Triazole n-linked carbamoyl cyclohexyl acids as lpa antagonists

Abstract

The present application provides compounds of Formula (I): Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate 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 62 / 607,399, filed December 19, 2017, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to novel substituted triazole compounds, compositions containing the same, and methods of using the same, such as methods of using the same to treat conditions related to one or more lysophosphatidylcholine (LPA) receptors. Background Technology

[0004] Lysophospholipids are membrane-derived bioactive lipid mediators, among which lysophosphatidic acid (LPA) is one of the most important in medicine. LPA is not a single molecular entity, but rather a group of endogenous structural variants of fatty acids with varying lengths and saturation levels (Fujiwara et al., J Biol. Chem., 2005, 280, 35038-35050). The main structural chain 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 similar 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). The 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 to phospholipid biosynthesis in both eukaryotic and prokaryotic cells, but it has recently emerged only as a signaling molecule. Such signaling molecules are rapidly produced and released by activated cells, particularly platelets, to influence target cells by acting on specific cell surface receptors (see, for example, Moolenaar et al., BioEssays, 2004, 26, 870-881, and van Leewen et al., Biochem. Soc. Trans., 2003, 31, 1209-1212). Besides being synthesized and processed into more complex phospholipids in the endoplasmic reticulum, LPA can also be generated after cell activation through the hydrolysis of pre-existing phospholipids; for example, the sn-2 position typically loses a fatty acid residue due to deacylation, leaving only the sn-1 hydroxyl group to esterify into a fatty acid. Furthermore, the key enzyme in LPA production, autotaxin (lysoPLD / NPP2), can be a product of oncogenes, as many tumor types upregulate autotaxin (Brindley, D., J. Cell Biochem. 2004, 92, 900-12). LPA concentrations in human plasma, serum, and human bronchoalveolar lavage fluid (BALF) have been reported, including measurements 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 influences a wide variety of biological responses, ranging from inducing cell proliferation, stimulating cell migration and neurite contraction, 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). As LPA responses in more and more cellular systems are tested, knowledge about the biology of LPA continues to grow. For example, in addition to stimulating cell growth and proliferation, LPA is now known to promote cell tension and the binding of cell surface fibronectin, which are important events 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 uncontrolled tissue healing process that leads to excessive accumulation and insufficient reabsorption of the extracellular matrix (ECM), ultimately resulting in peripheral organ failure (Rockey, DC et al., New Engl. J. Med., 2015, 372, 1138-1149). Overexpression of the LPA1 receptor has been reported in patients with idiopathic pulmonary fibrosis (IPF). LPA1 receptor knockout mice are protected from bleomycin-induced pulmonary fibrosis (Tager et al., Nature Med., 2008, 14, 45-54). The LPA1 antagonist BMS-986020 showed a significant reduction in the rate of FVC (forced vital capacity) decay in IPF patients in a 26-week clinical trial (Palmer et al., Chest, 2018, 154, 1061-1069). LPA pathway inhibitors (such as LPA1 antagonists) have shown to be chemopreventive antifibrotic agents for the treatment of hepatocellular carcinoma in rat models (Nakagawa et al., Cancer Cell, 2016, 30, 879-890).

[0009] Therefore, antagonizing LPA1 receptors may be applicable to the treatment of fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, arterial fibrosis, and systemic sclerosis, and thereby treat diseases caused by fibrosis (pulmonary fibrosis - idiopathic pulmonary fibrosis [IPF], liver fibrosis - non-alcoholic steatosis hepatitis [NASH], kidney fibrosis - diabetic nephropathy, systemic sclerosis - scleroderma, etc.). Summary of the Invention

[0010] The present invention provides novel substituted triazole compounds, including their stereoisomers, tautomers and pharmaceutically acceptable salts or solvates, suitable as antagonists against one or more lysophosphatidic acid (LPA) receptors, particularly LPA1 receptors.

[0011] The present invention also provides a method for manufacturing the compounds of the present invention and intermediates.

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

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

[0014] The compounds of this invention can be used in therapeutic applications.

[0015] The compounds of the present invention can be used to prepare medicaments for treating conditions in which the physiological activity of inhibiting LPA is applicable (such as diseases in which LPA receptors are involved, which relate to the etiology or pathology of the disease, or are otherwise associated with at least one symptom of the disease).

[0016] In another aspect, the present invention relates to a treatment for organ (liver, kidney, lung, heart, and the like, and skin) fibrosis, liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatosis (NASH), liver dysfunction, hepatic blood flow disorders and similar conditions), cell proliferation disorders [cancer (solid tumors, metastatic solid tumors, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL) and similar diseases) and invasive metastases of cancer cells and similar diseases], inflammation (psoriasis, nephropathy, pneumonia and similar diseases), gastrointestinal diseases (irritable bowel syndrome (IBS), inflammatory bowel disease (IB)). D) Abnormal pancreatic secretion and similar diseases, kidney disease, urinary tract-related diseases (symptoms associated with benign prostatic hyperplasia or neuropathy-related bladder disease, spinal cord tumors, herniated discs, spinal stenosis, symptoms derived from polyuria, lower urinary tract diseases (lower urinary tract obstruction and similar diseases), lower urinary tract inflammation, dysuria, urinary frequency and similar diseases), pancreatic diseases, abnormal angiogenesis-related diseases (arterial obstruction and similar diseases), scleroderma, brain-related diseases (cerebral infarction, cerebral hemorrhage and similar diseases), neuralgia, peripheral neuropathy and similar diseases, eye diseases (age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PvR), pemphigoid scarring, glaucoma filtration surgery scarring and similar diseases).

[0017] In another aspect, the present invention relates to a method for treating a disease, symptom, or condition, wherein LPA activation of at least one LPA receptor leads to a symptom or progression of the disease, symptom, or condition. These diseases, symptoms, or conditions may originate from one or more of the following causes: genetic, iatrogenic, immune, infectious, metabolic, tumorous, toxic, surgical, and / or traumatic.

[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 the compound of the present invention as described above.

[0019] In one aspect, the present invention provides the methods, compounds, pharmaceutical compositions, and agents described herein, comprising LPA receptor antagonists, particularly LPA1 antagonists.

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

[0021] These and other features of the invention will be set forth in an expanded form as disclosure continues. Detailed Implementation

[0022] I. Compounds of the present invention

[0023] In one aspect, the present invention particularly provides compounds of formula (I):

[0024]

[0025] Or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein:

[0026] X 1 X 2 X 3 and X 4 Each independently for CR 6 Or N; its constraint is X 1 X 2 X 3 or X 4 The two numbers in the middle do not exceed N;

[0027] Q 1 Q 2 and Q 3 One of them is NR 5 , and the other two are N; and the dashed circle represents an optional bond that forms an aromatic ring;

[0028] Y 1 For O or NR 3 ;

[0029] Y 2 for

[0030] Y 3 For O or NR 4a Its constraint is (1)Y 1 With Y 3 Not all are O, and (2) when Y 2 When Y is C(O), 1 Not O;

[0031] L is a covalent bond or is bounded by 0 to 4 Rs. 7 Replacement C 1-4 Alkylene;

[0032] R 1 (-CH2) a R 7 ;

[0033] a is an integer, either 0 or 1;

[0034] R 2 Each is independently a halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C3-6 cycloalkyl, C 4-6 Heterocyclic group, C 1-6 Alkylamino, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy;

[0035] n is an integer, 0, 1, or 2;

[0036] R 3 and R 4a Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, C 1-6 Alkyl groups, or haloalkoxy groups;

[0037] R 4 C 1-10 Alkyl, C 1-10 Deuterated alkyl groups (fully or partially deuterated), C 1-10 Halogenated, C 1-10 alkenyl, C 3-8 cycloalkyl, 6- to 10-membered aryl, 3- to 8-membered heterocyclic, -(C 1-6 alkylene)-(C 3-8 cycloalkyl), -(C 1-6 alkylene)-(6- to 10-aryl), -(C 1-6 alkylene group (-(3 to 8-membered heterocyclic group) or -(C 1-6 Alkylene (5- to 6-membered heteroaryl); wherein each of the alkyl, alkenyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups is independently bounded by 0 to 3 R groups, either individually or as part of other portions. 8 Replace; or alternatively, R 3 and R 4 Together with the atoms they are attached to, they form groups of 0 to 3 R 8 The replaced 4- to 9-membered heterocyclic components;

[0038] R 5 For hydrogen, C 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;

[0039] R 6 It is hydrogen, halogen, cyano, hydroxyl, amino, C 1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;

[0040] R 7 Halogen, oxo, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic group, alkylamino group, haloalkyl group, hydroxyalkyl group, aminoalkyl group, alkoxyalkyl group, haloalkoxyalkyl group, alkoxy group, or haloalkoxy group;

[0041] R 8 Each is independently a deuterium, halogen, hydroxyl, amino, cyano, or C group. 1-6 Alkyl, C 1-6 Deuterated alkyl groups (fully or partially deuterated), C 2-6 alkenyl, C 2-6 Alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, -CHO, phenyl, or 5- to 6-membered heteroaryl; or alternatively, two R 8 Together with the atoms they are connected to, they form independent groups consisting of 0 to 3 R atoms. 12 The substituted 3- to 6-membered carbon rings or 3- to 6-membered heterocycles;

[0042] R 9 Selected from -CN, -C(O)OR 10 -C(O)NR 11a R 11b ,

[0043]

[0044] R e C 1-6 Alkyl, C 3-6 Cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl;

[0045] R 10 It is hydrogen or C 1-10 alkyl;

[0046] R 11a and R 11b Each independently is hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic groups, alkylamino groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, alkoxyalkyl groups, haloalkoxyalkyl groups, alkoxy groups, or haloalkoxy groups; and

[0047] R 12 Halogen, cyano, hydroxyl, amino, C 1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5- to 6-membered heteroaryl.

[0048] In one implementation of formula (I), R 8 Each is independently a deuterium, halogen, hydroxyl, amino, cyano, or C group. 1-6 Alkyl, C 1-6 Deuterated alkyl groups (fully or partially deuterated), C 2-6 alkenyl, C 2-6 Alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5- to 6-membered heteroaryl; or alternatively, two R 8 Together with the atoms they are connected to, they form independent groups consisting of 0 to 3 R atoms. 12 The substituted 3- to 6-membered carbon rings or 3- to 6-membered heterocycles.

[0049] In one implementation of formula (I), X 1 For CR 6 , where R 6 It is hydrogen or C 1-4 Alkyl groups, such as methyl groups.

[0050] In any of the aforementioned embodiments of formula (I),

[0051] Part of

[0052]

[0053] In any of the aforementioned embodiments of formula (I),

[0054] Partially selected from

[0055] and

[0056] Y 4 It can be O or NH.

[0057] In any of the aforementioned embodiments of formula (I), L is a covalent bond or a methylene group.

[0058] In any of the aforementioned embodiments of formula (I), n is 0 or 1.

[0059] In any of the foregoing embodiments of formula (I), R 5 C 1-4 Alkyl group. In one embodiment, R 5a It is a methyl group.

[0060] In any of the foregoing embodiments of formula (I), R1 It is CO2H.

[0061] In any of the foregoing embodiments of formula (I), R 3 and R 4 Together with the N and O they are connected to, they form a group of 1 R 8 The replaced 5- to 7-membered heterocyclic portion; and R 8 It can be benzyl or phenyl.

[0062] In any of the foregoing embodiments of formula (I), R 4 C 1-10 Alkyl, C 1-10 Halogenated, C 3-6 cycloalkyl, -(C 1-4 alkylene)-(C 3-6 cycloalkyl), -(C 1-4 alkylene)-(C 1-6 alkoxy), or -(C 1-4 Alkylene-phenyl; wherein each of the alkylene, cycloalkylene, and phenyl groups is independently bound by 0 to 3 R groups, either alone or as part of other portions. 8 Replace; and R 8 Each is independently a halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; or alternatively, two R 8 Together with the atoms they are attached to, they form 3- to 6-membered carbon rings. The alkyl and alkylene groups are each independently straight-chain or branched chains; and the methylene and phenyl moieties of the benzyl group are each independently bounded by 0 to 3 R groups. 8 replace.

[0063] In any of the foregoing embodiments of formula (I), the compound is represented by formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIIf):

[0064]

[0065] Or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein:

[0066] Each R 7a Independently hydrogen, halogen, oxo, cyano, hydroxyl, amino, C 1-6 Alkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic groups, alkylamino groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, alkoxyalkyl groups, haloalkoxyalkyl groups, alkoxy groups, or haloalkoxy groups;

[0067] f is an integer 0, 1, or 2;

[0068] R 3 It is hydrogen or C 1-4 alkyl;

[0069] R 4 C 1-10 Alkyl, C 3-8 cycloalkyl, 6- to 10-membered aryl, -(C 1-6 alkylene)-(C 3-8 cycloalkyl), or -(C 1-6 Alkylene (6- to 10-membered aryl); wherein each of the alkyl, alkenyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups is independently bounded by 0 to 3 R groups, either individually or as part of other portions. 8 Replace; or alternatively, R 3 and R 4 Together with the N and O they are connected to, they form a network of 0 to 3 R... 8 The replaced 4- to 6-membered heterocyclic moieties;

[0070] n is 0 or 1; and

[0071] R 1 R 2 R 5 R 5a R 8 ;X 1 X 2 X 3 X 4 And Z is the same as defined above.

