Cyclohexylpyrazoloazines as LPA antagonists

Abstract

The present invention provides compounds of formula (I) 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 / 607,392, filed December 19, 2017; the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to novel substituted pyrazole 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 pyrazole 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 agents 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 (I):

[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] Q 2 N or NR 5b ;

[0028] Q 1 and Q 3 One of them is CR 5a , and the other is N or NR 5b ;

[0029] Dashed circles represent optional bonds forming aromatic rings;

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

[0031] Z is NR 8 or O;

[0032] The Y ring is a phenyl or an azine moiety; wherein the term "azine" refers to a 6-membered aromatic heterocyclic ring wherein the ring members are selected from CH and 1 to 4 nitrogens; and in one embodiment, the azine moiety is a ring moiety selected from pyridine, diazine (e.g., pyrimidine, pyrazine and pyridazine), triazine and tetrazine;

[0033] R 1 (-CH2) a R 9 ;

[0034] a is an integer 0 or 1;

[0035] R 2 are independently halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-6Cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl or haloalkoxy;

[0036] n is an integer 0, 1 or 2;

[0037] R 3 Halogen, cyano, hydroxyl, amino, oxo, -OR a 、-SR a , =S, -NR c R c , =NH, =N-OH, =NR a , =N-OR a 、-NO2、-S(O)2R a 、-S(O)2NHR b 、-S(O)2NR c R c 、-S(O)2OR b 、-OS(O)2R b 、-OS(O)2OR b 、-P(O)(OR b )(OR b )、-C(O)R b 、-C(NR b )R b 、-C(O)OR b 、-C(O)NR c R c 、-C(NR b )NR c R c 、-OC(O)R b 、-NR b C(O)R b 、-OC(O)OR b 、-NR b C(O)OR b 、-OC(O)NR c R c 、-NR b C(O)NR c R c 、-NR b C(NR b )R b 、-NR b C(NR b )NR c R c , C 1-6 Alkyl, C 1-6 Deuterated alkyl (completely or partially deuterated), C 1-6heteroalkyl, 6 to 10 membered aryl, arylalkyl, 5 to 10 membered heteroaryl, heteroarylalkyl, 3 to 8 membered carbocyclyl, carbocyclylalkyl, 4 to 8 membered heterocyclyl or heterocyclylalkyl; wherein the alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl and R a , itself or as part of another group, each independently composed of 0 to 5 R d replace;

[0038] R a Selected from C 1-6 Alkyl, C 1-6 deuterated alkyl (fully or partially deuterated), haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl;

[0039] R b are independently hydrogen or R a ;

[0040] R c Each independently is R b ; or alternatively, two R c Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocyclic group;

[0041] R d Each independently selected from R a , alkoxy, haloalkoxy, alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkoxy, alkylthio, halogen, cyano, hydroxy, amino, oxo, -OR a 、-SR a , =S, -NR c R c , =NH, =N-OH, =NR a , =N-OR a 、-NO2、-S(O)2R a , -S(O)2NHR b 、-S(O)2NR c R c 、-S(O)2OR b 、-OS(O)2R b 、-OS(O)2OR b 、-P(O)(OR b )(OR b )、-C(O)R b 、-C(NRb )R b 、-C(O)OR b 、-C(O)NR c R c 、-C(NR b )NR c R c 、-OC(O)R b 、-NR b C(O)R b 、-OC(O)OR b 、-NR b C(O)OR b 、-NR b C(O)NR c R c 、-NR b C(NR b )R b and-NR b C(NR b )NR c R c or alternatively, one or two R on an alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl group d With the R d The atoms joined together form a ring portion or a bridge portion;

[0042] R 4 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; or R 3 and R 4 together with the atoms to which they are attached, form a monocyclic or bicyclic moiety;

[0043] m is an integer 0, 1 or 2;

[0044] R 5a and R 6 are independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

[0045] R 5b For hydrogen, C 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

[0046] R7 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;

[0047] R 8 is hydrogen or C 1-4 alkyl;

[0048] R 9 Selected from -CN, -C(O)OR 10 、-C(O)NR 11a R 11b ,

[0049]

[0050] R e C 1-6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl or haloalkoxyalkyl;

[0051] R 10 is hydrogen or C 1-10 Alkyl; and

[0052] 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.

[0053] In one embodiment of Formula (I), X 1 CR 6 , where R 6 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl).

[0054] In any of the foregoing embodiments of Formula (I), R 5b is hydrogen or C 1-6 In another embodiment, R 5a For hydrogen.

[0055] In any of the foregoing embodiments of Formula (I), L is a covalent bond or a methylene group.

[0056] In any of the foregoing embodiments of formula (I),

[0057] Said Part of and

[0058] Y 1 , Y 2 , Y 3 and Y 4 are each independently N or CH, provided that Y 1 , Y 2 , Y 3 and Y 4 In one embodiment, Y 1 , Y 2 , Y 3 and Y 4 In another embodiment, both of Y 1 , Y 2 , Y 3 and Y 4 In another embodiment, three of Y are CH. 1 , Y 2 , Y 3 and Y 4 All are CH.

[0059] In any of the foregoing embodiments of formula (I),

[0060] Said Part of

[0061]

[0062] In any of the foregoing embodiments of formula (I),

[0063] R 3 Halogen, cyano, hydroxyl, amino, -OR a 、-SR a 、-NR c R c , C 1-6 Alkyl, C 1-6 heteroalkyl, 6 to 10 membered aryl, arylalkyl, 5 to 10 membered heteroaryl, heteroarylalkyl, 3 to 8 membered carbocyclyl, carbocyclylalkyl, 4 to 8 membered heterocyclyl or heterocyclylalkyl; wherein the alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl and R a , itself or as part of another group, each independently composed of 0 to 5 R d replace,

[0064] R a Selected from C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl;

[0065] R b are independently hydrogen or R a ;

[0066] R c Each independently is R b ; or alternatively, two R c Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocyclic group; and

[0067] R d Each independently selected from R a , alkoxy, haloalkoxy, alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkoxy, alkylthio, halogen, cyano, hydroxy, amino, oxo, -OR a 、-SR a and-NR c R c or alternatively, one or two R on an alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl group d With the R d The linked atoms together form part of a ring or a bridge.

[0068] In any of the foregoing embodiments of formula (I), the compound is represented by formula (IIa) or (IIb):

[0069] Y 1 , Y 2 and Y 3 are each independently N or CH;

[0070] R 7a is 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;

[0071] f is an integer 0, 1, 2 or 3;

[0072] R 5a and R 5b are independently hydrogen or C 1-4 Alkyl; and

[0073] R 1 , R 2 ,n,R3 , R 4 , m, X 1 , X 2 , X 3 , X 4 and Z are the same as defined above.

[0074] In one embodiment of Formula (IIa) or (IIb), X 1 CR 6 , where R 6 is hydrogen or C 1-4 alkyl.

[0075] In any of the foregoing embodiments of Formula (IIa) or (IIb), X 3 is N.

[0076] In any of the foregoing embodiments of formula (IIa) or (IIb),

[0077] Said Partially selected

[0078]

[0079] R 6a are independently halogen, cyano, hydroxyl, amino, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; and d is an integer of 0, 1 or 2.

[0080] In any of the foregoing embodiments of formula (IIa) or (IIb), L is a covalent bond or a methylene group, or f is 0 or 1. In one embodiment, R 7a For hydrogen.

[0081] In any of the foregoing embodiments of Formula (IIa) or (IIb), R 8 It is hydrogen or methyl.

[0082] In any of the foregoing embodiments of Formula (IIa) or (IIb), R 1 is CO2H. In one embodiment, R 2 For hydrogen.

[0083] In any of the foregoing embodiments of formula (IIa) or (IIb), the compound is represented by formula (IIIa) or (IIIb):

[0084]

[0085] Y 1 , Y 2 and Y 3 are each independently N or CH;

[0086] Z is O or NH;

[0087] R 2a is hydrogen, chlorine, fluorine or C 1-4 Alkyl; and

[0088] R 1 , R 3 , R 4 , m, X 1 , X 2 , X 3 and X 4 Same as defined above.

[0089] In one embodiment of Formula (IIIa) or (IIIb), Y 1 , Y 2 and Y 3 In another embodiment of formula (IIIa) or (IIIb), Y 1 , Y 2 and Y 3 In another embodiment of formula (IIIa) or (IIIb), Y 1 , Y 2 and Y 3 Both are CH.

[0090] In any of the foregoing embodiments of Formula (IIIa) or (IIIb),

[0091] Said Partially selected

[0092]

[0093] In any of the foregoing embodiments of Formula (IIIa) or (IIIb), R 1 is CO2H.

[0094] In any of the foregoing embodiments of Formula (IIIa) or (IIIb), X 1 CR 5 ;X 2 is N or CH; X 3 is N; and X 4 is N or CH; and R 5 is hydrogen, halogen, cyano, C 1-6 In one embodiment, X 4 For CH.

[0095] In any of the foregoing embodiments of Formula (IIIa) or (IIIb),

[0096] Said Part of And R 6a is hydrogen, methyl or ethyl.

[0097] In any of the foregoing embodiments of Formula (IIIa) or (IIIb),

[0098] Said Part of

[0099] And m is 0 or 1.

[0100] In one embodiment, R 4 C 1-4 Alkyl, C 1-4 alkoxy or halogen (eg, fluorine).

[0101] In any of the foregoing embodiments of Formula (IIIa) or (IIIb),

[0102] Said Part of And m is 0 or 1.

[0103] In any of the foregoing embodiments of Formula (IIIa) or (IIIb),

[0104] R 3 Halogen, cyano, hydroxyl, amino, -OR a 、-SR a 、-NR c R c , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 heteroalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, heteroarylalkyl, 3- to 8-membered carbocyclyl, carbocyclylalkyl, 4- to 8-membered heterocyclyl, or heterocyclylalkyl; wherein the alkyl, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, and R a , itself or as part of another group, each independently composed of 0 to 5 R d replace;

[0105] R a Selected from C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl;

[0106] R bare independently hydrogen or R a ;

[0107] R c Each independently is R b ; or alternatively, two R c Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocyclic group;

[0108] R d Each independently selected from R a , alkoxy, haloalkoxy, alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkoxy, alkylthio, halogen, cyano, hydroxy, amino, oxo, -OR a 、-SR a and-NR c R c or alternatively, one or two R on an alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl group d With the R d The linked atoms together form part of a ring or a bridge.

[0109] m is 0, 1 or 2; and

[0110] R 4 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.

[0111] In any of the foregoing embodiments of Formula (IIIa) or (IIIb), R 3 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, phenyl, benzyl, (6-membered heteroaryl containing 1 to 3 heteroatoms, each heteroatom independently selected from N, O and S), alkoxy, alkoxyalkyl, -O-cycloalkyl, -O-phenyl, -O-benzyl and -NH-alkyl; and the alkyl, alkoxy, haloalkyl, cycloalkyl, phenyl, benzyl and heteroaryl, by themselves or as part of another group, are each independently substituted by 0 to 3 R d Replace; and R dare independently halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Alkoxy.

[0112] 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.

[0113] In another embodiment of the present invention, the compound is selected from Examples 1 to 43 as described in the specification, or a stereoisomer, tautomer or a pharmaceutically acceptable salt or solvate thereof.

[0114] In another embodiment of the present invention, the compound is selected from Examples 1 to 20 as described in the specification, or a stereoisomer, tautomer or a pharmaceutically acceptable salt or solvate thereof.

[0115] 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 50 Value ≤ 100 nM; In another embodiment, the compounds of the present invention have hLPA1 IC 50 Value ≤50nM.

[0116] II. Other Embodiments of the Invention

[0117] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is an antagonist of at least one LPA receptor. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is an LPA1 antagonist. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is an LPA2 antagonist. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is an LPA3 antagonist.

[0118] In some embodiments, the present application provides a compound selected from an active metabolite, a tautomer, a pharmaceutically acceptable salt or a solvate of a compound of formula (I).

[0119] 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.

[0120] 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.

[0121] In another embodiment, the present invention provides a process for preparing a compound of the present invention.

[0122] In another embodiment, the present invention provides an intermediate for preparing a compound of the present invention.

[0123] In another embodiment, the present invention provides a pharmaceutical composition further comprising an additional therapeutic agent.

[0124] In another embodiment, the present invention provides a method for treating a 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] As used herein, "treating" or "treatment" encompasses treatment of 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.

[0129] 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 preferred aspects of the present invention mentioned in the present application. 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.

[0130] III. Chemistry

[0131] 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.

[0132] 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.

[0133] 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)).

[0134] 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.

[0135] 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.

[0136] "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.

[0137] "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.

[0138] "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.

[0139] 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.

[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. "Benzyl" may also be represented by the formula "Bn".

[0141] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. "C1 to C6 alkoxy" or "C 1-6 "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-.

[0142] 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.

[0143] 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".

[0144] 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".

[0145] 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".

[0146] 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.

[0147] 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.

[0148] As used herein by itself or as part of another group, the term "halogen" or "halo" refers to chlorine, bromine, fluorine and iodine, with chlorine or fluorine being preferred.

[0149] "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.

[0150] "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.

[0151] "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.

[0152] 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.

[0153] 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.

[0154] 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 stated for the ring may also be present on the bridge.

[0155] 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,

[0156]

[0157] 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.

[0158] 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 the 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 produces 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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).

[0163] 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.

[0164] 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.

[0165] 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).

[0166] 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.

[0167] 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.

[0168] 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

[0169]

[0170] 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 , 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 alkyl substituent described herein.

[0171] 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.

