresponding acid addition salts with additionally present basic centers can also be formed. The compounds of the present invention having at least one acidic group (e.g., COOH) can also form salts with alkali. Suitable salts formed with alkali are, for example, metal salts, such as alkali metal salts or alkaline earth metal salts, such as sodium, potassium or magnesium salts; or salts with ammonia or organic amines, such as morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di- or tri-low carbon number alkylamines, such as ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or mono-, di- or tri-hydroxy low carbon number alkylamines, such as mono-, di- or triethanolamine. In addition, corresponding inner salts can be formed. Also included are salts of free compounds or pharmaceutically acceptable salts thereof that are not suitable for medical use but can be used, for example, for separation or purification of formula (Ia) or (Ib).

[0168] Preferred salts of compounds of formula (Ia) or (Ib) containing a base include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate, nitrate or acetate.

[0169] Preferred salts of compounds of formula (Ia) or (Ib) containing an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.

[0170] In addition, the compounds of formula (Ia) or (Ib) may be in prodrug form. Any compound that is converted in vivo to produce a bioactive agent (i.e., a compound of formula Ia or Ib) is a prodrug within the scope and spirit of the present invention. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see:

[0171] a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds., Methods in Enzymology, 112: 309-396, Academic Press (1985);

[0172] b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", A Textbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers (1991);

[0173] c) Bundgaard, H., Adv.Drug Deliv.Rev., 8:1-38 (1992);

[0174] d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and

[0175] e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

[0176] The compounds of the invention contain carboxyl groups that can form physiologically hydrolyzable esters that act as prodrugs, i.e., "prodrug esters," which are hydrolyzed in vivo to yield the compounds of the invention themselves. Examples of physiologically hydrolyzable esters of the compounds of the invention include C1 to C6 alkyl, C1 to C6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthaloyl, methoxymethyl ... 1-6 Alkanoyloxy-C 1-6 C1 to C6 alkoxycarbonyloxy-C1 to C6 alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl), and other well-known physiologically hydrolyzable esters used in, for example, penicillin and cephalosporin technology. Such esters can be prepared by conventional techniques known in the art. "Prodrug esters" can be formed by reacting the carboxylic acid portion of the compounds of the invention with an alkyl or aryl alcohol, a halide or a sulfonate using procedures known to those skilled in the art. Such esters can be prepared by conventional techniques known in the art.

[0177] Prodrug preparation is well known in the art and is described, for example, in King, FD, ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, CG, ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999).

[0178] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and not by way of limitation, isotopes of hydrogen include deuterium and tritium. Deuterium has one proton and one neutron in its nucleus and has twice the mass of ordinary hydrogen. Deuterium can be found in moieties such as " 2 H" or "D". The term "deuterated" herein, by itself or used to modify a compound or group, means that one or more hydrogen atoms attached to carbon are replaced by deuterium atoms. Carbon isotopes include 13 C and 14 C.

[0179] Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using appropriately isotopically labeled reagents instead of the unlabeled reagents originally used. Such compounds have a variety of potential uses, such as standards and reagents for determining the ability of potential pharmaceutical compounds to bind to target proteins or receptors or for in vivo or in vitro imaging of compounds of the present invention bound to biological receptors.

[0180] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Preferably, the compounds of the invention do not contain N-halogen, S(O)2H or S(O)H groups.

[0181] The term "solvate" means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, the solvate is capable of separation, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in the solvate may exist in an ordered and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. In general, solvation methods are known in the art.

[0182] abbreviation

[0183] Abbreviations used herein are defined as follows: "1x" is once, "2x" is twice, "3x" is three times, "°C" is degrees Celsius, "eq" is equivalent, "g" is gram, "mg" is milligram, "L" is liter, "mL" is milliliter, "μL" is microliter, "N" is normality, "M" is molarity, "mmol" is millimole, "min" is minute, "h" is hour, "rt" is room temperature, "RT" is retention time, "RBF" is round bottom flask, "atm" is atmospheric pressure, "psi" is pounds per square inch, "conc." is concentrated, "RCM" is closed loop metathesis, "sat" or "sat'd" is saturated, "SFC" is supercritical fluid chromatography, "MW" is molecular weight, "mp" is melting point, "ee" is enantiomeric excess, "MS" or "Mass Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "HR" is high resolution, "HRMS" is high resolution mass spectrometry, "LCMS" is liquid chromatography mass spectrometry, "HPLC" is high pressure liquid chromatography, "RPMS" is liquid chromatography mass spectrometry, "HPLC" stands for reverse phase HPLC, "TLC" or "tlc" stands for thin layer chromatography, "NMR" stands for nuclear magnetic resonance spectroscopy, "nOe" stands for nuclear Overhauser effect spectroscopy, " 1 H" is a proton, "δ" is delta, "s" is a singlet, "d" is a doublet, "t" is a triplet, "q" is a quartet, "m" is a multiplet, "br" is a broad peak, "Hz" is hertz, and "α", "β", "γ", "R", "S", "E" and "Z" are stereochemical identifiers familiar to those skilled in the art.

[0184] Me Methyl

[0185] Et Ethyl

[0186] Pr Propyl

[0187] i-Pr Isopropyl

[0188] Bu Butyl

[0189] i-Bu Isobutyl

[0190] t-Bu tert-butyl

[0191] Ph Phenyl

[0192] Bn Benzyl

[0193] Boc or BOC tert-butoxycarbonyl

[0194] Boc2O Di-tert-butyl dicarbonate

[0195] AcO or HOAc Acetic acid

[0196] AlCl3 Aluminum chloride

[0197] AIBN Azobisisobutyronitrile

[0198] BBr3 Boron tribromide

[0199] BCl3 Boron trichloride

[0200] BEMP 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphabenzene

[0201] BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

[0202] Burgess reagent (1-methoxy-N-triethylammoniumsulfonyl-formimide ester

[0203] reagent)

[0204] CBz benzyloxycarbonyl

[0205] DCM or CH2Cl2 Dichloromethane

[0206] CH3CN or ACN Acetonitrile

[0207] CDCl3 deuterated chloroform

[0208] CHCl3 Chloroform

[0209] mCPBA or m-CPBA m-Chloroperbenzoic acid

[0210] Cs2CO3 Cesium carbonate

[0211] Cu(OAc)2 Copper(II) acetate

[0212] Cy2NMe N-Cyclohexyl-N-methylcyclohexylamine

[0213] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0214] DCE 1,2-Dichloroethane

[0215] DEA Diethylamine

[0216] DEAD Diethyl azodicarboxylate

[0217] Dess-Martin 1,1,1-Tris(acetoxy)-1,1-dihydro-1,2-benziodoxolan-3-(1H)-one

[0218] DIAD Diisopropyl azodicarboxylate

[0219] DIC or DIPCDI Diisopropylcarbodiimide

[0220] DIEA, DIPEA or Whitney diisopropylethylamine

[0221] Hunig's base

[0222] DMAP 4-dimethylaminopyridine

[0223] DME 1,2-Dimethoxyethane

[0224] DMF Dimethylformamide

[0225] DMSO Dimethyl sulfoxide

[0226] cDNA complementary DNA

[0227] Dppp (R)-(+)-1,2-Bis(diphenylphosphino)propane

[0228] DuPhos (+)-1,2-Bis((2S,5S)-2,5-diethylphospholyl)benzene

[0229] EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide

[0230] EDCI N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

[0231] EDTA Ethylenediaminetetraacetic acid

[0232] (S,S)-EtDuPhosRh(I) (+)-1,2-Bis((2S,5S)-2,5-diethylphospholyl)benzene(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate

[0233] Et3N or TEA Triethylamine

[0234] EtOAc Ethyl acetate

[0235] Et2O Ether

[0236] EtOH

[0237] GMF Glass Microfiber Filter

[0238] Grubbs II (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium

[0239] HCl

[0240] HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0241] HEPES 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid

[0242] Hex

[0243] HOBt or HOBT 1-Hydroxybenzotriazole

[0244] H2O2 Hydrogen Peroxide

[0245] IBX 2-iodooxybenzoic acid

[0246] H2SO4 sulfuric acid

[0247] Jones reagent (2M solution of CrO3 in aqueous H2SO4)

[0248] reagent)

[0249] K2CO3 Potassium carbonate

[0250] K2HPO4 Potassium Hydrogen Phosphate (Potassium Hydrogen Phosphate)

[0251] KOAc Potassium acetate

[0252] K3PO4 Tripotassium Phosphate

[0253] LAH Lithium Aluminum Hydride

[0254] LG Leaving Group

[0255] LiOH Lithium Hydroxide

[0256] MeOH Methanol

[0257] MgSO4 Magnesium sulfate

[0258] MsOH or MSA Methanesulfonic acid / methanesulfonic acid

[0259] NaCl Sodium chloride

[0260] NaH Sodium hydride

[0261] NaHCO3 Sodium bicarbonate

[0262] Na2CO3 Sodium carbonate

[0263] NaOH Sodium hydroxide

[0264] Na2SO3 Sodium sulfite

[0265] Na2SO4 Sodium sulfate

[0266] NBS N-bromosuccinimide

[0267] NCS N-Chlorosuccinimide

[0268] NH3 Ammonia

[0269] NH4Cl Ammonium chloride

[0270] NH4OH Ammonium Hydroxide

[0271] NH4 + HCO2 - Ammonium formate

[0272] NMM N-Methylmorpholine

[0273] OTf triflate or trifluoromethanesulfonate

[0274] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0275] Pd(OAc)2 Palladium(II) acetate

[0276] Pd / C Palladium / Carbon

[0277] Pd(dppf)Cl2 [1,1'-Bis(diphenylphosphino)-ferrocene]palladium(II) chloride

[0278] Ph3PCl2 Triphenylphosphine dichloride

[0279] PG Protecting Group

[0280] POCl3 Phosphorus oxychloride

[0281] PPTS Pyridinium p-toluenesulfonate

[0282] i-PrOH or IPA Isopropyl alcohol

[0283] PS Polystyrene

[0284] RT or rt Room temperature

[0285] SEM-Cl 2-(Trimethylsilyl)ethoxymethyl chloride

[0286] SiO2 Silicon Dioxide

[0287] SnCl2 Tin(II) chloride

[0288] TBAF Tetra-n-butylammonium fluoride

[0289] TBAI Tetra-n-butylammonium iodide

[0290] TFA Trifluoroacetic acid

[0291] THF Tetrahydrofuran

[0292] THP Tetrahydropyran

[0293] TMSCHN2 Trimethylsilyldiazomethane

[0294] TMSCH2N3 Trimethylsilylmethyl azide

[0295] T3P Propanephosphonic anhydride

[0296] TRIS Tris(hydroxymethyl)aminomethane

[0297] pTsOH p-Toluenesulfonic acid

[0298] IV. Biology

[0299] Lysophospholipids are membrane-derived bioactive lipid mediators. Lysophospholipids include, but are not limited to, lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA), sphingosine-1-phosphate (S1P), lysophosphatidylcholine (LPC), and sphingomyelinylphosphocholine (SPC). Lysophospholipids affect basic cellular functions, including cell proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions affect many biological processes, including neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis.

[0300] LPA acts in an autocrine and paracrine manner through specific G protein-coupled receptors (GPCRs). LPA binding to its cognate GPCRs (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) activates intracellular signaling pathways to produce a variety of biological responses.

[0301] Quantitatively, lysophospholipids such as LPA are minor lipid species compared to their major phospholipid counterparts (e.g., phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin). LPA has a role as a biological effector molecule and has a range of different physiological effects, such as (but not limited to) effects on blood pressure, platelet activation, and smooth muscle contraction; and a variety of cellular effects, including cell growth, cell rounding, axon retraction, and actin stress fiber formation and cell migration. The effects of LPA are primarily mediated by receptors.

[0302] LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) mediate a series of downstream signal transduction cascades through the activation of LPA. This includes (but is not limited to) mitogen-activated protein kinase (MAPK) activation, adenylate cyclase (AC) inhibition / activation, phospholipase C (PLC) activation / Ca 2+ Migration, arachidonic acid release, Akt / PKB activation, and activation of small GTPases, Rho, ROCK, Rac and Ras. Other pathways affected by LPA receptor activation include, but are not limited to, cyclic adenosine monophosphate (cAMP), cell division cycle 42 / GTP-binding protein (Cdc42), proto-oncogene serine / threonine-protein kinase Raf (c-RAF), proto-oncogene tyrosine-protein kinase Src (c-src), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun N-terminal kinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kB (NF-kB), N-methyl-D-aspartate (NMDA) receptor activation, phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA), protein kinase C (PKC), ras-related C3 botulinum toxin substrate 1 (RAC1). The actual pathway and endpoint achieved depends on a number of variables, including receptor usage, cell type, degree of expression of receptors or signaling proteins, and LPA concentration. Almost all mammalian cells, tissues, and organs co-express several LPA receptor subtypes, indicating that LPA receptors signal in a cooperative manner. LPA1, LPA2, and LPA3 have a high degree of amino acid sequence similarity.

[0303] LPA is produced by activated platelets, activated adipocytes, neuronal cells and other cell types. Serum LPA is produced by multiple enzymatic pathways involving monoacylglycerol kinase, phospholipase A1, secretory phospholipase A2 and lysophospholipase D (lysoPLD), including autotaxin. Several enzymes are involved in LPA degradation: lysophospholipases, lipid phosphate phosphatases and LPA acyltransferases such as endophilin. The LPA concentration in human serum is estimated to be 1 to 5 μM. Serum LPA is bound to albumin, low-density lipoprotein or other proteins, which may protect LPA from rapid degradation. LPA molecular species with different acyl chain lengths and saturation levels occur naturally, including 1-palmitoyl (16:0), 1-palmitoleoyl (16:1), 1-stearoyl (18:0), 1-oleoyl (18:1), 1-linoleoyl (18:2), and 1-arachidonyl (20:4) LPA. Alkyl LPAs, which are present in trace amounts, have similar biological activities to acyl LPAs, and different LPA species activate LPA receptor subtypes with different potencies.

[0304] LPA receptor

[0305] LPA1 (previously known as VZG-1 / EDG-2 / mrec1.3) binds to three types of G proteins i / o , G q and G 12 / 13 Through the activation of these G proteins, LPA induces a series of cellular responses through LPA1, including (but not limited to): cell proliferation, serum response element (SRE) activation, mitogen-activated protein kinase (MAPK) activation, adenylate cyclase (AC) inhibition, phospholipase C (PLC) activation, Ca 2+ Migration, Akt activation and Rho activation.

[0306] In adult mice, widespread expression of LPA1 is observed, specifically in the testes, brain, heart, lungs, small intestine, stomach, spleen, thymus, and skeletal muscle. Similarly, human tissues also express LPA1; it is present in the brain, heart, lungs, placenta, colon, small intestine, prostate, testes, ovaries, pancreas, spleen, kidneys, skeletal muscle, and thymus.

[0307] LPA2 (EDG-4) also binds to three types of G proteins (G i / o , G q and G 12 / 13) to mediate LPA-induced cell signaling. LPA2 expression has been observed in the testes, kidneys, lungs, thymus, spleen, and stomach of adult mice and in the testes, pancreas, prostate, thymus, spleen, and peripheral blood leukocytes of humans. LPA2 expression is upregulated in a variety of cancer cell lines, and several human LPA2 transcript variants with mutations in the 3'-untranslated region have been observed. Targeted deletion of LPA2 in mice has not shown obvious phenotypic abnormalities, but normal LPA signaling (e.g., PLC activation, Ca 2+ activation) has been demonstrated in primary cultures of mouse embryonic fibroblasts (MEFs). 2+ Generation of lpa1(- / -)lpa2(- / -) double-null mice revealed that many LPA-induced responses (including cell proliferation, AC inhibition, PLC activation, Ca 2+ Migration, JNK and Akt activation, and stress fiber formation) were absent or severely reduced in double-null MEFs. All of these responses were only partially affected in LPA1(- / -) or LPA2(- / -) MEFs, except AC inhibition, which was almost abolished in LPA1(- / -) MEFs. LPA2 is responsible for normal LPA-mediated signaling responses in at least some cell types (Choi et al., Biochemica et Biophysica Acta 2008, 1781, pp. 531-539).

[0308] LPA3 (EDG-7) is different from LPA1 and LPA2 in that it can bind to G i / o and G q Coupled, but with G 12 / 13 LPA3 is uncoupled and much less responsive to LPA species with saturated acyl chains. LPA3 mediates pleiotropic LPA-induced signaling, including PLC activation, Ca 2+ Migration, AC inhibition / activation, and MAPK activation. Overexpression of LPA3 in neuroblastoma cells leads to axonal elongation when stimulated by LPA, while overexpression of LPA1 or LPA2 causes axonal retraction and cell rounding. Expression of LPA3 was observed in the testes, kidneys, lungs, small intestine, heart, thymus, and brain of adult mice. In humans, it is found in the heart, pancreas, prostate, testes, lungs, ovaries, and brain (frontal cortex, hippocampus, and amygdala).

[0309] Compared with LPA1, LPA2, and LPA3, LPA4 (p2y9 / GPR23) has a divergent sequence and is more similar to the platelet-activating factor (PAF) receptor. 2+Transport and accumulation of cAMP, and functional coupling with G protein Gs for AC activation, as well as coupling with other G proteins. The LPA4 gene is expressed in the ovary, pancreas, thymus, kidney and skeletal muscle.

[0310] LPA5 (GPR92) is a member of the purinocluster of GPCRs and is most closely related structurally to LPA4. LPA5 is expressed in human heart, placenta, spleen, brain, lung, and intestine. LPA5 also shows extremely high expression in the CD8+ lymphocyte compartment of the gastrointestinal tract.

[0311] LPA6 (p2y5) is a purine cluster member of the GPCR and is most closely related structurally to LPA4. LPA6 is an LPA receptor coupled to the G12 / 13-Rho signaling pathway and is expressed in the inner root sheath of human hair follicles.

[0312] Illustrative Biological Activities

[0313] Wound healing

[0314] Normal wound healing occurs through a series of highly coordinated events in which cells, soluble factors, and matrix components work together to repair the injury. The healing response can be described as proceeding in four broadly overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Many growth factors and cytokines are released into the wound site to initiate and maintain the wound healing process.

[0315] Upon injury, damaged blood vessels activate platelets. Activated platelets play a key role in the subsequent repair process by releasing bioactive mediators to induce cell proliferation, cell migration, blood coagulation, and angiogenesis. LPA is one such mediator released by activated platelets; it induces platelet aggregation and produces mitogenic / migratory effects on surrounding cells such as endothelial cells, smooth muscle cells, fibroblasts, and keratinocytes.

[0316] Topical application of LPA to mouse skin wounds promoted the repair process (wound closure and increased thickness of new epithelium) by increasing cell proliferation / migration without causing secondary inflammation.

[0317] Growth factors and cytokines activate dermal fibroblasts so that they subsequently migrate from the wound edge into the temporary matrix formed by the fibrin clot, after which the fibroblasts proliferate and begin to restore the dermis by secreting and organizing the characteristic dermal extracellular matrix (ECM). The continuous deposition of more and more fibroblasts and ECM within the wound increases the rigidity of the matrix, which is achieved by applying small traction forces to the newly formed granulation tissue. The increase in mechanical stress, combined with transforming growth factor β (TGFβ), induces the expression of α-smooth muscle actin (α-SMA) and subsequently transforms fibroblasts into myofibroblasts. Myofibroblasts promote granulation tissue remodeling, which is completed by contraction of myofibroblasts and by the production of ECM components.

[0318] LPA regulates many important functions of fibroblasts in wound healing, including proliferation, migration, differentiation and contraction. Wound healing requires fibroblast proliferation in order to fill open wounds. In contrast, fibrosis is characterized by the vigorous proliferation and accumulation of myofibroblasts that actively synthesize ECM and proinflammatory cytokines. LPA can increase or inhibit the proliferation of cell types that play an important role in wound healing, such as epithelial cells and endothelial cells (EC), macrophages, keratinocytes and fibroblasts. The role of LPA1 in LPA-induced proliferation is provided by the following observations: fibroblasts isolated from LPA1 receptor knockout mice have reduced proliferation under LPA stimulation (Mills et al., Nat Rev. Cancer 2003; 3: 582-591). LPA induces cytoskeletal changes that are indispensable for fibroblast adhesion, migration, differentiation and contraction.

[0319] Fibrosis

[0320] Tissue injury initiates a complex series of host wound healing responses; if successful, these responses restore normal tissue structure and function. If absent, these responses can lead to tissue fibrosis and loss of function.

[0321] For most organs and tissues, the development of fibrosis involves multiple events and factors. Molecules involved in the development of fibrosis include proteins or peptides (profibrotic cytokines, chemokines, metalloproteinases, etc.) and phospholipids. Phospholipids involved in the development of fibrosis include platelet activating factor (PAF), phosphatidylcholine, sphingosine-1 phosphate (S1P) and lysophosphatidic acid (LPA).

[0322] Many muscular dystrophies are characterized by progressive weakness and wasting of muscle tissue, as well as extensive fibrosis. LPA treatment of cultured myoblasts has been shown to induce significant expression of connective tissue growth factor (CTGF). CTGF subsequently induces collagen, fibronectin and integrin expression and induces dedifferentiation of these myoblasts. LPA treatment induces reproducible and high levels of CTGF induction in a variety of cell types (JP Radere et al., LPA1 receptor activation promotes renal interstitial fibrosis, J. Am. Soc. Nephrol. 18 (2007) 3110-3118; N. Wiedmaier et al., Int J Med Microbiol; 298 (3-4): 231-43, 2008). CTGF is a profibrotic cytokine that signals downstream and in parallel with TGFβ.