[0072] In one embodiment of formula (IIa) or (IIb), by R 3 and R 4 The resulting heterocycle is substituted by one phenyl or one benzyl group.

[0073] In either of the foregoing embodiments of formula (IIa) or (IIb), R 1 It is CO2H.

[0074] In either of the foregoing embodiments of formula (IIa) or (IIb), X 1 For CR 6 , where R 6 It is hydrogen or C 1-4 Alkyl group. In one embodiment, X 1 It is CH or CCH3.

[0075] In either of the foregoing embodiments of formula (IIa) or (IIb), X 3 Let N be the number of elements in the array.

[0076] In either of the foregoing embodiments of formula (IIa) or (IIb), X 1 For CR 6 , where each R 6 Independently hydrogen, C 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Alkoxyalkyl. In another embodiment, X 1 X 2 X 3 and X 4 For CH.

[0077] In either of the foregoing embodiments of formula (IIa) or (IIb),

[0078] Partially selected from

[0079]

[0080] R 6a Each is independently a halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; and

[0081] d is an integer, 0, 1 or 2.

[0082] In either of the foregoing embodiments of formula (IIa) or (IIb),

[0083] Partially selected from

[0084] and

[0085] R 6 Each is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy.

[0086] In either of the foregoing embodiments of formula (IIa) or (IIb), f is 0 or 1. In one embodiment, R 7a It is hydrogen.

[0087] In either of the foregoing embodiments of formula (IIa) or (IIb), the compound is represented by formula (IIIa) or (IIIb):

[0088]

[0089] Or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein:

[0090] R 2a It is hydrogen, chlorine, fluorine or C 1-4 Alkyl; R 3 It is hydrogen or C 1-6 Alkyl; and R 1 R 4 X 1 X 2 X 3 and X 4 Same as defined above.

[0091] In one implementation of formula (IIIa) or (IIIb), Partially selected from

[0092]

[0093] In either of the foregoing embodiments of formula (IIIa) or (IIIb), R 1 It is CO2H.

[0094] In either of the foregoing embodiments of formula (IIIa) or (IIIb),

[0095] Partially selected from

[0096] and

[0097] R 6 Each can be independently hydrogen, CH3, CH2CH3, CH2OCH3, CHF2, or CF3.

[0098] In any of the foregoing embodiments of formula (IIIb), the compound is represented by formula (IV):

[0099]

[0100] Or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein:

[0101] R 2a It is hydrogen, chlorine, fluorine or C 1-4 Alkyl; R 3 It is hydrogen or C 1-6 Alkyl; and R 6 and R 4 Same as defined above. In one implementation, R 6 For hydrogen, C 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy. In another embodiment, R 6It is methyl or ethyl. In one embodiment, R 4 C 1-10 Alkyl, -(C 1-6 Alkylene) 0-1 -phenyl, or -(C 1-6 Alkylene) 0-1 -(C 3-8 (Cycloalkyl). In another embodiment, R 4 C 1-6 Alkyl group, -(CH2) 0-2 -(C 3-6 cycloalkyl), -(CHCH3)-(C 3-6 cycloalkyl), -(CH2) 1-2 -Phenyl, or -(CHCH3)-phenyl.

[0102] In either of the foregoing embodiments of formula (IIIa) or (IIIb), R 4 C 3-10 Alkyl, C 3-10 Halogenated, C 3-6 Cycloalkyl, phenyl, -(C 1-4 alkylene)-(C 1-3 alkoxy), -(C 1-4 alkylene)-(C 3-6 cycloalkyl), or benzyl; wherein the alkyl, alkylene, cycloalkyl, and benzyl groups are each independently marked with 0 to 3 R groups. 8 Replace; and R 8 Each independently constitutes a halogen, C 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; or alternatively, two R 8 Together with the atoms they are attached to, they form 3- to 6-membered carbon rings. Each of the alkyl and alkylene groups is independently a straight chain or a branched chain; and the methylene and phenyl moieties of the benzyl group are each independently surrounded by 0 to 3 R groups. 8 replace.

[0103] In either of the foregoing embodiments of formula (IIIa) or (IIIb), R 4 C 3-10 Alkyl, C 3-10 Halogenated groups, cyclobutyl groups, cyclopentyl groups, -(CH2) 1-2 -(C 1-3 alkoxy), -(CHR) 8a ) 1-2 -Cyclopropyl, -(CHR) 8a ) 1-2 -Cyclobutyl, or -(CHR 8a ) 1-2-Phenyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl and phenyl groups are each independently separated by 0 to 3 R groups. 8 Replace; or alternatively, the two Rs 8 Together with the atoms they are attached to, they form cyclopropyl groups; R 8a Each is independently hydrogen or methyl; and R 8 Each is independently halogen or C 1-4 alkyl.

[0104] In one embodiment of the invention, the compound is selected from any of the embodiments described in the specification, or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates.

[0105] In another embodiment of the invention, the compound is selected from Examples 1 to 240 as described in the specification, or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates.

[0106] In another embodiment of the invention, the compound is selected from Examples 1 to 145 as described in the specification, or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates.

[0107] In one embodiment of the present invention, the compound is selected from:

[0108]

[0109]

[0110] Or its pharmaceutically acceptable salts or solvates.

[0111] In one embodiment of the present invention, the compound is selected from:

[0112]

[0113] Or its pharmaceutically acceptable salts or solvates.

[0114] In another embodiment of the invention, the compound is selected from:

[0115]

[0116] Or its pharmaceutically acceptable salts or solvates.

[0117] In another embodiment of the invention, the compound is selected from:

[0118]

[0119] Or its pharmaceutically acceptable salts or solvates.

[0120] In another embodiment of the invention, the compound is selected from:

[0121]

[0122] Or its pharmaceutically acceptable salts or solvates.

[0123] In another embodiment of the invention, the compound is selected from:

[0124]

[0125] Or its pharmaceutically acceptable salts or solvates.

[0126] In another embodiment of the invention, the compound is selected from:

[0127]

[0128] Or its pharmaceutically acceptable salts or solvates.

[0129] In another embodiment of the invention, the compound is selected from:

[0130]

[0131] Or its pharmaceutically acceptable salts or solvates.

[0132] In another embodiment of the invention, the compound is selected from:

[0133]

[0134] Or its pharmaceutically acceptable salts or solvates.

[0135] In one embodiment, using LPA1 functional antagonist analysis, the compounds of the present invention possess hLPA1IC 50 Value ≤ 5000 nM; in another embodiment, the compound of the present invention has hLPA1 IC 50 Value ≤1000nM; in another embodiment, the compound of the present invention has hLPA1 IC 50 Value ≤ 500 nM; in another embodiment, the compound of the present invention has hLPA1 IC 50 Value ≤200 nM; in another embodiment, the compound of the present invention has hLPA1 IC 50 Value ≤100nM; in another embodiment, the compound of the present invention has hLPA1 IC 50 Value ≤ 50nM.

[0136] II. Other embodiments of the present invention

[0137] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is an antagonist of at least one LPA receptor. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is an LPA1 antagonist. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is an LPA2 antagonist. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is an LPA3 antagonist.

[0138] In some embodiments, this document provides compounds selected from active metabolites, tautomers, pharmaceutically acceptable salts or solvates of formula (I).

[0139] In another embodiment, the present invention provides a composition comprising at least one of the compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0140] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0141] In another embodiment, the present invention provides a method for preparing the compound of the present invention.

[0142] In another embodiment, the present invention provides an intermediate for preparing the compounds of the present invention.

[0143] In another embodiment, the present invention provides a pharmaceutical composition further comprising other therapeutic agents.

[0144] In another embodiment, the present invention provides a method for treating a condition associated with LPA receptor-mediated fibrosis, comprising administering to a patient requiring such treatment a therapeutically effective amount of at least one of the compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof. As used herein, the term “patient” encompasses all mammalian species.

[0145] In another embodiment, the present invention provides a method for treating a disease, condition, or symptom associated with abnormal regulation of lysophosphatidylcholine receptor 1 (LPA1) in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof. In one embodiment of the method, the disease, condition, or symptom is associated with pathological fibrosis, transplant rejection, cancer, osteoporosis, or inflammation. In one embodiment of the method, the pathological fibrosis is fibrosis of the lungs, liver, kidneys, heart, dermis, eyes, or pancreas. In one embodiment of the method, the disease, condition, or symptom is idiopathic pulmonary fibrosis (IPF), nonalcoholic steatosis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, and systemic sclerosis. In one implementation of this method, the cancer is cancer of the bladder, blood, bones, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitals, urogenital tract, head, kidneys, larynx, liver, lungs, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testis, or thyroid.

[0146] In another embodiment, the present invention provides a method for treating fibrosis in mammals, comprising administering a therapeutically effective amount of the compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, to a mammal in need. In one embodiment of the method, the fibrosis is idiopathic pulmonary fibrosis (IPF), nonalcoholic steatosis (NASH), chronic kidney disease, diabetic nephropathy, and systemic sclerosis.

[0147] In another embodiment, the present invention provides a method for treating pulmonary fibrosis (idiopathic pulmonary fibrosis), asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis (non-alcoholic steatosis), skin fibrosis, intestinal fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, intestinal cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant rejection, scleroderma, ocular fibrosis, age-related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenon, or neuralgia in mammals, the method comprising administering a therapeutically effective amount of the compound of the present invention or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates to the desired mammal.

[0148] As used herein, “treating” or “treatment” encompasses treating a disease state in mammals (particularly humans) and includes: (a) suppressing the disease state, i.e., halting its development; and / or (b) alleviating the disease state, i.e., promoting the remission of the disease state. As used herein, “treating” or “treatment” also includes preventive treatment of a disease state to reduce and / or minimize the risk of the disease state and / or reduce the risk of recurrence of the disease state, achieved by administering to the patient a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof. Such preventive therapies may be selected for patients based on factors known to increase the risk of developing a clinical disease state compared to the general population. For preventive treatment, a clinical disease state may or may not be present. Preventive therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as therapies that reduce or minimize the risk of developing a disease state in patients who have not yet presented with a clinical disease state, while secondary prevention is defined as minimizing or reducing the risk of recurrence or recurrence of the same or similar clinical disease state.

[0149] This invention may be practiced in other specific forms without departing from its spirit or essential characteristics. This invention encompasses all combinations of the preferred aspects of the invention mentioned herein. It should be understood that any and all embodiments of the invention may be combined with any other embodiments to describe further embodiments. It should also be understood that each individual element in an embodiment is an independent embodiment of itself. Furthermore, any element of one embodiment is intended to be combined with any and all other elements of any embodiment to describe another embodiment.

[0150] III. Chemistry

[0151] Throughout this specification and the appended claims, the specified chemical formulas or names shall encompass all stereoisomers, optical isomers, and racemic derivatives (if such isomers exist). Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of this invention. The compounds may also exist as numerous geometric isomers of C=N double bonds, C=N double bonds, ring systems, and the like, and all such stable isomers are covered in this invention. Cis and trans (or E- and Z-type) geometric isomers of the compounds of this invention have been described and can be isolated as mixtures of isomers or as separated isomers. The compounds of this invention can be isolated in optically active or racemic forms. The optically active form can be prepared by resolving the racemic form or by synthesis from an optically active starting material. All methods used to prepare the compounds of this invention and the intermediates prepared therein are considered part of this invention. When preparing enantiomers or diastereomers, they can be separated by conventional methods, such as chromatography or fractional crystallization. Depending on the processing conditions, the final products of this invention are obtained in either a free (neutral) form or a salt form. Both the free form and the salt of these final products are within the scope of this invention. Where necessary, one form of the compound can be converted to another. A free base or acid can be converted to a salt; a salt can be converted to a free compound or another salt; mixtures of isomers of this invention can be separated into individual isomers. The compounds, free forms, and salts of this invention can exist in a variety of tautomeric forms, wherein hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between atoms in the molecule are thus rearranged. It should be understood that all tautomeric forms, as long as they can exist, are included within this invention.

[0152] The term "stereoisomer" refers to isomers having the same composition but differing in the spatial arrangement of their atoms. 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 cannot be superimposed. The term "diastereomer" refers to a stereoisomer that is not a mirror image of another. The term "racemic mixture" or "racemic compound" refers to a composition consisting of two enantiomeric species in equimolar amounts, wherein the composition lacks optical activity.

[0153] The symbols “R” and “S” represent the configuration of the substituents surrounding the chiral carbon atom. The isomer 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 Recommendation 1996, Pure and Applied Chemistry, 68: 2193-2222 (1996)).

[0154] The term "chirality" refers to a structural characteristic of a molecule that makes it impossible for it to overlap with its mirror image. The term "isochirality" refers to the state of purity of enantiomers. The term "optical activity" refers to the degree to which isochiral molecules or non-racemic mixtures of chiral molecules rotate the plane of polarization.