[0172] According to the conventions used in the art, as used in the structural formulas of this application, the bonds pointing to the bold lines, such as Depicts bonds that are points of attachment of a moiety or substituent to the core or backbone structure.

[0173] 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.

[0174] It should be understood that in this application, 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 on.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] As used 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 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.

[0179] 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.

[0180] 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.

[0181] Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0182] 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:

[0183]

[0184] Therefore, the present invention is intended to encompass all possible tautomers, even when a structure depicts only one of them.

[0185] The phrase "pharmaceutically acceptable" is used in this application 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 problems or complications, commensurate with a reasonable benefit / risk ratio.

[0186] 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 a parent compound containing a basic or acidic portion. 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.

[0187] 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 of formula (I) or their pharmaceutically acceptable salts that are not suitable for medical use but can be used, for example, for separation or purification.

[0188] Preferred salts of compounds of formula (I) containing a basic group include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate, nitrate or acetate.

[0189] Preferred salts of compounds of formula (I) containing an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.

[0190] In addition, the compounds of formula (I) may be in the form of prodrugs. Any compound that is converted in vivo to obtain a bioactive agent (i.e., a compound of formula I) 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:

[0191] a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds., Methods in Enzymology, 112: 309-396, Academic Press (1985);

[0192] 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);

[0193] c) Bundgaard, H., Adv.Drug Deliv.Rev., 8:1-38 (1992);

[0194] d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and

[0195] e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

[0196] 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.

[0197] 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).

[0198] 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" in this application, 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.

[0199] The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar 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 the compounds of the present invention bound to biological receptors.

[0200] "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.

[0201] 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.

[0202] abbreviation

[0203] Abbreviations used in this application 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 normal concentration, "M" is molar concentration, "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.

[0204] Me Methyl

[0205] Et Ethyl

[0206] Pr Propyl

[0207] i-Pr Isopropyl

[0208] Bu Butyl

[0209] i-Bu Isobutyl

[0210] t-Bu tert-butyl

[0211] Ph Phenyl

[0212] Bn Benzyl

[0213] Boc or BOC tert-butoxycarbonyl

[0214] Boc2O Di-tert-butyl dicarbonate

[0215] AcO or HOAc Acetic acid

[0216] AlCl3 Aluminum chloride

[0217] AIBN Azobisisobutyronitrile

[0218] BBr3 Boron tribromide

[0219] BCl3 Boron trichloride

[0220] BEMP 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphabenzene

[0221] BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

[0222] Burgess reagent (1-methoxy-N-triethylammoniumsulfonyl-formimide ester

[0223] reagent)

[0224] CBz benzyloxycarbonyl

[0225] DCM or CH2Cl2 Dichloromethane

[0226] CH3CN or ACN Acetonitrile

[0227] CDCl3 deuterated chloroform

[0228] CHCl3 Chloroform

[0229] mCPBA or m-CPBA m-Chloroperbenzoic acid

[0230] Cs2CO3 Cesium carbonate

[0231] Cu(OAc)2 Copper(II) acetate

[0232] Cy2NMe N-Cyclohexyl-N-methylcyclohexylamine

[0233] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0234] DCE 1,2-Dichloroethane

[0235] DEA Diethylamine

[0236] Dess-Martin 1,1,1-Tris(acetoxy)-1,1-dihydro-1,2-benziodoxolan-3-(1H)-one

[0237] DIC or DIPCDI Diisopropylcarbodiimide

[0238] DIEA, DIPEA or Whitney diisopropylethylamine

[0239] Hunig's base

[0240] DMAP 4-dimethylaminopyridine

[0241] DME 1,2-Dimethoxyethane

[0242] DMF Dimethylformamide

[0243] DMSO Dimethyl sulfoxide

[0244] cDNA complementary DNA

[0245] Dppp (R)-(+)-1,2-Bis(diphenylphosphino)propane

[0246] DuPhos (+)-1,2-Bis((2S,5S)-2,5-diethylphospholyl)benzene

[0247] EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide

[0248] EDCI N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

[0249] EDTA Ethylenediaminetetraacetic acid

[0250] (S,S)-EtDuPhosRh(I) (+)-1,2-Bis((2S,5S)-2,5-diethylphospholyl)benzene(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate

[0251] Et3N or TEA Triethylamine

[0252] EtOAc Ethyl acetate

[0253] Et2O Ether

[0254] EtOH

[0255] GMF Glass Microfiber Filter

[0256] Grubbs II (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium

[0257] HCl

[0258] HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0259] HEPES 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid

[0260] Hex

[0261] HOBt or HOBT 1-Hydroxybenzotriazole

[0262] H2O2 Hydrogen Peroxide

[0263] IBX 2-iodooxybenzoic acid

[0264] H2SO4 sulfuric acid

[0265] Jones reagent (2M solution of CrO3 in aqueous H2SO4)

[0266] reagent)

[0267] K2CO3 Potassium carbonate

[0268] K2HPO4 Potassium Hydrogen Phosphate (Potassium Hydrogen Phosphate)

[0269] KOAc Potassium acetate

[0270] K3PO4 Tripotassium Phosphate

[0271] LAH Lithium Aluminum Hydride

[0272] LG Leaving Group

[0273] LiOH Lithium Hydroxide

[0274] MeOH Methanol

[0275] MgSO4 Magnesium sulfate

[0276] MsOH or MSA Methanesulfonic acid / methanesulfonic acid

[0277] NaCl Sodium chloride

[0278] NaH Sodium hydride

[0279] NaHCO3 Sodium bicarbonate

[0280] Na2CO3 Sodium carbonate

[0281] NaOH Sodium hydroxide

[0282] Na2SO3 Sodium sulfite

[0283] Na2SO4 Sodium sulfate

[0284] NBS N-bromosuccinimide

[0285] NCS N-Chlorosuccinimide

[0286] NH3 Ammonia

[0287] NH4Cl Ammonium chloride

[0288] NH4OH Ammonium Hydroxide

[0289] NH4 + HCO2 - Ammonium formate

[0290] NMM N-Methylmorpholine

[0291] OTf triflate or trifluoromethanesulfonate

[0292] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0293] Pd(OAc)2 Palladium(II) acetate

[0294] Pd / C Palladium / Carbon

[0295] Pd(dppf)Cl2 [1,1'-Bis(diphenylphosphino)-ferrocene]palladium(II) chloride

[0296] Ph3PCl2 Triphenylphosphine dichloride

[0297] PG Protecting Group

[0298] POCl3 Phosphorus oxychloride

[0299] PPTS Pyridinium p-toluenesulfonate

[0300] i-PrOH or IPA Isopropyl alcohol

[0301] PS Polystyrene

[0302] RT or rt Room temperature

[0303] SEM-Cl 2-(Trimethylsilyl)ethoxymethyl chloride

[0304] SiO2 Silicon Dioxide

[0305] SnCl2 Tin(II) chloride

[0306] TBAF Tetra-n-butylammonium fluoride

[0307] TBAI Tetra-n-butylammonium iodide

[0308] TFA Trifluoroacetic acid

[0309] THF Tetrahydrofuran

[0310] THP Tetrahydropyran

[0311] TMSCHN2 Trimethylsilyldiazomethane

[0312] TMSCH2N3 Trimethylsilylmethyl azide

[0313] T3P Propanephosphonic anhydride

[0314] TRIS Tris(hydroxymethyl)aminomethane

[0315] pTsOH p-Toluenesulfonic acid

[0316] IV. Biology

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] LPA receptor

[0323] LPA1 (previously known as VZG-1 / EDG-2 / mrec1.3) interacts with three types of G proteins G 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.

[0324] 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.

[0325] 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 causes normal LPA-mediated signaling responses in at least some cell types (Choi et al., Biochemica et Biophysica Acta 2008, 1781, pp. 531-539).

[0326] 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).

[0327] 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.

[0328] 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.

[0329] 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.

[0330] Illustrative Biological Activities

[0331] Wound healing

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] Fibrosis

[0338] 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.

[0339] 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).

[0340] Many muscular dystrophies are characterized by progressive weakness and wasting of muscle tissue, as well as extensive fibrosis. It has been shown that LPA treatment of cultured myoblasts induces significant expression of connective tissue growth factor (CTGF). CTGF subsequently induces the expression of collagen, fibronectin and integrin and induces dedifferentiation of these myoblasts. LPA treatment induces reproducible and high levels of CTGF induction in various 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 conducts signals downstream and in parallel with TGFβ.

[0341] 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).

[0342] 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).

[0343] 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).

[0344] 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).

[0345] Pulmonary fibrosis

[0346] 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.

[0347] 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.

[0348] 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).

[0349] The LPA-LPA1 pathway is critical in lung fibrosis, in fibroblast recruitment and vascular leakage.

[0350] 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.

[0351] Renal fibrosis

[0352] 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).

[0353] 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.

[0354] 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).

[0355] 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.

[0356] Liver fibrosis

[0357] 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.

[0358] Ocular fibrosis

[0359] 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.

[0360] 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.

[0361] 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.

[0362] Cardiac fibrosis

[0363] 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.

[0364] Treatment of fibrosis

[0365] In one aspect, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is used to treat or prevent fibrosis in mammals. In one aspect, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is used to treat fibrosis of organs or tissues of mammals. In one aspect, it is a method for preventing fibrotic conditions in mammals, the method comprising administering a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvate to a mammal with 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 organs or tissues. 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 tendency to produce organ or tissue fibrosis. In one aspect, the mammal is administered a compound of formula (I) or its pharmaceutically acceptable salt or solvate to prevent or minimize scarring after injury. In one aspect, injury includes surgery.

[0366] 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.

[0367] 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.

[0368] 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 (I), or a pharmaceutically acceptable salt or solvate 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.

[0369] In one aspect, the compound of formula (I) or its pharmaceutically acceptable salt or solvate 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, one or more agents include corticosteroids. In one aspect, one or more agents include immunosuppressants. In one aspect, one or more agents include B cell antagonists. In one aspect, one or more agents include uteroglobin.

[0370] In one aspect, the compound of formula (I) or its pharmaceutically acceptable salt or solvate 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, hyperplastic 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 (I) or its pharmaceutically acceptable salt or solvate is used to treat systemic sclerosis.

[0371] pain

[0372] 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).

[0373] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate 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.

[0374] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat muscle fiber pain. In one aspect, muscle fiber pain originates from the formation of fibrous scar tissue in contracted (spontaneous) muscles. Fibrosis makes tissues stick together and inhibits blood flow, causing pain.

[0375] cancer

[0376] 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).

[0377] 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.

[0378] 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).

[0379] 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).

[0380] 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.

[0381] 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.

[0382] 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 compound of formula (I) inhibits or reduces IL-8 expression in ovarian cancer cell lines.

[0383] In one aspect, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is used to treat cancer. In one aspect, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is used to treat malignant and benign proliferative diseases. In one aspect, the compound of formula (I) or its pharmaceutically acceptable salt or solvate 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 (I) or a pharmaceutically acceptable salt or solvate thereof and a second therapeutic agent, wherein the second therapeutic agent is an anticancer agent.

[0384] 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.

[0385] 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.

[0386] 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.

[0387] Respiratory and allergic diseases

[0388] 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).

[0389] 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.

[0390] 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.

[0391] 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).

[0392] 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.

[0393] 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 (I) or its pharmaceutically acceptable salt or solvate is used to treat various allergic conditions in mammals. In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat a respiratory disease, disorder or condition in a mammal. In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat asthma in a mammal. In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat chronic asthma in a mammal.

[0394] 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.

[0395] 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.

[0396] In one aspect, the present application provides a use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate 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 (I) or a pharmaceutically acceptable salt or solvate 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.

[0397] Nervous system

[0398] 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.

[0399] 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).

[0400] In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is provided for treating or preventing a nervous system disorder in a mammal. As used herein, the term "nervous system disorder" refers to a condition that alters 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.

[0401] In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate 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.

[0402] Cardiovascular disease

[0403] 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).

[0404] 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).

[0405] 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.

[0406] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat or prevent cardiovascular disease in a mammal.

[0407] As used in this application, 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.

[0408] In one aspect, the present application provides 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 (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition or medicament comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, at least once.

[0409] In one aspect, the present application provides a method for reducing cardiac reperfusion injury after myocardial ischemia and / or endotoxin shock, comprising administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof at least once.

[0410] In one aspect, the present application provides a method for reducing vasoconstriction in a mammal, comprising administering to the mammal at least once an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0411] In one aspect, the present application provides a method for reducing or preventing elevated blood pressure in a mammal, comprising administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof at least once.

[0412] Inflammation

[0413] 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.

[0414] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate 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, the LPA1 antagonist is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0415] 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.

[0416] Other diseases, illnesses or conditions

[0417] 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 a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a mammal. 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.

[0418] 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 (I) or a pharmaceutically acceptable salt or solvate 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 (I) or a pharmaceutically acceptable salt or solvate 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.

[0419] 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).

[0420] In certain aspects, a method for preventing or treating eosinophils and / or basophils and / or dendritic cells and / or neutrophils and / or monocytes and / or T cell recruitment comprises administering to a mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof at least once.

[0421] 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 (I) or a pharmaceutically acceptable salt or solvate thereof.

[0422] 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 (I) or a pharmaceutically acceptable salt or solvate thereof and determining whether the patient responds to the treatment.

[0423] In one aspect, the present application provides a compound of formula (I), a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, and a pharmaceutically acceptable solvate thereof, which is an LPA1 antagonist and is used to treat a patient suffering from 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 conditions or diseases in which an absolute or relative excess of LPA is present and / or observed.

[0424] 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.