[0323] Gingival epithelial cells involved in the development of gingival fibromyxoma have been found to express CTGF, which is exacerbated by treatment with LPA (A. Kantarci et al., J. Pathol. 210 (2006) 59-66).

[0324] LPA is associated with the progression of liver fibrosis. LPA induces astrocyte and hepatocyte proliferation in vitro. These activated cells are the main cell types responsible for ECM accumulation in the liver. In addition, LPA plasma levels increase during CCl4-induced liver fibrosis in rodents, or in humans, in hepatitis C virus-induced liver fibrosis (N. Watanabe et al., Plasma lysophosphatidic acid level and serum autotaxin activity are increased in liver injury in rats in relation to its severity, Life Sci. 81 (2007) 1009-1015; N. Watanabe et al., J. Clin. Gastroenterol. 41 (2007) 616-623).

[0325] Increased phospholipid concentrations in bronchoalveolar lavage fluid of rabbits and rodents injected with bleomycin have been reported (K. Kuroda et al., Phospholipid concentration in lung lavage fluid as biomarker for pulmonary fibrosis, Inhal. Toxicol. 18 (2006) 389-393; K. Yasuda et al., Lung 172 (1994) 91-102).

[0326] LPA is associated with heart disease and myocardial remodeling. Serum LPA levels increase in patients after myocardial infarction and LPA stimulates rat cardiac fibroblast proliferation and collagen production (Chen et al., FEBS Lett. 2006 Aug 21;580(19):4737-45).

[0327] Pulmonary fibrosis

[0328] In the lung, abnormalities in the wound healing response to injury contribute to the pathogenesis of fibrotic lung diseases. Fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), are associated with significant morbidity and mortality.

[0329] LPA is an important mediator of fibroblast recruitment in pulmonary fibrosis. LPA and LPA1 play a key pathogenic role in pulmonary fibrosis. Fibroblast chemotactic activity plays an important role in the lungs of patients with pulmonary fibrosis. The profibrotic effect of LPA1 receptor stimulation is explained by LPA1 receptor-mediated vascular leakage and enhanced fibroblast recruitment, both of which are profibrotic events. The LPA-LPA1 pathway has a role in mediating fibroblast migration and vascular leakage in IPF. The end result is an abnormal healing process characterized by this fibrotic condition.

[0330] LPA1 receptor is the highest LPA receptor expressed on fibroblasts from IPF patients. In addition, BAL obtained from IPF patients induces chemotaxis of human fetal lung fibroblasts, which is blocked by the dual LPA1-LPA3 receptor antagonist Ki16425. In the bleomycin-induced lung injury mouse experimental model, it was shown that the LPA level in bronchoalveolar lavage samples was higher than that in unexposed controls. Mice with LPA1 gene knockout are free from fibrosis after bleomycin attack, while fibroblast accumulation and vascular leakage are reduced. Compared to healthy controls, high LPA levels are observed in bronchoalveolar lavage samples of human individuals with IPF. The enhanced fibroblast chemotaxis activity in these samples is inhibited by Ki16425, indicating that the LPA-LPA receptor pathway mediates the migration of fibroblasts (Tager et al., Nature Medicine, 2008, 14, 45-54).

[0331] The LPA-LPA1 pathway is critical in lung fibrosis, in fibroblast recruitment and vascular leakage.

[0332] Activation of latent TGF-β by αvβ6 integrin plays a key role in the development of lung injury and fibrosis (Munger et al., Cell, Vol. 96, 319-328, 1999). LPA induces αvβ6 to mediate TGF-β activation on human lung epithelial cells (Xu et al., Am. J. Pathology, 2009, 174, 1264-1279). LPA induces αvβ6-mediated TGF-β activation mediated by LPA2 receptor. Compared with normal human lung tissue, LPA2 receptor expression is enhanced in epithelial cells and mesenchymal cells in the pulmonary fibrosis area of ​​IPF patients. The LPA-LPA2 pathway contributes to the activation of the TGF-β pathway in pulmonary fibrosis. In some embodiments, compounds that inhibit LPA2 show efficacy in treating pulmonary fibrosis. In some embodiments, compounds that inhibit LPA1 and LPA2 both show improved efficacy in treating pulmonary fibrosis compared to compounds that only inhibit LPA1 or LPA2.

[0333] In a 26-week clinical trial in IPF patients, the LPA1 antagonist BMS-986020 showed a significant reduction in the rate of FVC (forced vital capacity) decay (Palmer et al., Chest, 2018, 154, 1061-1069).

[0334] Renal fibrosis

[0335] LPA and LPA1 are involved in the etiology of renal fibrosis. LPA has an effect on the proliferation and contraction of mesangial cells and is therefore associated with proliferative glomerulonephritis (CN Noue et al., Clin. Sci. (Colch.) 1999, 96, 431-436). In an animal model of renal fibrosis [unilateral ureteral obstruction (UUO)], renal LPA receptors were found to be expressed in the order of LPA2>LPA3=LPA1>>LPA4 under basal conditions. This model simulates the development of renal fibrosis in an accelerated manner, including nephritis, fibroblast activation, and accumulation of extracellular matrix in the tubulointerstitium. UUO significantly induces LPA1 receptor expression. In parallel, renal LPA is produced in the conditioned medium of renal explants (3.3-fold increase). The contralateral kidney did not show significant changes in LPA release and LPA receptor expression. This indicates that the prerequisites for the role of LPA in fibrosis are met: production of the ligand (LPA) and induction of one of its receptors (LPA1 receptor) (JP Paradere et al., Biochimica et Biophysica Acta, 2008, 1781, 582-587).

[0336] In LPA1 receptor knockout (LPA1(- / -) mice, the development of renal fibrosis was significantly attenuated. UUO mice treated with the LPA receptor antagonist Ki16425 showed a profile very similar to that of LPA1(- / -) mice.

[0337] LPA can be involved in the intraperitoneal accumulation of monocytes / macrophages and LPA can induce the expression of the profibrotic cytokine CTGF in primary cultures of human fibroblasts (JS Koh et al., J. Clin. Invest., 1998, 102, 716-727).

[0338] LPA treatment of mouse epithelial kidney cell line MCT induces a rapid increase in the expression of the profibrotic cytokine CTGF. CTGF plays a key role in UUO-induced tubulointerstitial fibrosis (TIF) and is involved in the profibrotic activity of TGFβ. Co-treatment with the LPA receptor antagonist Ki16425 almost completely suppresses this induction. In one aspect, the profibrotic activity of LPA in the kidney is caused by the direct effect of LPA on renal cells involved in CTGF induction.

[0339] Liver fibrosis

[0340] LPA is involved in liver disease and fibrosis. Plasma LPA levels and serum autotaxin (the enzyme responsible for LPA production) are elevated in hepatitis patients and animal liver injury models associated with increased fibrosis. LPA also regulates liver cell function. Mouse hepatic stellate cells express LPA1 and LPA2 receptors and LPA stimulates hepatic myofibroblast migration.

[0341] Ocular fibrosis

[0342] LPA is involved in ocular wound healing. LPA1 and LPA3 receptors can be detected in normal rabbit corneal epithelial cells, keratinocytes and endothelial cells, and the expression of LPA1 and LPA3 in corneal epithelial cells increases after injury.

[0343] LPA and its homologues are present in the humoral fluid and lacrimal fluid of the rabbit eye, and these levels are increased in a rabbit corneal injury model.

[0344] LPA induces the formation of actin stress fibers in rabbit corneal endothelial cells and epithelial cells and promotes the contraction of corneal fibroblasts. LPA also stimulates the proliferation of human retinal pigment epithelial cells.

[0345] Cardiac fibrosis

[0346] LPA is involved in myocardial infarction and cardiac fibrosis. Increased serum LPA levels occur in patients after myocardial infarction (MI) and LPA stimulates rat cardiac fibroblast proliferation and collagen production (fibrosis). Both LPA1 and LPA3 receptors are highly expressed in human cardiac tissue.

[0347] Treatment of fibrosis

[0348] In one aspect, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat or prevent fibrosis in a mammal. In one aspect, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat fibrosis in an organ or tissue of a mammal. In one aspect, a method for preventing a fibrotic condition in a mammal, the method comprising administering a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof to a mammal having a risk of producing one or more fibrotic conditions. In one aspect, the mammal has been exposed to one or more environmental conditions known to increase the risk of fibrosis of an organ or tissue. In one aspect, the mammal has been exposed to one or more environmental conditions known to increase the risk of pulmonary fibrosis, liver fibrosis, or kidney fibrosis. In one aspect, the mammal has a genetic predisposition to produce organ or tissue fibrosis. In one aspect, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is administered to a mammal to prevent or minimize scarring after injury. In one aspect, injury includes surgery.

[0349] As used herein, the term "fibrosis" or "fibrotic disorder" refers to a condition associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or enhanced fibroblast recruitment, and includes, but is not limited to, fibrosis of individual organs or tissues, such as the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, muscle skeleton, and digestive tract.

[0350] Exemplary diseases, disorders or conditions involving fibrosis include, but are not limited to: lung diseases associated with fibrosis, such as idiopathic pulmonary fibrosis, pulmonary fibrosis secondary to systemic inflammation (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, ventilator-induced, non-pulmonary sepsis-induced, and aspiration-induced); chronic kidney disease (kidney fibrosis) associated with injury / fibrosis, such as glomerulonephritis secondary to systemic inflammation, Such as lupus and scleroderma, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allografts and Alport syndrome; intestinal fibrosis, such as scleroderma, and radiation-induced intestinal fibrosis; liver fibrosis, such as cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct damage, primary biliary cirrhosis, infection or virus-induced liver fibrosis (such as chronic HCV infection), and autoimmune hepatitis; head and neck fibrosis, such as radiation-induced; corneal scarring, such as LASIK (laser-assisted in situ keratoplasty, laser-assisted in situ keratomileusis), corneal transplantation, and trabeculectomy; hypertrophic scars and keloids, e.g., burn-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.

[0351] In one aspect, a mammal suffering from one of the following non-limiting exemplary diseases, disorders or conditions will benefit from treatment with a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof: atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pneumonia, intestinal adhesions, bladder fibrosis and cystitis, nasal passage fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

[0352] In one aspect, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is administered to a mammal suffering from organ or tissue fibrosis or an organ or tissue prone to fibrosis together with one or more other agents for treating fibrosis. In one aspect, the one or more agents include a corticosteroid. In one aspect, the one or more agents include an immunosuppressant. In one aspect, the one or more agents include a B cell antagonist. In one aspect, the one or more agents include uteroglobin.

[0353] In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat a skin disorder in a mammal. As used herein, the term "dermatological disorder" refers to a skin disorder. Such dermatological disorders include, but are not limited to, proliferative or inflammatory skin disorders such as atopic dermatitis, bullous disorders, collagen diseases, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scars, hypertrophic scars, keloids, Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, and urticaria. In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat systemic sclerosis.

[0354] pain

[0355] Since LPA is released after tissue damage, LPA1 plays an important role in the initiation of neuropathic pain. Unlike LPA2 or LPA3, LPA1 is expressed in dorsal root ganglia (DRG) and dorsal root neurons. Antisense oligodeoxynucleotides (AS-ODN) were used in LPA1 and LPA1 knockout mice to find that LPA-induced mechanical allodynia and hyperalgesia were mediated in an LPA1-dependent manner. LPA1 and downstream Rho-ROCK activation play a role in the initiation of neuropathic pain signaling. Pretreatment with Clostridium botulinum C3 exoenzyme (BoTXC3, Rho inhibitor) or Y-27632 (ROCK inhibitor) completely eliminated abnormal pain and hyperalgesia in nerve-injured mice. LPA also induces dorsal root demyelination, which is prevented by BoTXC3. No damage-induced dorsal root demyelination was observed in LPA1 knockout mice or wild-type mice injected with AS-ODN. LPA signaling appears to induce important neuropathic pain markers such as protein kinase Cγ (PKCγ) and voltage-gated calcium channel α2δ1 subunit (Caα2δ1) in an LPA1- and Rho-dependent manner (M. Inoue et al., Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling, Nat. Med. 10 (2004) 712-718).

[0356] In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat pain in a mammal. In one aspect, the pain is acute pain or chronic pain. In another aspect, the pain is neuropathic pain.

[0357] In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat muscle fiber pain. In one aspect, muscle fiber pain results from the formation of fibrous scar tissue in contracted (spontaneous) muscles. Fibrosis causes tissue adhesion and inhibits blood flow, causing pain.

[0358] cancer

[0359] Lysophospholipid receptor signaling plays a role in the etiology of cancer. Lysophosphatidic acid (LPA) and its G protein-coupled receptors (GPCRs) LPA1, LPA2 and / or LPA3 play a role in the development of several types of cancer. The initiation, progression and metastasis of cancer involve several parallel and sequential processes, including cell proliferation and growth, survival and resistance to apoptosis, cell migration, penetration of foreign cells into defined cell layers and / or organs, and promotion of angiogenesis. Control of each of these processes caused by LPA signaling under physiological and pathophysiological conditions emphasizes the potential therapeutic usefulness of regulating the LPA signaling pathway for the treatment of cancer, especially at the level of LPA receptors or ATX / lysoPLD. Autotaxin (ATX) is a pro-metastatic enzyme originally isolated from the conditioned medium of human melanoma cells that stimulates a variety of biological activities through the production of LPA, including angiogenesis and promotion of cell growth, migration, survival and differentiation (Mol Cancer Ther 2008; 7(10): 3352-62).

[0360] LPA signals through its own GPCRs, thereby activating multiple downstream effector pathways. Such downstream effector pathways play a role in cancer. LPA and its GPCRs are associated with cancer through major oncogenic signaling pathways.

[0361] LPA promotes tumorigenesis by increasing the activity and invasiveness of cells. LPA has been implicated in the initiation or progression of ovarian cancer. LPA is present in the ascites of ovarian cancer patients at significant concentrations (2-80 μM). Compared to normal ovarian surface epithelial cells, ovarian cancer cells constitutively produce increased amounts of LPA, a precursor of ovarian epithelial cancer. Compared to controls, elevated LPA levels were also detected in the plasma of patients with early ovarian cancer. Compared to normal ovarian surface epithelial cells, LPA receptors (LPA2 and LPA3) are also overexpressed in ovarian cancer cells. LPA stimulates Cox-2 expression by transcriptional activation and post-transcriptional enhancement of Cox-2 mRNA in ovarian cancer cells. The prostaglandins produced by Cox2 have been associated with a variety of human cancers, and pharmacological inhibition of Cox-2 activity reduces colon cancer development and reduces the size and number of adenomas in patients with familial adenomatous polyposis. LPA has also been implicated in the initiation or progression of prostate cancer, breast cancer, melanoma, head and neck cancer, intestinal cancer (colorectal cancer), thyroid cancer and other cancers (Gardell et al., Trends in Molecular Medicine, Vol. 12, No. 2, pp. 65-75, 2006; Ishii et al., Annu. Rev. Biochem, 73, 321-354, 2004; Mills et al., Nat. Rev. Cancer, 3, 582-591, 2003; Murph et al., Biochimica et Biophysica Acta, 1781, 547-557, 2008).

[0362] Cellular responses to LPA are mediated by lysophosphatidic acid receptors. For example, LPA receptors mediate migration and invasion of pancreatic cancer cell lines: antagonists of LPA1 and LPA3 (Ki16425) and LPA1-specific siRNA effectively blocked in vitro migration in response to LPA and peritoneal fluid (ascites) from pancreatic cancer patients; in addition, Ki16425 blocked LPA-induced and ascites-induced invasive activity of highly peritoneal metastatic pancreatic cancer cell lines (Yamada et al., J. Biol. Chem. 279, 6595-6605, 2004).

[0363] Colorectal cancer cell lines show significant expression of LPA1 mRNA and respond to LPA by cell migration and production of angiogenic factors. Overexpression of the LPA receptor plays a role in the pathogenesis of thyroid cancer. LPA3 was originally cloned from prostate cancer cells, consistent with the ability of LPA to induce autocrine proliferation of prostate cancer cells.

[0364] LPA has a stimulatory effect on cancer progression in many types of cancer. LPA is produced by prostate cancer cell lines and induces the proliferation of prostate cancer cell lines. LPA induces proliferation, migration, adhesion and secretion of angiogenic factors in human colon cancer DLD1 cells through LPA1 signaling. In other human colon cancer cell lines (HT29 and WiDR), LPA enhances cell proliferation and angiogenic factor secretion. In other colon cancer cell lines, LPA2 and LPA3 receptor activation causes cell proliferation. Genetic or pharmacological manipulation of LPA metabolism, specific blocking of receptor signaling and / or inhibition of downstream signal transduction pathways represent methods for cancer treatment.

[0365] LPA and other phospholipids have been reported to stimulate ovarian cancer cell lines to express interleukin-8 (IL-8). In some embodiments, high IL-8 concentrations in ovarian cancer are associated with poor initial response to chemotherapy and poor prognosis, respectively. In animal models, the expression of IL-8 and other growth factors (such as vascular endothelial growth factor (VEGF)) is associated with enhanced tumorigenicity, ascites formation, angiogenesis and invasiveness of ovarian cancer cells. In some aspects, IL-8 is an important regulator of cancer progression, drug resistance and prognosis of ovarian cancer. In some embodiments, the compounds of formula (Ia) or (Ib) inhibit or reduce IL-8 expression in ovarian cancer cell lines.

[0366] In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat cancer. In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat malignant and benign proliferative diseases. In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to prevent or reduce tumor cell proliferation, carcinoma, invasion and metastasis of pleural mesothelioma (Yamada, Cancer Sci., 2008, 99 (8), 1603-1610) or peritoneal mesothelioma, cancer pain, bone metastasis (Boucharaba et al., J. Clin. Invest., 2004, 114 (12), 1714-1725; Boucharaba et al., Proc. Natl. acad. Sci., 2006, 103 (25) 9643-9648). In one aspect, a method of treating cancer in a mammal comprises administering to the mammal a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof and a second therapeutic agent, wherein the second therapeutic agent is an anticancer agent.

[0367] As used herein, the term "cancer" refers to an abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, tend to metastasize (spread). Cancer types include, but are not limited to, solid tumors (such as tumors of the bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma)) or blood tumors (such as leukemia) at any stage of the disease, with or without metastasis.

[0368] Other non-limiting examples of cancer include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoma, ependymoma, esophageal cancer, Ewing's sarcoma, sarcoma) family of tumors, eye cancer, retinoblastoma, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom's macroglobulinemia ( macroglobulinemia), medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low-grade malignant potential tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pinealoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasmacytoma / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family of tumors, sarcoma, Kaposi's sarcoma, Sézary syndrome syndrome), skin cancer, small cell lung cancer, small intestinal cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms tumor.

[0369] Increased concentrations of LPA and vesicles in the ascites and breast cancer effusions of ovarian cancer patients suggest that they may be early diagnostic markers, prognostic indicators, or indicators of response to therapy (Mills et al., Nat. Rev. Cancer., 3, 582-591, 2003; Sutphen et al., Cancer Epidemiol. Biomarkers Prev. 13, 1185-1191, 2004). The LPA concentration in ascites samples was consistently higher than that in matched plasma samples.

[0370] Respiratory and allergic diseases

[0371] In one aspect, LPA is a contributor to the pathogenesis of respiratory diseases. In one aspect, respiratory diseases are asthma. The pro-inflammatory effects of LPA include mast cell degranulation, smooth muscle cell contraction, and dendritic cell release of cytokines. Airway smooth muscle cells, epithelial cells, and lung fibroblasts all show responses to LPA. LPA induces human bronchial epithelial cells to secrete IL8. Increased IL-8 concentrations were found in BAL fluids from patients with asthma, chronic obstructive pulmonary disease, pulmonary sarcoidosis, and acute respiratory distress syndrome, and IL-8 has been shown to aggravate respiratory inflammation and airway remodeling in asthmatic patients. LPA1, LPA2, and LPA3 receptors have all been shown to contribute to LPA-induced IL-8 production. Studies cloning multiple GPCRs activated by LPA have demonstrated the presence of LPA1, LPA2, and LPA3 mRNA in the lungs (JJAContos et al., Mol.Pharmacol.58,1188-1196,2000).

[0372] The activation of platelet-released LPA at the site of injury and its ability to promote fibroblast proliferation and contraction characterize LPA as a wound repair mediator. In the context of respiratory diseases, asthma is an inflammatory condition in which inappropriate airway "repair" processes cause structural "remodeling" of the airways. In asthma, cells of the airways undergo ongoing damage due to a variety of insults, including allergens, pollutants, other inhaled environmental agents, bacteria, and viruses, leading to the chronic inflammation that characterizes asthma.

[0373] In one aspect, in asthmatic individuals, the release of normal repair mediators (including LPA) is increased or the effect of repair mediators is inappropriately prolonged, resulting in inappropriate airway remodeling. The main structural features of the remodeled airways observed in asthma include thickening of the reticular layer (basement membrane-like structure is located just below the respiratory epithelial cells), increase in the number and activation of myofibroblast fibroblasts, thickening of the smooth muscle layer, increase in the number of mucus glands and mucus secretions, and changes in connective tissue and capillary beds in the entire respiratory wall. In one aspect, LPA contributes to these structural changes in the respiratory tract. In one aspect, LPA is related to acute airway hyperresponsiveness in asthma. The lumen of the remodeled asthmatic airways is narrower due to thickening of the respiratory wall, so the air flow is reduced. In one aspect, LPA contributes to long-term structural remodeling and acute overreaction of the asthmatic airways. In one aspect, LPA causes overreaction, which is the initial feature of acute exacerbation of asthma.