[0155] As used herein, the terms "alkyl" or "alkylene" are intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a 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 C2" 10 "alkyl" or "C" 1-10 "Alkyl" is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Alkyl group. "C1 to C2" 10 "alkylene" or "C" 1-10 "Alkylene" is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Alkylene. Additionally, for example, "C1 to C6 alkyl" or "C 1-6 "alkyl" indicates an alkyl group having 1 to 6 carbon atoms; and "C1 to C6 alkylene" or "C 1-6 "alkylene" indicates an alkylene having 1 to 6 carbon atoms; and "C1 to C4 alkyl" or "C 1-4 "alkyl" indicates an alkyl group having 1 to 4 carbon atoms; and "C1 to C4 alkylene" or "C 1-4 "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 atom 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 "CO alkyl" or "CO alkylene" is used, it is intended to indicate a direct bond. Additionally, the term "alkyl" 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, 1 to 6 carbon atoms, or 1 to 10 carbon atoms.

[0156] "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 alkyl carbon atom attached to the parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkoxy group (e.g., -OCH3, etc.), an alkylamino group (e.g., -NHCH3, -N(CH3)2, etc.), or a thioalkyl group (e.g., -SCH3). If the non-terminal carbon atom of an alkyl group not attached to the parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkyl ether (e.g., -CH2CH2-O-CH3, etc.), an alkylaminoalkyl group (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.), or a thioalkyl ether (e.g., -CH2-S-CH3). If the terminal carbon atom of an alkyl group is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is a hydroxyalkyl group (e.g., -CH2CH2-OH), an aminoalkyl group (e.g., -CH2NH2), or an alkylthiol group (e.g., -CH2CH2-SH). Heteroalkyl groups can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. C1-C6 heteroalkyl groups refer to heteroalkyl groups having 1 to 6 carbon atoms.

[0157] "Alkenyl" or "alkenyl" is intended to include hydrocarbon chains with straight or branched configurations, having a specified number of carbon atoms and one or more, preferably one or two, carbon-carbon double bonds that can exist along the chain at any stable point. For example, "C2 to C6 alkenyl" or "C 2-6 "Alkenyl" (or alkenylylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl groups include (but are not limited to) vinyl, 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.

[0158] "Alynyl" or "ethynyl" is intended to include hydrocarbon chains with straight or branched configurations having one or more, preferably one to three, carbon-carbon triple bonds that can exist along the chain at any stable point. For example, "C2 to C6 ethynyl" or "C 2-6 "Alynyl" (or ynylene) is intended to include C2, C3, C4, C5 and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentylyl and hexynyl.

[0159] As used herein, “araneyl” (also known as aryl), “heteroaryl alkyl”, “carbocyclic alkyl”, or “heterocyclic alkyl” refers to an acyclic alkyl group in which the atom is bonded to a carbon atom (typically terminal or sp). 3One of the hydrogen atoms of a carbon atom is replaced by an aryl, heteroaryl, carbocyclic, or heterocyclic group. Typical arylalkyl groups include (but are not limited to) benzyl, 2-phenylethyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, naphthobenzyl, 2-naphthophenylethyl-1-yl, and similar groups. Arylalkyl, heteroarylalkyl, carbocyclic, or heterocyclic alkyl groups may contain 4 to 20 carbon atoms and 0 to 5 heteroatoms; for example, the alkyl moiety may contain 1 to 6 carbon atoms.

[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 optionally be replaced by 1 to 5 groups, preferably 1 to 3 groups, 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".

[0161] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "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, "alkathio" or "thioalkoxy" means an alkyl group as defined above with a specified number of carbon atoms connected by a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0162] As used herein, either on its own or as part of another group, the terms "alkanoyl" or "alkyl carbonyl" refer to an alkyl group attached to a carbonyl group. For example, an alkyl carbonyl group may be represented by alkyl-C(O)-. "C1 to C6 alkyl carbonyl" (or alkyl carbonyl) is intended to include C1, C2, C3, C4, C5, and C6 alkyl-C(O)- groups.

[0163] As used herein or as part of another group, the terms "alkylsulfonyl" or "sulfonamide" refer to an alkyl or amino group attached to a sulfonyl group. For example, an alkylsulfonyl group may be represented by -S(O)₂R′, while a sulfonamide may be represented by -S(O)₂NR. c R d Indicated. R′ is a C1 to C6 alkyl group; and R c and R d Same as the definition of "amino" below.

[0164] As used herein, either on its own or as part of another group, the term "urethane" refers to an oxygen atom attached to an amide group. For example, urethane can be formed from N(R) c R d )-C(O)-O- represents, and R c and R d Same as the definition of "amino" below.

[0165] As used herein, either on its own or as part of another group, the term "amide group" refers to an amino group attached to a carbonyl group. For example, an amide group can be formed from N(R) c R d )-C(O)- represents, and R c and R d Same as the definition of "amino" below.

[0166] 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 they are attached to, they form 3- to 8-membered heterocycles, which are optionally substituted by one or more groups selected from: halogen, cyano, hydroxyl, amino, oxo, C 1-6 Alkyl, alkoxy, and aminoalkyl groups. When R c1 Or R c2 (or both) are C 1-6 When alkyl, the amino group can also be called alkylamino. Examples of alkylamino groups include (but are not limited to) methylamino, ethylamino, propylamino, isopropylamino, and similar groups. In one embodiment, the amino group is -NH2.

[0167] The term "aminoalkyl" refers to an alkyl group in which one of its hydrogen atoms is replaced by an amino group. For example, an aminoalkyl group can be formed by N(R) c1 R c2 )-alkylene- indicates. "C1 to C6" or "C 1-6 "Aminoalkyl (or aminoalkyl) is intended to include C1, C2, C3, C4, C5 and C6 aminoalkyl."

[0168] As used herein, either on its own or as part of another group, the term "halogen" or "halogen group" refers to chlorine, bromine, fluorine, and iodine, with chlorine or fluorine being preferred.

[0169] "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms substituted with one or more halogens. "C1 to C6 haloalkyl" or "C 1-6"Halogen alkyl" (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 "polyhalogen alkyl" refers to an "alkyl" as defined above that includes 2 to 9, preferably 2 to 5, halogen substituents (such as F or Cl, preferably F), such as polyfluoroalkyl, for example CF3CH2, CF3, or CF3CF2CH2.

[0170] "Haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above, having a specified number of carbon atoms connected by oxygen bridges. For example, "C1 to C6 haloalkoxy" or "C..." 1-6 "Haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include (but are not limited to) trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above having a specified number of carbon atoms linked by a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-. As used herein, the term "polyhaloalkoxy" refers to an "alkoxy" or "alkyloxy" group as defined above that includes 2 to 9, preferably 2 to 5, halogen substituents (such as F or Cl, preferably F), such as polyfluoroalkoxy groups, for example CF3CH2O, CF3O, or CF3CF2CH2O.

[0171] "Hydroxyalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms substituted with one or more hydroxyl groups (OH). "C1 to C6 hydroxyalkyl" (or hydroxyalkyl) is intended to include C1, C2, C3, C4, C5 and C6 hydroxyalkyl groups.

[0172] The term "cycloalkyl" refers to cycloalkyl groups, including monocyclic, bicyclic, or polycyclic 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 cycloalkyl groups. Examples of cycloalkyl groups include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornelalkyl. The definition of "cycloalkyl" includes branched cycloalkyl groups, such as 1-methylcyclopropyl and 2-methylcyclopropyl, and screwed and bridged cycloalkyl groups.

[0173] The term "cyclohexaalkyl" refers to cyclohexaalkyl compounds, including monocyclic, bicyclic, or polycyclic systems. "C3 to C7 cyclohexaalkyl" or "C 3-7"Cyclohexaalkyl" is intended to include C3, C4, C5, C6, and C7 cyclohexaalkyl groups. Examples of cyclohexaalkyl groups include (but are not limited to) oxetane, tetrahydrofuranyl, tetrahydropyranyl, aziridine, pyrrolidyl, piperidinyl, morpholinyl, and piperazinyl. The definition of "cyclohexaalkyl" includes branched cyclohexaalkyl groups such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridinylmethyl, pyridinylmethyl, pyrimidinylmethyl, and pyrazinylmethyl.

[0174] As used herein, “carbocyclic,” “carbocyclic group,” or “carbocyclic residue” is intended to mean any stable 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered monocyclic or bicyclic or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated, or aromatic. Examples of such carbocyclic rings include (but are not limited to) cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, 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, anthracene, and tetrahydronaphthalene (naphthalene). As shown above, the definition of a carbocyclic ring also includes bridging rings (e.g., [2.2.2]bicyclooctane). Unless otherwise specified, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl are preferred carbocyclic rings. When the term "carbocyclic" is used, it is intended to include "aryl". A bridging ring is formed when one or more carbon atoms are bonded to two non-adjacent carbon atoms. The bridge is preferably one or two carbon atoms. It should be noted that bridging always transforms a monocyclic ring into a tricyclic ring. When rings are bridged, the substituents described in the ring may also be present on the bridge.

[0175] Furthermore, as used herein, either osmotically or as part of another group, the term "carbocyclic" (including "cycloalkyl" and "cycloalkenyl") includes saturated or partially unsaturated (containing one or two double bonds) cyclic hydrocarbon groups containing one to three rings, including monocycloalkyl, bicycloalkyl, and tricycloalkyl groups, containing a total of 3 to 20 carbon atoms forming the rings, preferably 3 to 10 or 3 to 6 carbon atoms forming the rings, and which may be fused with one or two aromatic rings as described with respect to aryl, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and cyclododecyl, cyclohexenyl, etc.

[0176]

[0177] Any of the groups may optionally be substituted by 1 to 4 substituents, such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamide, alkylacylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol and / or alkylthio and / or any alkyl substituent.

[0178] As used herein, the term "bicyclic carbocyclic group" is intended to refer to a stable 9- or 10-membered carbocyclic ring system consisting of two fused rings composed of carbon atoms. Of the two fused rings, one is a benzo[a] ring fused to a second ring; and the second ring is a 5- or 6-membered saturated, partially unsaturated, or unsaturated carbocyclic ring. A bicyclic carbocyclic group may be attached to its side group at any carbon atom to produce a stable structure. If the resulting compound is stable, the bicyclic carbocyclic group described herein may be substituted at any carbon atom. Examples of bicyclic carbocyclic groups are (but are not limited to) naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

[0179] As used herein, the term "aryl" as used herein, either unilaterally or as part of another group, refers to a monocyclic or polycyclic (including bicyclic and tricyclic) aromatic hydrocarbon, including, for example, phenyl, naphthyl, anthracene, and phenanthrene. The aryl moiety is well known and described, for example, in Lewis, RJ ed., Hawley's Condensed Chemical Dictionary, 13th edition, John Wiley & Sons, Inc., New York (1997). In one embodiment, the term "aryl" means a monocyclic or bicyclic aromatic group (such as phenyl or naphthyl, including 1-naphthyl and 2-naphthyl) containing 6 to 10 carbons in the ring moiety. For example, "C6 or C..." 10 "Aryl" or "C" 6-10 "Aryl" refers to phenyl and naphthyl groups. Unless otherwise specified, "aryl," "C6 or C6," and "C6" are not part of the standard definition. 10 Aryl", "C" 6-10 The "aryl" or "aromatic residue" may be unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3 groups, wherein the groups are 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.

[0180] As used herein, the term "benzyl" refers to a methyl group in which one of its hydrogen atoms is replaced by a phenyl group, wherein the phenyl group may optionally be replaced 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.

[0181] As used herein, the terms “heterocyclic,” “heterocyclic group,” or “heterocyclic group” are intended to refer to 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) heterocycles that are saturated or partially unsaturated and contain a carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and include 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 terms “heterocyclic,” “heterocyclic group,” or “heterocyclic group” include non-aromatic ring systems such as heterocyclic alkyl and heterocyclic alkenyl groups. Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)). p (where p is 0, 1, or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent (if defined)). The heterocycle 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 heterocycle described herein may be substituted at a carbon atom or a nitrogen atom. The nitrogen in the heterocycle may optionally be quaternarily ammonized. Preferably, if the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle does not exceed 1. Examples of heterocyclic groups include (but are not limited to) azo-heterocyclic butyl, piperazinyl, piperidinyl, piperidinoneyl, piperinyl, pyranyl, morpholinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, morpholinyl, dihydrofurano[2,3-b]tetrahydrofuran.

[0182] As used herein, the terms "bicyclic heterocycle" or "bicyclic heterocyclic group" are intended to refer to a stable 9- or 10-membered heterocyclic system containing two fused rings composed of a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S. Of the two fused rings, one is a 5- or 6-membered monocyclic aromatic ring, comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, or a benzo[a] 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 comprises a 5-membered heterocycle, a 6-membered heterocycle, or a carbocyclic ring (with the constraint that if the second ring is a carbocyclic ring, then the first ring is not a benzo[a] ring).

[0183] Bicyclic heterocyclic groups can be attached to their side groups at any heteroatom or carbon atom that produces a stable structure. If the resulting compound is stable, the bicyclic heterocyclic group described herein can be substituted at a carbon or nitrogen atom. Preferably, if the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle 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-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromiumyl, 1,2,3,4-tetrahydroquinoxalinyl, and 1,2,3,4-tetrahydroquinazolinyl.