[0425] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate 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.

[0426] In one aspect, the present application provides a use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for treating or preventing ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis and papillary conjunctivitis in a mammal, comprising administering an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to the mammal at least once.

[0427] In one aspect, the present application provides a use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for treating or preventing Sjögren's disease or inflammation associated with dry eye in a mammal, comprising administering an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to the mammal at least once.

[0428] 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, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for treating or preventing osteoarthritis in a mammal, comprising administering an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to the mammal at least once.

[0429] 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, the present application provides a method for treating or preventing rheumatoid arthritis in a mammal by using a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, comprising administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof at least once.

[0430] 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, the present application provides a method for promoting adipose tissue formation in a mammal by using a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, comprising administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof at least once.

[0431] a. In vitro analysis

[0432] The effectiveness of the compounds of the invention as LPA1 inhibitors can be determined in an LPA1 functional antagonist assay as follows:

[0433] 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.

[0434] b. In vivo analysis

[0435] LPA challenge and plasma histamine assessment

[0436] 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.

[0437] 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).

[0438] 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.

[0439] V. Pharmaceutical compositions, preparations and combinations

[0440] In some embodiments, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition further contains at least one pharmaceutically acceptable inactive ingredient.

[0441] In some embodiments, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate 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.

[0442] 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).

[0443] 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, which includes administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate 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 (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method further comprises administering one or more additional therapeutically active agents in addition to the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0444] In some embodiments, the one or more other therapeutically active agents other than a compound of formula (I) or a pharmaceutically acceptable salt or solvate 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).

[0445] In some embodiments, one or more other therapeutically active agents other than a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof are other anti-fibrotic agents selected from the group consisting of pirfenidone, nintedanib, thalidomide, carumab, FG-3019, fulesomab, interferon α, lecithinized superoxide dismutase, simtuzumab, tanzester, 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.

[0446] In some embodiments, one or more other therapeutically active agents other than a compound of formula (I) or a pharmaceutically acceptable salt or solvate 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, p38MAPK inhibitors, pirfenidone, multikinase inhibitors, nintedanib, sorafenib.

[0447] In some embodiments, one or more other therapeutically active agents other than the compound of formula (I) or a pharmaceutically acceptable salt or solvate 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.

[0448] 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. 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.

[0449] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered orally.

[0450] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is topically administered. In such embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, massage agents, coatings, medicine 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 (I) or its pharmaceutically acceptable salt or solvate is topically administered to the skin.

[0451] In another aspect, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered by inhalation. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered by inhalation directly targeting the pulmonary system.

[0452] In another aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is formulated for intranasal administration. Such formulations include nasal sprays, nasal atomizers and the like.

[0453] In another aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is formulated as eye drops.

[0454] Another aspect is the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate 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, 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 in this application.

[0455] Any of the foregoing aspects are further embodiments, wherein: (a) an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate 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.

[0456] 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.

[0457] 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.

[0458] 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 (I) or a pharmaceutically acceptable salt or solvate thereof to a mammal in need thereof.

[0459] In one aspect, a medicament for treating an LPA-dependent or LPA-mediated disease or condition in a mammal is provided, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0460] In some cases, the present application discloses the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for treating an LPA-dependent or LPA-mediated disease or condition.

[0461] In some cases, the present application discloses the use of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for treating or preventing an LPA-dependent or LPA-mediated disease or condition.

[0462] 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 (I) or a pharmaceutically acceptable salt or solvate thereof.

[0463] 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.

[0464] 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.

[0465] 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.

[0466] In one aspect, the present application features an LPA-dependent or LPA-mediated disease or condition.

[0467] 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 (I) or a pharmaceutically acceptable salt or solvate thereof.

[0468] In one aspect, the organ fibrosis comprises lung fibrosis, kidney fibrosis or liver fibrosis.

[0469] 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 (I) or a pharmaceutically acceptable salt or solvate thereof. In one aspect, the mammal has been diagnosed with pulmonary fibrosis.

[0470] In one aspect, the compounds disclosed herein are used to treat idiopathic pulmonary fibrosis (common interstitial pneumonia) in a mammal.

[0471] In some embodiments, the compounds disclosed herein are used to treat diffuse parenchymal interstitial lung disease in mammals: 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-Prake syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease.

[0472] In some embodiments, the compounds disclosed herein are used to treat post-transplant fibrosis associated with chronic rejection in mammals: bronchiolitis obliterans of lung transplants.

[0473] In some embodiments, the compounds disclosed herein are used to treat skin fibrosis in mammals: scleroderma, Dupuytren's disease, keloids.

[0474] In one aspect, the compounds disclosed herein are used to treat liver fibrosis with or without cirrhosis in mammals: 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.

[0475] In one aspect, the compounds disclosed herein are used to treat renal fibrosis: tubulointerstitial fibrosis, glomerulosclerosis in mammals.

[0476] 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 (I) or a pharmaceutically acceptable salt or solvate thereof. In various embodiments, the agents are administered in any order, including simultaneously.

[0477] In any of the embodiments disclosed herein, the mammal is a human.

[0478] In some embodiments, the compounds provided herein are administered to humans.

[0479] In some embodiments, the compounds provided herein are administered orally.

[0480] 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.

[0481] In other embodiments, the compounds provided herein are used in the preparation of a medicament for inhibiting LPA1 activity.

[0482] An article of manufacture is provided comprising packaging material, a compound of formula (I) or a pharmaceutically acceptable salt or solvate 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.

[0483] VI. General Synthesis, Including Schemes

[0484] 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.

[0485] 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)).

[0486] Formula (I) compounds can be prepared by the illustrative 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.

[0487] Scheme 1 describes the synthesis of pyrazole-azinonyl (heteroaryl) cyclohexyl acids 14. Pyrazole 5-carboxylic acid 1 is reduced to the corresponding pyrazole 5-methanol (either by a two-step process, via an initial reaction with a chloroformate followed by low temperature reduction with NaBH4; or by direct reduction with diborane), which is then protected to give the protected hydroxypyrazole 2. Regioselective halogenation of pyrazole 2 provides 4-halopyrazole 3, which is then subjected to Suzuki-Miyaura coupling with 4-hydroxyaryl / heteroaryl boronic acid 4 to give 4-hydroxyaryl / heteroaryl pyrazole 5. Reaction of phenol / hydroxyheteroaryl pyrazole 5 with 3-hydroxycyclohexyl ester 6 under Mitsunobu reaction conditions (Kumara Swamy, KC, Chem. Rev., 2009, 109, 2551-2651) gives the corresponding pyrazole cycloalkyl ether ester 7. Deprotection of hydroxymethylpyrazole 7 provides cyclohexyl ester pyrazolol 8. Pyrazolol 8 is then reacted with PBr3 (or another mild brominating agent such as CBr4 / Ph3P) to give the corresponding bromide 9. Displacement of pyrazole bromide 9 with NaN3 (or other azide equivalent reagent) gives pyrazole azide 10, which is subjected to reduction (e.g. Staudinger reduction with Ph3P / water) to give pyrazolamine 11. Pyrazolamine 11 is then reacted with halopyridine / pyrimidine 12 in the presence of an appropriate base (nucleophilic aromatic substitution) or by transition metal (e.g. Pd) catalyzed amination to give pyrazolamino-azines 13. Deprotection of pyrazolamino-azines cyclohexyl esters 13 provides the desired pyrazolamino-azines cyclohexyl acids 14.

[0488] Solution 1

[0489]

[0490] Scheme 2 describes an alternative synthetic route for the synthesis of amino-aryl / heteroaryl pyrazole-aryloxycyclohexyl acids 14. Amino-azines 15 are reacted with bromides 10 in the presence of a base (e.g., NaH, etc.) or under transition metal catalytic conditions (e.g., Pd-ligand mediated) to afford amino-azines methylpyrazole-aryloxycyclohexyl esters 13. Subsequent ester deprotection of the cyclohexyl esters 13 affords the desired amino-azines pyrazole-aryl / heteroaryl-oxycyclohexyl acids 14.

[0491] Solution 2

[0492]

[0493] Scheme 3 describes a synthetic route for the synthesis of pyrazole-triazine aryloxycyclohexyl acids 19 and 21. Reaction of dihalotriazine 16 with pyrazole-amine 11 in the presence of a base affords halotriazinyl-pyrazole-aryloxycyclohexyl ester 17. Subsequent dehalogenation of halotriazine pyrazole 17 provides pyrazole-triazine 18. Deprotection of pyrazole-triazine cyclohexyl ester 18 provides pyrazole-triazine cyclohexyl acid 19. Alternatively, pyrazole-triazine cyclohexyl ester 19 is reacted with an alcohol (R) in the presence of a base. 4 OH) to replace the halogen of halogenated triazine-pyrazole 17 to give alkoxy triazine-pyrazole 20. Deprotection of pyrazole-alkoxy triazine cyclohexyl ester 20 gives pyrazole-triazine cyclohexyl acid 21.

[0494] Solution 3

[0495]

[0496] Scheme 4 describes the synthesis of pyrimidine-pyrazoloazines cyclohexyl acids 28. 4-Halopyrazole 3 is metallated (e.g., with n-BuLi or t-BuLi) and then reacted with a trialkyl borate to give the pyrazole 4-boronate (or alternatively, after hydrolysis, the corresponding boronic acid) 22. Mitsunobu reaction of an appropriately substituted 4-hydroxy-2-halopyrimidine 23 with a 3-hydroxycyclohexyl ester 8 gives the corresponding pyrimidinyloxycycloalkyl ester 24. Suzuki-Miyaura cross-coupling of the halopyrimidine 24 with the pyrazole boronate ester 22 provides pyrimidinyl-pyrazole 25. Deprotection of the hydroxymethylpyrazole 25 provides the alcohol, which is then subjected to the same sequence described in Scheme 1 (alcohol→bromide→azide→amine) to give the pyrimidinylpyrazolamine 26. Pyrazolamine 26 is then reacted with haloazines 12 in the presence of an appropriate base (nucleophilic aromatic substitution) or by transition metal (e.g., Pd) catalyzed amination to give pyrimidinyl-pyrazolamino-azines 27. Deprotection of pyrimidinyl-pyrazoloazines cyclohexyl esters 27 affords the desired pyrimidinyl-pyrazoloazines cyclohexyl acids 28.

[0497] Solution 4

[0498]

[0499] Scheme 5 describes an alternative synthesis of pyrazole-azines aryloxy-cyclohexyl acids 15. Protection of hydroxyaryl / heteroaryl-pyrazole 5 followed by alcohol deprotection affords pyrazolol 29, which is then converted (with a brominating agent such as PBr3 or CBr4 / Ph3P) to the corresponding pyrazole bromide 30, and subsequently to pyrazolamine 31 (via the two-step sequence in Scheme 1 with displacement of the bromide with NaN3 followed by Staudinger reduction of the azide product [Ph3P / H2O]). Pyrazolamine 31 is then subjected to base-mediated reaction or transition metal-catalyzed cross-coupling reaction (e.g., palladium-mediated) with haloazines 12 to afford pyrazolamino-azines 32. Deprotection of pyrazole-azines 32 affords hydroxy-aryl / hydroxyheteroaryl pyrazoles 33, which are then subjected to Mitsunobu reaction with hydroxy-cyclohexyl esters 8. The resulting pyrazole-azine-cyclohexyl ester 14 is then deprotected to provide the desired pyrazole-azine-cyclohexyl acid 15 (as described in Scheme 1).

[0500] Solution 5

[0501]

[0502] Scheme 6 describes the synthesis of pyrazole-ethyl-azinocyclohexyl acids 40. Oxidation of the pyrazolemethanol intermediate 9 to the corresponding aldehyde (e.g., Dess-Martin periodinane or Sven oxidation) followed by olefination (e.g., Wittig or Peterson olefination) provides the pyrazole terminal olefin 34. Hydroboration of the olefin 34 at the terminal carbon (e.g., with 9-BBN) followed by oxidative workup affords the corresponding pyrazoleethyl alcohol 35. The pyrazoleethyl alcohol 35 is then reacted with PBr3 (or another mild brominating agent such as CBr4 / Ph3P) to afford the corresponding bromide 36. Displacement of the bromide 36 with NaN3 (or other azide equivalent reagent) affords the pyrazole azide 37, which is reduced (e.g., Staudinger reduction with Ph3P / water) to afford the pyrazoleamine 38. Pyrazole amine 38 is then reacted with haloazines 12 in the presence of an appropriate base or by transition metal (e.g., Pd) catalyzed amination to afford pyrazole amino-azines 39, which are then ester deprotected to afford the desired pyrazole-ethyl-amino-aziridine aryloxycyclohexyl acids 40.

[0503] Solution 6

[0504]

[0505] Scheme 7 describes the synthesis of pyrazole amino-azinic acid 45. Cyclohexyl ether pyrazole alcohol 9 undergoes oxidation to generate pyrazole carboxylic acid 41 (e.g., direct oxidation to the acid with pyridinium dichromate; or by a two-step process via an aldehyde [Sven oxidation or Dess-Martin periodinane followed by oxidation to the acid with NaClO2, e.g., Lindgren, BO, Acta Chem. Scand. 1973, 27, 888]). Curtius rearrangement of isoxazole acid 41 in the presence of tert-butyl alcohol provides pyrazole NH-Boc-carbamate 42. Deprotection of pyrazole NH-Boc carbamate 42 under acidic conditions provides pyrazoleamine 43. Pyrazoleamine 43 then undergoes a transition metal-catalyzed cross-coupling reaction with halo-azines 12 to give pyrazoleamino-azine cyclohexyl esters 44, which are then ester-deprotected to give the desired pyrazole-aminoazine-aryloxycyclohexyl acids 45.