[0374] In addition to LPA-mediated cellular responses, several LPA signaling pathway components that lead to these responses are associated with asthma. EGF receptor upregulation is induced by LPA and is also found in asthmatic airways (M. Amishima et al., Am. J. Respir. Crit. Care Med. 157, 1907-1912, 1998). Chronic inflammation is a contributor to asthma, and several transcription factors activated by LPA are known to be involved in inflammation (Ediger et al., Eur Respir J 21: 759-769, 2003).

[0375] In one aspect, LPA stimulates fibroblast proliferation and contraction and extracellular matrix secretion, leading to fibroproliferative features of other respiratory diseases, such as peribronchiolar fibrosis present in chronic bronchitis, emphysema, and interstitial lung disease. Emphysema is also associated with mild fibrosis of the alveolar walls, a feature believed to represent an attempt to repair alveolar damage. In another aspect, LPA plays a role in fibrotic interstitial lung disease and bronchiolitis obliterans, in which collagen and myofibroblasts are increased. In another aspect, LPA is involved in several of the various syndromes that constitute chronic obstructive pulmonary disease.

[0376] In vivo administration of LPA induces airway hyperreactivity, itch scratching reaction, infiltration and activation of eosinophils and neutrophils, vascular remodeling and pain flexor reaction. LPA also induces histamine release from mouse and rat mast cells. In acute allergic reactions, histamine induces various reactions, such as smooth muscle contraction, plasma exudation and mucus production. Plasma exudation is important in the respiratory tract because leakage and subsequent airway wall edema lead to the development of airway hyperreactivity. Plasma exudation progresses to conjunctival swelling in ocular allergic conditions and to nasal obstruction in allergic rhinitis (Hashimoto et al., J Pharmacol Sci 100, 82-87, 2006). In one aspect, LPA-induced plasma exudation is mediated by one or more LPA receptors, by the release of histamine by mast cells. In one aspect, LPA receptors include LPA1 and / or LPA3. In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat various allergic conditions in mammals. In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat a respiratory disease, disorder or condition in a mammal. In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat asthma in a mammal. In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat chronic asthma in a mammal.

[0377] As used herein, the term "respiratory disease" refers to diseases that affect organs involved in breathing, such as the nose, pharynx, larynx, Eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal muscles) and nerves. Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and 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, childhood-onset asthma, adult-onset asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and / or airway inflammation and cystic fibrosis, and hypoxia.

[0378] As used herein, the term "asthma" refers to any disorder of the lungs characterized by changes in pulmonary airflow associated with airway constriction due to any cause (intrinsic, exogenous, or both; allergic or non-allergic). The term asthma may be used with one or more adjectives to indicate the cause.

[0379] In one aspect, provided herein is a use of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for treating or preventing chronic obstructive pulmonary disease in a mammal, comprising administering to the mammal an effective amount of at least one compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof at least once. In addition, chronic obstructive pulmonary disease includes (but is not limited to) chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or respiratory inflammation, and cystic fibrosis.

[0380] Nervous system

[0381] The nervous system is the major locus of LPA1 expression; it is regulated spatially and temporally throughout brain development. In mammals, oligodendritic glial cells (myelin-producing cells in the central nervous system (CNS)) express LPA1. In addition, Schwann cells (myelin-producing cells of the peripheral nervous system) also express LPA1, which is involved in regulating Schwann cell survival and morphology. These observations identify an important function for receptor-mediated LPA signaling in neurogenesis, cell survival, and myelination.

[0382] Exposure of peripheral nervous system cell lines to LPA causes rapid contraction of their processes, resulting in cell rounding, which is mediated in part by polymerization of the actin cytoskeleton. In one aspect, LPA causes neuronal degeneration under pathological conditions when the blood-brain barrier is damaged and serum components leak into the brain (Moolenaar, Curr. Opin. Cell Biol. 7: 203-10, 1995). Immortalized CNS neuroblast cell lines from the cerebral cortex also exhibit contractile responses to LPA exposure through Rho activation and myofibrotin interaction. In one aspect, LPA is associated with post-ischemic neural damage (J. Neurochem. 61, 340, 1993; J. Neurochem., 70: 66, 1998).

[0383] In one aspect, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is provided that is useful for treating or preventing a nervous system disorder in a mammal. As used herein, the term "nervous system disorder" refers to conditions that alter the structure or function of the brain, spinal cord, or peripheral nervous system, including but not limited to Alzheimer's Disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's Disease, those diseases found after blunt or surgical trauma (including postoperative cognitive dysfunction and spinal cord or brainstem injury), and neurological disorders such as degenerative disc disease and sciatica.

[0384] In one aspect, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is provided for use in treating or preventing a CNS disorder in a mammal. CNS disorders include, but are not limited to, multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, postoperative cognitive dysfunction, migraine, peripheral neuropathy / neuralgia, spinal cord injury, cerebral edema, and head injury.

[0385] Cardiovascular disease

[0386] The cardiovascular phenotype observed after targeted deletion of lysophospholipid receptors reveals the important role of lysophospholipid signaling in vascular development and maturation, atherosclerotic plaque formation, and heart rate maintenance (Ishii, I. et al., Annu. Rev. Biochem. 73, 321-354, 2004). Angiogenesis (the formation of new capillary networks from pre-existing vascular structures) is often enabled in wound healing, tissue growth, and myocardial angiogenesis after ischemic injury. Peptide growth factors (e.g., vascular endothelial growth factor (VEGF)) and lysophospholipids control the coordinated proliferation, migration, adhesion, differentiation, and assembly of vascular endothelial cells (VECs) and surrounding vascular smooth muscle cells (VSMCs). In one aspect, dysregulation of the process mediating angiogenesis causes atherosclerosis, hypertension, tumor growth, rheumatoid arthritis, and diabetic retinopathy (Osborne, N. and Stainier, DY Annu. Rev. Physiol. 65, 23-43, 2003).

[0387] Downstream signal transduction pathways caused by lysophospholipid receptors include Rac-dependent lamellar protrusion formation (e.g., LPA1) and Rho-dependent stress fiber formation (e.g., LPA1), which play an important role in cell migration and adhesion. Abnormal endothelial cell function can shift the balance from vasodilation to vasoconstriction and cause hypertension and vascular remodeling, which are risk factors for atherosclerosis (Maguire, JJ et al., Trends Pharmacol. Sci. 26, 448-454, 2005).

[0388] In addition to its overall progression, LPA also contributes to the early (barrier dysfunction and monocyte adhesion to the endothelium) and late stages (platelet activation and intra-arterial thrombosis) of atherosclerosis. In the early stages, LPA from many sources accumulates in lesions and activates its cognate GPCRs (LPA1 and LPA3) expressed on platelets (Siess, W. Biochim. Biophys. Acta 1582, 204-215, 2002; Rother, E. et al., Circulation 108, 741-747, 2003). This triggers platelet shape changes and aggregation, leading to intra-arterial thrombosis and potential myocardial infarction and stroke. LPA can also be a mitogen and motility factor for VSMCs and an activating factor for endothelial cells and macrophages to support its atherogenic activity. In one aspect, mammals with cardiovascular disease benefit from LPA receptor antagonists that prevent thrombus and neointimal plaque formation.

[0389] In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat or prevent cardiovascular disease in a mammal.

[0390] As used herein, the term "cardiovascular disease" refers to diseases that affect the heart, blood vessels, or both, including (but not limited to): arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; heart rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral occlusive arterial disease of a limb, organ, or tissue; reperfusion injury following ischemia of the brain, heart, or other organs or tissues; endotoxin, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities, inflammation, and dysfunction limited to a single organ or tissue.

[0391] In one aspect, provided herein is a method for preventing or treating vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke, comprising administering to the mammal an effective amount of at least one compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or medicament comprising a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, at least once.

[0392] In one aspect, provided herein is a method for reducing cardiac reperfusion injury after myocardial ischemia and / or endotoxin shock, comprising administering to the mammal at least once an effective amount of at least one compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0393] In one aspect, provided herein are methods for reducing vasoconstriction in a mammal, comprising administering to the mammal at least once an effective amount of at least one compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0394] In one aspect, provided herein is a method for reducing or preventing elevated blood pressure in a mammal, comprising administering to the mammal at least once an effective amount of at least one compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0395] Inflammation

[0396] LPA has been shown to regulate immune responses by regulating the activity / function of immune cells such as T / B lymphocytes and macrophages. In activated T cells, LPA activates IL-2 production / cell proliferation through LPA1 (Gardell et al., TRENDS in Molecular Medicine Vol. 12, No. 2, February 2006). LPA-induced expression of inflammatory response genes is mediated by LPA1 and LPA3 (Biochem Biophys Res Commun. 363 (4): 1001-8, 2007). In addition, LPA regulates the chemotaxis of inflammatory cells (Biochem Biophys Res Commun., 1993, 15; 193 (2), 497). It is known that immune cells respond to LPA for proliferation and cytokine secretion activity (J.Immunol.1999,162,2049), platelet aggregation activity in response to LPA, monocyte migration acceleration activity, NF-κB activation in fibroblasts, enhanced binding of fibronectin to the cell surface, and the like. Therefore, LPA is associated with various inflammatory / immune diseases.

[0397] In one aspect, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to treat or prevent inflammation in a mammal. In one aspect, an antagonist of LPA1 and / or LPA3 is used to treat or prevent inflammation / immune disorders in a mammal. In one aspect, an LPA1 antagonist is a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0398] Examples of inflammatory / immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic or xenogeneic transplant (organ, bone marrow, stem cells and other cells and tissues) transplant rejection, graft-versus-host disease, lupus erythematosus, inflammation, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, 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.

[0399] Other diseases, illnesses or conditions

[0400] According to one aspect, a method for treating, preventing, reversing, stopping or slowing the progression of an LPA-dependent or LPA-mediated disease or condition (once it becomes clinically apparent) or treating symptoms associated with or related to an LPA-dependent or LPA-mediated disease or condition, by administering to a mammal a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject already has an LPA-dependent or LPA-mediated disease or condition at the time of administration, or is at risk of developing an LPA-dependent or LPA-mediated disease or condition.

[0401] In certain aspects, LPA1 activity in a mammal is modulated directly or indirectly by administering a therapeutically effective amount of at least one compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof (at least once). Such modulation includes, but is not limited to, reducing and / or inhibiting LPA1 activity. In other aspects, LPA activity in a mammal is modulated directly or indirectly (including reducing and / or inhibiting) by administering a therapeutically effective amount of at least one compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof (at least once). Such modulation includes, but is not limited to, reducing and / or inhibiting the amount and / or activity of an LPA receptor. In one aspect, the LPA receptor is LPA1.

[0402] In one aspect, LPA has a contractile effect on bladder smooth muscle cells isolated from the bladder and promotes the growth of prostate-derived epithelial cells (J. Urology, 1999, 162, 1779-1784; J. Urology, 2000, 163, 1027-1032). In another aspect, LPA contracts the urinary tract and prostate in vitro and increases intraurethral pressure in vivo (WO 02 / 062389).

[0403] In certain aspects, a method for preventing or treating the recruitment of eosinophils and / or basophils and / or dendritic cells and / or neutrophils and / or monocytes and / or T cells comprises administering to a mammal an effective amount of at least one compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof at least once.

[0404] In certain aspects, a method for treating cystitis (including, for example, interstitial cystitis) comprises administering to the mammal at least once a therapeutically effective amount of at least one compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0405] According to one aspect, the methods described herein include diagnosing or determining whether a patient has an LPA-dependent or LPA-mediated disease or condition by administering to the subject a therapeutically effective amount of a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof and determining whether the patient responds to the treatment.

[0406] In one aspect, provided herein are compounds of Formula (Ia) or (Ib), pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, which are LPA1 antagonists and are useful for treating patients with one or more LPA-dependent or LPA-mediated conditions or diseases, including but not limited to pulmonary fibrosis, renal fibrosis, liver fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, arthritis, allergies, psoriasis, inflammatory 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 in which an absolute or relative excess of LPA is present and / or observed.

[0407] In any of the foregoing aspects, 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, pulmonary or pleural fibrosis, peritoneal fibrosis, arthritis, allergies, cancer, cardiovascular disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, and cancer.

[0408] In one aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is used to improve decreased corneal sensitivity caused by corneal surgery (such as laser-assisted in situ keratoplasty (LASIK) or cataract surgery), decreased corneal sensitivity caused by corneal degeneration, and dry eye symptoms caused thereby.

[0409] In one aspect, provided herein is a use of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for treating or preventing ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis and papillary conjunctivitis in a mammal, comprising administering to the mammal an effective amount of at least one compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof at least once.

[0410] In one aspect, provided herein is a use of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for treating or preventing Sjögren's disease or inflammation associated with dry eye in a mammal, comprising administering to the mammal an effective amount of at least one compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof at least once.

[0411] In one aspect, LPA and LPA receptors (e.g., LPA1) are involved in the pathogenesis of osteoarthritis (Kotani et al., Hum. Mol. Genet., 2008, 17, 1790-1797). In one aspect, provided herein is a use of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for treating or preventing osteoarthritis in a mammal, comprising administering to the mammal an effective amount of at least one compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof at least once.

[0412] In one aspect, LPA receptors (e.g., LPA1, LPA3) contribute to the pathogenesis of rheumatoid arthritis (Zhao et al., Mol. Pharmacol., 2008, 73(2), 587-600). In one aspect, provided herein is a method for treating or preventing rheumatoid arthritis in a mammal using a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, comprising administering to the mammal an effective amount of at least one compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof at least once.

[0413] In one aspect, LPA receptors (e.g., LPA1) contribute to adipogenesis. (Simon et al., J. Biol. Chem., 2005, Vol. 280, No. 15, p. 14656). In one aspect, provided herein is a use of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for promoting adipose tissue formation in a mammal, comprising administering to the mammal an effective amount of at least one compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof at least once.

[0414] a. In vitro analysis

[0415] The effectiveness of the compounds of the invention as LPA1 inhibitors can be determined in an LPA1 functional antagonist assay as follows:

[0416] Chinese hamster ovary cells overexpressing human LPA1 were plated overnight (15,000 cells / well) in DMEM / F12 medium (Gibco, catalog number 11039) in poly-D-lysine coated 384-well microplates (Greiner bio-one, catalog number 781946). After overnight culture, cells were loaded with calcium indicator dye (AAT Bioquest Inc, catalog number 34601) at 37°C for 30 minutes. Cells were then equilibrated to room temperature for 30 minutes before analysis. Test compounds dissolved in DMSO were transferred to a 384-well non-binding surface plate (Corning, catalog number 3575) using a Labcyte Echo sonic dispenser and diluted to a final concentration of 0.5% DMSO with assay buffer [1X HBSS with calcium / magnesium (Gibco catalog number 14025-092), 20 mM HEPES (Gibco catalog number 15630-080), and 0.1% fatty acid-free BSA (Sigma catalog number A9205)]. Diluted compounds were added to cells via FDSS6000 (Hamamatsu) at final concentrations ranging from 0.08 nM to 5 μM and then incubated at room temperature for 20 minutes, at which time LPA (Avanti Polar Lipids catalog number 857130C) was added at a final concentration of 10 nM to stimulate the cells. Compound IC 50 The IC value was defined as the concentration of test compound that inhibited the calcium flux induced by LPA alone by 50%. The IC was determined by fitting the data to a 4-parameter logistic equation (GraphPad Prism, San Diego CA). 50 value.

[0417] b. In vivo analysis

[0418] LPA challenge and plasma histamine assessment.

[0419] Compounds were orally administered to CD-1 female mice 2 hours prior to LPA challenge. Mice were then administered 0.15 mL of 0.1% BSA / PBS (2 μg / μL) containing LPA via the tail vein (IV). Exactly 2 minutes after LPA challenge, mice were euthanized by decapitation and trunk blood was collected. These samples were centrifuged together and individual 75 μL samples were frozen at -20°C until histamine analysis.

[0420] Plasma histamine analysis was performed by standard EIA (enzyme immunoassay) methods. Plasma samples were thawed and diluted 1:30 in PBS containing 0.1% BSA. The EIA protocol for histamine analysis was followed as outlined by the manufacturer (Histamine EIA, Oxford Biomedical Research, EA#31).

[0421] The LPA used in the analysis was prepared as follows: LPA (1-oleoyl-2-hydroxy-sn-glycero-3-phosphate (sodium salt), 857130P, Avanti Polar Lipids) was prepared at a total concentration of 2 μg / μL in 0.1% BSA / PBS. 13 mg of LPA was weighed and 6.5 mL of 0.1% BSA was added, vortexed and sonicated for about 1 hour until a clear solution was obtained.

[0422] V. Pharmaceutical compositions, preparations and combinations

[0423] In some embodiments, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable inactive ingredient.

[0424] In some embodiments, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically 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, ocular administration or ear administration. In some embodiments, the pharmaceutical 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.

[0425] In some embodiments, the pharmaceutical composition further comprises one or more other therapeutically active agents selected from the group consisting of corticosteroids (e.g., dexamethasone or fluticasone), immunosuppressants (e.g., tacrolimus and pimecrolimus), analgesics, anticancer agents, anti-inflammatory agents, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists (e.g., montelukast or zafirlukast), leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A2 inhibitors, and lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, decongestants, antihistamines (e.g., loratidine), mucolytics, anticholinergics, antitussives, expectorants, anti-infectives (e.g., fusidic acid), acid, especially for the treatment of atopic dermatitis), antifungal agents (e.g., clotriazole, especially for atopic dermatitis), anti-IgE antibody therapy (e.g., omalizumab), beta-2 adrenergic agonists (e.g., albuterol or salmeterol), other PGD2 antagonists acting at other receptors (such as DP antagonists), PDE4 inhibitors (e.g., cilomilast), drugs that modulate cytokine production (e.g., TACE inhibitors), drugs that modulate the activity of the Th2 cytokines IL-4 and IL-5 (e.g., blocking monoclonal antibodies and soluble receptors), PPARγ agonists (e.g., rosiglitazone and pioglitazone), 5-lipoxygenase inhibitors (e.g., zileuton).

[0426] In some embodiments, the pharmaceutical composition further comprises one or more other anti-fibrotic agents selected from the group consisting of pirfenidone, nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferon alpha, lecithinized superoxide dismutase, simtuzumab, tanzisertib, tralokinumab, hu3G9, AM-152, IFN-γ-1b, IW-001, PRM-151, PXS-25, pentoxifylline / N-acetyl-cysteine, pentoxifylline / vitamin E, salbutamol sulfate, sulfate), [Sar9,Met(O2)11]-substance P, pentoxifylline, mercaptamine bitartrate, obeticholic acid, aramchol, GFT-505, icosapentaenoic acid ethyl ester, metformin, metreleptin, muromonab-CD3, oltipraz, IMM-124-E, MK-4074, PX-102, RO-5093151. In some embodiments, a method is provided comprising administering a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof to a human suffering from an LPA-dependent or LPA-mediated disease or condition. In some embodiments, the human has been administered one or more other therapeutically active agents in addition to a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering one or more additional therapeutically active agents in addition to the compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0427] In some embodiments, the one or more other therapeutically active agents other than a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof are selected from the group consisting of: corticosteroids (e.g., dexamethasone or fluticasone), immunosuppressants (e.g., tacrolimus and pimecrolimus), analgesics, anticancer agents, anti-inflammatory agents, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists (e.g., montelukast or zafirlukast), leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A2 inhibitors and lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, decongestants, antihistamines (e.g., loratadine), mucolytics, anticholinergics, antitussives , expectorants, anti-infectives (e.g., fusidic acid, especially for the treatment of atopic dermatitis), antifungals (e.g., clotrimazole, especially for atopic dermatitis), anti-IgE antibody therapy (e.g., omalizumab), beta-2 adrenergic agonists (e.g., salbutamol or salmeterol), other PGD2 antagonists acting at other receptors (such as DP antagonists), PDE4 inhibitors (e.g., cilomilast), drugs that modulate cytokine production (e.g., TACE inhibitors), drugs that modulate the activity of Th2 cytokines IL-4 and IL-5 (e.g., blocking monoclonal antibodies and soluble receptors), PPARγ agonists (e.g., rosiglitazone and pioglitazone), 5-lipoxygenase inhibitors (e.g., zileuton).

[0428] In some embodiments, the one or more other therapeutically active agents other than the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof are other anti-fibrotic agents selected from the group consisting of pirfenidone, nintedanib, thalidomide, carumab, FG-3019, fusofumab, interferon α, lecithinized superoxide dismutase, simtuzumab, tanzesterti, talokinasumab, hu3G9, AM-152, IFN-γ-1b, IW-001, PRM-151 , PXS-25, pentoxifylline / N-acetyl-cysteine, pentoxifylline / vitamin E, salbutamol sulfate, [Sar9,Met(O2)11]-substance P, pentoxifylline, thioethylamine bitartrate, obeticholic acid, alemirod, GFT-505, eicosapent ethyl, metformin, metreleptin, muromonab-CD3, oltipraz, IMM-124-E, MK-4074, PX-102, RO-5093151.

[0429] In some embodiments, the one or more other therapeutically active agents other than a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof are selected from ACE inhibitors, ramipril, AII antagonists, irbesartan, antiarrhythmics, dronedarone, PPARα activators, PPARγ activators, pioglitazone, rosiglitazone, prostaglandins, endothelin receptor antagonists, elastase inhibitors, calcium antagonists, beta blockers, diuretics, aldosterone receptor antagonists, eplerenone, renin inhibitors, Rho kinase inhibitors, soluble guanylate cyclase (sGC) activators, sGC sensitizers, PDE inhibitors, PDE5 inhibitors, NO donors, digitalis drugs, ACE / NEP inhibitors, statins, bile acid reabsorption inhibitors, PDGF antagonists, vasopressin antagonists, drainage diuretics, NHE1 inhibitors, factor Xa antagonists, factor XIIIa antagonists, anticoagulants, antithrombotic agents, platelet inhibitors, profibrotic agents, thrombin-activatable fibrinolysis inhibitor (TAFI), PAI-1 inhibitors, coumarins, heparin, thrombin antagonists, serotonin antagonists, COX inhibitors, aspirin, therapeutic antibodies, GPIIb / IIIa antagonists, ER antagonists, SERMs, tyrosine kinase inhibitors, RAF kinase inhibitors, p38 MAPK inhibitors, pirfenidone, multikinase inhibitors, nintedanib, sorafenib.