[0184] The definition of a heterocycle also includes bridging rings. A bridging ring is formed when one or more atoms (i.e., C, O, N, or S) are bonded to two non-adjacent carbon or nitrogen atoms. Examples of bridging 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 bridging always transforms a monocyclic ring into a tricyclic ring. When rings are bridged, the substituents described in the definition of the ring may also be present on the bridge.

[0185] As used herein, the term "heteroaryl" is intended to refer to stable monocyclic and polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons that include at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. Heteroaryls include (but are not limited to) pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolyl, thiazolyl, indolyl, pyrroleyl, oxazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazoleyl, benzimidazolyl, indololinyl, benzodioxane, and benzodioxane. Heteroaryls may be substituted or unsubstituted. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent (if defined)). Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., N→O and S(O)). p (where p is 0, 1, or 2).

[0186] Examples of heteroaryl groups include (but are not limited to) acridinel, acridinel, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenel, benzooxazolyl, benzooxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolel, benzoisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazolel, 4aH-carbazolel, carbolinyl, chromanyl, chromenyl, cenyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazolidyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-indazolel, imidazolyl Zolopyridyl, indolenyl, indololinyl, indolazinyl, indolyl, 3H-indolyl, indigoryl, isobenzofuranyl, isochoryl, isoindazoleyl, isoindololinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, naphridyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolopyridyl, oxazolyl Alkyl-pteridyl (oxazolidinylperimidinyl), hydroxyindole, pyrimidinyl, phenanthridine, phenanthrololinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrazinyl, pyrazolylalkyl, pyrazololinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridopyrazolyl, pyridopyrazolyl, pyridopyridinyl, pyrrolinyl, 2-pyrrolidone, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl Quinoxolinyl, quininecycloyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianyl, thiazolyl, thiophene, thiazolylpyridyl, thiophene-thiazolyl, thiophene-oxazolyl, thiophene-imidazolyl, thiophene, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthonyl.

[0187] Examples of 5- to 10-membered heteroaryl groups include (but are not limited to) pyridyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, imidazoalkyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolalkyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-inzolyl, benzofuranyl, benzothiofuranyl, benzotetrazoleyl, benzotriazolyl, benzoisooxazolyl, benzooxazolyl, hydroxyindolyl, benzooxazolinyl, benzothiazolyl, benzoisothiazolyl, indorubicinyl, isoquinolinyl, octahydroisoquinolinyl, isoxazolopyridyl, quinazolinyl, isothiazolopyridyl, thiazopyridyl, oxazolopyridyl, imidazopyridyl, and pyrazolopyridyl. Examples of 5- to 6-membered heteroaryl groups include (but are not limited to) pyridyl, furanyl, thiophenyl, pyrroloyl, pyrazolyl, pyrazinyl, imidazolyl, imidazoalkyl, indoleyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolalkyl, thiadiazinicyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. In some embodiments, the heteroaryl group is selected from benzothiazolyl, imidazopyridyl, pyrrolopyridyl, quinolinyl, and indoleyl.

[0188] Unless otherwise specified, "carbocyclic" or "heterocyclic" includes one to three other rings fused to a carbocyclic or heterocyclic ring (such as aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl rings), for example...

[0189]

[0190] Optionally, it may be substituted by one, two, or three groups selected from the following: hydrogen, halogen, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cyclohexaalkyl, cyclohexaalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl. Heteroaryl alkenyl, heteroaryl heteroaryl, heteroaryloxy, hydroxyl, nitro, cyano, thiol, alkyl thio, aryl thio, heteroaryl thio, arylthioalkyl, alkoxyaryl thio, alkyl carbonyl, aryl carbonyl, alkylamino carbonyl, arylamino carbonyl, alkoxycarbonyl, amino carbonyl, alkyl carbonyloxy, aryl carbonyloxy, alkyl carbonylamino, aryl carbonylamino, aryl carbonylamino, aryl sulfinyl, aryl sulfinylalkyl, aryl sulfonylamino and aryl sulfonylamino carbonyl and / or any of the alkyl substituents described herein.

[0191] When any of the terms alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl are used as part of another group, the number of carbon atoms and ring membership are the same as defined in the term itself. For example, alkoxy, haloalkoxy, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, alkylthio and similar groups each independently contain the same number of carbon atoms as defined with respect to the term "alkyl", such as 1 to 4 carbon atoms, 1 to 6 carbon atoms, 1 to 10 carbon atoms, etc. Similarly, cycloalkoxy, heterocyclooxy, cycloalkylamino, heterocycloamino, aralkylamino, arylamino, aryloxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy and similar groups each independently contain the same ring member as defined with respect to the terms "cycloalkyl", "heterocyclic", "aryl" and "heteroaryl", such as 3 to 6, 4 to 7, 6 to 10, 5 to 10, 5 or 6, etc.

[0192] According to the conventions used in this field, such as the keys pointing to bold lines used in the structural formulas herein, such as Describes the bond as a connection point between a part or substituent and the core or main chain structure.

[0193] According to the conventions used in this art, the wave or wave key in the structure, such as This is used to depict the stereosymmetry centers of the carbon atoms connected to X′, Y′, and Z′, and is intended to represent two enantiomers in a single diagram. That is, structural formulas with features such as wavy bonds individually represent various enantiomers, such as... And its racemic mixtures. When a wave or wave bond is attached to a double bond (such as C=C or C=N), it includes cis or trans (or E- and Z-) geometric isomers or mixtures thereof.

[0194] It should be understood that in this document, if the carbocyclic or heterocyclic portion is connected to a specified acceptor by bonding with different ring atoms or otherwise without specifying a particular connection point, all possible points are considered as expected points, whether via a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" refers to 2-pyridyl, 3-pyridyl, or 4-pyridyl, and the term "thiophenyl" refers to 2-thiophenyl or 3-thiophenyl, and so on.

[0195] If a bond to a substituent crosses with a bond between two atoms in the linking ring, then such a substituent may bond to any atom in that ring. If the listed substituents do not indicate that such a substituent bonds to atoms in the remainder of the compound, then such a substituent may bond to any atom in the substituent. Combinations of substituents and / or variables are permitted only if such combinations produce a stable compound.

[0196] Those skilled in the art will recognize that the substituents and other portions of the compounds of the present invention should be selected to provide sufficiently stable compounds, thereby providing pharmaceutically suitable compounds that can be formulated into acceptable stable pharmaceutical compositions. Compounds of the present invention having such stability are intended to fall within the scope of this invention.

[0197] The term "counter ion" is used to refer to negatively charged substances, such as chloride ions, bromide ions, hydroxide ions, acetate ions, and sulfate ions. 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.

[0198] As mentioned herein, the term "substituted" means that at least one hydrogen atom (attached to a carbon atom or heteroatom) is replaced by a non-hydrogen group, with the constraint that the valence remains constant and the substitution produces a stable compound. When the substituent is oxo (i.e., =O), two hydrogen atoms on the atom are replaced. Oxo-substituents are not present on aromatic moieties. When a ring system (e.g., a carbocyclic or heterocyclic ring) is referred to as being substituted with a carbonyl group or double bond, it is desirable that the carbonyl group or double bond is part of the ring (i.e., within it). As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). The term "substituted" in relation to alkyl, cycloalkyl, heteroalkyl, cyclohexyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclic and heterocyclic groups means, respectively, alkyl, cycloalkyl, heteroalkyl, cyclohexyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclic and heterocyclic groups, wherein one or more hydrogen atoms attached to a carbon atom or heteroatom are each independently substituted by one or more non-hydrogen substituents.

[0199] In the presence of nitrogen atoms (e.g., amines) in the compounds of the present invention, these can be converted into N-oxides by treatment with oxidizing agents (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the present invention. Therefore, the nitrogen atoms shown and claimed are considered to encompass the nitrogen shown and its N-oxide (N→O) derivatives.

[0200] When any variable appears more than once in any component or formula, its definition for each occurrence is independent of its definition for every other occurrence. Thus, for example, if a group is shown to be substituted by 0, 1, 2, or 3 R groups, then the group is either unsubstituted when it is substituted by 0 R groups or substituted by at most three R groups, and R is chosen independently according to the definition of R for each occurrence.

[0201] Furthermore, combinations of substituents and / or variables are only permitted if such combinations produce stable compounds.

[0202] 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 the migration of atoms or groups within the molecule. For example, those skilled in the art will readily understand that, as defined above, 1,2,3-triazole exists in two tautomeric forms:

[0203]

[0204] Therefore, the present invention is intended to cover all possible tautomers, even when the structure only describes one of them.

[0205] The phrase “pharmaceutically acceptable” is used in this article to refer to compounds, substances, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0206] The compounds of the present invention may exist in salt form, which is also within the scope of the present invention. Pharmaceutically acceptable salts are preferred. As used herein, “pharmaceutically acceptable salt” refers to a derivative of a compound of the present invention, wherein the parent compound is modified by preparing its acid salt or base salt. Pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety using conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; generally, non-aqueous media (such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. A list of suitable salts is available in Remington’s Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference.

[0207] If the compounds of the present invention have, for example, at least one basic center, they can form acid addition salts. These acid addition salts are formed by acids such as: strong inorganic acids, such as mineral acids, such as sulfuric acid, phosphoric acid, or hydrohalic acid; organic carboxylic acids, such as alkyl carboxylic acids having 1 to 4 carbon atoms (e.g., acetic acid), which are unsubstituted or substituted with, for example, halogens (e.g., chloroacetic acid); saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or terephthalic acid; hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; amino acids (e.g., aspartic acid, glutamic acid, lysine, or arginine) or benzoic acid; or organic sulfonic acids, such as (C1-C4)alkyl or aryl sulfonic acids, which are unsubstituted or substituted with, for example, halogens (e.g., methanesulfonic acid or p-toluenesulfonic acid). If necessary, corresponding acid addition salts having additionally present basic centers can also be formed. Compounds of the present invention having at least one acidic group (e.g., COOH) can also form salts with bases. Suitable salts formed with bases are, for example, metal salts, such as alkali metal 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 alkylamines, such as ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl, or dimethylpropylamine, or mono-, di-, or tri-hydroxy low-carbon alkylamines, such as mono-, di-, or triethanolamine. Furthermore, corresponding internal salts can be formed. Salts of free compounds of formula (I) or their pharmaceutically acceptable salts, which are not suitable for pharmaceutical use but can be used, for example, for the separation or purification, are also included.

[0208] Preferred salts of compounds of formula (I) containing a base include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate, nitrate or acetate.

[0209] Preferred salts of compounds of formula (I) containing acid groups include sodium, potassium and magnesium salts, as well as pharmaceutically acceptable organic amines.

[0210] Furthermore, compounds of formula (I) may have a prodrug form. Any compound that is converted in vivo to yield a bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of this invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:

[0211] a) Bundgaard, H. (ed.), Design of Prodrugs, Elsevier (1985), and Widder, K. et al. (eds.), Methods in Enzymology, 112: 309-396, Academic Press (1985);

[0212] b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, A Textbook of Drug Design and Development, pp. 113-191, edited by Krosgaard-Larsen, P. et al., Harwood Academic Publishers (1991);

[0213] c) Bundgaard, H., Adv.Drug Deliv.Rev., 8: 1-38 (1992);

[0214] d) Bundgaard, H. et al., J. Pharm. Sci., 77: 285 (1988); and

[0215] e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

[0216] The compounds of this invention contain a carboxyl group capable of forming a physiologically hydrolyzable ester, which acts as a prodrug, i.e., a "prodrug ester," and is hydrolyzed in vivo to produce the compound of this invention itself. Examples of physiologically hydrolyzable esters of the compounds of this invention include C1 to C6 alkyl, C1 to C6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthaloyl, methoxymethyl, C... 1-6 Alkyloxy-C 1-6 Alkyl groups (e.g., acetoxymethyl, neopentyloxymethyl, or propionyloxymethyl), C1 to C6 alkoxycarbonyl-C1 to C6 alkyl groups (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)-methyl), and other well-known physiologically hydrolyzable esters used in penicillin and cephalosporin techniques. Such esters can be prepared using conventional techniques known in the art. "Prodrug esters" can be formed by reacting the carboxylic acid moiety of the compounds of the present invention with an alkyl or aryl alcohol, a halide, or a sulfonate using steps known to those skilled in the art. Such esters can be prepared using conventional techniques known in the art.

[0217] Prodrug preparation is well known in the art and described in, for example, 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).

[0218] This invention is intended to include all isotopes of atoms present in the compounds of this invention. Isotopes include atoms with the same number of atoms but different mass numbers. As a general example, but not limitingly, 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 produced from atoms such as… 2 The symbol "H" or "D" indicates that the carbon is replaced by a deuterium atom. The term "deuteration," used here to refer to the substitution of one or more hydrogen atoms attached to carbon with deuterium atoms, whether for the carbon itself or for modifying compounds or groups. Carbon isotopes include... 13 C and 14 C.

[0219] The isotopically labeled compounds of the present invention can generally be prepared using 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 originally used unlabeled reagents. Such compounds have a variety of potential uses, such as as standards and reagents for determining the ability of potential pharmaceutical compounds to bind to target proteins or receptors, or for imaging of the compounds of the present invention binding to biological receptors in vivo or in vitro.