[0506] Solution 7

[0507]

[0508] Scheme 8 describes an alternative synthetic route to the synthesis of pyrazole-azines cyclohexyl acids 14 and pyrimidine-pyrazole-azines cyclohexyl acids 28. 4-Halopyrazole aldehyde 46 (e.g., available by deprotection of pyrazolol 3 followed by Dess-Martin or Swern oxidation) is converted to the intermediate pyrazole aldehyde boronate ester 47 (via Pd-mediated borylation with B2Pin2; e.g., Ishiyama, T. et al., J. Org. Chem. 1995, 60, 7508-7510). Suzuki-Miyaura cross-coupling of 4-haloarene / heteroarene-oxycyclohexyl ester 24 with pyrazole aldehyde boronate ester 47 affords pyrazole aldehyde oxycycloalkyl ester 48. Formation of the imine of pyrazole aldehyde 48 with appropriately substituted amino-azines 15 (e.g. catalyzed by a Lewis acid such as Ti(OiPr)3Cl) followed by reductive amination (e.g., with NaBH(OAc)3, see Abdel-Magid, AF et al., J. Org. Chem. 1996, 61, 3849-3862; or with NaBH3CN) provides the corresponding pyrazole amino-azine cyclohexyl ester. Acid deprotection of the pyrazole-azine cyclohexyl ester provides aryl / heteroaryl-pyrazole-azine cyclohexyl acid 14. The corresponding Suzuki-Miyaura cross-coupling reaction of 4-halopyrimidinyloxycyclohexyl ester 20 with pyrazole aldehyde boronate ester 47 provides pyrimidine-pyrazole aldehyde 49. Imine formation of pyrimidine-pyrazole aldehyde 49 with appropriately substituted amino-azines 15 followed by reductive amination also affords the corresponding pyrimidine-pyrazoleamino-azine cyclohexyl ester. Acid deprotection of the pyrimidine-pyrazole-azine cyclohexyl ester provides pyrimidine-pyrazole-azineoxycyclohexyl acid 22.

[0509] Solution 8

[0510]

[0511] Scheme 9 describes the synthesis of pyrazole-azines cyclohexyl acids 56. Reaction of 4-hydroxyaryl / heteroaryl boronate esters 4 with 3-hydroxycyclohexyl esters 6 under Mitsunobu reaction conditions (Kumara Swamy, KC, Chem. Rev., 2009, 109, 2551-2651) affords the corresponding aryl / heteroaryloxycycloalkyl esters 50. Bromination of protected 1,5-dialkyl-1H-pyrazole-4-carboxylate 51 affords bromopyrazole 52. Suzuki-Miyaura coupling reaction of bromopyrazole 41 with aryl / heteroaryl boronate esters 50 (or the corresponding boronic acid) affords the corresponding pyrazole-aryl / heteroaryloxycycloalkyl esters 53. The pyrazole ester of 53 is selectively deprotected to the corresponding pyrazole carboxylic acid 54, which is then 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, as in Scheme 1) to the corresponding pyrazolol 55. The cyclohexyl ester-pyrazolol 55 is then converted to the pyrazolamino-azinic acid 56 via the same synthetic sequence as described in Scheme 1 (i.e., 8→14).

[0512] Solution 9

[0513]

[0514] VII. Examples

[0515] 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 in the present application or can be prepared using them.

[0516] 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.

[0517] Microwave reactions were performed in microwave reaction vessels (0.2-0.5 mL; 0.5-2 mL; 2-5 mL; 10-20 mL) under microwave (2.5 GHz) irradiation using a 400 W Biotage Initiator instrument.

[0518] HPLC / MS and preparative / analytical HPLC methods used in characterization or purification examples

[0519] 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.

[0520] 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.

[0521] The term HPLC refers to a Shimadzu high performance liquid chromatography instrument that uses one of the following methods:

[0522] 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.

[0523] Mobile phase A: water containing 0.05% TFA: CH3CN (95:5)

[0524] Mobile phase B: CH3CN:water (95:5) containing 0.05% TFA

[0525] TFA buffer pH=2.5; flow rate: 1 mL / min; wavelength: 254 nm, 220 nm.

[0526] 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.

[0527] Mobile phase A: water containing 0.05% TFA: CH3CN (95:5)

[0528] Mobile phase B: CH3CN:water (95:5) containing 0.05% TFA

[0529] TFA buffer pH=2.5; flow rate: 1 mL / min; wavelength: 254 nm, 220 nm.

[0530] HPLC-3: Chiralpak AD-H, 4.6×250mm, 5μm.

[0531] Mobile phase: 30% EtOH-mobile phase (1:1) / 70% CO2

[0532] Flow rate = 40 mL / min, 100 bar, 35°C; Wavelength: 220 nm

[0533] HPLC-4: Waters Acquity UPLC BEH C18, 2.1x50 mm, 1.7-μm particles;

[0534] Mobile phase A: 5:95 CH3CN:water containing 10 mM NH4OAc;

[0535] Mobile phase B: 95:5 CH3CN:water containing 10 mM NH4OAc;

[0536] 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.

[0537] HPLC-5: Waters Acquity UPLC BEH C18, 2.1x50 mm, 1.7-μm particles;

[0538] Mobile phase A: 5:95 CH3CN:water containing 0.1% TFA;

[0539] Mobile phase B: 95:5 CH3CN:water containing 0.1% TFA;

[0540] 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.

[0541] Intermediate 1. trans-3-((6-(5-(bromomethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester

[0542]

[0543] Intermediate 1A. 4-Bromo-1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole

[0544]

[0545] pTsOH.H2O (0.050 g, 0.262 mmol) was added to a solution of (4-bromo-1-methyl-1H-pyrazol-5-yl)methanol (1.0 g, 5.2 mmol) and 3,4-dihydro-2H-pyran (1.32 g, 15.7 mmol) in DCM (10 mL) at 0°C. The reaction was warmed to room temperature and stirred at room temperature overnight. The reaction was cooled to 0°C and neutralized to pH 7 with saturated NaHCO3 aqueous solution. The mixture was distributed between DCM (10 mL) and water (10 mL), and the aqueous layer was extracted with DCM (3x10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2; EtOAc / hexane) to give the title compound (1.40 g, 5.09 mmol, 97% yield) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ7.41(s,1H),4.72(d,J=12.9Hz,1H),4.65(dd,J=4.1,3.0Hz,1H),4.58(d,J=12.9Hz,1H),3.93(s,3H),3.88(ddd,J=11. 6,8.3,3.1Hz,1H),3.57(dddd,J=11.0,5.0,3.9,1.4Hz,1H),3.49(d,J=5.5Hz,2H),1.85–1.75(m,1H),1.75–1.66(m,1H),1.66–1.48(m,4H). [M+H] + =275.1.

[0546] Intermediate 1B. 1-Methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0547]

[0548] A mixture of intermediate 1A (469 mg, 1.71 mmol), KOAc (502 mg, 5.11 mmol), bis(pinacolato)diboron (649 mg, 2.56 mmol) in 1,4-dioxane (10 mL) was degassed with N2 for 5 min. PdCl2(dppf) (125 mg, 0.170 mmol) was added and the reaction was degassed with N2 again for 5 min. The reaction vessel was sealed and heated at 85 °C for 10 h, then cooled to room temperature. The mixture was partitioned between EtOAc (10 mL) and water (10 mL), and the aqueous phase was extracted with EtOAc (3x10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the crude title compound (717 mg, 0.89 mmol, 52.2% yield) as a yellow colorless oil. [M+H] + =323.1.

[0549] Intermediate 1C. trans-3-((6-bromopyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester

[0550]

[0551] To 6-bromopyridine-3-ol (300mg, 1.72mmol), (±)-cis-3-hydroxycyclohexanecarboxylic acid isopropyl ester (353mg, 1.90mmol), Et3N (0.264mL, 1.90mmol) and Ph3P (497mg, 1.90mmol) in THF (2mL) 0 ℃ mixture was added DIAD (0.369mL, 1.90mmol) dropwise over 15min. The reaction was stirred at room temperature overnight and then distributed between EtOAc (5mL) and water (5mL). The aqueous layer was extracted with EtOAc (3x10mL). The combined organic extracts were washed with brine (5mL), dried (MgSO4) and concentrated in vacuo. The crude product was subjected to chromatographic separation (SiO2; EtOAc / hexane) to obtain the title compound (255mg, 0.745mmol, 43.2% yield) as a white solid. 1 H NMR (500MHz, CDCl3) δ8.07(d,J=3.2Hz,1H),7.36(d,J=8.8Hz,1H),7.14(dd,J=8.7,3.1Hz,1H),5.02(hept,J=6.3Hz ,1H),4.61(dq,J=8.7,5.3,4.2Hz,1H),2.76(tt,J=9.0,4.4Hz,1H),2.03–1.51(m,8H),1.24(dd,J=6.3,1.9Hz,6H). [M+H] + =342.

[0552] Intermediate 1D. trans-isopropyl 3-((6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

[0553]

[0554] To a solution of intermediate 1B (717 mg, 0.891 mmol) in 1,4-dioxane (2 mL) was added intermediate 1C (254 mg, 0.742 mmol) and K2HPO4 (388 mg, 2.23 mmol), a second generation XPhos precatalyst (29 mg, 0.037 mmol) and water (2 mL). The mixture was evacuated and backfilled with Ar, repeated 3 times. The mixture was stirred at 60 ° C for 24 h, then cooled to room temperature and stirred at room temperature for 24 h. The mixture was extracted with EtOAc (3x5 mL), dried (MgSO4), and concentrated in vacuo to give a crude product. The crude material was subjected to chromatographic separation (12 g SiO2, a continuous gradient of 0 to 100% EtOAc in hexane in 12 min) to give the title compound (212 mg, 0.42 mmol, 56% yield) as a light yellow oil. 1 H NMR (500MHz, CDCl3) δ8.30 (d, J = 2.9Hz, 1H), 7.76 (s, 1H), 7.46–7.39 (m, 1H), 7. 28–7.21(m,1H),5.08–4.94(m,3H),4.72(dd,J=4.5,3.0Hz,1H),4.65(tq,J=5.5 ,2.8Hz,1H),3.97(s,3H),3.88(ddd,J=11.3,7.9,3.2Hz,1H),3.56–3.45(m,1H ), 2.80 (tt, J=9.8, 4.1Hz, 1H), 2.09–1.48 (m, 14H), 1.24 (dd, J=6.3, 1.8Hz, 6H). [M+H] + =458.1.

[0555] Intermediate 1E. trans-3-((6-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester

[0556]

[0557] To the solution of intermediate 1D (212mg, 0.463mmol) in MeOH (5mL), PPTS (12mg, 0.046mmol) is added. The mixture is heated at 60°C for 4h, then cooled to room temperature, quenched with saturated NaHCO3 aqueous solution (2mL) and concentrated in vacuo to remove MeOH. Residue is extracted with EtOAc (3x5mL). The combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is subjected to chromatographic separation (4g SiO2, continuous gradient of 0 to 100% EtOAc in hexane, 12min), title compound (75mg, 0.201mmol, 43.3% yield) is obtained as colorless oil. 1 H NMR (500MHz, CDCl3) δ8.15(d,J=2.9Hz,1H),7.66(s,1H),7.43(d,J=8.8Hz,1H),7.26(dd,J=8.8,2.9Hz,1H),6.93(s,1H),4.95(hept,J=6.2 Hz,1H),4.65(s,2H),4.58(dq,J=5.8,2.8Hz,1H),3.85(3,3H),2.72(tt,J=9.0,4.3Hz,1H),1.99–1.46(m,8H),1.17(dd,J=6.3,2.3Hz,6H). [M+H] + =374.2.

[0558] Intermediate 1

[0559] At 0 ℃, by PBr3(0.040mL, 0.426mmol) is added to the solution of intermediate 1E(53mg, 0.142mmol) in DME(1.5mL).The reaction is stirred at room temperature overnight, then cooled to 0 ℃, and neutralized to pH 7 with saturated NaHCO3 aqueous solution.Mixture is distributed between DCM(5mL) and water (3mL), and water layer is extracted with DCM(3x3mL).The organic extracts combined are dried (MgSO4) and concentrated in vacuo.Residue is subjected to chromatographic separation (SiO2; EtOAc / hexane), obtain the title compound (55mg, 0.126mmol, 89% yield) as white solid. 1H NMR (500MHz, CDCl3) δ8.34(d,J=2.8Hz,1H),7.74(s,1H),7.45(d,J=8.8Hz,1H),7.32–7.24(m,1H),5.11(s,2H),5.04(p,J=6.2 Hz,1H),4.68(tt,J=5.5,3.0Hz,1H),3.96(s,3H),2.80(dd,J=9.4,4.2Hz,1H),2.09–1.53(m,8H),1.26(dd,J=6.2,2.5Hz,6H). [M+H] + =436.0.

[0560] Intermediate 2. Isopropyl (1S,3S)-3-((2-(5-(aminomethyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0561]

[0562] Intermediate 2A. (4-Bromo-1-methyl-1H-pyrazol-5-yl)methanol

[0563]

[0564] A mixture of 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid (5.0 g, 24.4 mmol) and BH3.THF (36.6 mL of a 1 M solution in THF, 36.6 mmol) in THF (50 mL) was stirred at 50 °C for 2 days; at this time, LCMS showed that the reaction was complete. The reaction was cooled to room temperature, carefully quenched with 1N aqueous HCl and stirred at room temperature for 1 h, and then the mixture was extracted with EtOAc (3X50 mL). The combined organic extracts were concentrated in vacuo. The residue was chromatographed (80 g SiO2; continuous gradient from 0% to 100% EtOAc in hexanes, 25 min) to give the title compound (3.60 g, 18.9 mmol, 77% yield) as a white solid. LCMS, [M+H] + =193.0.