[0430] In some embodiments, one or more other therapeutically active agents other than a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof are selected from Gremlin-1 mAb, PA1-1 mAb, Promedior (PRM-151; recombinant human pentraxin-2); FGF21, TGFβ antagonists, αvβ6 and αvβpan antagonists; FAK inhibitors, TG2 inhibitors, LOXL2 inhibitors, NOX4 inhibitors, MGAT2 inhibitors, GPR120 agonists.

[0431] The pharmaceutical preparations described herein can be administered to a subject in a variety of ways by a variety of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, or transdermal administration routes. The pharmaceutical preparations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, extended release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and immediate and controlled release mixed formulations.

[0432] In some embodiments, the compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is administered orally.

[0433] In some embodiments, the compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salt is topically administered. In such embodiments, the compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salt is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, coatings, medicated sticks, medicated bandages, balms, creams or ointments. Such pharmaceutical compositions may contain solubilizers, stabilizers, tension enhancers, buffers and preservatives. In one aspect, the compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salt is topically administered to the skin.

[0434] In another aspect, the compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is administered by inhalation. In one embodiment, the compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is administered by inhalation directly targeting the pulmonary system.

[0435] In another aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is formulated for intranasal administration. Such formulations include nasal sprays, nasal atomizers, and the like.

[0436] In another aspect, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is formulated as eye drops.

[0437] Another aspect is the use of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating a disease, disorder, or condition, wherein the activity of at least one LPA receptor leads to the pathology and / or symptoms of the disease or condition. In one embodiment of this aspect, the LPA is selected from LPA1, LPA2, LPA3, LPA4, LPA5, and LPA6. In one aspect, the LPA receptor is LPA1. In one aspect, the disease or condition is any disease or condition specified herein.

[0438] Any of the foregoing aspects are further embodiments, wherein: (a) an effective amount of a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is administered systemically to a mammal; and / or (b) an effective amount of the compound is administered orally to a mammal; and / or (c) an effective amount of the compound is administered intravenously to a mammal; and / or (d) an effective amount of the compound is administered by inhalation; and / or (e) an effective amount of the compound is administered by nasal administration; or and / or (f) an effective amount of the compound is administered to a mammal by injection; and / or (g) an effective amount of the compound is administered topically to a mammal; and / or (h) an effective amount of the compound is administered by ocular administration; and / or (i) an effective amount of the compound is administered rectally to a mammal; and / or (j) an effective amount is administered non-systemically or topically to a mammal.

[0439] Any of the foregoing aspects are other embodiments comprising a single administration of an effective amount of the compound, including other embodiments wherein the compound is administered (i) once; (ii) multiple times during a day to a mammal; (iii) constantly; or (iv) continuously.

[0440] Any of the foregoing aspects are other embodiments comprising multiple administrations of an effective amount of a compound, including other embodiments wherein (i) the compound is administered continuously or intermittently, such as in a single dose; (ii) the interval between multiple administrations is every 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to a mammal every 12 hours; (v) the compound is administered to a mammal every 24 hours. In other or alternative embodiments, the method includes a drug holiday, wherein administration of the compound is suspended or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the drug holiday is 2 days to 1 year in length.

[0441] Also provided is a method for inhibiting the physiological activity of LPA in a mammal, which comprises administering a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

[0442] In one aspect, provided is a medicament for treating an LPA-dependent or LPA-mediated disease or condition in a mammal, comprising a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0443] In some cases, disclosed herein is the use of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating an LPA-dependent or LPA-mediated disease or condition.

[0444] In some cases, disclosed herein is the use of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for treating or preventing an LPA-dependent or LPA-mediated disease or condition.

[0445] In one aspect, is a method for treating or preventing an LPA-dependent or LPA-mediated disease or condition in a mammal, comprising administering a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0446] In one aspect, LPA-dependent or LPA-mediated diseases or conditions include, but are not limited to, organ or tissue fibrosis, scarring, liver disease, dermatological conditions, cancer, cardiovascular disease, respiratory diseases or conditions, inflammation, gastrointestinal diseases, kidney disease, urinary tract related diseases, inflammation of the lower urinary tract, dysuria, frequent urination, pancreatic disease, arterial blockage, cerebral infarction, cerebral hemorrhage, pain, peripheral neuropathy, and muscle fiber pain.

[0447] In one aspect, the LPA-dependent or LPA-mediated disease or condition is a respiratory disease or condition. In some embodiments, the respiratory disease or condition is asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, or acute respiratory distress syndrome.

[0448] In some embodiments, the LPA-dependent or LPA-mediated disease or condition is selected from idiopathic pulmonary fibrosis; cystic fibrosis; other diffuse parenchymal lung diseases of different etiologies, including iatrogenic drug-induced fibrosis, occupational and / or environmentally induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, pulmonary alveolar proteinosis, Langerhans cell granulomatosis, pulmonary lymphangioleiomyomatosis, genetic diseases (Hermansky-Pudlak syndrome, Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, 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); renal fibrosis; tubulointerstitial fibrosis; glomerulonephritis; focal segmental glomerulosclerosis; IgA nephropathy; hypertension; Alport; intestinal fibrosis; hepatic fibrosis; cirrhosis; alcohol-induced hepatic fibrosis; toxic / drug-induced hepatic fibrosis; hemochromatosis; nonalcoholic steatosis hepatitis (NASH); biliary injury; primary biliary cirrhosis; infection-induced hepatic fibrosis; virus-induced hepatic fibrosis; and autoimmune hepatitis; corneal scarring; hypertrophic scarring; Dupuytren's disease disease), keloids, skin fibrosis; cutaneous scleroderma; spinal cord injury / fibrosis; myelofibrosis; vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease, chronic lymphocytic leukemia, tumor metastasis, transplant rejection, endometriosis, neonatal respiratory distress syndrome, and neuralgia.

[0449] In one aspect, described herein are LPA-dependent or LPA-mediated diseases or conditions.

[0450] In one aspect, a method for treating or preventing organ fibrosis in a mammal is provided, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0451] In one aspect, the organ fibrosis comprises lung fibrosis, kidney fibrosis or liver fibrosis.

[0452] In one aspect, a method of improving lung function in a mammal is provided, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. In one aspect, the mammal has been diagnosed with pulmonary fibrosis.

[0453] In one aspect, the compounds disclosed herein are used to treat idiopathic pulmonary fibrosis (common interstitial pneumonia) in a mammal.

[0454] In some embodiments, the compounds disclosed herein are used to treat diffuse parenchymal interstitial lung disease in a mammal: iatrogenic drug-induced, occupational / environmental (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases (scleroderma and others), pulmonary alveolar proteinosis, Langerhans cell granulomatosis, pulmonary lymphangioleiomyomatosis, Hermansky-Präk syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease.

[0455] In some embodiments, the compounds disclosed herein are used to treat post-transplant fibrosis associated with chronic rejection in mammals: bronchiolitis obliterans of lung transplantation.

[0456] In some embodiments, the compounds disclosed herein are used to treat skin fibrosis in a mammal: scleroderma, Dupuytren's disease, keloids.

[0457] In one aspect, the compounds disclosed herein are used to treat liver fibrosis with or without cirrhosis in a mammal: toxic / drug-induced (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, hepatitis C virus, HCV), non-alcoholic liver disease (NAFLD, NASH), metabolic and autoimmune diseases.

[0458] In one aspect, the compounds disclosed herein are used to treat renal fibrosis: tubulointerstitial fibrosis, glomerulosclerosis in a mammal.

[0459] In any of the foregoing aspects relating to the treatment of LPA-dependent diseases or conditions, are other embodiments comprising administering at least one other agent in addition to a compound having a structure of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. In various embodiments, the agents are administered in any order, including simultaneously.

[0460] In any of the embodiments disclosed herein, the mammal is a human.

[0461] In some embodiments, the compounds provided herein are administered to humans.

[0462] In some embodiments, the compounds provided herein are administered orally.

[0463] In some embodiments, the compounds provided herein are used as antagonists of at least one LPA receptor. In some embodiments, the compounds provided herein are used to inhibit the activity of at least one LPA receptor or to treat a disease or condition that would benefit from inhibiting the activity of at least one LPA receptor. In one aspect, the LPA receptor is LPA1.

[0464] In other embodiments, the compounds provided herein are used in the formulation of a medicament for inhibiting LPA1 activity.

[0465] An article of manufacture is provided comprising packaging material, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof within the packaging material, and a label indicating that the compound or composition or a pharmaceutically acceptable salt, tautomer, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate thereof is used to inhibit the activity of at least one LPA receptor or to treat, prevent or alleviate one or more symptoms of a disease or condition that would benefit from inhibiting the activity of at least one LPA receptor.

[0466] VI. General Synthesis, Including Schemes

[0467] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the following methods and synthetic methods known in the art of organic synthetic chemistry or variations thereof as known to those skilled in the art. Preferred methods include (but are not limited to) the following methods. The reaction is carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for achieving the transformation. It should be understood by those skilled in the art of organic synthesis that the functional groups present on the molecule should be consistent with the proposed transformation. Sometimes, this requires judgment to modify the order of synthetic steps or to select a particular method scheme rather than another to obtain the desired compound of the present invention.

[0468] It will also be appreciated that another major consideration in the planning of any synthetic route in the art is the careful selection of protecting groups for protecting reactive functional groups present in the compounds described herein. An authoritative description of a variety of alternatives for trained practitioners is Greene et al., (Protective Groups in Organic Synthesis, 4th edition, Wiley-Interscience (2006)).

[0469] Formula (Ia) or (Ib) compounds can be prepared by the exemplary methods described in the following schemes and working examples and the relevant open literature procedures used by those skilled in the art. Exemplary reagents and procedures for these reactions are presented below and in the working examples. The protection and removal of protecting groups in the following methods can be carried out by procedures generally known in the art (see, for example, Wuts, PGM, Greene's Protective Groups in Organic Synthesis, 5th edition, Wiley (2014)). General methods for organic synthesis and functional group transformations are found in: Trost, BM et al., eds., Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, NY (1991); Smith, MB et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. 7th ed., Wiley, New York, NY (2013); Katritzky, AR et al., eds., Comprehensive Organic Functional Group Transformations II, 2nd ed., Elsevier Science Inc., Tarrytown, NY (2004); Larock, RC, Comprehensive Organic Transformations, 2nd ed., Wiley-VCH, New York, NY (1999), and references therein.

[0470] Scheme 1 describes the synthesis of N-carbamoylisoxazole-aryloxycyclohexyl acids 15 and 16. 4-Halo (preferably bromo)phenyl or azine (e.g., pyridine)benzoic acid 1 is converted to the corresponding acid chloride (e.g., with SOCl2 or oxalyl chloride / catalytic amount of DMF). The acid chloride intermediate is reacted with the appropriate β-enamine ester 2 and then condensed with hydroxylamine to give the corresponding 5-halo (hetero)aryl-isoxazole 4-carboxylate 3. Ester 3 is deprotected, and the resulting acid is reduced (e.g., directly with diborane; or by a two-step process in which the acid is reacted with an alkyl chloroformate and then reduced with, e.g., NaBH4 at low temperature), and the resulting alcohol is protected to give 5-halo (hetero)aryl-isoxazole protected alcohol 4. In the presence of an appropriate palladium catalyst, the reaction of bromoaryl-isoxazole or bromoheteroaryl-isoxazole 4 with pinacol diboronate (e.g. Ishiyama, T. et al., J. Org. Chem. 1995, 60, 7508-7510) provides the corresponding pinacol boronate ester 5, which is then oxidized with hydrogen peroxide to give the corresponding phenol or hydroxyheteroarene 6 (Fukumoto, S. et al., WO 2012137982). Under Mitsunobu reaction conditions, the reaction of phenol / hydroxyheteroarene 6 with 3-hydroxycyclohexyl ester 7 (Kumara Swamy, KC, Chem. Rev., 2009, 109, 2551-2651) gives the corresponding isoxazole cycloalkyl ether ester 8. Deprotection of hydroxymethylisoxazole 8 provides cyclohexyl ester isoxazole alcohol 9. Isoxazolol 9 is then reacted with PBr (or another mild brominating agent such as CBr / PhP) to afford the corresponding bromide 10. Displacement of isoxazole bromide 10 with NaN (or other azide equivalent reagent) affords isoxazole azide 11, which is reduced (e.g., Staudinger reduction with PhP / water) to afford isoxazole amine 12. Isoxazole amine 12 is reacted with an appropriate acylating agent 13 (e.g., chloroformate or 4-nitrophenyl carbonate) to afford cyclohexylisoxazole NH carbamate 14. Deprotection of cyclohexyl ester 14 affords NH-carbamoylmethylisoxazole-aryloxycyclohexyl acid 15. Cyclohexylisoxazole NH-carbamate 14, treated with an appropriate base (e.g., NaH), followed by reaction with an alkyl halide (R3X) affords isoxazole N,N-disubstituted cyclohexylcarbamate, which is then deprotected to afford N,N-dialkyl-carbamoylisoxazole-aryloxycyclohexyl acid 16.

[0471] Solution 1

[0472]

[0473]

[0474] Scheme 2 describes an alternative synthesis of N-carbamoylisoxazole-aryloxycyclohexyl acids 15 and 16. The haloisoxazole ester 17 is deprotected and the acid is reduced (e.g., by a two-step, one-pot reaction with an alkyl chloroformate followed by low-temperature reduction with NaBH4, or directly with diborane) to the corresponding alcohol, which is protected as the haloisoxazole alcohol 18. The 4-hydroxyaryl / heteroaryl halide 19 is subjected to Mitsunobu reaction with the 3-hydroxycyclohexyl ester 7 to afford the 4-haloaryloxycyclohexyl ester 20. This 4-haloaryloxy ester 20 is then converted to the corresponding 4-boronate-aryloxy ester 21 with pinacol diboronate in the presence of an appropriate palladium catalyst (e.g., Ishiyama, T. et al., J. Org. Chem. 1995, 60, 7508-7510; the boronate ester can also be converted to the corresponding boronic acid). The boronate ester 21 was then subjected to Suzuki-Miyaura coupling with the halogenated isoxazole 18 to afford the corresponding isoxazole-aryl / heteroaryloxycycloalkyl ester 8. The isoxazole ether 8 was then converted to the N-carbamoylisoxazole-aryloxycyclohexyl acids 15 and 16 by the same synthetic sequence as described in Scheme 1.

[0475] Solution 2

[0476]

[0477] Scheme 3 describes another alternative synthetic route to N-carbamoylisoxazole-aryloxycyclohexyl acids 15 and 16. Appropriately protected haloisoxazole alcohols 18 are metallated (e.g., with n-butyllithium) and reacted with a boronating agent B(OR)3 to provide isoxazole boronate esters 22. Isoxazole boronate esters 22 are then subjected to Suzuki-Miyaura coupling reaction with appropriate 4-hydroxyaryl / heteroaryl halides 23 to directly provide 4-haloaryl / heteroaryl-isoxazoles 6. Reaction of phenol / hydroxyheteroarene 6 with 3-hydroxycyclohexyl esters 7 under Mitsunobu reaction conditions provides the corresponding isoxazolyloxycycloalkyl esters 8, which are then reacted further through the same synthetic sequence as described in Scheme 1 to provide N-carbamoylisoxazole-aryloxycyclohexyl acids 15 and 16.

[0478] Solution 3

[0479]

[0480] Scheme 4 describes the synthesis of N-carbamoylisoxazole-aryloxycyclohexyl acids 15 and 16 via a synthetic route involving the initial preparation of a fully elaborated isoxazole N-carbamate intermediate. Isoxazole alcohol 18 is deprotected and then converted to the corresponding isoxazole amine 25 using the same three-step sequence described in Scheme 1 (from alcohol 9 to amine 12, by conversion to bromide with PBr3 or CBr4 / Ph3P, displacement of the bromide with NaN3, and reduction of the azide with Ph3P / water). Isoxazole amine 25 is reacted with an appropriate acylating agent 13 (e.g., chloroformate or 4-nitrophenyl carbonate) to afford isoxazole NH carbamate 26. The halogenated isoxazole carbamate 26 is then subjected to Suzuki-Miyaura cross-coupling reaction with appropriately substituted 4-hydroxy-aryl / heteroaryl boronate / boronic acid 27 to provide the corresponding hydroxyaryl / hydroxyheteroaryl isoxazole carbamate 28, which is then subjected to Mitsunobu reaction with 3-hydroxycyclohexyl ester 7 to provide the corresponding isoxazolyloxycycloalkyl ester 14. The isoxazole N-carbamate cycloalkyl ester 14 is then further reacted to provide N-carbamoylisoxazole-aryloxycyclohexyl acids 15 and 16 via the same synthetic sequence as described in Scheme 1.

[0481] Solution 4

[0482]

[0483] Scheme 5 describes the synthesis of isoxazole N-linked carbamate cyclohexyl acids 31 and 32. Cyclohexyl ether isoxazole alcohol 9 is oxidized to isoxazole carboxylic acid 29 (e.g., directly to the acid with pyridinium dichromate, or by a two-step process via the aldehyde [Swern oxidation or Dess-Martin periodinane followed by oxidation with NaClO2 to the acid, e.g., Lindgren, BO, Acta Chem. Scand. 1973, 27, 888]). 4 Curtius rearrangement of isoxazole acid 29 in the presence of -OH provides isoxazole NH-carbamate 30. Deprotection of isoxazole NH-carbamate cyclohexyl ester 30 provides isoxazole NH-carbamate cyclohexyl acid 31. Alternatively, isoxazole NH-carbamate cyclohexyl ester 30 is deprotonated with a suitable base and reacted with an alkyl R 3 Alkylation of the isoxazole N,N-dialkylcarbamate acid 32 was performed by alkylation of the isoxazole with a halide (as shown in Scheme 1).

[0484] Solution 5

[0485]

[0486] Scheme 6 describes the synthesis of N-ureido-isoxazole-aryloxycyclohexyl acids 35 and 37. Isoxazolamide 12 undergoes reaction with carbamoyl chloride 34 (e.g., prepared by reaction of secondary amine 33 with triphosgene) to give the corresponding ureido-isoxazole cyclohexyl ester, which is then deprotected to give N,N'-dialkyl-ureido-isoxazole-aryloxycyclohexyl acid 35. In a complementary synthetic route, isoxazolamide 13 undergoes direct reaction with triphosgene to give isoxazole carbamoyl chloride 36, which is reacted with primary amine R 3 -NH2 (or with secondary amine 33) to give (after ester deprotection) the corresponding N-alkyl-ureido-isoxazole aryloxycyclohexyl acid 37 (reacting with secondary amine to give N,N'-dialkylureido-isoxazole acid 35). Alternatively, isoxazole amine 12 can also be reacted with isocyanate R 3 Direct reaction of the NCO afforded N-alkyl-ureido-isoxazole cyclohexyl acid 37 after ester deprotection.

[0487] Solution 6

[0488]

[0489] Scheme 7 describes the isomeric carbamic acids (3-aryl-4H-1λ 3

[0063] The synthesis of 4-isoxazol-4-yl) esters 45. Appropriately substituted 4-halo (e.g., bromo) aryl / heteroaryl aldehydes 38 are reacted with hydroxylamine to give oximes 39, which are then chlorinated (e.g., with N-chlorosuccinimide) to provide imidoyl chlorides 40. Reaction of imidoyl chlorides 40 with acetoacetates 41 in the presence of a base provides isoxazole esters 42. Deprotection of isoxazole esters 42 followed by reduction of the isoxazole acid (either directly with diborane or by a two-step process of reduction of the corresponding carboxylic anhydride with NaBH4) and alcohol protection provides protected isoxazole alcohols 43, which are converted to the corresponding hydroxyaryl isoxazoles 44 by reaction with B2(pin)2 in a Pd-mediated reaction followed by H2O2 oxidation. Reaction of phenol / hydroxy-heteroarene 44 with 3-hydroxycyclohexyl ester 7 under Mitsunobu reaction conditions provides the corresponding isoxazole cyclohexyl ether ester 45, which is then further reacted according to the synthetic sequence described in Scheme 1 to give cyclohexylisoxazole NH-carbamate acid 46.

[0490] Solution 7

[0491]

[0492] VII. Examples

[0493] The following examples are provided as illustrative examples, as part of the scope and specific embodiments of the present invention, and are not intended to limit the scope of the present invention. Unless otherwise indicated, abbreviations and chemical symbols have their common and customary meanings. Unless otherwise indicated, the compounds described herein have been prepared, isolated and characterized using the schemes and other methods disclosed herein or can be prepared using them.

[0494] When appropriate, the reactions were carried out under an atmosphere of dry nitrogen (or argon). Solvents. Reagent grade or HPLC grade solvents were used in other reactions. Unless otherwise stated, all commercial reagents were used as received.

[0495] Microwave reactions were performed under microwave (2.5 GHz) irradiation in a microwave reaction vessel using a 400 W Biotage Initiator instrument.

[0496] HPLC / MS and preparative / analytical HPLC methods used in characterization or purification examples

[0497] Typically, NMR (nuclear magnetic resonance) spectra were obtained in the indicated solvents using Bruker or JEOL 400 MHz and 500 MHz instruments. All chemical shifts (ppm) are reported relative to tetramethylsilane using the solvent resonance as an internal standard. 1 HNMR spectral data are typically reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, sep = septet, m = multiplet, app = apparent), coupling constant (Hz) and integration.