[0220] "Stable compound" and "stable structure" mean a compound that is sufficiently robust to withstand separation from the reaction mixture to a suitable purity and formulation into an effective therapeutic agent. Preferably, the compounds of the present invention do not contain N-halogens, S(O)₂H or S(O)H groups.

[0221] The term "solvent" refers to the physical association of the compound of the present invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, the solvate can be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in the solvate can be present in an ordered and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvent" encompasses both solution phases and separable solvates. Exemplary solvates include (but are not limited to) hydrates, ethanolates, methanolates, and isopropanolates. Generally, solvation methods are known in the art.

[0222] abbreviation

[0223] The abbreviations used in this article are defined as follows: "1x" for once, "2x" for twice, "3x" for three times, "°C" for degrees Celsius, "eq" for equivalent, "g" for gram, "mg" for milligram, "L" for liter, "mL" for milliliter, "μL" for microliter, "N" for equivalent concentration, "M" for molar concentration, "mmol" for millimole, "min" for minute, "h" for hour, "rt" for room temperature, "RT" for retention time, "RBF" for round-bottom flask, "atm" for atmospheric pressure, "psi" for pounds per square inch, "conc." for concentration, "RCM" for dead-cycle metathesis, "sat" or "sat'd" for saturation, "SFC" for supercritical fluid chromatography, "MW" for molecular weight, "mp" for melting point, "ee" for enantiomer excess, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectrometry, "HR" for high resolution, "HRMS" for high-resolution mass spectrometry, "LCMS" for liquid chromatography-mass spectrometry, "HPLC" for high-performance liquid chromatography, "RP" for high-performance liquid chromatography, etc. "HPLC" stands for reversed-phase HPLC, "TLC" or "tlc" stands for thin-layer chromatography, "NMR" stands for nuclear magnetic resonance spectroscopy, and "nOe" stands for nuclear Overhauser effect spectroscopy. 1 "H" represents the proton, "δ" represents δ (delta), "s" represents a singlet, "d" represents a doublet, "t" represents a triplet, "q" represents a quartet, "m" represents a multiplet, "br" represents a broad peak, "Hz" represents Hertz, and "α", "β", "γ", "R", "S", "E" and "Z" are stereochemical symbols familiar to those skilled in the art.

[0224] Me methyl

[0225] Et Ethyl

[0226] Pr propyl

[0227] i-Pr isopropyl

[0228] Bu Butyl

[0229] i-Bu Isobutyl

[0230] t-Bu tert-butyl

[0231] Ph phenyl

[0232] Bn benzyl

[0233] Boc or BOC tert-butoxycarbonyl

[0234] Boc2O ditert-butyl dicarbonate

[0235] AcO or HOAc acetic acid

[0236] AlCl3 (aluminum chloride)

[0237] AIBN (Azobisisobutyronitrile)

[0238] BBr3 Boron tribromide

[0239] BCl3 Boron trichloride

[0240] BEMP 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphazene

[0241] BOP reagent benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

[0242] Burgess reagent: 1-Methoxy-N-triethylammonium sulfonyl-formimide ester

[0243] CBz Benzyloxycarbonyl

[0244] DCM or CH2Cl2 dichloromethane

[0245] CH3CN or ACN acetonitrile

[0246] CDCl3 (deuterated chloroform)

[0247] CHCl3 chloroform

[0248] mCPBA or m-CPBA m-chloroperbenzoic acid

[0249] Cs2CO3 (cesium carbonate)

[0250] Cu(OAc)₂ Copper acetate(II)

[0251] Cy2NMe N-Cyclohexyl-N-methylcyclohexylamine

[0252] DAST (diethylamino) sulfur trifluoride

[0253] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0254] DCE 1,2-Dichloroethane

[0255] DEA diethylamine

[0256] Dess-Martin 1,1,1-Tris(acetoxy)-1,1-dihydro-1,2-benzoiodazaoxacyclopentan-3-(1H)-one

[0257] DIC or DIPCDI diisopropylcarbodiimide

[0258] DIEA, DIPEA, or Whitney diisopropylethylamine

[0259] Hunig's base

[0260] DMAP 4-Dimethylaminopyridine

[0261] DME 1,2-dimethoxyethane

[0262] DMF (dimethylformamide)

[0263] DMSO (dimethyl sulfoxide)

[0264] cDNA complementary DNA

[0265] Dppp (R)-(+)-1,2-bis(diphenylphosphine)propane

[0266] DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphosphacyclopentyl)benzene

[0267] EDC N-(3-Dimethylaminopropyl)-N′-Ethylcarbodiimide

[0268] EDCI N-(3-Dimethylaminopropyl)-N′-Ethylcarbodiimide Hydrochloride

[0269] EDTA (ethylenediaminetetraacetic acid)

[0270] (S,S)-EtDuPhosRh(I) (+)-1,2-bis((2S,5S)-2,5-diethylphosphacyclopentyl)benzene(1,5-cyclooctadiene)rhodium(I)trifluoromethanesulfonate

[0271] Et3N or TEA triethylamine

[0272] EtOAc (ethyl acetate)

[0273] Et2O diethyl ether

[0274] EtOH (ethanol)

[0275] GMF Glass Microfiber Filter

[0276] Grubbs II (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium

[0277] HCl hydrochloric acid

[0278] HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylureonium hexafluorophosphate

[0279] HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid

[0280] Hexane

[0281] HOBt or HOBT 1-hydroxybenzotriazole

[0282] H2O2 Hydrogen peroxide

[0283] IBX 2-iodobenzoic acid

[0284] H2SO4 sulfuric acid

[0285] Jones' reagent: a 2M solution of CrO3 in aqueous H2SO4.

[0286] K2CO3 (potassium carbonate)

[0287] K2HPO4 Dipotassium hydrogen phosphate (potassium hydrogen phosphate)

[0288] KOAc potassium acetate

[0289] K3PO4 (tripotassium phosphate)

[0290] LAH Lithium Aluminum Hydrogen

[0291] LDA Lithium diisopropylamide

[0292] LG leaving group

[0293] LiOH (Lithium hydroxide)

[0294] MeOH (methanol)

[0295] MgSO4 Magnesium sulfate

[0296] MsOH or MSA Methylsulfonic acid / Methanesulfonic acid

[0297] NaCl (sodium chloride)

[0298] Sodium hydride (NaH)

[0299] NaHCO3 (Sodium bicarbonate)

[0300] Na2CO3 (Sodium carbonate)

[0301] NaOH (sodium hydroxide)

[0302] Na2SO3 Sodium sulfite

[0303] Na2SO4 Sodium sulfate

[0304] NBS N-bromosuccinimide

[0305] NCS N-chlorosuccinimide

[0306] NH3 ammonia

[0307] NH4Cl ammonium chloride

[0308] NH4OH ammonium hydroxide

[0309] NH4 + HCO2 - Ammonium formate

[0310] NMM N-methylmorpholine

[0311] OTf trifluoromethanesulfonate or trifluoromethanesulfonate

[0312] Pd2(dba)3 tris(dibenzylacetone)dipalladium(0)

[0313] Pd(OAc)₂ Palladium(II) acetate

[0314] Pd / C Palladium / Carbon

[0315] Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) dichloride

[0316] Ph3PCl2 Triphenylphosphine dichloride

[0317] PG protecting group

[0318] POCl3 (phosphorus oxychloride)

[0319] PPTS (Pyridinium p-toluenesulfonate)

[0320] i-PrOH or IPA isopropanol

[0321] PS (Polystyrene)

[0322] RT or rt room temperature

[0323] SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride

[0324] SiO2 (silicon dioxide)

[0325] SnCl2 (St-II Chloride)

[0326] TBAF Tetra-n-Butylammonium Fluoride

[0327] TBAI Tetrabutylammonium Iodide

[0328] TFA (trifluoroacetic acid)

[0329] THF Tetrahydrofuran

[0330] THP Tetrahydropyran

[0331] TMSCHN2 Trimethylsilyldiazomethane

[0332] TMSCH2N3 Trimethylsilylmethyl azide

[0333] T3P propanephosphonic anhydride

[0334] TRIS Tris(hydroxymethyl)aminomethane

[0335] pTsOH p-Toluenesulfonic acid

[0336] IV. Biology

[0337] Lysophospholipids are membrane-derived bioactive lipid mediators. Lysophospholipids include (but are not limited to) lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycerol-3-phosphate; LPA), sphingosine-1-phosphate (S1P), lysophosphatidylcholine (LPC), and sphingosine monophosphate choline (SPC). Lysophospholipids influence fundamental 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.

[0338] LPA acts via specific G protein-coupled receptors (GPCRs) in both autocrine and paracrine modes. LPA binds to its homologous GPCRs (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6), activating intracellular signaling pathways to produce a variety of biological responses.

[0339] In terms of quantity, lysophospholipids (such as LPA) are trace lipids compared to their major phospholipid counterparts (e.g., phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin). LPA acts as a biological effector molecule and has a range of physiological functions, such as (but not limited to) effects on blood pressure, platelet activation, and smooth muscle contraction; and various cellular effects, including cell growth, cell rounding, axonal retraction, and actin stress fiber formation and cell migration. The effects of LPA are primarily mediated by receptors.

[0340] LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) mediate a series of downstream signaling cascades via LPA activation. 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 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), glycosaminoglycan 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), and ras-associated C3 botulinum toxin substrate 1 (RAC1). The actual pathway and endpoints depend on a range of variables, including receptor usage, cell type, expression levels of the receptor or signaling protein, and LPA concentration. Almost all mammalian cells, tissues, and organs co-express several LPA receptor subtypes, which instruct LPA receptors to signal in a cooperative manner. LPA1, LPA2, and LPA3 share high amino acid sequence similarity.

[0341] LPA is produced by activated platelets, activated adipocytes, neurons, and other cell types. Serum LPA is produced via multiple enzymatic pathways involving monoacylglycerol kinase, phospholipase A1, secretory phospholipase A2, and lysophospholipase D (lysoPLD), including autocrine motor factors. Several enzymes are involved in LPA degradation: lysophospholipases, lipid phospholipases, and LPA acyltransferases such as endophilins. The concentration of LPA in human serum is estimated to be 1 to 5 μM. Serum LPA binds to albumin, low-density lipoprotein, or other proteins, which may protect LPA from rapid degradation. Naturally occurring LPA molecules with varying acyl chain lengths and saturation levels include 1-palmitoyl (16:0), 1-palmitoyl (16:1), 1-stearoyl (18:0), 1-oleoyl (18:1), 1-linoleoyl (18:2), and 1-arachidonyl (20:4) LPA. Trace amounts of alkyl LPAs exhibit similar biological activities to acyl LPAs, and different LPA types activate LPA receptor subtypes with varying efficacies.

[0342] LPA receptor

[0343] LPA1 (formerly known as VZG-1 / EDG-2 / mrec1.3) is associated with three types of G proteins. i / o G q and G 12 / 13 Coupling. Through the activation of these G proteins, LPA induces a series of cellular responses via LPA1, including (but not limited to): cell proliferation, activation of serum response components (SRE), activation of mitogen-activated protein kinase (MAPK), inhibition of adenylate cyclase (AC), activation of phospholipase C (PLC), and Ca2+. 2+ Migration, Akt activation, and Rho activation.

[0344] Widespread expression of LPA1 has been observed in adult mice, and it is clearly present in the testes, brain, heart, lungs, small intestine, stomach, spleen, thymus, and skeletal muscle. Similarly, LPA1 is also expressed in human tissues; it is present in the brain, heart, lungs, placenta, colon, small intestine, prostate, testes, ovaries, pancreas, spleen, kidneys, skeletal muscle, and thymus.

[0345] LPA2 (EDG-4) also interacts with three types of G proteins (G... i / o G q and G 12 / 13LPA2 is coupled 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 various cancer cell lines, and several human LPA2 transcriptomorphs with mutations in the 3′-untranslated region have been observed. Target loss of LPA2 in mice has not shown significant phenotypic abnormalities, but normal LPA signaling (e.g., PLC activation, Ca2+) has been confirmed in primary cultures of mouse embryonic fibroblasts (MEFs). 2+ Significant loss of migration and stress fiber formation. The generation of LPA1(- / -)LPA2(- / -) double-empty mice showed that many LPA-induced responses (including cell proliferation, AC inhibition, PLC activation, Ca) were significantly reduced. 2+ Migration, JNK and Akt activation, and stress fiber formation were absent or severely reduced in double-empty MEFs. Except for AC inhibition (which was almost absent in LPA1(- / -) MEFs), all the aforementioned responses were only partially affected in LPA1(- / -) or LPA2(- / -) MEFs. LPA2 induces normal LPA-mediated signaling responses in at least some cell types (Choi et al., Biochemica et Biophysica Acta 2008, 1781, pp. 531-539).

[0346] LPA3 (EDG-7) differs from LPA1 and LPA2 in that it can interact with G... i / o and G q Coupled, but with G 12 / 13 It is not coupled and responds far less to LPA species with saturated acyl chains. LPA3 can mediate pleiotropic LPA-induced signaling, including PLC activation and Ca2+ activation. 2+ Migration, AC inhibition / activation, and MAPK activation. When stimulated by LPA, overexpression of LPA3 in neuroblastoma cells leads to axonal elongation, while overexpression of LPA1 or LPA2 causes axonal contraction and cell rounding. LPA3 expression has been observed in the testes, kidneys, lungs, small intestine, heart, thymus, and brain of adult mice. In humans, it has been found in the heart, pancreas, prostate, testes, lungs, ovaries, and brain (frontal cortex, hippocampus, and amygdala).