[0565] Intermediate 2B. 4-Bromo-1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole

[0566]

[0567] p-TsOH.H2O (0.050 g, 0.262 mmol) was added to a room temperature solution of intermediate 2A (1.0 g, 5.23 mmol) and 3,4-dihydro-2H-pyran (1.32 g, 15.7 mmol) in DCM (10 mL) at 0 ° C. The reaction was warmed to room temperature and stirred at room temperature overnight. The mixture was cooled to 0 ° C, neutralized to pH 7 with saturated NaHCO3 aqueous solution, and then distributed between DCM (10 mL) and H2O (10 mL). The aqueous layer was extracted with DCM (3x10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (40 g SiO2; a continuous gradient of 0%-80% EtOAc / hexane lasted 14 min) to give the title compound (1.40 g, 5.1 mmol, 97% yield) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ7.41(s,1H),4.72(d,J=12.9Hz,1H),4.65(dd,J=4.1,3.0Hz,1H),4.58(d,J=12.9Hz,1H),3.93(s,3H),3.88(ddd,J=11. 6,8.3,3.1Hz,1H),3.57(dddd,J=11.0,5.0,3.9,1.4Hz,1H),3.49(d,J=5.5Hz,2H),1.85–1.75(m,1H),1.75–1.66(m,1H),1.66–1.48(m,4H). [M+H] + =275.1.

[0568] Intermediate 2C. 1-Methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0569]

[0570] Ar was bubbled vigorously through a stirred mixture of Intermediate 2B (550 mg, 2.00 mmol), KOAc (589 mg, 6.00 mmol) and B2Pin2 (761 mg, 3.00 mmol) in 1,4-dioxane (10 mL) for 5 min. Pd(dppf)Cl2-CH2Cl2 (163 mg, 0.20 mmol) was added and the reaction was flushed with Ar and then heated to 100 °C for 16 h; LCMS analysis after 16 h indicated the reaction was complete. The reaction mixture was cooled to room temperature and partitioned between CH2Cl2 (20 mL) and H2O (10 mL); the resulting mixture was stirred vigorously. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude product was used in the next step without further purification.

[0571] Intermediate 2D. 2-Bromo-4-methylpyrimidin-5-ol

[0572]

[0573] A mixture of 2-chloro-4-methylpyrimidin-5-ol (500 mg, 3.46 mmol) and HBr (30 wt.% in HOAc; 3 mL) was heated to 110°C overnight, after which LCMS indicated the reaction was complete. The reaction mixture was cooled to room temperature, then poured into ice and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with saturated aqueous NaCO, water and brine, then dried (NaSO) and concentrated in vacuo to give the title compound (630 mg, 3.33 mmol, 96% yield) as an off-white solid. [M+H] + =189.1.

[0574] Intermediate 2E. 4-Methyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrimidin-5-ol

[0575]

[0576] A mixture of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (101 mg, 0.14 mmol), 2C (552 mg, 1.71 mmol), 2D (270 mg, 1.43 mmol), 2M NaCO aqueous solution (3.6 mL, 7.14 mmol) in MeCN (7 mL) was heated at 100 °C for 1 h in a microwave reactor, then cooled to room temperature, diluted with saturated NaHCO aqueous solution and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine, dried (NaSO) and concentrated in vacuo. The crude product was chromatographed (80 g SiO, continuous gradient of 0%-90% EtOAc in hexanes) to give the title compound (250 mg, 0.82 mmol, 58% yield) as a beige solid. 1H NMR(500MHz, CDCl3)δ8.85(d,J=1.42Hz,1H),8.14(d,J=1.41Hz,1H),5.15(m,2H),4.98(m,1H),4.69(m,1H),4.13(s,3H),3.8 2(ddd,J=11.33,7.90,3.08Hz,1H),3.49(m,1H),2.74(tt,J=11.5,3.67Hz,1H),2.15(m,1H),1.98–1.50(m,13H),1.20(m,6H). [M+H]+=305.1.1H NMR (500MHz, DMSO-d6) δ8.17(s,1H),7.86(s,1H),5.26(d,J=11.9Hz,1H),5.09(d,J=11.9H z,1H),4.77-4.69(m,1H),3.87(s,3H),3.85-3.77(m,2H),2.37(s,3H),1.73-1.39(m,6H).

[0577] Intermediate 2F. Isopropyl (1S,3S)-3-((4-methyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0578]

[0579] A mixture of (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (435 mg, 1.73 mmol), toluene (8 mL) and Bu3P (0.43 mL, 1.73 mmol) was stirred at room temperature for 30 min, after which intermediate 2E (210 mg, 0.69 mmol) and (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid isopropyl ester (231 mg, 1.24 mmol) were added in sequence. The reaction mixture was heated at 85 °C for 9 h, after which LC / MS indicated the formation of the desired product. The reaction was cooled to room temperature and diluted with CH2Cl2; the mixture was filtered and the filtrate was concentrated in vacuo. The crude oil was chromatographed (80 g SiO2; a continuous gradient from 0% to 90% EtOAc / hexane over 25 min, held at 90% EtOAc / hexane for 20 min) to give the title compound (190 mg, 0.40 mmol, 58% yield) as a light yellow oil. 1 H NMR(500MHz, CDCl3)δ8.98(s,1H),8.09(s,1H),5.51(t,J=6.90Hz,1H),5.43(s,1H),4.98(m,1H),4.80( d,J=6.88,2H),4.07(s,3H),2.72(tt,J=11.5,3.67Hz,1H),2.15(m,1H),1.98–1.50(m,7H),1.20(m,6H). [M+H] + =473.2.

[0580] Intermediate 2G. Isopropyl (1S,3S)-3-((2-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0581]

[0582] To a solution of intermediate 2F (463 mg, 0.98 mmol) in MeOH (5 mL) was added PPTS (0.932 g, 3.71 mmol). The reaction mixture was heated at 60 ° C for 2 h, then cooled to room temperature and diluted with water and saturated NaHCO3 aqueous solution. The mixture was extracted with EtOAc (3X 10 mL). The combined organic extracts were concentrated in vacuo and chromatographed (40 g SiO2; 0% to 100% EtOAc continuous gradient in hexane for 12 min, then kept at 100% EtOAc for 10 min) to give the title compound (323 mg, 0.79 mmol, 81% yield) as a white solid. LCMS, [M+H]+=389.3.1H NMR (500MHz, DMSO-d6) δ8.43(s,1H),7.88(s,1H),5.48(t,J=5.7Hz,1H),5.00(d,J=5.8Hz,2H),4.90(p,J=6.3H z,1H),4.82(s,1H),3.90(s,3H),2.67(d,J=10.3Hz,1H),2.42(s,3H),2.04–1.44(m,8H),1.18(d,J=6.2Hz,6H).

[0583] Intermediate 2H. Isopropyl (1S,3S)-3-((2-(5-(bromomethyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0584]

[0585] To a 0°C solution of Intermediate 2G (423 mg, 1.089 mmol) in DCM (15 mL) was added PBr3 (0.15 mL, 1.63 mmol). The reaction was stirred at room temperature overnight, then cooled to 0°C and neutralized with saturated aqueous NaHCO3 to 4% ethanol. The mixture was partitioned between DCM (20 mL) and water (10 mL), and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (24 g SiO2; a continuous gradient of 0% to 100% EtOAc in hexanes over 12 min) to give the title compound (450 mg, 0.997 mmol, 92% yield) as a white solid. LCMS, [M+H] + =451.2. 1H NMR (400MHz, CDCl3) δ8.26(s,1H),8.11(s,1H),5.24(s,2H),5.05(hept,J=6.3Hz,1H),4.74(dp,J=5.1,2.7H z,1H),3.97(s,3H),2.78(tt,J=9.8,4.0Hz,1H),2.52(s,3H),2.16–1.56(m,8H),1.27(dd,J=6.2,2.2Hz,6H).

[0586] Intermediate 2I. Isopropyl (1S,3S)-3-((2-(5-(azidomethyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0587]

[0588] To a solution of intermediate 2H (500 mg, 1.11 mmol) in DMF (2 mL) was added NaN3 (72 mg, 1.11 mmol), and the reaction was stirred at 80 ° C for 1 h; at this time, LCMS analysis indicated that the reaction was complete. The reaction mixture was cooled to room temperature, partitioned between EtOAc and water (10 mL each), and the resulting mixture was stirred at room temperature for 15 min. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude product was chromatographed (24 g SiO2; a continuous gradient of 0% to 100% EtOAc in hexanes over 12 min) to give the title compound (368 mg, 0.890 mmol, 80% yield) as a colorless oil. LCMS, [M+H] + =414.3. 1 H NMR(500MHz, CDCl3)δ8.25(s,1H),8.14(s,1H),5.09–5.03(m,1H),5.02(s,2H),4.74(dp,J=5.2,2.7Hz,1 H), 3.96 (s, 3H), 2.78 (tq, J = 8.0, 4.1Hz, 1H), 2.52 (s, 3H), 2.15–1.57 (m, 8H), 1.27 (dd, J = 6.3, 2.5Hz, 6H).

[0589] Intermediate 2

[0590] Ph3P (257 mg, 0.981 mmol) was added to a solution of intermediate 2I (338 mg, 0.817 mmol) in THF (6 mL) and H2O (2.0 mL), the reaction was stirred at room temperature overnight, and then absorbed into EtOAc and water (10 mL each). The resulting mixture was stirred at room temperature for 15 min, after which the organic layer was separated. The aqueous layer was extracted with EtOAc (3x5 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residual crude product was chromatographed (12 g SiO2; 100% EtOAc for 10 min, then a continuous gradient of 0% to 75% MeOH in EtOAc for 4 min, and maintained for 10 min; flow rate = 30 mL / min) to give the title compound (269 mg, 0.694 mmol, 85% yield) as a viscous yellow oil. LCMS, [M+H] + =388.3. 1 H NMR (500MHz, CD3CN) δ8.28(s,1H),7.90(s,1H),4.97(hept,J=6.2Hz,1H),4.73(dp,J=5.4,2.8Hz,1H),4.09(br s,2H),3.88(s,3H),2.75(tt,J=9.9,4.0Hz,1H),2.44(s,3H),2.11–1.53(m,8H),1.22(d,J=6.3Hz,6H).

[0591] Intermediate 3. Isopropyl (1S,3S)-3-((2-(5-formyl-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0592]

[0593] Intermediate 3A. 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carbaldehyde

[0594]

[0595] A mixture of 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (2.50 g, 13.2 mmol), bis(pinacolato)diboron (5.04 g, 19.8 mmol), KOAc (3.89 g, 39.7 mmol) and PdCl2(dppf) (0.484 g, 0.661 mmol) in 1,4-dioxane (50 mL) was degassed and then heated at 80 °C under N2 for 18 h before cooling to room temperature. The reaction mixture was diluted with EtOAc, then filtered and concentrated in vacuo. The residue was chromatographed (80 g SiO2; continuous gradient from 0% to 50% EtOAc in hexanes over 20 min) to give the title compound (3.0 g, 12.7 mmol, 96% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ10.27(s,1H),7.78(s,1H),4.19(s,3H),1.34(s,12H); 11 B NMR (128MHz, CDCl3) δ29.2 (br s, 1B).

[0596] Intermediate 3B. 2-Chloro-5-methoxy-4-methylpyrimidine

[0597]

[0598] A degassed mixture of 2,4-dichloro-5-methoxypyrimidine (5.70 g, 31.8 mmol), trimethylcyclotriboroxane (5.34 mL, 38.2 mmol) and K3PO4 (13.5 g, 63.7 mmol) in THF (50 mL) was sealed and stirred at 65°C for 16 h, then cooled to room temperature. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted twice with EtOAc; the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed (220 g SiO2; continuous gradient of 0% to 30% EtOAc in hexanes over 25 min) to give the title compound (1.6 g, 10.28 mmol, 32.3%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 3.92 (s, 3H), 2.45 (s, 3H).

[0599] 3C.2-Chloro-4-methylpyrimidin-5-ol

[0600]

[0601] To a -78 °C solution of intermediate 3B (1.60 g, 10.09 mmol) in DCM (20 mL) was added BBr (3.82 mL, 40.4 mmol) dropwise. The reaction mixture was slowly warmed to room temperature, stirred at room temperature for 16 h, then carefully quenched with saturated aqueous NaHCO (pH adjusted to ~4) and partitioned between EtOAc and water. The aqueous phase was extracted twice with EtOAc; the combined organic layers were dried (MgSO) and concentrated in vacuo. The crude product was chromatographed (40 g SiO; continuous gradient of 0-100% EtOAc in hexanes over 15 min) to give the title compound (1.33 g, 9.20 mmol, 91% yield) as a white solid. 1 HNMR (400MHz, DMSO-d6) δ10.63(s,1H),8.11(s,1H),2.34(s,3H).