[0498] Collected in d6-DMSO 1 In the examples of H NMR spectroscopy, a water suppression procedure is usually employed. This procedure effectively suppresses the water signal and any proton peaks in the same interval (usually between 3.30-3.65 ppm) that would affect the overall proton integration.

[0499] The term HPLC refers to a Shimadzu high performance liquid chromatography instrument that uses one of the following methods:

[0500] HPLC-1: Sunfire C18 column (4.6 x 150 mm) 3.5 μm, gradient from 10 to 100% B:A over 12 min, then hold at 100% B for 3 min.

[0501] Mobile phase A: water containing 0.05% TFA: CH3CN (95:5)

[0502] Mobile phase B: CH3CN:water (95:5) containing 0.05% TFA

[0503] TFA buffer pH=2.5; flow rate: 1 mL / min; wavelength: 254 nm, 220 nm.

[0504] HPLC-2: XBridge Phenyl (4.6 x 150 mm) 3.5 μm, gradient from 10 to 100% B:A over 12 min, then hold at 100% B for 3 min.

[0505] Mobile phase A: water containing 0.05% TFA: CH3CN (95:5)

[0506] Mobile phase B: CH3CN:water (95:5) containing 0.05% TFA

[0507] TFA buffer pH=2.5; flow rate: 1 mL / min; wavelength: 254 nm, 220 nm.

[0508] HPLC-3: Chiralpak AD-H, 4.6×250mm, 5μm.

[0509] Mobile phase: 30% EtOH-mobile phase (1:1) / 70% CO2

[0510] Flow rate = 40 mL / min, 100 bar, 35°C; Wavelength: 220 nm

[0511] HPLC-4: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-μm particles;

[0512] Mobile phase A: 5:95 CH3CN:water containing 10 mM NH4OAc;

[0513] Mobile phase B: 95:5 CH3CN:water containing 10 mM NH4OAc;

[0514] Temperature: 50°C; Gradient: 0-100% B over 3 min, then 0.75-min hold at 100% B; Flow rate: 1.11 mL / min; Detection: UV at 220 nm.

[0515] HPLC-5: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-μm particles;

[0516] Mobile phase A: 5:95 CH3CN:water containing 0.1% TFA;

[0517] Mobile phase B: 95:5 CH3CN:water containing 0.1% TFA;

[0518] Temperature: 50°C; Gradient: 0-100% B in 3 min, then 0.75-min hold at 100% B; Flow rate: 1.11 mL / min; Detection: UV at 220 nm.

[0519] Intermediate 1. Isopropyl (1S, 3S)-3-((6-(4-(aminomethyl)-3-methylisoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

[0520]

[0521] Intermediate 1A. (E)-tert-Butyl 2-(5-bromo-6-methylpicolinoyl)-3-(methylimino)butanoate

[0522]

[0523] Pyridine (13.75mL, 170mmol) was added dropwise to a suspension of 5-bromo-6-methylpicolinyl chloride (7.97g, 34mmol) and (E)-3-(methylimino)butyric acid tert-butyl ester (6.40g, 37.4mmol) in THF (100mL) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 16h, then distributed between EtOAc (100mL) and water (100mL). The aqueous phase was extracted with EtOAc (2x 100mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the crude title compound (13.0g, 104% yield) as a yellow oil. [M+H]+=369.2.

[0524] Intermediate 1B. tert-Butyl 5-(5-bromo-6-methylpyridin-2-yl)-3-methylisoxazole-4-carboxylate

[0525]

[0526] A mixture of intermediate 1A (12.55 g, 34 mmol) and NH2OH.HCl (3.54 g, 51.0 mmol) in EtOH (136 mL) was stirred at 60 ° C for 20 h and then cooled to room temperature. The volatiles were removed in vacuo. The residue was distributed between EtOAc (50 mL) and saturated Na2CO3 aqueous solution (50 mL) and water. The organic layer was washed with water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (750 g SiO2; a continuous gradient of 0% to 20% EtOAc / DCM over 10 min) to give the title compound (6.73 g, 19 mmol, 56% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ7.97 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 2.77 (s, 3H), 2.51 (s, 3H), 1.57 (s, 9H). ). LCMS, [M+H]+=352.9.

[0527] Intermediate 1C. 5-(5-bromo-6-methylpyridin-2-yl)-3-methylisoxazole-4-carboxylic acid

[0528]

[0529] TFA (20 mL) was added dropwise to a solution of intermediate 1B (3.0 g, 8.49 mmol) in DCM (40 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to give the title compound (2.52 g, 8.49 mmol, 100% yield) as a brown solid. 1 H NMR (500MHz, CDCl3) δ8.21 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 2.80 (s, 3H), 2.64 (s, 3H). LC-MS, [M+H]+=297.1.

[0530] Intermediate 1D. (5-(5-bromo-6-methylpyridin-2-yl)-3-methylisoxazol-4-yl)methanol

[0531]

[0532] 1M B H3.THF (21.2 mL, 21.2 mmol) in THF was added dropwise to a 0°C solution of intermediate 1C (2.52 g, 8.49 mmol) in THF (50 mL). After the addition was complete, the reaction was heated at 60°C for 2 h and then cooled to room temperature. The reaction mixture was quenched with HOAc (1 mL) and MeOH (10 mL). The mixture was stirred at room temperature for 30 min and then concentrated in vacuo. The crude product was chromatographed (80 g SiO2; a continuous gradient of 0 to 50% EtOAc / hexane over 20 min, kept at 50% EtOAc for 10 min) to give the title compound (1.45 g, 5.12 mmol, 60.3% yield) as a white solid. 1H NMR (500MHz, CDCl3) δ8.01(d,J=8.3Hz,1H),7.71(d,J=8.3Hz,1H),5.93(t,J=6.8Hz,1H),4.62(d,J=6.8Hz,2H),2.75(s,3H),2.36(s,3H). LC-MS, [M+H]+=283.1.

[0533] Intermediate 1E. 5-(5-Bromo-6-methylpyridin-2-yl)-3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole

[0534]

[0535] To a room temperature solution of intermediate 1D (1.45 g, 5.12 mmol) in DCM (30 mL) was added 3,4-dihydro-2H-pyran (1.17 mL, 12.8 mmol) and PPTS (64 mg, 0.26 mmol). The reaction was stirred at room temperature overnight, then quenched with saturated aqueous NaHCO3 and extracted twice with EtOAc. The combined organic extracts were washed with H2O, brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (120 g SiO2; a continuous gradient of 0-30% EtOAc / hexanes over 35 min) to give the title compound (1.4 g, 74% yield) as a white solid. 1 H NMR(500MHz, CDCl3)δ7.90(d,J=8.3Hz,1H),7.59(d,J=8.3Hz,1H),5.09–4.94(m,2H),4.75(t,J=3.6Hz, 1H), 3.91 (ddd, J=11.6, 8.6, 3.1Hz, 1H), 3.58–3.46 (m, 1H), 2.70 (s, 3H), 2.41 (s, 3H), 1.85–1.48 (m, 8H). LC-MS,[M+H] + =367.2.

[0536] Intermediate 1F. 2-Methyl-6-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)pyridin-3-ol

[0537]

[0538] To a solution of KOH (0.642 g, 11.4 mmol) in H2O (10 mL) was added Intermediate 1E (1.40 g, 3.81 mmol) and 1,4-dioxane (10 mL). The solution was degassed with N2, then di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.259 g, 0.61 mmol) and Pd2dba3 (0.140 g, 0.152 mmol) were added. The reaction mixture was degassed with N2 and stirred at 85°C overnight, then cooled to room temperature, acidified with 1N aqueous HCl, and extracted twice with EtOAc. The combined organic extracts were washed with H2O, brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (80 g SiO2; continuous gradient of 0-50% EtOAc / hexanes over 20 min, then held at 50% EtOAc / hexanes for 15 min) to give the title compound (760 mg, 2.50 mmol, 65.5% yield) as a beige solid. 1 H NMR (500MHz, CDCl3) δ7.56(d,J=8.4Hz,1H),7.09(d,J=8.4Hz,1H),6.54(s,1H),5.07(d,J=11.8Hz,1H),4.99(d,J=11.8Hz,1H),4.78( dd,J=4.3,3.0Hz,1H),3.95(ddd,J=11.6,8.3,3.1Hz,1H),3.56(dt,J=10.6,4.9Hz,1H),2.51(s,3H),2.40(s,3H),1.87–1.48(m,6H).

[0539] LCMS, [M+H]+=305.3.

[0540] Intermediate 1G. Isopropyl (1S,3S)-3-((2-methyl-6-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

[0541]

[0542] A solution of (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (1.26 g, 5.0 mmol) and Bu3P (1.25 mL, 5.0 mmol) in 1,4-dioxane (20 mL) was stirred at room temperature for 30 min. Intermediate 1F (760 mg, 2.50 mmol) and (1S, 3R)-3-hydroxycyclohexane-1-isopropyl formate (837 mg, 4.49 mmol) were added sequentially. The reaction mixture was heated to 85 ° C and maintained for 9 h under 1 atm of N2, then cooled to room temperature and diluted with DCM (10 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The crude oil was chromatographed (80 g SiO2; continuous gradient of 0-50% EtOAc / hexanes over 25 min, hold at 50% for 20 min) to afford the title compound (618 mg, 1.308 mmol, 52.4% yield) as a light yellow oil. LC-MS, [M+H] + =473.2.

[0543] Intermediate 1H. (1S,3S)-3-((6-(4-(hydroxymethyl)-3-methylisoxazol-5-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester

[0544]

[0545] To a solution of intermediate 1G (618 mg, 1.31 mmol) in MeOH (12 mL) was added PPTS (49 mg, 0.20 mmol). The reaction was heated at 60 °C overnight, then cooled to room temperature, neutralized with saturated aqueous NaHCO3 and concentrated in vacuo. The mixture was diluted with H2O and extracted twice with EtOAc. The combined organic extracts were washed with H2O, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (40 g SiO2; a continuous gradient of 0-100% EtOAc / hexanes over 15 min and held for 10 min) to give the title compound (460 mg, 91% yield) as a white solid. LC-MS, [M+H]+=389.2.

[0546] Intermediate 1I. Isopropyl (1S,3S)-3-((6-(4-(bromomethyl)-3-methylisoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

[0547]

[0548] At 0 ° C, PBr3 (0.21mL, 2.25mmol) was added to a solution of intermediate 1H (350mg, 0.90mmol) in DME (8mL). The reaction was stirred at room temperature overnight, then cooled to 0 ° C and neutralized with saturated NaHCO3 aqueous solution. The mixture was distributed between DCM (10mL) and H2O (5mL), and the water layer was extracted with DCM (3x 5mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (40g SiO2; 0% to 20%: EtOAc / hexane continuous gradient lasted 20min) to obtain the title compound as a white solid (355mg, 0.79mmol, 87% yield). LC-MS, [M+H]+=451.0.

[0549] Intermediate 1J. (1S,3S)-3-((6-(4-(azidomethyl)-3-methylisoxazol-5-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester

[0550]

[0551] To a solution of intermediate II (350 mg, 0.78 mmol) in DMF (6 mL) was added NaN3 (50 mg, 0.78 mmol). The reaction was stirred at 80 °C for 1 h, then cooled to room temperature, and EtOAc and H2O (10 mL each) were added. The resulting mixture was stirred at room temperature for 15 min, after which the organic layer was dried (Na2SO4) and concentrated in vacuo to afford the title compound (320 mg, 0.78 mmol, 100% yield) as a white solid. LC-MS, [M+H]+=414.1.

[0552] Intermediate 1

[0553] To a solution of intermediate 1J (320 mg, 0.775 mmol) in THF (5 mL) and H2O (1.67 mL) was added Ph3P (203 mg, 0.775 mmol) and the reaction mixture was stirred at room temperature overnight before EtOAc and brine (10 mL each) were added. The mixture was stirred at room temperature for 5 min before the organic layer was separated, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed (12 g SiO2; 0% to 10% MeOH / CH2Cl2 for 20 min; flow rate = 30 mL / min) to give the title compound (290 mg, 0.748 mmol, 97% yield) as a light brown oil. LCMS, [M+H]+ = 388.2. 1H NMR(500MHz, CDCl3)δ7.74(d,J=8.5Hz,1H),7.26(d,J=8.8Hz,1H),5.10-5.00(m,1H),4.78-4.70(m,1H), 3.93(s,2H),2.83-2.73(m,1H),2.56(s,3H),2.37(s,3H),2.14-1.58(m,8H),1.27(dd,J=6.3,2.2Hz,6H).

[0554] Intermediate 2. Isopropyl (1S, 3S)-3-((6-(4-(aminomethyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate

[0555]

[0556] Intermediate 2A. (5-(5-bromopyridin-2-yl)-3-methylisoxazol-4-yl)methanol

[0557]

[0558] BH3.THF (14.8mL of 1M solution in THF, 14.8mmol) is added dropwise to 5-(5-bromopyridin-2-yl)-3-methylisoxazole-4-carboxylic acid (1.67g, 5.90mmol) (Nagasue, H., JP2017095366) in THF (25mL). The reaction is stirred at 60 ° C for 2h, then cooled to 0 ° C, and quenched with HOAc (1mL) and MeOH (10mL) at 0 ° C. The mixture is warmed to room temperature, and stirred at room temperature for 30min, then concentrated in vacuo. MeOH (30mL) is added, and the mixture is stirred at room temperature for 30min, then concentrated in vacuo. The residue is diluted with saturated NaHCO3 aqueous solution (15mL) and extracted with EtOAc (5x 20mL). The combined organic extracts are washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (40 g SiO2, continuous gradient from 0 to 100% EtOAc over 15 min) to afford the title compound (1.20 g, 4.46 mmol, 76% yield) as a white solid. 1 H NMR (500MHz, CDCl3) δ8.75 (dd, J = 2.3, 0.7Hz, 1H), 8.05 (dd, J = 8.5, 2.4Hz, 1H), 7.90 (dd, J = 8.5, 0.8Hz, 1H), 4.63 (s, 2H), 2.36 (s, 3H). [M+H]+=269.

[0559] Intermediate 2B. 5-(5-bromopyridin-2-yl)-3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole

[0560]

[0561] p-TsOH.H2O (18 mg, 0.096 mmol) was added to a solution of intermediate 2A (516 mg, 1.92 mmol) and 3,4-dihydro-2H-pyran (0.53 mL, 5.75 mmol) in DCM (6 mL) at 0°C. The reaction was stirred at room temperature for 48 h, then cooled to 0°C and neutralized to pH ˜7 with saturated aqueous NaHCO3. The mixture was partitioned between DCM (10 mL) and water (10 mL); the aqueous layer was extracted with DCM (3× 10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (40 g SiO2, a continuous gradient of 0 to 50% EtOAc / hexane over 15 min) to give the title compound (640 mg, 1.81 mmol, 94% yield) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ8.74(dd,J=2.4,0.8Hz,1H),7.93(dd,J=8.5,2.3Hz,1H),7.79(dd,J=8.5,0.8Hz,1H),5.03(d,J=12.1Hz,1H),4 .93(d,J=12.1Hz,1H),4.74(t,J=3.6Hz,1H),3.91(ddd,J=11.5,8.5,3.1Hz,1H),3.59–3.45(m,1H),2.42(s,3H),1.86–1.49(m,6H). [M+H]+=353.3.

[0562] Intermediate 2C. 6-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)pyridin-3-ol

[0563]

[0564] A mixture of Pd2(dba)3 (100 mg, 0.11 mmol), di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (185 mg, 0.44 mmol), KOH (610 mg, 10.9 mmol) and intermediate 2B (640 mg, 1.81 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was evacuated and flushed with argon three times. The reaction mixture was stirred at 85 °C for 14 h, then cooled to room temperature and carefully acidified to pH ~4 with 1N HCl aqueous solution. EtOH (2 mL) was added to the mixture, which was extracted with EtOAc (8 x 5 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (40 g SiO2, continuous gradient from 0 to 100% EtOAc / hexanes over 14 min) to afford the title compound (275 mg, 0.95 mmol, 52.3% yield) as a slightly colored oil. 1 H NMR (500MHz, CDCl3) δ8.33(d,J=2.8Hz,1H),7.72(d,J=8.6Hz,1H),7.26(dd,J=8.6,2.8Hz,1H),5.02(d,J=11.9Hz,1H),4.91(d,J=12.0Hz,1 H),4.77(dd,J=4.5,2.9Hz,1H),3.94(ddd,J=11.5,8.0,3.2Hz,1H),3.55(dtd,J=10.7,4.7,4.2,2.3Hz,1H),2.40(s,3H),1.86–1.45(m,6H). [M+H]+=291.1.

[0565] Intermediate 2D. Isopropyl (1S,3S)-3-((6-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

[0566]

[0567] To the 0 ℃ mixture of intermediate 2C (275 mg, 0.95 mmol), (1S, 3R)-3-hydroxy-cyclohexanecarboxylic acid isopropyl ester (318 mg, 1.7 mmol), EtN (0.238 mL, 1.7 mmol) and PPh (447 mg, 1.7 mmol) in THF (4 mL) was added DIAD (0.33 mL, 1.7 mmol) dropwise over 5 min. The reaction was stirred at room temperature for 5 days, then diluted with H2O (3 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was subjected to chromatographic separation (40 g SiO2, a continuous gradient of 0 to 60% EtOAc / hexane over 20 min) to give the title compound (217 mg, 0.473 mmol, 50.0% yield) as a slightly colored oil. 1 H NMR (500MHz, CDCl3) δ8.37(d,J=2.9Hz,1H),7.82(d,J=8.8Hz,1H),7.31(dd,J=8.8,3.0Hz,1H),5.08–4.97(m,2H),4.96–4.90(m,1H),4.77–4.66(m,2 H),3.93(ddd,J=11.7,8.4,3.2Hz,1H),3.57–3.46(m,1H),2.80(tt,J=8.7 ,4.4Hz,1H),2.40(s,4H),2.03–1.48(m,14H),1.25(dd,J=6.2,2.4Hz,6H). [M+H]+=459.3.

[0568] Intermediate 2E. Isopropyl (1S,3S)-3-((6-(4-(hydroxymethyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

[0569]

[0570] To a solution of intermediate 2D (175 mg, 0.382 mmol) in MeOH (3 mL) was added PPTS (9.59 mg, 0.038 mmol). The mixture was heated at 60 ° C for 2 h, then cooled to room temperature, quenched with saturated NaHCO3 aqueous solution (2 mL) and concentrated in vacuo to remove MeOH. The residue was extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (12 g SiO2; 0% to 100% EtOAc: continuous gradient of hexane lasted 11 min) to give the title compound (75 mg, 53% yield) as a white solid. 1H NMR (500MHz, CDCl3) δ8.35(d,J=2.9Hz,1H),7.93(d,J=8.7Hz,1H),7.44(dd,J=8.8,2.9Hz,1H),6.14(t,J=6.8Hz,1H),5.04(hept,J=6.2Hz, 1H), 4.74 (dp, J=5.8, 2.8Hz, 1H), 4.60 (d, J=6.7Hz, 2H), 2.80 (tt, J=8.7, 4.2Hz, 1H), 2.34 (s, 3H), 2.08–1.55 (m, 8H), 1.22 (d, J=6.2Hz, 6H). [M+H]+=375.2.

[0571] Intermediate 2F. Isopropyl (1S,3S)-3-((6-(4-(bromomethyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

[0572]

[0573] At 0 ° C, PBr (0.16 mL, 1.67 mmol) was added to a solution of intermediate 2E (208 mg, 0.56 mmol) in DME (4 mL). The reaction was stirred at room temperature for 1 h, then cooled to 0 ° C and neutralized to pH 7 with saturated NaHCO aqueous solution. The mixture was distributed between DCM (5 mL) and H2O (3 mL); the aqueous layer was extracted with CH2Cl2 (3 x 5 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (12 g SiO2; a continuous gradient of 0% to 60% EtOAc: hexane lasted 11 min) to give the title compound (198 mg, 0.45 mmol, 80% yield) as a white solid. 1 H NMR (500MHz, CDCl3) δ8.43(d,J=2.9Hz,1H),7.86(d,J=8.8Hz,1H),7.36(dd,J=8.8,2.9Hz,1H),5.06(dq,J=12.5,6.3Hz,1H),5.01(s, 2H), 4.76 (qd, J=5.5, 4.8, 2.5Hz, 1H), 2.82 (dtd, J=8.8, 6.5, 4.1Hz, 1H), 2.42 (s, 3H), 2.07–1.57 (m, 8H), 1.27 (dd, J=6.3, 2.9Hz, 6H). [M+H]+=438.0.

[0574] Intermediate 2G. Isopropyl (1S,3S)-3-((6-(4-(azidomethyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

[0575]

[0576] To a solution of intermediate 2F (192 mg, 0.44 mmol) in DMF (2 mL) was added NaN3 (57 mg, 0.88 mmol), the reaction was stirred at 80 °C for 1 h, then cooled to room temperature, and EtOAc and H2O (10 mL each) were added. The resulting mixture was stirred at room temperature for 15 min, after which the organic layer was separated, dried (Na2SO4), and concentrated in vacuo to give the crude product. The material was chromatographed (4 g SiO2; 0% to 60% EtOAc / hexanes over 12 min; flow rate = 18 mL / min) to give the title compound (148 mg, 0.368 mmol, 84% yield) as a colorless oil. LC-MS, [M+H]+ = 400.2. 1 HNMR (500MHz, CDCl3) δ8.30(d,J=2.9Hz,1H),7.78(d,J=8.6Hz,1H),7.27(dd,J=8.8,2.9Hz,1H),4.96(hept,J=6.2Hz,1H),4.67(br s,3H),2.78–2.66(m,1H),2.30(s,3H),1.97–1.47(m,8H),1.19–1.16(m,6H).