[0347] Compared to LPA1, LPA2, and LPA3, LPA4 (p2y9 / GPR23) has a divergent sequence and a stronger similarity to the platelet-activating factor (PAF) receptor. LPA4 mediates LPA-induced calcium channel blockade. 2+It migrates and accumulates cAMP, and is functionally coupled with G proteins 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.

[0348] LPA5 (GPR92) is a member of the purinocluster of GPCRs and is structurally most closely related to LPA4. LPA5 is expressed in the human heart, placenta, spleen, brain, lungs, and intestines. LPA5 also shows extremely high expression in the CD8+ lymphocyte compartments of the gastrointestinal tract.

[0349] LPA6 (p2y5) is a member of the purine cluster of GPCRs and is structurally most closely associated with 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.

[0350] Explanatory biological activity

[0351] wound healing

[0352] Normal wound healing occurs through a series of highly coordinated events in which cells, soluble factors, and matrix components work together to repair damage. The healing response can be described as proceeding in four broadly overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Numerous growth factors and cytokines are released into the wound site to initiate and maintain the wound healing process.

[0353] Upon injury, damaged blood vessels activate platelets. Activated platelets play a crucial role in subsequent repair by releasing bioactive mediators that induce cell proliferation, cell migration, blood clotting, and angiogenesis. LPA is one such mediator released by activated platelets; it induces platelet aggregation and promotes mitosis / migration in surrounding cells such as endothelial cells, smooth muscle cells, fibroblasts, and keratinocytes.

[0354] Topical application of LPA to mouse skin wounds promotes the repair process (wound closure and increased new epithelial thickness) by increasing cell proliferation / migration without causing secondary inflammation.

[0355] Growth factors and cytokines activate dermal fibroblasts, which then migrate from the wound edge into a temporary matrix formed by fibrin aggregates. Subsequently, fibroblasts proliferate and begin dermal remodeling through secretion and the production of tissue-specific extracellular matrix (ECM). The increasing deposition of fibroblasts and ECM within the wound increases matrix rigidity, achieved by applying small traction forces to the newly formed granulation tissue. This increased mechanical stress, combined with transforming growth factor β (TGFβ), induces α-smooth muscle actin (α-SMA) expression, subsequently transforming fibroblasts into myofibroblasts. Myofibroblasts promote granulation tissue remodeling, which is accomplished through myofibroblast contraction and the production of ECM components.

[0356] LPA regulates many important functions of fibroblasts in wound healing, including proliferation, migration, differentiation, and contraction. Wound healing requires fibroblast proliferation to fill open wounds. In contrast, fibrosis is characterized by the dramatic proliferation and accumulation of myofibroblasts that actively synthesize ECM and pro-inflammatory cytokines. LPA can increase or inhibit the proliferation of cell types that play an important role in wound healing, such as epithelial and endothelial cells (ECs), macrophages, keratinocytes, and fibroblasts. The role of LPA1 in LPA-induced proliferation is provided by the observation that fibroblasts isolated from LPA1 receptor knockout mice exhibit reduced proliferation upon LPA stimulation (Mills et al., Nat Rev. Cancer 2003; 3: 582-591). LPA induces cytoskeletal changes essential for fibroblast adhesion, migration, differentiation, and contraction.

[0357] fibrosis

[0358] Tissue damage 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.

[0359] For most organs and tissues, the development of fibrosis involves a variety of 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).

[0360] Multiple muscle dystrophys are characterized by progressive muscle weakness and wasting, as well as widespread fibrosis. LPA treatment has been shown to induce significant expression of connective tissue growth factor (CTGF) in cultured myoblasts. CTGF subsequently induces the expression of collagen, fibronectin, and integrins, and induces dedifferentiation in these myoblasts. LPA treatment has induced reproducible and high levels of CTGF in various cell types (JPPradere 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 pro-fibrotic cytokine that transduces signals downstream and in parallel with TGFβ.

[0361] Treatment with LPA has been found to exacerbate CTGF expression in gingival epithelial cells involved in the development of gingival fibromyxoma (A. Kantarci et al., J. Pathol. 210(2006) 59-66).

[0362] LPA is associated with the progression of liver fibrosis. LPA induces the proliferation of stellate cells and hepatocytes in vitro. These activated cells are the main cell types responsible for the accumulation of ECM in the liver. In addition, plasma LPA levels are elevated in rodents during CCl4-induced liver fibrosis, or in humans during 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).

[0363] Increased phospholipid concentrations in bronchoalveolar lavage fluid have been reported in rabbits and rodents injected with bleomycin (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).

[0364] LPA is associated with heart disease and myocardial remodeling. Serum LPA levels increase after myocardial infarction in patients and LPA stimulates the proliferation of cardiac fibroblasts and collagen production in rats (Chen et al., FEBS Lett. 2006 Aug 21; 580(19): 4737-45).

[0365] pulmonary fibrosis

[0366] In the lungs, abnormal wound healing responses to injury contribute to the pathogenesis of fibrotic lung diseases. Fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), are associated with high morbidity and mortality.

[0367] LPA is a crucial mediator of fibroblast recruitment in pulmonary fibrosis. Both LPA and LPA1 play key pathogenic roles in pulmonary fibrosis. Fibroblast chemotaxis plays a vital role in the lungs of patients with pulmonary fibrosis. The pro-fibrotic effect of LPA1 receptor stimulation is explained by LPA1 receptor-mediated vascular leakage and enhanced fibroblast recruitment (both pro-fibrotic events). The LPA-LPA1 pathway mediates fibroblast migration and vascular leakage in IPF. The ultimate result is an abnormal healing process characteristic of this fibrotic condition.

[0368] The LPA1 receptor is the LPA receptor most highly expressed in fibroblasts from IPF patients. Furthermore, BAL derived from IPF patients induces chemotaxis in human fetal lung fibroblasts, which is blocked by the dual LPA1-LPA3 receptor antagonist Ki16425. In a mouse model of bleomycin-induced lung injury, LPA levels in bronchoalveolar lavage samples were higher than in unexposed controls. LPA1 knockout mice were protected from fibrosis after bleomycin challenge, with reduced fibroblast accumulation and vascular leakage. High LPA levels were observed in bronchoalveolar lavage samples from human individuals with IPF compared to healthy controls. The enhanced fibroblast chemotactic activity in these samples was inhibited by Ki16425, suggesting that the LPA-LPA receptor pathway mediates fibroblast migration (Tager et al., Nature Medicine, 2008, 14, 45-54).

[0369] The LPA-LPA1 pathway is crucial in pulmonary fibrosis, in fibroblast recruitment, and in vascular leakage.

[0370] Activation of potential TGF-β by αvβ6 integrin plays a crucial role in the development of lung injury and fibrosis (Munger et al., Cell, Vol. 96, 319-328, 1999). LPA induces αvβ6-mediated TGF-β activation on human lung epithelial cells (Xu et al., Am.J. Pathology, 2009, 174, 1264-1279). LPA-induced αvβ6-mediated TGF-β activation is mediated by the LPA2 receptor. Compared to normal human lung tissue, LPA2 receptor expression is enhanced in epithelial and mesenchymal cells in the fibrotic regions 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 have shown therapeutic efficacy in pulmonary fibrosis. In some embodiments, compounds that inhibit both LPA1 and LPA2 have shown improved therapeutic efficacy in pulmonary fibrosis compared to compounds that inhibit only LPA1 or LPA2.

[0371] In a 26-week clinical trial of IPF patients, the LPA1 antagonist BMS-986020 showed a significant reduction in the rate of FVC (forced vital capacity) decay (Palmer et al., Chest, 2018, 154, 1061-1069).

[0372] Renal fibrosis

[0373] LPA and LPA1 are involved in the pathogenesis of renal fibrosis. LPA plays a role in both the proliferation and contraction of glomerular membrane cells, and is therefore associated with proliferative glomerulonephritis (CNInoue 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 LPA2 > LPA3 = LPA1 >> LPA4 under basal conditions. This model simulates the development of renal fibrosis in an accelerated manner, including nephritis, fibroblast activation, and the accumulation of extracellular matrix in the renal tubulointerstitium. UUO significantly induced LPA1 receptor expression. In parallel, renal LPA was produced in the conditioned medium of the 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 prerequisite for the role of LPA in fibrosis is met: the production of the ligand (LPA) and the induction of one of its receptors (LPA1 receptor) (JPPradere et al., Biochimica et Biophysica Acta, 2008, 1781, 582-587).

[0374] In LPA1 receptor gene knockout (LPA1(- / -) mice), the development of renal fibrosis was significantly reduced. UUO mice treated with the LPA receptor antagonist Ki16425 had a very similar profile to LPA1(- / -) mice.

[0375] LPA can participate in the intraperitoneal accumulation of monocytes / macrophages and 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).

[0376] LPA treatment of the mouse epithelial kidney cell line MCT induces a rapid increase in the expression of the pro-fibrotic cytokine CTGF. CTGF plays a key role in UUO-induced tubulointerstitial fibrosis (TIF) and is involved in the pro-fibrotic activity of TGFβ. Co-treatment with the LPA receptor antagonist Ki16425 almost completely inhibits this induction. In one aspect, the pro-fibrotic activity of LPA in the kidney is due to the direct action of LPA on renal cells involved in CTGF-induced fibrosis.

[0377] liver fibrosis

[0378] LPA is involved in liver disease and fibrosis. In hepatitis patients and animal models of liver injury associated with increased fibrosis, plasma LPA levels and serum autocrine motor factors (enzymes responsible for producing LPA) are elevated. LPA also regulates hepatic cell function. Mouse hepatic stellate cells express LPA1 and LPA2 receptors, and LPA stimulates the migration of hepatic myofibroblasts.

[0379] ocular fibrosis

[0380] LPA is involved in eye 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 is increased in injured corneal epithelial cells.

[0381] LPA and its homologs are present in the aqueous humor and lacrimal fluid of rabbit eyes, and these levels are increased in a rabbit corneal injury model.

[0382] LPA induces the formation of actin stress fibers in rabbit corneal endothelial and epithelial cells and promotes corneal fibroblast contraction. LPA also stimulates the proliferation of human retinal pigment epithelial cells.

[0383] Cardiac fibrosis

[0384] LPA is involved in myocardial infarction and cardiac fibrosis. Increased serum LPA levels are observed in patients following myocardial infarction (MI), and LPA stimulates the proliferation of cardiac fibroblasts and collagen production in rats (fibrosis). Both LPA1 and LPA3 receptors are highly expressed in human cardiac tissue.

[0385] Treatment of fibrosis

[0386] In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat or prevent fibrosis in mammals. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat fibrosis of an organ or tissue in a mammal. In one aspect, a method for preventing fibrotic conditions in mammals includes administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal at risk of developing one or more fibrotic conditions. In one aspect, the mammal has been exposed to one or more environmental conditions known to increase the risk of fibrosis of an organ or tissue. In one aspect, the mammal has been exposed to one or more environmental conditions known to increase the risk of pulmonary fibrosis, liver fibrosis, or kidney fibrosis. In one aspect, the mammal has a genetic predisposition to developing organ or tissue fibrosis. In one aspect, administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal is used to prevent or minimize scarring following injury. In one aspect, the injury includes surgery.

[0387] As used herein, the term “fibrosis” or “fibrotic disorder” refers to a condition associated with the 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, peritoneum, skin, cornea, retina, muscles and bones, and digestive tract.

[0388] Examples of diseases, conditions, or illnesses 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 fibrotic 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 (renal fibrosis) associated with injury / fibrosis, such as glomerulonephritis secondary to systemic inflammation. Conditions such as lupus and scleroderma, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allografting, and Allport syndrome; intestinal fibrosis, such as scleroderma and radiation-induced intestinal fibrosis; liver fibrosis, such as cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatosis (NASH), bile duct injury, primary biliary cirrhosis, infection- or virus-induced liver fibrosis (e.g., chronic HCV infection), and autoimmune hepatitis; head and neck fibrosis, such as radiation-induced fibrosis; and corneal scarring, such as LASIK (laser-assisted in situ keratoplasty). In situ keratomileusis), corneal transplantation and trabeculectomy; hypertrophic scars and keloids, such as burn induction or surgery; and other fibrotic diseases, such as sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease.

[0389] In one aspect, mammals suffering from one of the following non-limiting exemplary diseases, conditions, or illnesses will benefit from therapy with a compound of formula (I) or a pharmaceutically acceptable salt thereof: atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pneumonia, intestinal adhesions, bladder fibrosis and cystitis, nasal passage fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

[0390] In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered, together with one or more other agents for the treatment of fibrosis, to a mammal suffering from organ or tissue fibrosis or whose organ or tissue is prone to 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.

[0391] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat skin conditions in mammals. As used herein, the term "dermatological condition" refers to a skin condition. Such dermatological conditions include (but are not limited to) proliferative or inflammatory skin conditions such as atopic dermatitis, bullous conditions, collagen diseases, psoriasis, scleroderma, psoriatic foci, 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 a pharmaceutically acceptable salt thereof is used to treat systemic sclerosis.