[0602] Intermediate 3D. Isopropyl (1S,3S)-3-((2-chloro-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0603]

[0604] To a solution of intermediate 3C (1.30 g, 9.0 mmol), (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid isopropyl ester (3.01 g, 16.2 mmol) and Bu3P (4.44 mL, 18.0 mmol) in 1,4-dioxane (50 mL) was added (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (4.54 g, 18.0 mmol) at room temperature. The reaction mixture was stirred at 75 °C for 3 days, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was chromatographed (80 g SiO2; continuous gradient of 0% to 30% EtOAc in hexanes over 25 min) to give the title compound (1.72 g, 5.50 mmol, 61.1% yield) as a clear oil. 1 H NMR (500MHz, CDCl3) δ8.14 (s, 1H), 5.04 (spt, J = 6.2Hz, 1H), 4.71 (br d,J=2.2Hz,1H),2.75(tt,J=8.9,4.3Hz,1H),2.49(s,3H),2.10-1.84(m,4H),1.78-1.59(m,4H),1.26(dd,J=6.2,2.9Hz,6H).

[0605] Intermediate 3

[0606] A mixture of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd(amphos)Cl2; 0.204 g, 0.288 mmol), intermediate 3A (1.630 g, 6.91 mmol), intermediate 3D (1.72 g, 5.50 mmol) and 2M Na2CO3 aqueous solution (8.63 mL, 17.3 mmol) in MeCN (50 mL) was degassed and sealed. The reaction mixture was microwaved at 120°C for 1.5 h and then cooled to room temperature. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted 3 times with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed (80 g SiO2; a continuous gradient of 0%-50% EtOAc in hexanes over 25 min) to give the title compound (1.0 g, 2.59 mmol, 45% yield) as an oil. [M+H]+=387.2;1H NMR (400MHz, CDCl3) δ10.88(s,1H),8.26(s,1H),8.11(s,1H),5.03(spt,J=6.2Hz,1H),4.80-4.72(m,1H),4. 22(s,3H),2.82-2.71(m,1H),2.50(s,3H),2.14-1.87(m,4H),1.80-1.57(m,4H),1.25(dd,J=6.3,1.9Hz,6H).

[0607] Intermediate 4. (1S,3S)-3-((2-(5-(aminomethyl)-1-methyl-1H-pyrazol-4-yl)-4-ethyl-pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester

[0608]

[0609] Intermediate 4A. 2-Chloro-4-ethylpyrimidin-5-ol

[0610]

[0611] To a room temperature solution of 2-chloro-4-ethyl-5-methoxypyrimidine (4.0 g, 23.2 mmol) in DCM (46 mL) was slowly added 1 M BBr (46.3 mL, 46.3 mmol) in CH2Cl2 under N2. The reaction was stirred at room temperature for two days, after which ice was carefully added and the pH was adjusted to ~6 with 50% aqueous NaOH. The mixture was extracted three times with EtOAc; the combined organic extracts were concentrated in vacuo. The crude product was chromatographed (120 g SiO2; continuous gradient from 0% to 50% EtOAc in hexanes) to give 2-chloro-4-ethylpyrimidin-5-ol (2.0 g, 10.0 mmol, 43% yield). LCMS, [M+H]+=159.2.

[0612] Intermediate 4B. Isopropyl (1S,3S)-3-((2-chloro-4-ethylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0613]

[0614] To a room temperature solution of intermediate 4A (1.32 g, 8.3 mmol), (1S,3R)-3-hydroxy-cyclohexane-1-carboxylic acid isopropyl ester (2.79 g, 15 mmol) and Ph3P (6.55 g, 25 mmol) in THF (20 mL) was slowly added DEAD (3.95 mL, 25 mmol). The reaction was stirred at 50 °C for 2 days and then concentrated in vacuo. The residue was chromatographed (120 g SiO2, a continuous gradient of 0 to 50% EtOAc in hexanes at 50 mL / min for 40 min, then 100% EtOAc for 30 min) to give the title compound (0.83 g, 2.03 mmol, 24.4% yield). LCMS, [M+H] + =327.2.

[0615] Intermediate 4C. Isopropyl (1S,3S)-3-((4-ethyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0616]

[0617] A mixture of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.18 g, 0.25 mmol), Intermediate 2C (3.64 g, 5.1 mmol) and Intermediate 4B (0.83 g, 2.03 mmol) in 2M aqueous Na2CO3 (3.81 mL, 7.62 mmol) and 1,4-dioxane (5 mL) was heated at 120°C for 1.5 h in a microwave reactor and then cooled to room temperature. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (3x20 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed (40 g SiO2; then 80 g SiO2; continuous gradient of 0%-100% EtOAc in hexanes) to give the title compound (1.37 g, 2.39 mmol, 94% yield) as a dark oil. LCMS, [M+H] + =487.3.

[0618] Intermediate 4D. Isopropyl (1S,3S)-3-((4-ethyl-2-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0619]

[0620] A mixture of intermediate 4C (1.37 g, 2.82 mmol) and PPTS (0.071 g, 0.282 mmol) in MeOH (5 mL) was heated at 60 °C overnight, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM and saturated aqueous NaHCO3; the organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was chromatographed (40 g SiO2; continuous gradient from 0% to 100% EtOAc in hexanes) to give the title compound (0.868 g, 2.16 mmol, 77% yield). LCMS, [M+H] + =403.3.

[0621] Intermediate 4E. Isopropyl (1S,3S)-3-((2-(5-(bromomethyl)-1-methyl-1H-pyrazol-4-yl)-4-ethylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0622]

[0623] PBr3 (610 μl, 3.35 mmol) was added to a 0°C solution of intermediate 4D (540 mg, 1.34 mmol) in THF (5 mL). The reactant was stirred at room temperature overnight, then cooled to 0°C and neutralized with saturated NaHCO3 aqueous solution. The mixture was distributed between EtOAc (100 mL) and water (10 mL), and the aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (40 g SiO2; a continuous gradient of 0% to 100% EtOAc in hexane over 20 min) to give the title compound (375 mg, 0.8 mmol, 60% yield) as a white solid. LCMS, [M+H] + =467.2.

[0624] Intermediate 4F. Isopropyl (1S,3S)-3-((2-(5-(azidomethyl)-1-methyl-1H-pyrazol-4-yl)-4-ethylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0625]

[0626] A mixture of intermediate 4E (375 mg, 0.806 mmol) and NaN3 (79 mg, 1.21 mmol) in DMF (5 mL) was stirred at 80 °C for 1 h, then cooled to room temperature and partitioned between EtOAc and water. The mixture was stirred at room temperature for 15 min. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound (0.35 g, 0.737 mmol, 91% yield) as a clear oil. [M+H] + =428.2.

[0627] Intermediate 4

[0628] To a solution of intermediate 4F (0.25 g, 0.59 mmol) in THF (5 mL) and H2O (1 mL) was added Ph3P (0.169 mg, 0.643 mmol). The reaction was stirred at room temperature overnight; LCMS analysis indicated the reaction was complete. The reaction mixture was partitioned between EtOAc and water; the resulting mixture was stirred at room temperature. After 15 min, the organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (24 g SiO2; a continuous gradient of 0% to 100% EtOAc in hexanes over 20 min, then a continuous gradient of 0% to 15% MeOH in CH2Cl2 over 20 min) to give the title compound (130 mg, 0.324 mmol, 55.4% yield) as a white foam. 21 H 31N5O3, LCMS, [M+H] + =402.3; 1 H NMR(CDCl3)δ:8.26(s,1H),8.10(s,1H),5.32(s,1H),5.05(dt,J=12.6,6.2Hz,1H),4.73(br s,1H),4.21(s,2H),3.97(s,3H),2.89(q,J=7.4Hz,2H),2.68-2.82(m,1H ),1.58-2.23(m,8H),1.36(t,J=7.6Hz,3H),1.27(dd,J=6.3,2.2Hz,6H).

[0629] Intermediate 5. 3-(4-(((1S,3S)-3-(isopropoxycarbonyl)cyclohexyl)oxy)phenyl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid

[0630]

[0631] Intermediate 5A. 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid methyl ester

[0632]

[0633] To a 0°C solution of 1,5-dimethyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.14 mmol) in DCM / MeOH (7 mL each) was added 2M TMSCHN2 (4.28 mL, 8.56 mmol) in hexanes. The reaction mixture was stirred at 0°C for 1 h, then warmed to room temperature and stirred overnight at room temperature, then concentrated in vacuo. The crude product was chromatographed (80 g SiO2; continuous gradient of 0% to 50% EtOAc in hexanes over 20 min) to give the title compound (900 mg, 5.84 mmol, 82% yield). LCMS, [M+H] + =155.2.

[0634] Intermediate 5B. 3-Bromo-1,5-dimethyl-1H-pyrazole-4-carboxylic acid methyl ester

[0635]

[0636] To a solution of intermediate 5A (1.10 g, 7.14 mmol) in MeCN (14.3 mL) was added HOAc (4.1 mL, 71.4 mmol) and Br2 (0.44 mL, 8.56 mmol). The reaction mixture was stirred at room temperature for 16 h, then washed with saturated aqueous sodium thiosulfate solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (80 g SiO2; a continuous gradient of 0% to 50% EtOAc in hexanes over 20 min) to give the title compound (400 mg, 25%). 1 H NMR (400MHz, CDCl3) δ3.79-3.71(m,3H), 3.68-3.60(m,3H), 2.45-2.33(m,3H).

[0637] Intermediate 5C. (1S,3S)-3-(4-bromophenoxy)cyclohexane-1-carboxylic acid isopropyl ester

[0638]

[0639] To a solution of 4-bromophenol (500 mg, 2.89 mmol) and (1S, 3R)-3-hydroxycyclohexane-1-carboxylic acid isopropyl ester (538 mg, 2.89 mmol) in toluene (5.8 mL) were added Bu3P (2.20 mL, 8.67 mmol) and (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (2.20 g, 8.67 mmol) dropwise. The reaction mixture was heated at 50 °C for 2 h and then cooled to room temperature. Hexane (6 mL) was added to the mixture; a white solid precipitated and was filtered off. The filtrate was concentrated in vacuo. The crude product was chromatographed (80 g SiO2; a continuous gradient of 0% to 50% EtOAc in hexane over 20 min) to give the title compound (400 mg, 1.17 mmol, 40.6% yield). 1 H NMR (400MHz, CDCl3) δ7.28-7.20(m,2H),6.75-6.64(m,2H),4.95-4.82(m,1H),4.52-4.38(m,1H) ,2.73-2.58(m,1H),2.16-2.01(m,2H),1.98-1.67(m,2H),1.64-1.49(m,4H),1.19-1.04(m,6H).

[0640] Intermediate 5D. Isopropyl (1S,3S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)cyclohexane-1-carboxylate

[0641]

[0642] To a mixture of intermediate 5C (1.3 g, 3.8 mmol), bispinacolatodiboron (1.5 g, 5.8 mmol), KOAc (1.15 g, 12 mmol) in 1,4-dioxane (8 mL) was added Xphos Pd G2 precatalyst (76 mg, 0.096 mmol) at room temperature. The mixture was heated at 80 °C for 16 h, then cooled to room temperature and washed with saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (3X 20 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was chromatographed (80 g SiO2; a continuous gradient of 0% to 50% EtOAc in hexanes over 20 min) to give the title compound (1.00 g, 67%). 1 H NMR (400MHz, CDCl3) δ7.81-7.71(m,2H),7.00-6.88(m,2H),5.09-4.96(m,1H),4.74-4.62(m,1H),2.89-2.73(m,1H),2.11-2. 04(m,1H),1.97-1.86(m,2H),1.80-1.70(m,1H),1.67-1.59(m,2H),1.40-1.34(m,12H),1.32-1.28(m,2H),1.27-1.21(m,6H).

[0643] Intermediate 5E. Methyl 3-(4-(((1S,3S)-3-(isopropoxycarbonyl)cyclohexyl)oxy)phenyl)-1,5-dimethyl-1H-pyrazole-4-carboxylate

[0644]

[0645] A mixture of Intermediate 5D (32 mg, 0.082 mmol), Intermediate 5B (19 mg, 0.082 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7 mg, 8 μmol) in MeCN (1 mL) and water (0.05 mL) was stirred at 100 °C for 1 h in a microwave reactor and then cooled to room temperature. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 50 mL); the combined organic layers were washed with water and brine (50 mL each), dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed (12 g SiO2; a continuous gradient of 0% to 50% EtOAc in hexanes over 10 min) to give the title compound (20 mg, 0.048 mmol, 59.2% yield) as a clear oil. 1 H NMR (400MHz, CDCl3) δ7.61-7.46(m,2H),7.08-6.85(m,2H),5.14-4.94(m,1H),4.73-4.58(m,1H),3.90-3.82(m,3H),3.81-3.70(m,3H) ,2.88-2.74(m,1H),2.62-2.48(m,3H),2.17-2.03(m,1H),1.97-1.87(m,3H),1.84-1.72(m,1H),1.65-1.53(m,3H),1.33-1.20(m,6H).

[0646] Intermediate 5

[0647] A mixture of intermediate 1E (60 mg, 0.145 mmol) and LiI (97 mg, 0.724 mmol) in DMF (0.5 mL) was heated at 180 ° C for 30 min in a microwave reactor, then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (C18 30x100 mm column; detected at 220 nm; flow rate = 40 mL / min; 0% B to 100% B continuous gradient lasted 10 min + 100% B for 2 min, wherein A = 90: 10: 0.1 H2O: MeCN: TFA, B = 90: 10: 0.1 MeCN: H2O: TFA) to give the title compound (20 mg, 0.050 mmol, 34.5% yield). LCMS, [M + H] + =401.2.