[0577] Intermediate 2H. Isopropyl (1S,3S)-3-((6-(4-(aminomethyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

[0578]

[0579] To a solution of intermediate 2G (148 mg, 0.371 mmol) in THF (1.8 mL) and H2O (0.6 mL) was added Ph3P (146 mg, 0.556 mmol). The reaction was stirred at 60 °C for 3 h, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in CH2Cl2 and chromatographed (4 g SiO2; 100% EtOAc for 4 min, 100% to 20% EtOAc / MeOH for 40 min, then 4 min; flow rate = 18 mL / min) to give the title compound (109 mg, 0.29 mmol, 79% yield) as a colorless oil. LCMS, [M+H]+ = 374.1. 1H NMR (500MHz, CD3OD) δ8.13(d,J=2.9Hz,1H),7.60–7.45(m,1H),7.21(dt,J=9.3,2.1Hz,1H),4.71(m,1H),4.52(br s,1H),3.63(s,2H),2.54–2.45(m,1H),2.01(s,3H),1.77–1.25(m,8H),0.94(d,J=6.3Hz,6H).

[0580] Intermediate 2

[0581] A solution of intermediate 2H (16 mg, 0.043 mmol) and LiOH.H2O (36 mg, 0.86 mmol) in THF (0.2 mL), water (0.5 mL) and MeOH (0.5 mL) was stirred at room temperature for 14 h and then concentrated in vacuo. The residual mixture was neutralized with 1N aqueous HCl to pH = 3-4 and then extracted with EtOAc (5 x 5 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. LCMS, [M+H] + =332.1.

[0582] Intermediate 3. Isopropyl (1S,3S)-3-(4-(4-(aminomethyl)-3-methylisoxazol-5-yl)phenoxy)cyclohexane-1-carboxylate

[0583]

[0584] 3A. (5-(4-Bromophenyl)-3-methylisoxazol-4-yl)methanol

[0585]

[0586] To a solution of 5-(4-bromophenyl)-3-methylisoxazole-4-carboxylic acid (synthesized according to the procedure described in US2011 / 82164A1, 2.0 g, 7.09 mmol) in THF (50 mL) was added BH3·THF (28.4 mL of a 1 M solution in THF, 28.4 mmol) in portions at 0°C, the solution was warmed to room temperature and stirred at room temperature overnight. The reaction mixture was carefully quenched with H2O, acidified with 1N aqueous HCl (50 mL), stirred at room temperature for 1 h, and then extracted twice with EtOAc. The combined organic extracts were washed with H2O, brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient of 35-75% EtOAc in hexanes) to give the title compound (1.65 g, 87% yield) as a white solid. LC-MS, [M+H] + =268.1 H NMR (CDCl 3, 400MHz) δ7.73-7.64 (m, 4H), 4.66 (d, J = 5.1Hz, 2H), 2.42 (s, 3H).

[0587] 3B. 5-(4-bromophenyl)-3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole 113

[0588]

[0589] To a solution of (5-(4-bromophenyl)-3-methylisoxazol-4-yl)methanol (626 mg, 2.33 mmol) in CH2Cl2 (10 mL) was added 3,4-dihydro-2H-pyran (0.64 mL, 7.0 mmol) and PPTS (29 mg, 0.12 mmol). After stirring overnight at room temperature, the mixture was quenched with saturated aqueous NaHCO3 and extracted twice with EtOAc. The combined organic extracts were washed with H2O, brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient of 35-100% EtOAc / hexanes) to give the title compound (811 mg, 99% yield) as a white solid. LC-MS, [M+H] + =358. 1 H NMR (500MHz, CDCl3) δ7.82-7.55(m,4H),4.69(m,1H),4.65(m,1H),4.46(m,1H),3.87(m,1H),3.54(m,1H),2.37(s,3H),1.86-1.55(m,6H).

[0590] 3C.4-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)phenol 167nmr-115

[0591]

[0592] To a solution of KOH (2.70 g, 48.1 mmol) in H2O (50 mL) were added intermediate 1B (5.65 g, 16.0 mmol) and dioxane (50 mL) in sequence, and the solution was degassed with N2. t-BuXphos (0.545 g, 1.28 mmol) and Pd2(dba)3 (0.294 g, 0.321 mmol) were added, and the suspension was degassed with N2 and then stirred at 90°C overnight. The reaction mixture was cooled to room temperature, acidified with 1N aqueous HCl and extracted twice with EtOAc. The combined organic extracts were washed with H2O, brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient of 25-75% EtOAc / hexane) to give the title compound (3.63 g, 78% yield) as a white solid. LC-MS, [M+H] + =290. 1 H NMR (500MHz, CDCl3) δ7.72(d,J=8.8Hz,2H),6.94(d,J=8.8Hz,2H),4.70(m,1H),4.66(d,J=12.4Hz,1H) ,4.48(d,J=12.4Hz,1H),3.89(m,1H),3.53(m,1H),2.36(s,3H),1.88-1.70(m,2H),1.65-1.57(m,4H).

[0593] 3D. Isopropyl (1S,3S)-3-(4-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)phenoxy)cyclohexane-1-carboxylate

[0594]

[0595] To a room temperature solution of intermediate 3C (500 mg, 1.73 mmol), (1S,3R)-3-hydroxycyclohexanecarboxylic acid isopropyl ester (547 mg, 2.94 mmol), Et3N (0.41 mL, 2.94 mmol) and Ph3P (770 mg, 2.94 mmol) in THF (10 mL) was added DEAD (1.34 mL, 2.94 mmol) in portions over 15 min. The reaction mixture was stirred at room temperature for 2 days, then concentrated in vacuo, diluted with H2O, acidified with 1N aqueous HCl and extracted twice with EtOAc. The combined organic extracts were washed with H2O, brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient of 15-70% EtOAc / hexanes) to give the title compound (458 mg, 58% yield) as a white solid. LC-MS, [M+H] +=458. 1 H NMR (500MHz, CDCl3) δ7.75(d,J=8.8Hz,2H),7.03(d,J=8.8Hz,2H),5.02(m,1H),4.70(m,1H),4.66(d,J=12.4Hz,1H),4.48(d,J=12.4 Hz,1H),3.88(m,1H),3.54(m,1H),2.80(m,1H),2.35(s,3H),2.08-1.97(m,2H),1.93-1.80(m,3H),1.78-1.52(m,10H),1.24(m,6H).

[0596] 3E. Isopropyl (1S,3S)-3-(4-(4-(hydroxymethyl)-3-methylisoxazol-5-yl)phenoxy)cyclohexane-1-carboxylate

[0597]

[0598] To a room temperature solution of intermediate 3D (458 mg, 1.00 mmol) in MeOH (10 mL) was added PPTS (25 mg, 0.10 mmol). The reaction was stirred at room temperature overnight, then heated at 50 °C for 2 h and cooled to room temperature. The mixture was basified to pH ~7 with saturated aqueous NaHCO3 and concentrated in vacuo. The mixture was diluted with H2O and extracted twice with EtOAc. The combined organic extracts were washed with H2O, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient of 15-70% EtOAc / hexanes) to give the title compound (263 mg, 70% yield) as a white solid. LC-MS, [M+H] + =374. 1 H NMR (500MHz, CDCl3) δ7.71(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),5.42(s,2H),5.05(m,1H),4.74(m,1 H), 2.83 (m, 1H), 2.45 (s, 3H), 2.04 (m, 2H), 1.92 (m, 2H), 1.82-1.58 (m, 5H), 1.27 (dd, J = 6.3, 1.4Hz, 6H).

[0599] Intermediate 3

[0600] Intermediate 3 was prepared from Intermediate 3E using the same synthetic sequence as used to synthesize Intermediate 1 from Intermediate 1H. LCMS, [M+H] + =373.2. 1H NMR (500MHz, CDCl3) δ7.72-7.68(m,2H),7.05-7.00(m,2H),5.07-4.98(m,1H),4.72-4.66( m,1H),3.83(s,2H),2.84-2.76(m,1H),2.36(s,3H),2.07-1.53(m,8H),1.27-1.21(m,6H).

[0601] Example 1. (1S,3S)-3-((6-(4-(((((4-fluorobenzyl)oxy)carbonyl)amino)methyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid

[0602]

[0603] A solution of (4-fluorophenyl)methanol (8.1 mg, 0.06 mmol), 1,1'-carbonyldiimidazole (10.4 mg, 0.06 mmol) and LiOH.H2O (3 mg, 1.1 μmol) in toluene (0.5 mL) was stirred at 60 °C for 2 h. To this mixture was added intermediate 3 (8 mg, 0.02 mmol) and the reaction was stirred at 60 °C overnight and then cooled to room temperature. The mixture was partitioned between EtOAc and H2O; the organic layer was separated. The aqueous phase was extracted with EtOAc and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. LiOH.H2O (7.1 mg, 0.17 mmol) was added to the crude product in THF (0.8 mL), H2O (0.4 mL) and MeOH (0.4 mL) at room temperature and the reaction mixture was stirred at room temperature overnight and concentrated in vacuo. H2O (5 mL) was added and the pH of the mixture was adjusted to ~3 with 1N aqueous HCl. The mixture was extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (2 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative LC / MS: column: Waters XBridge C18, 19 x 200 mm, 5-μm particles; guard column: Waters XBridge C18, 19 x 10 mm, 5-μm particles; mobile phase A: 5:95 MeCN:H2O with 0.1% TFA; mobile phase B: 95:5 MeCN:H2O with 0.1% TFA; gradient: 20-80% B over 15 min, then hold at 100% B for 5-min; flow rate: 20 mL / min. Fractions containing the desired product were combined and concentrated by centrifugal evaporation to give the title compound (4.2 mg, 8.69 μmol, 41% yield). LCMS, [M+H] + =484.1. 1H NMR(500MHz,DMSO-d6)δ8.45(br s,1H),7.84(br d,J=8.5Hz,1H),7.59(br d,J=8.2Hz,1H),7.53-7.46(m,1H),7.43-7.35(m,2H),7.23-7.15(m,2H),5.00(s,2H),4.88-4.79(m,1H),4.48(br d,J=4.9Hz,2H),2.72-2.61(m,1H),2.27(s,3H),2.00-1.48(m,8H). hLPA1 IC 50 =9nM.

[0604] Example 2. (1S,3S)-3-(4-(4-((((3,3-dimethylbutyloxy)carbonyl)amino)methyl)-3-methylisoxazol-5-yl)phenoxy)cyclohexanecarboxylic acid

[0605]

[0606] 2A. tert-Butyl 5-(4-bromophenyl)-3-methylisoxazole-4-carboxylate

[0607]

[0608] A mixture of 5-(4-bromophenyl)-3-methylisoxazole-4-carboxylic acid (5.0 g, 17.7 mmol), tert-butyl 2,2,2-trichloroacetimidate (4.76 mL, 26.6 mmol) and BF3.OEt2 (0.23 mL, 1.77 mmol) in DCM (10 mL) / hexane (10 mL) was stirred at room temperature for 18 h, followed by the addition of 5 g NaHCO3. The reaction mixture was stirred at room temperature for 3 h, then filtered through diatomaceous earth, which was washed with EtOAc until the washings were no longer UV active. The combined filtrate was concentrated in vacuo. The crude product was chromatographed (220 g SiO2, a continuous gradient of 0% to 20% EtOAc / hexane over 35 min) to give the title compound (5.50 g, 92% yield) as a white solid. LCMS, [M+H] + =338.0. 1 H NMR (500MHz, CDCl3) δ7.79-7.75(m,2H),7.64-7.60(m,2H),2.48(s,3H),1.53(s,9H).

[0609] 2B. tert-Butyl 3-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole-4-carboxylate

[0610]

[0611] Ar was vigorously bubbled through a mixture of 2A (5.50 g, 16.3 mmol), KOAc (4.79 g, 48.8 mmol) and bis(pinacolato)diboron (6.19 g, 24.4 mmol) in THF (60 mL) for 5 min. Pd(dppf)Cl2-CH2Cl2 (1.33 g, 1.63 mmol) was added and the reaction mixture was rinsed with Ar, then heated to 80°C and maintained for 16 h, cooled to room temperature. LCMS analysis at this point indicated that the reaction was complete. The reaction mixture was partitioned between DCM and water, and the resulting mixture was vigorously stirred. The organic layer was separated, dried (Na2SO4), and then concentrated in vacuo. The crude product was chromatographed (120 g SiO2; a continuous gradient of 0 to 15% EtOAc in hexane over 40 min, maintained at 15% EtOAc / hexane for 10 min) to give the title compound (6.5 g, 98% yield) as a white solid. LCMS, [M+H] + =386.2.

[0612] 2C. tert-Butyl 5-(4-hydroxyphenyl)-3-methylisoxazole-4-carboxylate

[0613]

[0614] To a solution of 2B (6.26 g, 16.3 mmol), THF (100 mL) and HOAc (4.88 g, 81 mmol) was added 30% H2O2 aqueous solution (9 mL, 105 mmol) and the reaction was stirred at room temperature for 1.5 h; at which point TLC indicated the reaction was complete. Water (25 mL) was added and most of the THF was removed in vacuo; the remaining aqueous solution was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo to give a brown crude oil. The crude product was chromatographed (330 g SiO2; a continuous gradient of 0% to 35% EtOAc in hexanes over 40 min) to give the title compound (3.48 g, 78% yield) as a white solid. LCMS, [M+Na] + =298.0. 1 H NMR (500MHz, CDCl3) δ7.86-7.80(m,2H),6.94-6.89(m,2H),2.47(s,3H),1.54(s,9H).

[0615] 2D. tert-Butyl 5-(4-(((1S,3S)-3-(isopropoxycarbonyl)cyclohexyl)oxy)phenyl)-3-methyl-isoxazole-4-carboxylate

[0616]

[0617] To a 0°C mixture of 2C (495 mg, 2.66 mmol), Et3N (0.4 mL, 2.95 mmol) and Ph3P (775 mg, 2.95 mmol) in THF (10 mL) was added DIAD (0.60 mL, 2.95 mmol) dropwise over 15 min. The reaction was warmed to room temperature and stirred overnight at room temperature before water was added; the mixture was acidified with 1N aqueous HCl and extracted 3 times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude oil was chromatographed (80 g SiO2; a continuous gradient of 0% to 20% EtOAc in hexanes over 30 min, held at 20% EtOAc / hexanes for 20 min) to give the title compound (360 mg, 55% yield) as a colorless oil. LCMS, [M+H] + =444.1.

[0618] 2E. 5-(4-(((1S,3S)-3-(isopropoxycarbonyl)cyclohexyl)oxy)phenyl)-3-methylisoxazole-4-carboxylic acid

[0619]

[0620] TFA (2.5 mL) was added dropwise to a solution of 2D (360 mg, 0.81 mmol) in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to give the crude title compound as a beige oil. The material was used directly in the next step without further purification. LCMS, [M+H] + =388.1.

[0621] 2F. Isopropyl (1S, 3S)-3-(4-(4-(chlorocarbonyl)-3-methylisoxazol-5-yl)phenoxy)cyclohexanecarboxylate

[0622]

[0623] A mixture of 2E (0.32 g, 0.81 mmol), oxalyl chloride (0.10 mL, 1.22 mmol) and a drop of DMF in DCM (5 mL) was stirred at room temperature for 24 h and then concentrated in vacuo. The residue was azeotroped 3 times with DCM to give the crude title compound as a beige solid which was used in the next step without further purification.

[0624] 2G. Isopropyl (1S,3S)-3-(4-(4-(2-diazoacetyl)-3-methylisoxazol-5-yl)phenoxy)cyclohexanecarboxylate

[0625]

[0626] To a solution of crude 2F (material from the previous reaction) in THF (4 mL) / MeCN (4 mL) was added TMSCHN2 (1.60 mL of a 2M solution in hexanes, 3.25 mmol) at 0 °C (gas formation evolution). The reaction mixture was warmed to room temperature and stirred at room temperature overnight (at which point LCMS indicated product formation). The reaction mixture was concentrated in vacuo. The pale yellow oily product was chromatographed (40 g SiO2; a continuous gradient of 0% to 30% EtOAc / hexanes over 35 min, kept at 30% EtOAc for 10 min) to give the title compound (175 mg, 0.43 mmol, 52% yield) as a brown oil. LCMS, [M+H] + =412.1.

[0627] 2H. 2-(5-(4-(((1S,3S)-3-(isopropoxycarbonyl)cyclohexyl)oxy)phenyl)-3-methylisoxazol-4-yl)acetic acid

[0628]

[0629] To a solution of 2G (170 mg, 0.41 mmol) in THF (3 mL) and water (1.5 mL) was added AgNO3 (74 mg, 0.43 mmol). The yellow-green solution was stirred overnight and then diluted with EtOAc (100 mL). The organic layer was washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (145 mg, 0.36 mmol, 87% yield) as a beige solid. LCMS, [M+H] + =402.1. 1 H NMR (500MHz, CDCl3) δ7.63(d,J=8.8Hz,2H),7.03(d,J=8.8Hz,2H),5.08-4.98(m,1H),4.72-4.65(m ,1H),3.57(s,2H),2.84-2.76(m,1H),2.33(s,3H),2.03-1.52(m,8H),1.24(dd,J=6.2,2.1Hz,6H).

[0630] Example 2

[0631] To a solution of 2H (10 mg, 0.03 mmol) in toluene (0.8 mL) were added Et3N (6 μL, 0.04 mmol), Ph2PON3 (8 mg, 0.03 mmol), and 3,3-dimethylbutan-1-ol (5 mg, 0.05 mmol) in sequence. The mixture was heated at 80 °C overnight, then cooled to room temperature and partitioned between EtOAc and water. The organic layer was separated; the aqueous phase was extracted with EtOAc, and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the crude N-dimethylbutoxycarbamate. This material was dissolved in THF (0.8 mL) / water (0.4 mL) / MeOH (0.4 mL), and LiOH.H2O (8.4 mg, 0.20 mmol) was added at room temperature. The reaction was stirred at room temperature overnight, then concentrated in vacuo; H2O (5 mL) was added, and the pH was adjusted to ~3 with 1N aqueous HCl. The mixture was extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (2 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative LC / MS: Column: Waters XBridge C18, 19 x 200 mm, 5-μm particles; Guard column: Waters XBridge C18, 19 x 10 mm, 5-μm particles; Mobile phase A: 5:95 MeCN:H2O with 0.1% TFA; Mobile phase B: 95:5 MeCN:H2O with 0.1% TFA; Gradient: 40-80% B over 20 min, then 5-min hold at 100% B; Flow rate: 20 mL / min. Fractions containing the desired product were combined and concentrated by centrifugal evaporation to give the title compound (5.6 mg, 0.01 mmol, 49% yield) as an oil. LCMS, [M+H] + =459.1. 1 H NMR (500MHz, DMSO-d6) δ7.70(br d,J=7.9Hz,2H),7.58(br s,1H),7.12(br d,J=8.5Hz,2H),4.79-4.73(m,1H),4.16(br d,J=5.2Hz,2H),4.04(br t,J=6.7Hz,2H),2.71-2.61(m,1H),2.27(s,3H),2.00-1.43(m,10H),0.91(br s,9H). hLPA1 IC 50 =9.9nM.

[0632] The following examples were synthesized according to the procedures described for the preparation of Examples 1 and 2.

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643] Example 30. (±)-trans-3-(4-(3-methyl-4-((((R)-1-phenylethoxy)carbonyl)amino)isoxazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid

[0644]

[0645] Example 31. (±)-cis-3-(4-(3-methyl-4-((((R)-1-phenylethoxy)carbonyl)amino)isoxazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid

[0646]

[0647] 30A. (R)-1-(5-(4-hydroxyphenyl)-3-methylisoxazol-4-yl)carbamic acid phenylethyl ester

[0648]

[0649] To a solution of (R)-1-(5-(4-bromophenyl)-3-methylisoxazol-4-yl)phenylethyl carbamate (4.3 g, 10.7 mmol; prepared according to Example 1 of WO2010 / 141761) and B2(OH)2 (1.25 g, 13.9 mmol) in THF (30 mL) and MeOH (12 mL) was added iPr2NEt (4.49 mL, 25.7 mmol). The mixture was degassed with N2 and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)Pd(II)Cl2 (0.152 g, 0.21 mmol) was added. The mixture was degassed with N2 and heated at 50°C for 6 h and then cooled to room temperature. The mixture was diluted with water, acidified with 1N HCl aqueous solution and extracted 3 times with EtOAc. The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The residue was taken up in MeOH (100 mL) and water (30 mL) before adding 30% aqueous H2O2 (1.07 mL, 10.5 mmol). The reaction was stirred overnight then partially concentrated in vacuo, diluted with water and extracted 3 times with EtOAc. The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient of 25-75% EtOAc / hexanes) to give the title compound (1.62 g, 45% yield) as a white solid. LC-MS, [M+H] + =339. 1 H NMR (400MHz, CD3OD) δ7.61 (br d, J = 8.4Hz, 2H), 7.48-7.32 (m, 5H), 6.85 (br d, J = 8.4Hz, 2H), 5.83 (m, 1H), 2.16 (s, 3H), 1.62 (br d, J = 6.4Hz, 3H).

[0650] 30B. Ethyl 3-(4-(3-methyl-4-((((R)-1-phenylethoxy)carbonyl)amino)isoxazol-5-yl)phenoxy)cyclohexane-1-carboxylate

[0651]

[0652] To a solution of 30A (50 mg, 0.15 mmol) and ethyl 3-hydroxycyclohexanecarboxylate (25 mg, 0.15 mmol) in THF (2 mL) was added Ph3P (47 mg, 0.18 mmol) and DEAD (28 μL, 0.18 mmol) at 0°C. The reaction was warmed to room temperature and stirred at room temperature for 2 h, then concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient of 15-70% EtOAc / hexanes) to afford the title compound as a mixture of cis and trans isomers (27 mg, 37% yield). LC-MS, [M+H] + =493.