[0392] pain

[0393] Because LPA is released after tissue injury, LPA1 plays an important role in the initiation of neuropathic pain. Unlike LPA2 or LPA3, LPA1 is expressed in the dorsal root ganglion (DRG) and dorsal root neurons. Treatment of LPA1- and LPA1-knockout mice with antisense oligodeoxynucleotides (AS-ODN) revealed that LPA-induced mechanical aberrant pain 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 extracellular enzyme (BoTXC3, a Rho inhibitor) or Y-27632 (a ROCK inhibitor) completely eliminated aberrant pain and hyperalgesia in mice with nerve injury. LPA also induces dorsal root demyelination, which is prevented by BoTXC3. Damage-induced dorsal root demyelination was not 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 (Caαt2δ1), in an LPA1- and Rho-dependent manner (M. Inoue et al., Initiation of neuropathic pain requires lysophosphatidicacid receptor signaling, Nat. Med. 10 (2004) 712-718).

[0394] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat pain in mammals. In one aspect, the pain is acute or chronic. In another aspect, the pain is neuralgia.

[0395] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat fibromuscular pain. In another aspect, fibromuscular pain arises from the formation of fibrous scar tissue in contracting (spontaneous) muscles. Fibrosis causes tissue adhesion and inhibits blood flow, resulting in pain.

[0396] cancer

[0397] Lysophospholipid receptor signaling plays a role in the pathogenesis 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. Cancer initiation, progression, and metastasis involve several parallel and sequential processes, including cell proliferation and growth, survival and anti-apoptosis, cell migration, infiltration of foreign cells into defined cell layers and / or organs, and promotion of angiogenesis. Controlling each of these processes induced by LPA signaling under physiological and pathophysiological conditions underscores the potential therapeutic usefulness of modulating LPA signaling pathways for cancer treatment, especially at the LPA receptor or ATX / lysoPLD level. Autocrine motor factor (ATX), a transferase originally isolated from conditioned medium of human melanoma cells, stimulates a variety of biological activities through LPA production, including angiogenesis and promotion of cell growth, migration, survival, and differentiation (Mol Cancer Ther 2008; 7(10): 3352-62).

[0398] LPA activates multiple downstream effector pathways through its own GPCRs. These downstream effector pathways play a role in cancer. LPA and its GPCRs are associated with cancer through major oncogenic signaling pathways.

[0399] LPA promotes tumorigenesis by increasing cellular activity and invasiveness. LPA has been involved in the initiation or progression of ovarian cancer. LPA is present in significant concentrations (2-80 μM) in the ascites fluid of patients with ovarian cancer. Compared to normal ovarian surface epithelial cells, ovarian cancer cells constitutively produce increased amounts of LPA, a precursor to ovarian epithelial cancer. Elevated LPA levels have also been detected in the plasma of patients with early-stage ovarian cancer compared to controls. LPA receptors (LPA2 and LPA3) are also overexpressed in ovarian cancer cells compared to normal ovarian surface epithelial cells. LPA stimulates Cox-2 expression in ovarian cancer cells through transcriptional activation and post-transcriptional enhancement of Cox-2 mRNA. Cox2-prostaglandins have been associated with various human cancers, and pharmacological inhibition of Cox-2 activity reduces colon cancer development and decreases the size and number of adenomas in patients with familial adenomatous polyposis. LPA is also involved in the initiation or progression of prostate cancer, breast cancer, melanoma, head and neck 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).

[0400] Cellular responses to LPA are mediated through lysophosphatidylcholine receptors. For example, LPA receptors mediate the migration and invasion of pancreatic cancer cell lines: LPA1 and LPA3 (Ki16425) and LPA1-specific siRNA antagonists effectively block the in vitro migration of LPA and peritoneal fluid (ascites) in response to pancreatic cancer patients; in addition, Ki16425 blocks the invasive activity of LPA-induced and ascites-induced highly peritoneal metastatic pancreatic cancer cell lines (Yamada et al., J. Biol. Chem. 279, 6595-6605, 2004).

[0401] Colorectal cancer cell lines showed significant expression of LPA1 mRNA and responded to LPA through cell migration and the production of angiogenic factors. Overexpression of the LPA receptor plays a role in the pathogenesis of thyroid cancer. LPA3, originally cloned from prostate cancer cells, exhibits the same ability as LPA to induce autocrine proliferation in prostate cancer cells.

[0402] LPA has a stimulatory effect on cancer progression in many types of cancer. LPA is produced by and induces the proliferation of prostate cancer cell lines. LPA induces proliferation, migration, adhesion, and angiogenesis factor secretion in human colon cancer DLD1 cells via LPA1 signaling. In other human colon cancer cell lines (HT29 and WiDR), LPA enhances cell proliferation and angiogenesis factor secretion. In other colon cancer cell lines, activation of LPA2 and LPA3 receptors induces cell proliferation. Genetic or pharmacological manipulation of LPA metabolism, specific blockade of receptor signaling, and / or inhibition of downstream signaling pathways represent approaches to cancer therapy.

[0403] LPA and other phospholipids have been reported to stimulate the expression of interleukin-8 (IL-8) in ovarian cancer cell lines. In some embodiments, high IL-8 concentrations in ovarian cancer have been associated with poor initial response to chemotherapy and poor prognosis. In animal models, the expression of IL-8 and other growth factors (such as vascular endothelial growth factor (VEGF)) has been associated with enhanced tumorigenicity, ascites formation, angiogenesis, and invasiveness of ovarian cancer cells. In some respects, IL-8 is an important regulator of cancer progression, drug resistance, and prognosis in ovarian cancer. In some embodiments, the compound of formula (I) inhibits or reduces IL-8 expression in ovarian cancer cell lines.

[0404] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat cancer. In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat malignant and benign proliferative diseases. In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to prevent or reduce tumor cell proliferation, carcinoma, invasion and metastasis of pleural mesothelioma (Yamada, Cancer Sci., 2008, 99(8), 1603-1610) or peritoneal mesothelioma cancer pain, bone metastasis (Boucharaba et al., J. Clin. Invest., 2004, 114(12), 1714-1725; Boucharaba et al., Proc. Natl. acad. Sci., 2006, 103(25) 9643-9648). In one aspect, a method for treating cancer in a mammal, the method comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof and a second therapeutic agent, wherein the second therapeutic agent is an anticancer agent.

[0405] As used in this article, the term "cancer" refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, tend to metastasize (spread). Types of cancer include (but are not limited to) solid tumors at any stage of the disease, with or without metastasis (such as tumors of the bladder, intestines, brain, breast, endometrium, heart, kidneys, lungs, lymphoid tissue (lymphoma), ovaries, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma)) or hematologic malignancies (such as leukemia).

[0406] Other non-limiting examples of cancer include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoma / band tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brainstem glioma, brain tumor, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, and Ewing's sarcoma. Sarcoma (a type of cancer) family of tumors, ocular cancer, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gastrointestinal stromal cell tumors, germ cell tumors, gliomas, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi's sarcoma, renal 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, Waldenström macroglobulinemia (Waldenström macroglobulinemia) Macroglobulinemia, medulloblastoma, medullary epithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's 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, low-grade malignant potential ovarian tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumors, pineal cell tumors and supratentorial primitive neuroectodermal tumors, pituitary adenoma, plasmacytoma / multiple myeloma, pleural pulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family, 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, Waldenström macroglobulinemia, Wilms tumor.

[0407] Increased concentrations of LPA and vesicles in ascites and breast cancer fluid from ovarian cancer patients suggest they may serve as 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). LPA concentrations in ascites samples were consistently higher than in matched plasma samples.

[0408] Respiratory and allergic diseases

[0409] In one area, LPA is a contributor to the pathogenesis of respiratory diseases, specifically asthma. The pro-inflammatory effects of LPA include mast cell degranulation, smooth muscle cell contraction, and dendritic cell cytokine release. Respiratory smooth muscle cells, epithelial cells, and lung fibroblasts all show responses to LPA. LPA induces the secretion of IL-8 by human bronchial epithelial cells. Increased IL-8 concentrations have been found in BAL fluids from patients with asthma, chronic obstructive pulmonary disease, pulmonary sarcoma, and acute respiratory distress syndrome, and IL-8 has been shown to exacerbate airway inflammation and 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 (J.A. Contos et al., Mol. Pharmacol. 58, 1188-1196, 2000).

[0410] Platelet-released LPA is activated at the site of injury and can promote fibroblast proliferation and contraction, thus acting as a wound repair mediator. In respiratory diseases, asthma is an inflammation in which inappropriate airway "repair" processes lead to structural "remodeling" of the airway. In asthma, airway cells undergo ongoing damage due to various sources of harm, including allergens, pollutants, other inhaled environmental mediators, bacteria, and viruses, resulting in chronic inflammation characteristic of asthma.

[0411] In one aspect, in individuals with asthma, increased release of normal repair mediators (including LPA) or inappropriately prolonged action of these mediators leads to inappropriate airway remodeling. Key structural features of remodeled airways observed in asthma include thickening of the reticular layer (a basement membrane-like structure located just beneath the airway epithelial cells), increased number and activation of myofibroblasts and fibroblasts, thickening of the smooth muscle layer, increased number of mucous glands and mucus secretion, and changes in connective tissue and capillary beds throughout the airway walls. In one aspect, LPA contributes to these structural changes in the airways. In one aspect, LPA is involved in acute airway hyperresponsiveness in asthma. The lumen of the remodeled asthmatic airway is narrower due to thickened airway walls, thus reducing airflow. In one aspect, LPA contributes to long-term structural remodeling and acute overreaction of the asthmatic airway. In one aspect, LPA leads to overreaction, which is the initial characteristic of acute asthma exacerbations.

[0412] Besides LPA-mediated cellular responses, several components of the LPA signaling pathway leading to these responses are associated with asthma. EGF receptor upregulation is induced by LPA and is also observed in the asthmatic airway (M. Amishima et al., Am. J. Respir. Crit. Care Med. 157, 1907–1912, 1998). Chronic inflammation is a contributing factor to asthma, and several transcription factors that activate LPA are known to be involved in inflammation (Ediger et al., Eur Respir J 21: 759–769, 2003).

[0413] In one aspect, LPA stimulates fibroblast proliferation and contraction, as well as extracellular matrix secretion, leading to fibrotic features in other respiratory diseases, such as peribronchial 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 obliterative bronchiolitis, where both collagen and myofibroblasts are increased. In yet another aspect, LPA is involved in several of the various syndromes constituting chronic obstructive pulmonary disease (COPD).

[0414] In vivo administration of LPA induces respiratory hyperresponsiveness, pruritus-scratching response, eosinophil and neutrophil infiltration and activation, vascular remodeling, and pain-sensing flexor responses. LPA also induces histamine release from mast cells in mice and rats. In acute anaphylactic reactions, histamine induces various responses 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 respiratory hyperresponsiveness. 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 via histamine release from mast cells. In one aspect, LPA receptors include LPA1 and / or LPA3. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat various allergic conditions in mammals. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat respiratory diseases, symptoms, or conditions in mammals. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat asthma in mammals. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat chronic asthma in mammals.

[0415] As used herein, the term "respiratory disease" refers to a disease affecting organs involved in breathing, such as the nose, pharynx, larynx, Eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., the diaphragm and intercostal muscles), and nerves. Respiratory diseases include (but are not limited to) asthma, adult respiratory distress syndrome and allergic (exogenous) 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 pulmonary fibrosis and / or respiratory tract inflammation and cystic fibrosis, and hypoxia.

[0416] As used herein, the term "asthma" refers to any condition of the lungs characterized by changes in lung airflow associated with airway constriction due to any cause (internal, external, or both; allergic or non-allergic). The term asthma may be used with one or more adjectives to indicate the cause.

[0417] In one aspect, this document provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of chronic obstructive pulmonary disease (COPD) in mammals, including administering an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof to the mammal at least once. Additionally, COPD includes (but is not limited to) chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or respiratory tract inflammation, and cystic fibrosis.

[0418] Nervous system

[0419] The nervous system is a major locus for LPA1 expression; it is spatially and temporally regulated throughout brain development. In mammals, LPA1 is expressed by oligodendroglial cells (myelinating cells in the central nervous system (CNS)). Additionally, Schwann cells (myelinating cells in the peripheral nervous system) also express LPA1, and are involved in regulating Schwann cell survival and morphology. These observations identify the important functions of receptor-mediated LPA signaling in neurogenesis, cell survival, and myelination.

[0420] Peripheral nervous system cell lines exposed to LPA experience rapid contraction, leading to cell rounding, partially mediated by actin cytoskeleton polymerization. In one aspect, LPA induces 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 a contractile response to LPA exposure via Rho activation and myofibrillar interactions. In one aspect, LPA is associated with neuronal injury following ischemia (J. Neurochem. 61, 340, 1993; J. Neurochem. 70: 66, 1998).

[0421] In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for the treatment or prevention of neurological disorders in mammals. As used herein, the term “neurological disorder” means 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 conditions found following blunt force or surgical trauma (including postoperative cognitive impairment and spinal cord or brainstem injury), and neurological disorders such as degenerative disc disease and sciatica.