[0648] Example 1. trans-3-((6-(1-methyl-5-(((4-phenylpyrimidin-2-yl)amino)methyl)-1H-pyrazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0649]

[0650] To a -78°C solution of 4-phenylpyrimidine-2-amine (20 mg, 0.113 mmol) in THF (0.5 mL) was added n-BuLi (0.071 mL of a 1.5 M solution in hexanes, 0.113 mmol). The mixture was warmed to room temperature and stirred at room temperature for 5 min. A solution of intermediate 1 (20 mg, 0.046 mmol) in THF (0.5 mL) was quickly added and the mixture was stirred at room temperature for 48 h. MeOH (0.5 mL) and LiOH.H2O (64 mg, 1.52 mmol) in water (1 mL) were added to the reaction mixture, which was stirred at room temperature for 18 h. The volatiles were removed in vacuo and the residue was taken up in H2O (1 mL). The aqueous mixture was adjusted to pH~5 with 1N HCl aqueous solution and extracted with EtOAc (3x2 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: XBridge C18, 19x200mm, 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: 8-43% B over 23 min, then hold at 100% B for 5-min; Flow rate: 20 mL / min to obtain the desired product. The material was further purified by preparative LC / MS: Column: XBridge Shield RP18, 19x200mm, 5-μm particles; Mobile phase A: 5:95 MeCN:H2O containing 10-mM NH4OAc; Mobile phase B: 95:5 MeCN:H2O containing 10-mM NH4OAc; Gradient: 15-55% B over 25 min, then hold at 100% B for 5-min; Flow rate: 20 mL / min. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (1 mg; 2% yield). LCMS, [M+H] + =485.2. 1 HNMR(500MHz,DMSO-d6)δ8.37(s,2H),8.03(s,2H),7.85(s,1H),7.66(d,J=8.7Hz,1H),7.53–7.41(m,4H),7.23–7.15(m,1H),4.99(br s,2H),4.74(s,1H),3.96(s,3H),2.72–2.64(m,1H),2.03–1.48(m,8H). hLPA1 IC 50 =122nM.

[0651] Example 2. (1S,3S)-3-((2-(5-(((4-isopropoxypyrimidin-2-yl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid

[0652]

[0653] 2-Chloro-4-isopropoxypyrimidine (4 mg, 0.02 mmol) and iPr2NEt (9 μL, 0.05 mmol) were added to a room temperature solution of intermediate 2 (5 mg, 0.01 mmol) in n-BuOH (0.7 mL). The reaction was stirred at 180 ° C for 80 min and then cooled to room temperature. THF (0.8 mL) / MeOH (0.4 mL) / H2O (0.4 mL) was added to the reaction mixture and LiOH.H2O (3 mg, 0.07 mmol) was then added at room temperature. The reaction was stirred at room temperature overnight and then concentrated in vacuo and the residue was diluted with H2O (5 mL). The pH of the mixture was adjusted to ~5 with 1N HCl aqueous solution and extracted with EtOAc (3x5 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, 19x200mm, 5-μm particles; Guard column: Waters XBridge C18, 19x10mm, 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: 15-55% B over 20 min, then hold at 100% B for 4-min; Flow rate: 20 mL / min. Fractions containing the desired product were combined and concentrated by centrifugal evaporation to give the title compound (6.5 mg, 8.7 μmol, 67% yield). LCMS, [M+H]+=482.3. 1 H NMR (500MHz, DMSO-d6) δ8.42(s,1H),8.06(br s,1H),7.93(s,1H),6.23(br d,J=6.1Hz,1H),5.26-5.16(m,1H),5.06(br s,2H),4.84-4.77(m,1H),3.92(s,3H),2.68-2.60(m,1H),2.42(s,3H),2.06-1.44(m,8H),1.22(d,J=6.1Hz,6H). hLPA1 IC 50 =29nM.

[0654] Example 3. (1S,3S)-3-((2-(5-(((4-ethoxypyrimidin-2-yl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid

[0655]

[0656] To a solution of intermediate 2 (10 mg, 0.026 mmol) in n-BuOH (1.2 mL) was added 2-chloro-4-ethoxypyrimidine (5 mg, 0.031 mmol) and iPr2NEt (9 μl, 0.052 mmol). The mixture was heated at 180 ° C for 3 h in a microwave reactor and then cooled to room temperature. THF (0.5 mL) / H2O (0.5 mL) / MeOH (0.5 mL) and LiOH.H2O (6 mg, 0.13 mmol) were added to the reaction mixture and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo, the residue was diluted with H2O (1 mL), and the mixture was then adjusted to pH~5 with 1N HCl aqueous solution and extracted with EtOAc (3x2 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: XBridge C18, 19x200mm, 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: 10-55% B over 20 min, then hold at 100% B for 4-min; Flow rate: 20 mL / min. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (bis-TFA salt, 8.7 mg, 47% yield; 96% purity by LC-MS). LCMS, [M+H] + =454.2. 1 H NMR(500MHz,DMSO-d6)δ8.46(s,1H),8.07(d,J=6.0Hz,1H),7.91(s,1H),6.13(dd,J=5.9,2.3Hz,1H),5.03br s,2H),4.83(s,1H),4.22(q,J=7.1Hz,2H),3.95(s,3H),2.67(t,J=8.9Hz,1H),2.44(s,3H),2.09–1.48(m,8H),1.24(t,J=7.2Hz,3H). hLPA1 IC 50 =22nM.

[0657] The examples in Table 1 below were synthesized according to the procedures described for the preparation of Examples 1 and 2.

[0658] Table 1

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666] Example 18. (1S,3S)-3-((2-(5-((4-isopropoxypyrimidin-2-yl)amino)-1-methyl-1H-pyrazol-4-yl)-4-methyl-pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid

[0667]

[0668] 18A. Isopropyl (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0669]

[0670] A mixture of (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (3.47 g, 13.8 mmol) and Bu3P (3.44 mL, 13.8 mmol) in toluene (30 mL) was stirred at room temperature in a pressure vial for 30 min, followed by the addition of 2-bromo-4-methylpyrimidine-5-ol (1.3 g, 6.88 mmol) and (1S, 3R)-3-hydroxycyclohexane-1-carboxylic acid isopropyl ester (2.31 g, 12.4 mmol). The reaction mixture was heated at 85 ° C for 9 h and then cooled to room temperature. The mixture was diluted with DCM (10 mL), filtered and concentrated in vacuo. The crude oily product was chromatographed (120 g SiO2; continuous gradient of 0% to 90% EtOAc:hexanes over 25 min, hold at 90% for 20 min) to afford the title compound (1.80 g, 5.04 mmol, 73.3% yield) as a light yellow oil. 1H NMR(500MHz,DMSO-d6)δ8.32(d,J=3.7Hz,1H),4.90(p,J=6.4Hz,1H),4.80(s, 1H), 2.70–2.59 (m, 1H), 2.38 (s, 3H), 2.01–1.46 (m, 8H), 1.18 (d, J = 6.3Hz, 6H). [M+H]+=357.

[0671] 18B. tert-Butyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate

[0672]

[0673] Ar was vigorously bubbled through a stirred mixture of tert-butyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (1.5 g, 5.74 mmol), KOAc (1.69 g, 17.2 mmol) and B2pin2 (2.19 g, 8.62 mmol) in 1,4-dioxane (20 mL) for 5 min. Pd(dppf)Cl2-CH2Cl2 (0.47 g, 0.57 mmol) was added, the reaction flask was flushed with Ar, and then heated to 100 ° C and maintained for 16 h. LCMS analysis after 16 h indicated that the reaction was complete. The reaction mixture was cooled to room temperature, then DCM and H2O (20 mL each) were added, and the resulting mixture was vigorously stirred. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was used in the next step without further purification. [M+H]+=309.2.

[0674] 18C. tert-Butyl 4-(5-(((1S,3S)-3-(isopropoxycarbonyl)cyclohexyl)oxy)-4-methylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

[0675]

[0676] A mixture of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.169 g, 0.239 mmol), 18B (0.884 g, 2.87 mmol) and 18A (0.854 g, 2.392 mmol) in 2M NaCO aqueous solution (5.98 mL, 12.0 mmol) and MeCN (12 mL) was heated to 100 °C in a microwave reactor for 1 h and then cooled to room temperature. The mixture was diluted with saturated NaHCO aqueous solution and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried (NaSO) and concentrated in vacuo. The crude product was chromatographed (80 g SiO, continuous gradient of 0%-90% EtOAc:hexane) to give the title compound (1.08 g, 2.36 mmol, 98% yield) as a beige solid. [M+H] = 459.3.

[0677] 18D. 4-(5-(((1S,3S)-3-(isopropoxycarbonyl)cyclohexyl)oxy)-4-methylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

[0678]

[0679] To a solution of 18C (1.08 g, 2.355 mmol) in DCM (20 mL) was added TFA (9.07 mL, 118 mmol) dropwise. The reaction was stirred at room temperature for 20 h and then concentrated in vacuo to give the crude title compound (1.20 g, 2.89 mmol, >100% yield) as a colored oil which was used in the next step without further purification. 1 H NMR(500MHz,DMSO-d6)δ8.62(s,1H),8.14(s,1H),4.94–4.87(m,2H),4.12(s,3H) ,2.72–2.62(m,1H),2.49(s,3H),2.08–1.44(m,8H),1.19(dd,J=6.4,1.9Hz,6H). [M+H]+=403.2.

[0680] 18E. Isopropyl (1S, 3S)-3-((2-(5-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0681]

[0682] A mixture of crude 18D (600 mg, 1.49 mmol), (PhO)PON (0.58 mL, 2.68 mmol), tert-butyl alcohol (331 mg, 2.23 mmol), EtN (0.83 mL, 5.95 mmol) in toluene (3 mL) was stirred at 80 °C for 2 h, then cooled to room temperature and concentrated in vacuo. The crude product was chromatographed (80 g SiO; 0% to 100% EtOAc: hexane continuous gradient over 25 min) to give the title compound (248 mg, 0.524 mmol, 35.2% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3) (about 1:1 rotamers) δ 8.71 (s, 1H), 8.23 ​​(s, 0.5H), 8.04 (s, 0.5H), 5.05 (p, J = 6.3 Hz, 1H), 4.76 (s, 0.5H), 4.72 (s, 0.5H), 3.89 (s, 3H), 2.82-2.72 (m, 1H), 2.51 (br s, 3H), 2.15-1.47 (m, 8H), 1.27 (br s, 15H). [M+H]+ = 474.3.

[0683] 18F. (1S,3S)-3-((2-(5-amino-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester

[0684]

[0685] To a solution of 18E (238 mg, 0.503 mmol) in DCM (5 mL) was added TFA (3.87 mL, 50.3 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 20 h, then concentrated in vacuo, azeotroped with toluene (3 x 5 mL), and dried in vacuo for 24 h to give the title compound (TFA salt; 220 mg, 0.561 mmol, 92% yield) as a light oil. 1 H NMR (500 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.64 (s, 1H), 6.31 (s, 2H), 4.89 (p, J = 6.2 Hz, 1H), 4.71 (s, 1H), 2.70–2.63 (m, 1H), 2.39 (s, 3H), 2.00–1.42 (m, 8H), 1.18 (d, J = 6.2 Hz, 6H). (The proton of the -CH3 group on the pyrazole was not observed due to suppression of water). [M+H]+ = 374.3.

[0686] Embodiment 18

[0687] A mixture of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5 mg, 8 μmol), 18F (15 mg, 0.04 mmol), 2-chloro-4-isopropoxypyrimidine (8 mg, 0.05 mmol), BINAP (5 mg, 8 μmol), Pd2(dba)3 (2 mg, 4 μmol) and Cs2CO3 (20 mg, 0.06 mmol) in toluene (1 mL) was heated to 110°C in a sealed tube overnight, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in THF (0.5 mL), MeOH (0.5 mL) and H2O (0.5 mL). LiOH.H2O (17 mg, 0.4 mmol) was added and the reaction was stirred at room temperature for 14 h, then concentrated in vacuo. The residue was taken up in EtOAc (2 mL) / H2O (1 mL), and the solution was adjusted to pH ~5 with 1N aqueous HCl. The mixture was extracted with EtOAc (3x2 mL); the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DMF and purified by preparative LC / MS: Column: XBridge C18, 200 mm x 19 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: 0 min at 18% B, 20 min at 18-58% B, then 4 min at 100% B; Flow rate: 20 mL / min; Column temperature: 25C. The fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (bis-TFA salt, 1 mg, 3% yield; purity by LC-MS 84%). LCMS, [M+H] + =468.4. 1 H NMR(500MHz,DMSO-d6)δ8.31(s,1H),8.08(d,J=5.7Hz,1H),7.92(s,1H),6.18(d,J=5.7Hz,1H),5.10–4.9 8(m,1H),4.75(s,1H),3.72(s,3H),2.68–2.59(m,1H),2.27(s,3H),2.01–1.47(m,8H),1.21–1.15(m,6H). hLPA1 IC50=1014nM.

[0688] The examples in Table 2 below were synthesized by the procedure described for the preparation of Example 18.