[0653] Example 30 and Example 31

[0654] To a room temperature solution of 30B (26 mg, 0.053 mmol) in MeOH (0.75 mL) and THF (0.75 mL) was added aqueous LiOH (0.75 mL of a 2M solution, 1.50 mmol). The reaction was heated at 50°C for 30 min, then cooled to room temperature, acidified (1 N aqueous HCl) and extracted three times with EtOAc. The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (Phenomenex Lumina Axia; 30X 250 mm column; continuous gradient of 60-70% MeCN / H2O containing 0.1% TFA) to give the title compounds Example 30 (racemic cis isomer) and Example 31 (racemic trans isomer).

[0655] Peak 1: Example 30 (12 mg, 50% yield). LC-MS, [M+H] + =465. 1 H NMR (400MHz, CD3OD) δ8.92(br s,1H),7.67(br d,J=7.9Hz,2H),7.44(br s,5H),6.97(br d,J=8.1Hz,2H),5.81(m,1H),4.40(m,1H),2.53(br s,1H),2.40(m,1H),2.17(s,3H),2.95(m,2H),1.63(m,3H),1.57-1.33(m,5H). hLPA1 IC 50 =434nM.

[0656] Peak 2: Example 31 (6 mg, 25% yield). LC-MS, [M+H] + =465. 1H NMR (400MHz, CD3OD) δ8.93(br s,1H),7.68(br d,J=8.1Hz,2H),7.51-7.18(m,5H),7.01(br d,J=8.4Hz,2H),5.82(m,1H),4.76(br s,1H),2.81(m,1H),2.17(s,3H),2.10-1.84(m,4H),1.82-1.65(m,3H),1.65-1.59(m,3H),1.44-1.32(m,1H). hLPA1 IC 50 =41nM.

[0657] Example 32. (±)-trans-3-(4-(4-((((R)-1-cyclopropylethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid

[0658]

[0659] Example 33. (±)-cis-3-(4-(4-((((R)-1-cyclopropylethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid

[0660]

[0661] The title compounds were prepared by the same synthetic sequence used to prepare Examples 30 and 31 starting from (R)-1-(5-(4-bromophenyl)-3-methylisoxazol-4-yl)carbamic acid cyclopropylethyl ester (synthesized according to the procedure of Example 3b of WO2010 / 141761). The two crude diastereoisomeric products were purified by reverse phase preparative HPLC (Phenomenex Lumina Axia; 30X 250 mm column; continuous gradient of 60-70% MeCN / H2O containing 0.1% TFA) to give the title compounds Example 32 (racemic trans isomer) and Example 33 (racemic cis isomer).

[0662] Peak 1: Example 33, LC-MS, [M+H] + =429. 1H NMR(500MHz,CDCl3)δ7.73(br d,J=8.5Hz,2H),6.96(d,J=8.8Hz,2H),4.31(m,2H),2.54-2.40(m,2H),2.28(s,3H),2. 16(m,1H),2.07-1.95(m,2H),1.57-1.12(m,7H),1.11-0.80(m,1H),0.61-0.18(m,4H). hLPA1 IC 50 =84nM.

[0663] Peak 2: Example 32, LC-MS, [M+H] + =429. 1 H NMR(500MHz,CDCl3)δ7.73(br d,J=8.5Hz,2H),6.99(d,J=8.8Hz,2H),4.70(m,1H),4.31(m,1H),2.89(m,1H),2.28(s,3H),2.13(m, 2H),2.01-1.85(m,4H),1.81-1.59(m,4H),1.49-1.41(m,1H),1.10-0.83(m,1H),0.61-0.25(m,4H). hLPA1 IC 50 =84nM.

[0664] Example 34. (1S,3S)-3-((6-(4-((((R)-1-cyclopropylethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0665]

[0666] The title compound was synthesized from 5-(5-bromopyridin-2-yl)-3-methylisoxazole-4-carboxylic acid (prepared according to Example 71 of US 2011 / 301142) and (R)-1-cyclopropyl-ethan-1-ol according to the procedure described in US 2011 / 301142 (Example 71) (Mendeleev Commun., 2003, 13, 124–125) to give (R)-1-(5-(5-bromopyridin-2-yl)-3-methylisoxazole-4-yl)carbamic acid cyclopropylethyl ester. 5-(5-bromopyridin-2-yl)-3-methylisoxazole-4-carboxylic acid was converted to the title compound by the same synthetic sequence as used to prepare Examples 30 and 31 starting from Intermediate 30A. LC-MS, [M+H] + =430. 1H NMR (500MHz, DMSO-d6) δ8.63(br s,1H),8.13(br s,1H),7.51(d,J=8.8Hz,1H),7.33(m,1H),4.56(br s,1H),2.39(m,1H),1.93(s,3H),1.75-1.20(m,9H),1.08-0.72(m,3H),0.29--0.08(m,4H). hLPA1 IC 50 =30nM.

[0667] Example 35. (1S,3S)-3-((6-(4-((3-benzylureido)methyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0668]

[0669] A solution of intermediate 2 (3 mg, 9 μmol), benzyl isocyanate (6 mg, 0.045 mmol) and i-Pr2NEt (0.047 mL, 0.27 mmol) in THF (0.2 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by preparative LC / MS: Column: XBridge C18, 19x200 mm, 5-μm particles; Mobile phase A: 5:95 MeCN:H2O containing 10 mM aqueous NH4OAc; Mobile phase B: 95:5 MeCN:H2O containing 10 mM aqueous NH4OAc; Gradient: 15-55% B over 19 min, then 5-min hold at 100% B; Flow rate: 20 mL / min. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (0.5 mg, 7% yield; 82% purity estimated by LCMS). LCMS, [M+H] + =465.1. 1 H NMR (500MHz, DMSO-d6) δ8.43(s,1H),7.86(d,J=8.6Hz,1H),7.61(d,J=8.9Hz,1H),7.38–7.14(m,5H),6.61(br s,1H),6.35(t,J=6.0Hz,1H),4.84(s,1H),4.39(d,J=6.0Hz,2H),4.19(d,J=6.0Hz,2H),2.69–2.62(m,1H),2.32(s,3H),2.11–1.50(m,8H). hLPA1 IC 50 =229nM.

[0670] Example 36. (1S,3S)-3-((6-(4-((((hexyloxy)carbonyl)amino)methyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0671]

[0672] 36A. 4-(Bromomethyl)-5-(5-bromopyridin-2-yl)-3-methylisoxazole

[0673]

[0674] To a 0°C solution of intermediate 2A (900 mg, 3.34 mmol) in DCM (15 mL) under N2 was added PBr3 (0.64 mL, 6.69 mmol) dropwise. The reaction was stirred at 0°C for 30 min, then diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4) and concentrated in vacuo to give the title compound (900 mg, 81%) as a white solid. LCMS [M+H] + =333.0.

[0675] 36B. 4-(Azidomethyl)-5-(5-bromopyridin-2-yl)-3-methylisoxazole

[0676]

[0677] A mixture of 36A (1.0 g, 3.0 mmol) and NaN (0.39 g, 6.0 mmol) in DMF (15 mL) was stirred at 90 °C for 16 h under N, then cooled to room temperature and poured into water (75 mL). The solid product was filtered off, washed with water (20 mL) and dried in vacuo to give the title compound as a white solid (0.80 g, 90%). LCMS [M+H] + =296.0; 1 H NMR (400MHz, DMSO-d6) δ 8.89 (s, 1H), 8.29 (dd, J = 8.40Hz, 2.40Hz, 1H), 7.91 (dd, J = 8.40Hz, 2.40Hz, 1H), 4.77 (s, 2H), 2.31 (s, 3H).

[0678] 36C. (5-(5-bromopyridin-2-yl)-3-methylisoxazol-4-yl)methanamine

[0679]

[0680] A mixture of 36B (1.0 g, 3.40 mmol) and Ph3P (1.78 g, 6.8 mmol) in THF (20 mL) and water (10 mL) was stirred at room temperature for 16 h under N2 and then concentrated in vacuo to give the crude title compound (2.8 g) as a yellow oily liquid, which was used in the next step without further purification. LCMS [M+H] + =270.0.

[0681] 36D. tert-Butyl ((5-(5-bromopyridin-2-yl)-3-methylisoxazol-4-yl)methyl)carbamate

[0682]

[0683] To a room temperature solution of 36C (2.80 g, 3.13 mmol) in THF (30 mL) and water (10 mL) was added NaHCO (0.79 g, 9.40 mmol) and (Boc) O (0.95 mL, 4.1 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (25 mL), dried (NaSO) and concentrated in vacuo to give the title compound as a white solid (0.8 g, 69%). LCMS [M+H] + =368.0; 1 H NMR (400MHz, CDCl3) δ8.76 (s, 1H), 7.98 (dd, J = 8.60Hz, 2.40Hz, 1H), 7.82 (d, J = 8 .40Hz,1H),5.72(br.s.,1H),4.38(d,J=6.40Hz,2H),2.45(s,3H),1.43(s,9H).

[0684] 36E. tert-Butyl ((3-methyl-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)isoxazol-4-yl)methyl)carbamate

[0685]

[0686] To a degassed solution of 36D (700 mg, 1.9 mmol), bis(pinacolato)diboron (725 mg, 2.85 mmol) and KOAc (560 mg, 5.70 mmol) in 1,4-dioxane (30 mL) was added 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride-CH2Cl2 complex (78 mg, 0.095 mmol). The reaction mixture was stirred at 90 °C for 16 h, then cooled to room temperature and filtered through The filter pad was washed with EtOAc (50 mL). The combined filtrates were concentrated in vacuo and the crude product was chromatographed (SiO2; 30% EtOAc in hexanes) to afford the title compound as a brown liquid (2.10 g) which was used in the next step without further purification. LCMS [M+H] + =416.

[0687] 36F. tert-Butyl ((5-(5-hydroxypyridin-2-yl)-3-methylisoxazol-4-yl)methyl)carbamate

[0688]

[0689] A mixture of 36E (2.0 g, 4.82 mmol) and NaBO3.H2O (0.96 g, 9.6 mmol) in THF (25 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (2 x 100 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was chromatographed (40 g SiO2, isocratic elution with 60% EtOAc in hexanes) to give the title compound (640 mg, 44%) as a pale yellow liquid. LC-MS [M+H] + =306.2

[0690] 36G. (1S,3S)-3-((6-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid ethyl ester

[0691]

[0692] To a solution of 36F (0.60 g, 1.97 mmol) in THF (25 mL) was added di-tert-butyl azodicarboxylate (1.36 g, 5.9 mmol) and Ph3P (1.55 g, 5.9 mmol). The reaction mixture was purged with N2 for 10 min; then (1S,3R)-ethyl 3-hydroxycyclohexanecarboxylate (0.68 g, 3.94 mmol) was added. The reaction mixture was stirred at 60 °C for 16 h, then cooled to room temperature and concentrated in vacuo. The crude product was chromatographed (24 g SiO2, isocratic elution with 35% EtOAc in hexanes) to give the title compound (0.60 g, 57%) as a light yellow liquid. LCMS [M+H] + =460.

[0693] 36H. (1S,3S)-3-((6-(4-(aminomethyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid ethyl ester

[0694]

[0695] To a 0°C solution of 36G (1.0 g, 2.2 mmol) in CH2Cl2 (20 mL) was added 4N HCl in dioxane (0.756 mL, 21.8 mmol) under N2. The reaction was warmed to room temperature and stirred at room temperature for 12 h, then concentrated in vacuo to afford the title compound as a light yellow solid (0.42 g, 54%). LCMS [M+H] + =360.

[0696] 36I. (1S,3S)-3-((6-(4-((((hexyloxy)carbonyl)amino)methyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid ethyl ester

[0697]

[0698] To a room temperature solution of 36G (30 mg, 0.083 mmol) in CH2Cl2 (5 mL) was added hexyl chloroformate (14 mg, 0.083 mmol), Et3N (42 mg, 0.42 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with water (20 mL) and extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound (30 mg) as a light yellow liquid. LCMS [M+H] + =488.4.

[0699] Embodiment 36

[0700] To a solution of 36I (20 mg, 0.041 mmol) in THF / water / THF / MeOH (2 mL each) was added LiOH.H2O (2 mg, 0.08 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with water (20 mL), neutralized with 1.5 N aqueous HCl (2 mL) and extracted with 5% MeOH in CHCl3 (25 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative HPLC (X-Bridge Phenyl (250X 4.6) mm 5μm column; flow rate 1 mL / min; mobile phase A: 10 mM aqueous NH4OAc; mobile phase B: MeCN; time (min) / %B: 0 / 20, 20 / 100, 30 / 100; retention time: 10.6 min) to give the title compound (3 mg, 16%) as a white solid. LCMS [M+H]+ =460.2; 1 H NMR (400MHz, CD3OD) δ8.55(d,J=3Hz,1H),7.87(d,J=8.5Hz,1H),7.57(dd,J=8.8Hz,2.8Hz,1H),4.72-4.76(m,1H),4.50(s,2H),4.03(t,J=6. 8Hz,2H),2.76-2.81(m,1H),2.39(s,3H),2.00-2.10(m,1H),1.85-1.9 5(m,3H),1.50-1.80(m,6H),1.30-1.40(m,6H),0.88(t,J=7.2Hz,3H);

[0701] hLPA1 IC 50 =46nM.

[0702] Example 37. (1S,3S)-3-((6-(4-(((((3,5-difluorobenzyl)oxy)carbonyl)amino)methyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0703]

[0704] 37A. (1S,3S)-3-((6-(4-(((((3,5-difluorobenzyl)oxy)carbonyl)amino)methyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid ethyl ester

[0705]

[0706] To a solution of 36H (30 mg, 0.083 mmol) in CH2Cl2 (5 mL) was added Et3N (58 μL, 0.417 mmol) followed by 3,5-difluorobenzyl(4-nitrophenyl)carbonate (65 mg, 0.083 mmol). The reaction was stirred at room temperature for 16 h and then concentrated in vacuo. The crude product was chromatographed (12 g SiO2, isocratic elution with 35% EtOAc in hexanes) to give the crude title compound (20 mg, 45%) as a pale yellow liquid. LCMS [M+H] + =530.2.

[0707] Embodiment 37

[0708] To a solution of 37A (20 mg, 0.041 mmol) in THF / water / MeOH (2 mL each) was added LiOH.H2O (2 mg, 0.082 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with water (20 mL), neutralized with 1.5 N aqueous HCl (2 mL) and extracted with 5% MeOH in CHCl3 (2 x 10 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative HPLC (Sunfire C18 (250X19) mm 5μm column; flow rate: 15 mL / min; mobile phase A: 0.1% CH3CO2NH4 aqueous solution; mobile phase B: MeCN; time (min) / %B: 0 / 40, 21 / 85; retention time: 12.31 min) to give the title compound (4 mg, 20%) as a white solid. LC-MS [M+H] + =502.2; 1 H NMR (400MHz, CD3OD) δ8.45(s,1H),7.86(d,J=8.0Hz,1H),7.55(d,J=8.8Hz,1H),6.95(d,J=6.4Hz,1H),6.87(t,J=9.2Hz ,1H),5.06(s,2H),4.72-4.76(m,1H),4.50(s,2H),2.72(br.s.,1H),2.34(s,3H),1.85-2.10(m,5H),1.60-1.80(m,4H). hLPA1 IC 50 =27nM

[0709] The following examples were synthesized according to the procedures described for the preparation of Examples 36 and 37.

[0710]

[0711]

[0712]

[0713]

[0714] Example 48. (1S,3S)-3-((6-(4-((((benzyloxy)carbonyl)amino)methyl)-3-methylisoxazol-5-yl)-4-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0715]

[0716] 48A. (1S,3S)-3-((6-(4-((Boc((benzyloxy)carbonyl)amino)methyl)-3-methyl-isoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid ethyl ester

[0717]

[0718] To a room temperature solution of ethyl (1S,3S)-3-((6-(4-(hydroxymethyl)-3-methylisoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate (prepared as for Example 1H except using ethyl (1S,3R)-3-hydroxycyclohexane-1-carboxylate (250 mg, 0.69 mmol)) in toluene (10 mL) was added DEAD (233 mg, 1.34 mmol), Ph3P (350 mg, 1.34 mmol). The reaction was stirred at room temperature for 5 min before benzyl tert-butyliminodicarboxylate (235 mg, 0.94 mmol) was added. The reaction mixture was stirred at 75 °C for 22 h before being cooled to room temperature and concentrated in vacuo. The crude product was chromatographed (24 g SiO2, isocratically eluted with 20% EtOAc in hexanes) to give the title compound (240 mg, 59%) as a light yellow oil. LCMS [M+H] + =608.6.

[0719] 48B. (1S,3S)-3-((6-(4-((((benzyloxy)carbonyl)amino)methyl)-3-methylisoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid ethyl ester

[0720]

[0721] To a solution of 48A (80 mg, 0.13 mmol) in CH2Cl2 (3 mL) was added TFA (0.20 mL, 2.63 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give the title compound as a colorless oil (45 mg, 67%). LCMS [M+H] + =508.5.

[0722] Embodiment 48

[0723] To a solution of 48B (40 mg, 0.079 mmol) in THF / MeOH (1 mL each) was added LiOH.H2O (9 mg, 0.39 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 3 h, then diluted with 1.5 N aqueous HCl (10 mL) and extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative HPLC (Sunfire C18 (150X19) mm 5μm column; flow rate: 15.0 mL / min; mobile phase A: 0.1% HCO2H aqueous solution; mobile phase B: MeCN; time (min) / %B: 0 / 50, 34 / 85; retention time: 10.8 min) to give the title compound (8 mg, 21%) as a white solid. LCMS [M+H] + =480.2; 1 H NMR (400MHz, CD3OD) δ7.71(d,J=8.4Hz,1H),7.45(d,J=8.4Hz,1H),7.20-7.40(m,5H),5.08( s,2H),4.51(s,2H),2.70-2.80(m,1H),2.50(s,3H),2.34(s,3H),1.50-2.20(m,9H); 50 =5nM.

[0724] Example 49. (1S,3S)-3-((6-(4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-3-methyl-isoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid

[0725]

[0726] To a 0°C solution of Example 48 (22 mg, 0.046 mmol) in anhydrous THF (2 mL) was added NaH (6 mg of a 60% dispersion in oil, 0.28 mmol) under N2, followed by CH3I (29 μL, 0.46 mmol). The reaction was warmed to room temperature and stirred at room temperature for 16 h, then diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in THF / MeOH (2 mL each), and a solution of LiOH.H2O (5.5 mg, 0.23 mmol) in water (2 mL) was added. The reaction mixture was stirred at room temperature for 6 h, then diluted with 1.5 N HCl aqueous solution (10 mL) and extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative HPLC (Sunfire C18 (150X 19) mm 5μm column; flow rate 17mL / min; mobile phase A: 0.1% HCO2H aqueous solution; mobile phase B: MeCN; time (min) / %B: 0 / 10, 10 / 50, 23 / 50, 23.5 / 100, room temperature: 21.1min) to give the title compound as a white solid (14mg, 49%). LCMS [M+H] + =494.4; 1 H NMR (300MHz, CDCl3) δ7.68(d,J=8.7Hz,1H),7.20-7.50(m,5H),7.18(d,J=8.7Hz,1H),5.19(s,2H),5.03(s,2H),4.7 2(s,1H),2.80-3.00(m,1H),2.83(s,3H),2.49(s,3H),2.10-2.30(m,5H),1.90-2.10(m,3H)1.60-1.80(m,3H); hLPA1 IC 50 =6nM.

[0727] Example 50. (1S,3S)-3-((6-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylisoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0728]

[0729] To the solution of Example 48 (70mg, 0.12mmol) in water (1mL), 47% HBr aqueous solution (13 μL, 0.23mmol) is added. The reaction mixture is stirred at room temperature for 2h, then diluted with water (10mL) and extracted with CH2Cl2 (2x 10mL). The organic extracts merged are concentrated in vacuo to obtain the crude triazole amine (32mg) as a light yellow oil. The amine is dissolved in CH2Cl2 (4mL), and TEA (0.129mL, 0.926mmol), di-tert-butyl dicarbonate (43 μL, 0.19mmol) and DMAP (5.7mg, 0.046mmol) are added. The reaction mixture is stirred at room temperature for 6h, then diluted with water (10.0mL) and extracted with CH2Cl2 (2x 20mL). The organic layer merged is washed with brine (15mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative HPLC (Sunfire C18 (150X19) mm 5μm column; flow rate: 15.0 mL / min; mobile phase A: 0.1% HCO2H aqueous solution; mobile phase B: MeCN; time (min) / %B: 0 / 50, 32 / 80; retention time: 11.2 min) to give the title compound (6 mg, 14%) as a light pink solid. LCMS [M+H] + =446.2; 1 H NMR (400MHz, CD3OD) δ7.72(d,J=8.8Hz,1H),7.48(d,J=8.8Hz,1H),4.75-4.80(br.s.,1H),4.43(s,2H),2.70-2.90(m,1H) ,2.54(s,3H),2.35(s,3H),2.00-2.20(m,1H),1.84-2.00(m,2H),1.60-1.80(m,4H),1.20-1.40(m,1H),1.43(s,9H); IC 50 =44nM.