[0689] Table 2

[0690]

[0691] Example 21. (1S,3S)-3-((2-(5-(((4-ethoxypyrimidin-2-yl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)-4-ethylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid

[0692]

[0693] To a solution of intermediate 4 (15 mg, 0.037 mmol) in n-BuOH (0.7 mL) was added 2-chloro-4-ethoxypyrimidine (7 mg, 0.045 mmol) and iPr2NEt (65 μl, 0.374 mmol) at room temperature. The mixture was stirred at 180 ° C for 3 h, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in THF (0.5 mL) and MeOH (0.1 mL), 4N LiOH aqueous solution (0.093 mL, 0.374 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was filtered and purified by preparative HPLC ( Axia 5μ C18 30x100mm column); detection at 220nm; flow rate = 40mL / min; continuous gradient from 0% B to 100% B over 10min + 2min hold time at 100% B, where A = 90:10:0.1 H2O:MeOH:TFA, B = 90:10:0.1 MeOH:H2O:TFA) to give the title compound (8.7mg, 0.017mmol, 46.6% yield). LCMS, [M+H] + =482.4. 1 H NMR (500MHz, DMSO-d6) δ: 8.43 (s, 1H), 8.07 (br d, J = 6.1Hz, 1H), 7.94 (s, 1H), 7.03-7.39 (m, 1H), 6.30 (br d,J=6.1Hz,1H),4.92-5.31(m,2H),4.84(brs,1H),4.24(br d,J=6.4Hz,2H),3.92(s,1H),3.58-3.80(m,2H),2.78(q,J=7.6Hz,2H),2.60(br t,J=10.2Hz,1H),1.40-2.17(m,8H),1.22(m,6H); hLPA1 IC 50 =5nM.

[0694] The examples in Table 3 below were synthesized by the procedure described for the preparation of Example 21.

[0695] Table 3

[0696]

[0697]

[0698]

[0699]

[0700] Example 28: (1S,3S)-3-((2-(5-(((4-ethoxypyrimidin-2-yl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid

[0701]

[0702] To a solution of (1S,3S)-isopropyl 3-((2-(5-formyl-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (prepared in the same manner as Intermediate 3 except starting with 2-chloro-5-methoxypyrimidine, 15 mg, 0.040 mmol), 4-ethoxypyrimidin-2-amine (8.4 mg, 0.060 mmol) in MeOH (0.5 mL) was added HOAc (12 μL, 0.20 mmol). The reaction mixture was heated at 65 °C for 2 h and then cooled to room temperature. NaBH3CN (5.1 mg, 0.081 mmol) was added and the reaction was stirred at room temperature for 2 h. Saturated aqueous NaHCO3 (1 mL) was added and the aqueous layer was extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with brine (3 mL), dried (MgSO4) and concentrated in vacuo to give the crude amino-pyrimidine reductive amination product. The crude product was dissolved in THF and water (0.5 mL each). LiOH.H2O (8.5 mg, 0.2 mmol) was added; the reaction was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was taken up in EtOAc (2 mL) / water (1 mL) and the pH was adjusted to ~5 with 1N HCl aqueous solution. The mixture was extracted with EtOAc (3x2 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative LC / MS (column: XBridge C18, 200 mm x 19 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: 8% B for 0 min, 8-48% B for 20 min, then 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25°C. Fraction collection was triggered by MS and UV signals) to give the title compound (11.9 mg, 43% yield; LCMS purity = 100%). LCMS, [M+H] + =454.4. 1 H NMR (500MHz, DMSO-d6) δ8.57(s,2H),8.28(br s,1H),8.05(d,J=6.0Hz,1H),7.93(s,1H),6.16(d,J=6.1Hz,1H),5.03(s,2H),4.82(s,1H),4.15(br s,2H),3.94(s,3H),2.70–2.62(m,1H),2.02–1.46(m,8H),1.20(t,J=7.2Hz,3H). hLPA1 IC 50 =23nM

[0703] Example 29: ((1S,3S)-3-((2-(5-(((4-ethoxypyrimidin-2-yl)(methyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid

[0704]

[0705] To a 0°C solution of Example 28 (4.6 mg, 10 μmol) in THF (0.5 mL) was added NaH (4 mg, 60% dispersion in mineral oil, 0.1 mmol). The mixture was stirred for 10 min, then MeI (7 μL; 0.11 mmol) was added. The reaction mixture was stirred at room temperature overnight, then quenched by adding a solution of LiOH.H2O (2.1 mg, 0.050 mmol) in water (0.5 mL). The reaction was stirred at room temperature for 2 h, then concentrated in vacuo. The residue was taken up in EtOAc (2 mL) / water (1 mL) and adjusted to pH~5 with 1N HCl aqueous solution. The mixture was extracted with EtOAc (3x2 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative LC / MS (column: XBridge C18, 200 mm x 19 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: 0 min at 9% B, 20 min at 9-49% B, then 4 min at 100% B; flow rate: 20 mL / min; column temperature: 25°C. Fraction collection was triggered by UV signal) to give the title compound (2 mg, 29% yield; purity by LCMS = 100%). LCMS, [M+H] + =468.1. 1 H NMR (500MHz, DMSO-d6) δ8.56(s,2H),8.14(d,J=5.6Hz,1H),7.99(s,1H),6.10(d,J=5.6Hz,1H),5.54(s,2H),4.82(s ,1H),4.30(q,J=7.0Hz,2H),3.74(s,3H),2.91(s,3H),2.71-2.61(m,1H),2.02–1.46(m,8H),1.28(t,J=7.1Hz,3H). hLPA1IC 50 =151nM.

[0706] Example 30: trans-3-((6-(5-(([1,1'-biphenyl]-3-yloxy)methyl)-1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0707]

[0708] A mixture of intermediate 1 (5 mg, 0.011 mmol) and [1,1'-biphenyl]-3-ol (3.9 mg, 0.023 mmol) was azeotroped with toluene ((3 x 0.5 mL) and then taken up into CHCl3 (57 μL) and Ag2CO3 (9.5 mg, 0.034 mmol) was added. The reaction mixture was stirred at room temperature for 72 h. LCMS showed the formation of [M+H] + =526.2. The mixture was diluted with DCM (1 mL) and filtered through a syringe filter to remove silver salts; the filtrate was concentrated in vacuo. MeOH (0.5 mL) and LiOH.H2O (9 mg, 0.22 mmol) in water (0.5 mL) were added to the above crude biphenyl ether in THF (0.5 mL). The reaction mixture was stirred at room temperature for 14 h, and then the organic volatiles were removed in vacuo. The pH was adjusted to ~5 with 1N HCl aqueous solution. The mixture was extracted with EtOAc (5x5 mL); the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative LC / HPLC (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: 20-60% B over 25 min, then hold at 100% B for 5-min; flow rate: 20 mL / min) to give the title compound (0.3 mg, 5.5% yield; LCMS purity = 98%). LCMS, [M+H] + =483.9. 1 H NMR (500 MHz, DMSO-d6) δ 8.33 (d, J = 2.8 Hz, 1H), 7.93 (s, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.50 (dd, J = 8.9, 2.9 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.35 (dq, J = 14.3, 7.4 Hz, 4H), 7.30 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 5.79 (s, 2H), 4.72 (s, 1H), 3.93 (s, 3H), 1.99–1.42 (m, 8H); (the proton α attached to the acid was not observed due to water suppression).

[0709] hLPA1 IC 50 =104nM.

[0710] The compounds in the following table were prepared according to the procedures described above for the preparation of specific examples.

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718] Example 43. (1S,3S)-3-((2-(5-(((4-isopropyl-1,3,5-triazin-2-yl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid

[0719]

[0720] 43A. Isopropyl (1S,3S)-3-((2-(5-(((4-chloro-6-isopropyl-1,3,5-triazin-2-yl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0721]

[0722] A mixture of intermediate 2 (15 mg, 0.04 mmol), 2,4-dichloro-6-isopropyl-1,3,5-triazine (11 mg, 0.06 mmol) and iPr2NEt (0.03 mL, 0.16 mmol) in THF (0.7 mL) was stirred at room temperature for 120 min and then used in the next step. LCMS, [M+H] + =543.3.

[0723] 43B. Isopropyl (1S,3S)-3-((2-(5-(((4-isopropyl-1,3,5-triazin-2-yl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate

[0724]

[0725] 10% Pd / C (11 mg, 0.01 mmol) was added to a solution of 43A (21 mg, 0.04 mmol) in THF (5 mL) at room temperature under Ar. Ar was replaced with H2 and the reaction was stirred overnight under 1 atm of H2 before the catalyst was filtered off. The filtrate was concentrated in vacuo. The residual crude product was used in the next step without further purification. LCMS, [M+H] + =509.3.

[0726] Embodiment 43

[0727] To a solution of 43B (20 mg, 0.04 mmol) in THF (0.8 mL) / MeOH (0.4 mL) / H2O (0.4 mL) was added LiOH.H2O (8 mg, 0.20 mmol) at room temperature. The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was diluted with H2O (5 mL), the pH was adjusted to ~5 with 1N HCl aqueous solution, and extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine (2 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative LC / MS (column: XBridge C18, 200 mm x 19 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: 13% B for 0 min, 13-53% B for 20 min, then 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25°C. Fraction collection was triggered by MS and UV signals) to give the title compound (9.1 mg, 39% yield) as a colorless oil. LCMS, [M+H]+=467.4. 1 H NMR(500MHz,DMSO-d6)δ8.61-8.36(m,2H),7.90(s,1H),5.11-4.99(m,2H),4.79(br s,1H),3.93(s,3H),2.79-2.61(m,2H),2.40(s,3H),2.05-1.43(m,8H),1.22-1.03(m,6H). hLPA1 IC 50 =28nM.

[0728] 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 in this application. 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 represented by formula (IIa): or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)OR 10 ; R 10 is hydrogen or C 1-10 alkyl; Said Partially selected R 6a C 1-6 alkyl; d is an integer 0 or 1; R 5a is hydrogen; R 5b C 1-4 alkyl; R 7a is hydrogen; f is an integer 0 or 1; Z is NR 8 ; R 8 is hydrogen or methyl; Y 1 is CH; Y 2 and Y 4 are each independently N or CH; R 3 For-OR a 、-NR c R c , C 1-6 alkyl, 6-10 membered aryl, 5-10 membered heteroaryl containing 1 N, or 3-8 membered monocyclic saturated hydrocarbon ring group; wherein the alkyl, aryl, heteroaryl and monocyclic saturated hydrocarbon ring group, by themselves or as part of another group, are each independently substituted by 0 to 5 R d replace, R a Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, 6- to 10-membered aryl, and 3- to 8-membered monocyclic saturated hydrocarbon ring group; R c are independently hydrogen or C 1-6 alkyl; R d Each independently selected from C 1-6 Alkoxy and halogen; R 4 are each independently halogen or C 1-6 Alkyl; and m is an integer of 0 or 1.

2. A compound represented by formula (IIIa) or formula (IIIb): or a pharmaceutically acceptable salt thereof, wherein Z is NH; Said Part of R 1 is CO2H; R 2a is hydrogen; Said Part of R 6a is hydrogen, methyl or ethyl; Said Part of Said Part of m is 0 or 1; R 3 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, phenyl, 6-membered heteroaryl containing 1 N heteroatom, -OC 3-6 Cycloalkyl, -O-phenyl and -NH-C 1-6 Alkyl; and said alkyl, alkoxy, cycloalkyl, phenyl and heteroaryl, by themselves or as part of another group, are each independently substituted by 0 to 3 R d replace; R d are each independently halogen or C 1-6 alkoxy; and R 4 are each independently halogen or C 1-6 alkyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Said Part of R 6a It is hydrogen or methyl.

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Said Part of R 6a is hydrogen, methyl or ethyl.

5. The compound according to any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof, wherein Said Part of And m is 0 or 1.

6. The compound according to any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof, wherein Said Part of and m is 0 or 1.

7. The compound according to any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof, wherein Said Part of and m is 0.

8. The compound according to any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof, wherein R 3 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, phenyl, pyridyl, -OC 3-6 Cycloalkyl, -O-phenyl and -NH-C 1-6 Alkyl; and said alkyl, alkoxy, cycloalkyl and phenyl, by themselves or as part of another group, are each independently substituted by 0 to 3 R d replace; and R d are each independently halogen or C 1-6 Alkoxy.

9. A compound selected from: or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 9 or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 9 or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable diluent.

12. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11, in the preparation of a medicament for treating a disease, disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1), wherein the disease, disorder or condition is pathological fibrosis, transplant rejection, cancer, osteoporosis or inflammation.

13. The use according to claim 12, wherein the pathological fibrosis is pulmonary, liver, kidney, heart, skin, eye or pancreatic fibrosis.

14. The use according to claim 12, wherein the disease, disorder or condition is idiopathic pulmonary fibrosis (IPF) or systemic sclerosis.

15. The use according to claim 12, wherein the disease, disorder or condition is non-alcoholic steatohepatitis (NASH).

16. The use according to claim 12, wherein the cancer is a cancer of the blood, bone, brain, breast, central nervous system, colon, esophagus, gallbladder, genitals, urogenital tract, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, pancreas, skin, spleen, small intestine, large intestine, stomach or thyroid.

17. The use according to claim 12, wherein the cancer is cancer of the bladder, cervix, endometrium, head, ovary, prostate or testicle.

18. The use of claim 12, wherein the disease, disorder or condition is selected from the group consisting of pulmonary fibrosis, renal fibrosis, liver fibrosis, skin fibrosis, intestinal fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, intestinal cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, tumor metastasis, transplant organ rejection or eye fibrosis.

19. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11, in the preparation of a medicament for treating a disease, disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1), wherein the disease, disorder or condition is neuropathic pain.

20. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11, in the preparation of a medicament for treating a disease, disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1), wherein the disease, disorder or condition is non-alcoholic fatty liver disease (NAFLD) or chronic kidney disease.

21. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11, in the preparation of a medicament for treating a disease, disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1), wherein the disease, disorder or condition is diabetic nephropathy.

22. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11, in the preparation of a medicament for treating a disease, disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1), wherein the disease, disorder or condition is asthma, chronic obstructive pulmonary disease (COPD), acute kidney injury, cancer pain, scleroderma, age-related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis or Raynaud's phenomenon.

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