[0730] Example 51. (1S,3S)-3-((2-methyl-6-(3-methyl-4-(((phenylmethyl)sulfonamido)methyl)isoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0731]

[0732] 51A. (1S,3S)-3-((2-methyl-6-(3-methyl-4-(((phenylmethyl)sulfonamido)methyl)isoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid ethyl ester

[0733]

[0734] To a solution of ethyl (1S,3S)-3-((6-(4-(aminomethyl)-3-methylisoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate (synthesized as for Intermediate 1 except using ethyl (1S,3R)-3-hydroxycyclohexane-1-carboxylate; 40 mg, 0.11 mmol) in CH2Cl2 (3 mL) were added benzylsulfonyl chloride (20 mg, 0.11 mmol) followed by Et3N (75 μL, 0.54 mmol). The reaction mixture was stirred at room temperature for 3 h; water (10 mL) was added and the mixture was extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound (40 mg, 71%) as a light yellow oil. LCMS [M+H] + =528.2.

[0735] Embodiment 51

[0736] To a solution of 51A (40 mg, 0.076 mmol) in THF / MeOH (1 mL each) was added a solution of LiOH.HO (9 mg, 0.38 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 2 h, then diluted with 1.5 N aqueous HCl (10 mL) and extracted with CHCl (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried (NaSO) and concentrated in vacuo. The crude product was purified by preparative HPLC (X-Bridge Phenyl (250X 19) mm 5μm column; flow rate 17 mL / min; mobile phase A: 10 mM NHOAc aqueous solution; mobile phase B: MeCN; time (min) / %B: 0 / 10, 10 / 80, 18 / 80, 18.5 / 100; retention time: 13.2 min.) to give the title compound (12 mg, 31%) as a white solid. LCMS [M+H] + =500.1; 1 H NMR (300MHz, DMSO-d6) δ7.70(d,J=8.7Hz,1H),7.56(d,J=8.7Hz,1H),7.40-7.50(br.s.,1H),7.31(br.s.,5H),4.83(br.s. hLPA1IC50 =620nM.

[0737] Example 52. (±)-trans-3-((5-(4-((((benzyloxy)carbonyl)amino)methyl)-3-methyl-isoxazol-5-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid

[0738]

[0739] 52A. (Z)-3-(Methylamino)but-2-enoic acid tert-butyl ester

[0740]

[0741] A mixture of tert-butyl 3-oxobutanoate (14.5 ml, 87 mmol) and methylamine (33% solution in EtOH; 23.9 mL, 192 mmol) was stirred at room temperature for 16 h and then concentrated in vacuo to give the title compound (15 g, 88 mmol, 100% yield) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ8.46 (br s, 1H), 4.42 (s, 1H), 2.90 (d, J = 5.2Hz, 3H), 1.90 (s, 3H), 1.48 (s, 9H).

[0742] 52B.5-Chloropyrazine-2-carbonyl chloride

[0743]

[0744] To a mixture of 5-chloropyrazine-2-carboxylic acid (1.0 g, 6.31 mmol) in DCM (6.3 mL) at 0°C was added oxalyl chloride (6.3 mL, 12.6 mmol) and a few drops of DMF. The mixture was stirred at room temperature overnight and then concentrated in vacuo to afford the title compound, which was used in the next step without further purification.

[0745] 52C. (E)-tert-Butyl 2-(5-chloropyrazine-2-carbonyl)-3-(methylimino)butanoate

[0746]

[0747] Over 10 min, a solution of 52B (1.0 g, 5.65 mmol) in DCM was added dropwise to a 0 °C solution of 9A (0.97 g, 5.65 mmol) and pyridine (1.83 mL, 22.6 mmol) in THF (28 mL). The reaction was stirred at room temperature for 24 h, then concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated; the aqueous phase was extracted 3 times with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the crude title compound as a yellow oil which was used in the next step without further purification.

[0748] 52D. tert-Butyl 5-(5-chloropyrazin-2-yl)-3-methylisoxazole-4-carboxylate

[0749]

[0750] A mixture of crude 52C (1.90 g, 6.1 mmol) and NH2OH.HCl (0.64 g, 9.14 mmol) in EtOH (58 mL) / water (2.9 mL) was stirred at 60 °C for 3 days and then concentrated in vacuo. The mixture was partitioned between EtOAc and water; the organic layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed (40 g SiO2, continuous gradient of 0-50% EtOAc in hexanes over 15 min) to give the title compound (1.30 g, 4.40 mmol, 72.1% yield) as an off-white solid. 1 H NMR (500MHz, CDCl3) δ9.01 (d, J = 1.4 Hz, 1H), 8.76 (d, J = 1.4 Hz, 1H), 2.55 (s, 3H), 1.55 (s, 9H).

[0751] 52E. (±)-trans-tert-butyl 5-(5-((3-(ethoxycarbonyl)cyclohexyl)oxy)pyrazin-2-yl)-3-methylisoxazole-4-carboxylate

[0752]

[0753] A mixture of 52D (166 mg, 0.56 mmol), racemic trans-3-hydroxy-cyclohexanecarboxylic acid ethyl ester (193 mg, 1.12 mmol) and Cs2CO3 (366 mg, 1.12 mmol) in MeCN (2.5 mL) was stirred at 80 °C for 18 h and then cooled to room temperature. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, dried (MgSO4), and concentrated in vacuo. The crude product was chromatographed (12 g SiO2; continuous gradient from 0% to 30% EtOAc in hexanes over 10 min) to give the title compound (150 mg, 0.348 mmol, 61.9% yield) as a clear oil. LCMS [M+H] + =432.3; 1 H NMR (500MHz, CDCl3) δ8.74(d,J=1.4Hz,1H),8.31(d,J=1.4Hz,1H),5.53-5.46(m,1H),4.14(q,J=7.0Hz,2H),2.79(tt,J=1 0.9, 3.9Hz, 1H), 2.50 (s, 3H), 2.21 (dt, J = 14.0, 4.1Hz, 1H), 2.04-1.93 (m, 2H), 1.78-1.43 (m, 14H), 1.26 (t, J = 7.2Hz, 3H).

[0754] 52F. (±)-trans-5-(5-((-3-(ethoxycarbonyl)cyclohexyl)oxy)pyrazin-2-yl)-3-methyl-isoxazole-4-carboxylic acid

[0755]

[0756] A mixture of 52E (150 mg, 0.348 mmol) and TFA (0.268 mL, 3.48 mmol) in DCM (3 mL) was stirred at room temperature for 4 h and then concentrated in vacuo to afford the title compound as a light yellow solid (130 mg, 0.346 mmol, 100% yield). LCMS [M+H] + =376.1; 1 H NMR (500MHz, CDCl3) δ9.01(d,J=1.4Hz,1H),8.21(d,J=1.1Hz,1H),5.67-5.49(m,1H),4.28-4.05(m,2H),2.80(t t,J=10.4,3.9Hz,1H),2.62(s,3H),2.27-2.10(m,1H),2.04-1.88(m,3H),1.84-1.36(m,4H),1.32-1.19(m,3H).

[0757] 52G. (±)-trans-3-((5-(4-(chlorocarbonyl)-3-methylisoxazol-5-yl)pyrazin-2-yl)oxy)cyclohexanecarboxylic acid ethyl ester

[0758]

[0759] A mixture of 52F (130 mg, 0.346 mmol) and 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.055 mL, 0.416 mmol) in DCM (2 mL) was stirred at room temperature for 1 h and then concentrated in vacuo to give the title compound (136 mg, 0.345 mmol, 100% yield) as a yellow oil, which was used in the next reaction without further purification.

[0760] 52H.(±)-trans-3-((5-(4-(hydroxymethyl)-3-methylisoxazol-5-yl)pyrazin-2-yl)oxy)cyclohexanecarboxylic acid ethyl ester

[0761]

[0762] A solution of 52G (136 mg, 0.35 mmol) in THF (2 mL) was added dropwise to a suspension of NaBH4 (20 mg, 0.53 mmol) in EtOH (2 mL) at -78 °C. The reaction was stirred at -78 °C for 1 h (LCMS showed the reaction was complete). The pH of the reaction mixture was adjusted to ~4 with 1N aqueous HCl; the mixture was extracted twice with EtOAc. The combined organic extracts were washed with water, dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (12 g SiO2; continuous gradient from 0% to 50% EtOAc in hexanes over 10 min) to give the title compound (72 mg, 0.20 mmol, 58% yield) as a clear oil. LCMS [M+H] + =362.2; 1 H NMR(500MHz, CDCl3)δ8.75(d,J=1.4Hz,1H),8.21(d,J=1.4Hz,1H),5.59-5.44(m,1H),4.66-4.51(m,2H),4.2 1-4.07(m,2H),2.87-2.69(m,1H),2.36(s,3H),2.24-2.12(m,1H),2.03-1.38(m,7H),1.26(t,J=7.2Hz,3H).

[0763] Embodiment 52

[0764] Example 52 was synthesized from 52H using the same procedure as described for the synthesis of Example 48. LCMS [M+H] + =467.1; 1 H NMR (500MHz, CDCl3) δ8.75-8.59(m,1H),8.21(s,1H),7.38-7.27(m,5H),5.93(brs,1H),5.49(br s,1H),5.18-4.94(m,2H),4.41(br s,2H),2.85(tt,J=10.7,3.7Hz,1H),2.44(s,3H),2.31-1.36(m,8H); hLPA1 IC 50 =111nM.

[0765] Example 53: (1S,3S)-3-((6-(3-methyl-4-(((2-phenylethyl)sulfonamido)methyl)isoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0766]

[0767] 2-phenylethanesulfonyl chloride (6.6 mg, 0.032 mmol) was added to a solution of intermediate 2H (4 mg, 10.7 μmol) in EtOAc (0.5 mL) and saturated NaHCO3 aqueous solution (0.5 mL). The mixture was stirred at room temperature for 30 min and then extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the crude sulfonamide cyclohexyl ester. LCMS, [M+H]+=542.3. The crude ester was dissolved in THF / MeOH / H2O (0.5 mL each) and LiOH.H2O (9 mg, 214 μmol) was added. The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo to remove the organic solvent. The pH of the residual aqueous layer was adjusted to ~4 with 1N HCl aqueous solution and the mixture was extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give cyclohexyl acid. The crude material was purified by preparative LC / MS (column: XBridge C18, 19x200 mm, 5-μm particles; mobile phase A: 5:95 MeCN:H2O containing 10-mM aqueous NH4OAc; mobile phase B: 95:5 MeCN:H2O containing 10-mM aqueous NH4OAc; gradient: 0-100% B over 15 min, then hold at 100% B for 4 min; flow rate: 20 mL / min) to give partially purified cyclohexyl acid. The material was further purified by preparative LC / MS (column: XBridge C18, 19 x 200 mm, 5-μm particles; mobile phase A: 5:95 MeCN:H2O containing 0.1% TFA; mobile phase B: 95:5 MeCN:H2O containing 0.1% TFA; gradient: 30-70% B over 20 min, then hold at 100% B for 5-min; flow rate: 20 mL / min) to give the title compound (3.0 mg, 54% yield; purity by LCMS = 97%). LCMS, [M+H]+ = 500.0. 1H NMR (500MHz, DMSO-d6) δ8.26(d,J=2.8Hz,1H),7.84(d,J=8.8Hz,1H),7.56(dd,J= 8.8,2.9Hz,1H),7.41(t,J=5.6Hz,1H),7.26(t,J=7.5Hz,2H),7.20(t,J=7.4Hz,1H ),7.11(d,J=7.5Hz,2H),4.75(s,1H),4.44(d,J=5.5Hz,2H),3.33–3.23(m,2H),2. 87(dd,J=10.3,6.4Hz,2H),2.62(t,J=9.8Hz,1H),2.31(s,3H),1.98–1.44(m,8H). hLPA1 IC 50 =4nM.

[0768] Example 54. (1S,3S)-3-((6-(3-methyl-4-((3-phenylpropionamido)methyl)isoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0769]

[0770] The title compound was synthesized from intermediate 2H and 3-phenylpropionyl chloride using the same procedure as in the preparation of Example 53. LCMS, [M+H]+=463.9. 1 H NMR (500MHz, DMSO-d6) δ8.43(d,J=2.8Hz,1H),8.04(t,J=5.4Hz,1H),7.82(d,J=8.8Hz,1H),7.58(dd,J=8.8,2.9Hz,1H),7.20(t,J=7.5Hz,2H),7.14( d,J=7.6Hz,3H),4.82(s,1H),4.49(d,J=5.2Hz,2H),2.78(t,J=7.6Hz,2H) ,2.70–2.61(m,1H),2.38(t,J=7.6Hz,2H),2.15(s,3H),2.01–1.46(m,8H). hLPA1 IC 50 =255nM.

[0771] Example 55. (1S,3S)-3-((6-(3-methyl-4-((((((S)-pentan-2-yl)oxy)carbonyl)amino)methyl)isoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0772]

[0773] To a solution of intermediate 2H (3 mg, 8.03 μmol) and (S)-4-nitrophenylpentane-2-yl carbonate (3 mg, 0.012 mmol) in THF (0.2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.011 mL, 0.064 mmol). The mixture was stirred at room temperature for 12 h, then THF / MeOH / water (0.5 mL each) was added, followed by LiOH.HO (7 mg, 16 μmol). The reaction mixture was stirred at room temperature for 14 h, then the organic solvent was removed in vacuo. The pH was adjusted to ~4 with 1N HCl aqueous solution, and the mixture was extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative LC / MS (column: XBridge C18, 19 x 200 mm, 5-μm particles; mobile phase A: 5:95 MeCN:H2O containing 10-mM aqueous NH4OAc; mobile phase B: 95:5 MeCN:H2O containing 10-mM aqueous NH4OAc; gradient: 20-60% B over 19 min, then hold at 100% B for 5-min; flow rate: 20 mL / min) to give the title compound (2.9 mg, 79% yield; LCMS purity = 98%). LCMS [M+H] + =446.2. 1 H NMR (500MHz, DMSO-d6) δ8.45(d,J=2.8Hz,1H),7.84(d,J=8.7Hz,1H),7.59(d,J=9.0Hz,1H),7.22(s,1H),4.84(s,1H),4.66(br s,1H),4.44(d,J=5.4Hz,2H),2.71–2.62(m,1H),2.28(s,3H),2.05–0.69(m,18H). hLPA1 IC 50 =23nM.

[0774] Example 56. (1S,3S)-3-((6-(4-((((benzyloxy)carbonyl)amino)methyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0775]

[0776] Example 57. (1R,3R)-3-((6-(4-((((benzyloxy)carbonyl)amino)methyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0777]

[0778] To a 0°C solution of trans-3-((6-(4-(aminomethyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid isopropyl ester (20 mg, 0.054 mmol; synthesized using the same sequence as Intermediate 2H but using cis-3-hydroxycyclohexane-1-carboxylic acid isopropyl ester) in EtOAc (1 mL) and saturated aqueous NaHCO3 (1 mL) was added benzyl chloroformate (15 μL, 0.11 mmol) dropwise. The reaction mixture was stirred at room temperature for 48 h and then extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude benzyl carbamate was chromatographed (4 g SiO2; continuous gradient of 0-70% EtOAc in hexanes over 10 min) to afford isopropyl trans-3-((6-(4-((((benzyloxy)carbonyl)amino)methyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (23 mg, 0.045 mmol, 85% yield). LCMS [M+H] + =508.1.

[0779] The crude cyclohexyl ester was dissolved in THF / MeOH (1 mL each); LiOH.H2O (38 mg, 0.91 mmol) in water (1 mL) was added and the reaction mixture was stirred at room temperature for 14 h. The organic solvent was removed in vacuo. The pH of the residue was adjusted to ~4 with 1N aqueous HCl and the mixture was extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the crude cyclohexyl acid. The crude material was purified by preparative LC / MS (column: XBridge C18, 19 x 200 mm, 5-μm particles; mobile phase A: 5:95 MeCN:H2O with 0.1% TFA; mobile phase B: 95:5 MeCN:H2O with 0.1% TFA; gradient: 30-70% B over 20 min, then 5-min hold at 100% B; flow rate: 20 mL / min) to give partially purified material. The material was purified by chiral separation (Instrument: PIC Solution Prep-200; Column: Chiralpak IC, 21 x 250 mm, 5 μm; Mobile phase: 25% EtOH / 75% CO2; Flow conditions: 45 mL / min, 150 bar, 40°C; Detector wavelength: 220 nm; Injection details: 0.5 mL of 8 mg / mL solution in EtOH) to give two enantiomers.

[0780] Example 56: By LCMS analysis, the analytical purity of the first eluting enantiomer was 96%, and its chiral purity was estimated to be 83.2% ee. LC-MS [M+H]+ =466.3. 1 H NMR(500MHz,DMSO-d6)δ8.46(s,1H),7.85(d,J=8.8Hz,1H),7.59(d,J=8.9Hz,1H),7.49(s,1H),7.43–7.25( m,5H),5.03(s,2H),4.84(s,1H),4.49(d,J=5.4Hz,2H),2.72–2.64(m,1H),2.28(s,3H),2.04–1.48(m,8H). hLPA1 IC 50 =4nM

[0781] Example 57: The analytical purity of the second eluting enantiomer was 95% by LCMS analysis, and its chiral purity was estimated to be 75.6% ee. LC-MS [M+H] + =466.1. 1 H NMR(500MHz,DMSO-d6)δ8.46(s,1H),7.85(d,J=8.8Hz,1H),7.59(d,J=8.9Hz,1H),7.49(s,1H),7.43–7.25( m,5H),5.03(s,2H),4.84(s,1H),4.49(d,J=5.4Hz,2H),2.72–2.64(m,1H),2.28(s,3H),2.04–1.48(m,8H). hLPA1 IC 50 =49nM.

[0782] The following examples were synthesized according to the procedures described for the preparation of Examples 36, 49 and 55.

[0783]

[0784]

[0785]

[0786]

[0787] Other features of the present invention should become clear in the process of the above description of the exemplary embodiments, which are provided to illustrate the present invention and are not intended to limit the present invention. The present invention can be embodied in other specific forms without departing from the spirit or basic attributes of the present invention. The present invention encompasses all combinations of the preferred aspects of the present invention described herein. It should be understood that any and all embodiments of the present invention can be combined with any one or more other embodiments to describe other embodiments. It should also be understood that each individual element of the embodiment is its own independent embodiment. In addition, any element of the embodiment is intended to be combined with any and all other elements of any embodiment to describe other embodiments.

Claims

1. A compound according to formula (Ia): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Said Partially selected Y 1 is -NH- or -N(CH3)-; Y 2 for Y 3 is O; L is -CH2-; R 1 is CO2H; R 4 C 1-10 Alkyl, C 3-8 Cycloalkyl, 6- to 10-membered aryl, -(C 1-6 Alkylene)-(C 3-8 Cycloalkyl), -(C 1-6 alkylene)-(6- to 10-membered aryl), -(C 1-4 Alkylene)-(C 1-3 wherein the alkyl, alkylene, cycloalkyl, aryl, by itself or as part of another moiety, is each independently substituted by 0 to 3 R 8 replace; R 5 is -CH3; and R 8 are independently halogen, C 1-6 Alkyl, C 1-6 Alkoxyalkyl, C 1-6 Alkoxy.

2. The compound according to claim 1, which is represented by formula (I'a):

3. The compound according to any one of claims 1 to 2, wherein R 4 C 1-10 Alkyl, C 3-6 Cycloalkyl, -(C 1-4 Alkylene)-(C 3-6 wherein the alkyl, alkylene, cycloalkyl and benzyl are each independently substituted by 0 to 3 R 8 replace.

4. The compound according to claim 1, wherein R 4 C 3-10 Alkyl, C 3-6 Cycloalkyl, -(C 1-4 Alkylene)-(C 1-3 Alkoxy), -(C 1-4 Alkylene)-(C 3-6 Cycloalkyl) or -(C 1-4 wherein the alkyl, alkylene, cycloalkyl and phenyl are each independently substituted by 0 to 3 R 8 replace.

5. The compound according to claim 4, wherein R 4 C 3-10 Alkyl, cyclobutyl, cyclopentyl, -(CH2) 1-2 -(C 1-3 Alkoxy), -(CHR 8a ) 1-2 -cyclopropyl, -(CHR 8a )-cyclobutyl or -(CHR 8a )-phenyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl and phenyl are each independently substituted by 0 to 3 R 8 replace; R 8a are each independently hydrogen or methyl; and R 8 are each independently halogen or C 1-4 alkyl.

6. A compound or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein the compound is selected from:

7. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 6 or stereoisomers, tautomers or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier or diluent.

8. Use of a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the treatment of a disease, disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1).

9. The use according to claim 8, wherein the disease, disorder or condition is pathological fibrosis, transplant rejection, cancer, osteoporosis or inflammation.

10. The use according to claim 9, wherein the pathological fibrosis is lung, liver, kidney, heart, skin, eye or pancreatic fibrosis.

11. The use according to claim 8, wherein the disease, disorder or condition is idiopathic pulmonary fibrosis (IPF), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, and systemic sclerosis.

12. The use according to claim 8, wherein the disease, disorder or condition is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), diabetic nephropathy and systemic sclerosis.

13. The use according to claim 9, wherein the cancer is a cancer of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitals, urogenital tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle or thyroid.

14. Use of a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7 for treating fibrosis in a mammal in need thereof.

15. The use according to claim 14, wherein the fibrosis is idiopathic pulmonary fibrosis (IPF) and systemic sclerosis.

16. Use of a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for treating a mammal in need thereof for the following diseases: pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis, skin fibrosis, intestinal fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, intestinal cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant rejection, scleroderma, ocular fibrosis, age-related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenon, or neuralgia.

17. The use according to claim 16, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

18. The use according to claim 16, wherein the liver fibrosis is non-alcoholic steatosis hepatitis.

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