[0422] In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for the treatment or prevention of CNS conditions in mammals. CNS conditions include (but are not limited to) multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, postoperative cognitive impairment, migraine, peripheral neuropathy / neuralgia, spinal cord injury, cerebral edema, and head injury.

[0423] Cardiovascular disease

[0424] Cardiovascular phenotypes observed following the loss of lysophospholipid receptor targeting reveal the crucial 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 typically activated in wound healing, tissue growth, and myocardial angiogenesis following 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 peripheral vascular smooth muscle cells (VSMCs). In one aspect, dysregulation of processes mediating angiogenesis contributes to atherosclerosis, hypertension, tumor growth, rheumatoid arthritis, and diabetic retinopathy (Osborne, N. and Stainier, DYAnnu. Rev. Physiol. 65, 23-43, 2003).

[0425] Downstream signaling pathways induced by hemolysin receptors include Rac-dependent lamellar projection formation (e.g., LPA1) and Rho-dependent stress fiber formation (e.g., LPA1), which play important roles in cell migration and adhesion. Endothelial cell dysfunction can shift the balance from vasodilation to vasoconstriction, leading to hypertension and vascular remodeling, which are risk factors for atherosclerosis (Maguire, JJ et al., Trends Pharmacol. Sci. 26, 448-454, 2005).

[0426] In addition to its overall progression, LPA contributes to both early (barrier dysfunction and endothelial mononuclear cell adhesion) and late (platelet activation and intra-arterial thrombosis) stages of atherosclerosis. In the early stages, LPA from various sources accumulates in lesions and activates its homologous 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 morphology changes and aggregation, leading to intra-arterial thrombosis and potential myocardial infarction and stroke. LPA also acts as a mitogen and kinase inhibitor for VSMCs and as an activator for endothelial cells and macrophages, supporting its atherogenic activity. In one aspect, mammals with cardiovascular disease benefit from LPA receptor antagonists that prevent thrombosis and neointimal plaque formation.

[0427] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat or prevent cardiovascular diseases in mammals.

[0428] As used herein, the term “cardiovascular disease” refers to any disease affecting the heart or blood vessels or both, including (but not limited to): arrhythmias (atria or ventricles or both); atherosclerosis and its sequelae; angina pectoris; arrhythmia; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis; stroke; peripheral obstructive 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 migraines); vascular abnormalities, inflammation, or dysfunction limited to a single organ or tissue.

[0429] In one aspect, this article 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 thereof, or a pharmaceutical composition or agent comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, at least once.

[0430] In one aspect, this article provides a method for reducing cardiac reperfusion injury following 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 thereof at least once.

[0431] In one aspect, this article provides a method for reducing vasoconstriction in mammals, comprising administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof at least once.

[0432] In one aspect, this article provides a method for reducing or preventing elevated blood pressure in mammals, comprising administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof at least once.

[0433] inflammation

[0434] LPA has been shown to regulate immune responses by modulating the activity / function of immune cells, such as T / B lymphocytes and macrophages. In activated T cells, LPA activates IL-2 production / cell proliferation via 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). Immune cells are known to respond to LPA with increased proliferation and cytokine secretion (J. Imuunol. 1999, 162, 2049), platelet aggregation, accelerated monocyte migration, NF-κB activation in fibroblasts, enhanced binding of fibronectin to cell surfaces, and similar effects. Therefore, LPA is associated with various inflammatory / immune diseases.

[0435] In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat or prevent inflammation in mammals. In one aspect, an antagonist of LPA1 and / or LPA3 is used to treat or prevent inflammatory / immune disorders in mammals. In one aspect, an LPA1 antagonist is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0436] 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 xenograft (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.

[0437] Other diseases, symptoms or conditions

[0438] According to one aspect, a method for treating, preventing, reversing, halting, 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 is accomplished by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal. In some 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.

[0439] In some aspects, LPA1 activity in mammals is directly or indirectly modulated by administering a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof (at least once). Such modulation includes, but is not limited to, reducing and / or inhibiting LPA1 activity. In other aspects, LPA activity in mammals is directly or indirectly modulated (including reducing and / or inhibiting) by administering a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof (at least once). Such modulation includes, but is not limited to, reducing and / or inhibiting the amount and / or activity of LPA receptors. In one aspect, the LPA receptor is LPA1.

[0440] In one respect, LPA has a contractile effect on bladder smooth muscle cells isolated from the bladder and promotes the growth of prostatic epithelial cells (J. Urology, 1999, 162, 1779-1784; J. Urology, 2000, 163, 1027-1032). In another respect, LPA causes contraction of the urinary tract and prostate in vitro and increases intraurethral pressure in vivo (WO 02 / 062389).

[0441] In some aspects, a method for the prevention or treatment of eosinophil and / or basophilic granulocytes and / or dendritic cells and / or neutrophils and / or monocytes and / or T cells recruitment comprises administering to a mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof at least once.

[0442] In some aspects, a method for treating cystitis (including, for example, interstitial cystitis) includes administering to the mammal a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof at least once.

[0443] According to one aspect, the method described herein includes diagnosing or determining whether a patient has an LPA-dependent or LPA-mediated disease or condition, which is achieved by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject and determining whether the patient responds to treatment.

[0444] In one aspect, this document provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable prodrug, and a pharmaceutically acceptable solvate thereof, which are LPA1 antagonists and are intended for the treatment of patients 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 pulmonary fibrosis, arthritis, allergies, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative disorders, and inflammatory conditions. In some embodiments, LPA-dependent conditions or diseases include those in which an absolute or relative excess of LPA is present and / or observed.

[0445] In any of the foregoing aspects, LPA-dependent or LPA-mediated diseases or conditions include (but are not limited to) organ fibrosis, asthma, allergic conditions, 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.

[0446] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to improve corneal sensitivity reduction caused by corneal surgery (such as laser-assisted in situ keratoplasty (LASIK) or cataract surgery), corneal sensitivity reduction caused by corneal degeneration, and dry eye symptoms caused therefrom.

[0447] In one aspect, this document provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis and papillary conjunctivitis in mammals, including administering an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof to the mammal at least once.

[0448] In one aspect, this document provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of Hughren's disease or inflammation with dry eye in mammals, including administering an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof to the mammal at least once.

[0449] 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 another aspect, this document provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of osteoarthritis in mammals, including administering an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof to the mammal at least once.

[0450] 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 another aspect, this document provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of rheumatoid arthritis in mammals, including administering an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof to the mammal at least once.

[0451] 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 another aspect, this document provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for promoting adipose tissue formation in mammals, comprising administering an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof to the mammal at least once.

[0452] a. In vitro analysis

[0453] The effectiveness of the compounds of this invention as LPA1 inhibitors can be determined in LPA1 functional antagonist analysis as follows:

[0454] 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, the cells were loaded with calcium indicator dye (AAT Bioquest Inc, catalog number 34601) at 37°C for 30 minutes. The cells were then equilibrated relative to room temperature for 30 minutes before analysis. The test compound dissolved in DMSO was transferred to a 384-well unbound surface disk (Corning, catalog 3575) using a LabcyteEcho sonic dispenser and diluted to a final concentration of 0.5% DMSO with analysis buffer [1X HBSS containing calcium / magnesium (Gibco catalog 14025-092), 20 mM HEPES (Gibco catalog 15630-080), and 0.1% fatty acid-free BSA (Sigma catalog A9205)]. The diluted compound was added to cells at a final concentration ranging from 0.08 nM to 5 μM using FDSS 6000 (Hamamatsu) and incubated at room temperature for 20 min. At this point, LPA (AvantiPolar Lipids catalog 857130C) was added at a final concentration of 10 nM to stimulate the cells. The IC50 of the compound was measured. 50The IC50 value was defined as the concentration of the test compound that inhibited LPA-induced calcium flux by 50%. The IC50 was determined by fitting the data to a 4-parameter logarithmic equation (GraphPad Prism, San Diego CA). 50 value.

[0455] b. In vivo analysis

[0456] LPA attack and plasma histamine assessment.

[0457] Two hours prior to LPA challenge, CD-1 female mice were orally administered the compound. The mice were then administered 0.15 mL of 0.1% BSA / PBS (2 μg / μL) containing LPA via tail vein (IV). Exactly two minutes after LPA challenge, the 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.

[0458] Plasma histamine analysis was performed using a standard EIA (enzyme immunoassay) method. 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).

[0459] The LPA used in the analysis was prepared as follows: A total concentration of 2 μg / μL LPA (1-oleoyl-2-hydroxy-sn-glycerol-3-phosphate (sodium salt), 857130P, Avanti Polar Lipids) was prepared in 0.1% BSA / PBS. 13 mg of LPA was weighed and 6.5 mL of 0.1% BSA was added. The mixture was vortexed and sonicated for approximately 1 hour until a clear solution was obtained.

[0460] V. Pharmaceutical compositions, formulations and combinations

[0461] In some embodiments, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable inactive ingredient.

[0462] In some embodiments, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable inactive ingredient. In one aspect, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, inhalation, nasal administration, topical administration, ocular administration, or ocular administration. In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, inhaler, nasal spray solution, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, lotion, eye drop, or ear drop.

[0463] In some embodiments, the pharmaceutical composition further comprises one or more other therapeutically active agents selected from: 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, autocrine motor factor inhibitors, decongestants, antihistamines (e.g., loratidine), mucolytics, anticholinergics, antitussives, expectorants, and anti-infectives (e.g., fusidic acid). Antifungal drugs (e.g., clotrimazole, especially for atopic dermatitis), anti-IgE antibody therapy (e.g., omalizumab), β-2 adrenergic agonists (e.g., albuterol or salmeterol), other PGD2 antagonists acting on other receptors (e.g., DP antagonists), PDE4 inhibitors (e.g., cilomilast), drugs that regulate cytokine production (e.g., TACE inhibitors), drugs that regulate 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), and 5-lipoxygenase inhibitors (e.g., zileuton).

[0464] In some embodiments, the pharmaceutical composition further comprises one or more other antifibrotic agents selected from the following: pirfenidone, nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferon α, lecithinized superoxide dismutase, simtuzumab, tanzisertib, tralokinumab, hu3G9, AM-152, IFN-γ-1b, IW-001, PRM-151, PXS-25, pentoxifylline / N-acetylcysteine, pentoxifylline / vitamin E, salbutamol sulfate. Sulfate), [Sar9,Met(O2)11]-substance P, pentoxifylline, mercaptoethylamine bitartrate, obeticholic acid, aramchol, GFT-505, ethyl eicosapentaenoic acid, metformin, metreleptin, muromonab-CD3, oltipraz, IMM-124-E, MK-4074, PX-102, RO-5093151. In some embodiments, a method is provided comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a human suffering from an LPA-dependent or LPA-mediated disease or condition. In some embodiments, the human has been administered one or more other therapeutically active agents other than a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method further includes administering one or more other therapeutically active agents other than the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0465] In some embodiments, one or more other therapeutically active agents other than the compound of formula (I) or a pharmaceutically acceptable salt thereof are selected from: 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, autocrine motor factor inhibitors, decongestants, antihistamines (e.g., loratadine), mucolytics, anticholinergics, antitussives, expectorants. Antibiotics, anti-infectives (e.g., closporine, especially for the treatment of atopic dermatitis), antifungal drugs (e.g., clotrimazole, especially for atopic dermatitis), anti-IgE antibody therapy (e.g., omalizumab), β-2 adrenergic agonists (e.g., salmeterol or terbutaline), other PGD2 antagonists acting on other receptors (such as DP antagonists), PDE4 inhibitors (e.g., silostaphin), drugs that regulate cytokine production (e.g., TACE inhibitors), drugs that regulate 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), and 5-lipoxygenase inhibitors (e.g., ziloutong).

[0466] In some embodiments, one or more other therapeutically active agents besides the compound of formula (I) or a pharmaceutically acceptable salt thereof are selected from other antifibrotic agents such as: pirfenidone, nintedanib, thalidomide, kalurumab, FG-3019, flesozumab, interferon α, lecithinized superoxide dismutase, cintuzumab, tanzserte, tarozinbab, hu3G9, AM-152, IFN-γ-1b, IW-001, PRM-151, and PX. S-25, Pentoxothecobalaine / N-acetylcysteine, Pentoxothecobalaine / Vitamin E, Salbutamol Sulfate, [Sar9,Met(O2)11]-Substance P, Pentoxothecobalaine, Mercaptoethylamine Tartrate, Obeticholic Acid, Aremerol, GFT-505, Eicosapentaenoic Acid Ethyl Eicosapentaenoic Acid, Metformin, Metriptine, Morotumab-CD3, Otepram, IMM-124-E, MK-4074, PX-102, RO-5093151.

[0467] In some embodiments, one or more other therapeutically active agents, other than the compound of formula (I) or a pharmaceutically acceptable salt thereof, are selected from ACE inhibitors, ramipril, ALL antagonists, irbesartan, antiarrhythmic drugs, dronedarone, PPARα activators, PPARγ activators, pioglitazone, rosiglitazone, prostaglandins, endothelin receptor antagonists, elastase inhibitors, calcium channel blockers, beta-blockers, diuretics, aldosterone receptor antagonists, eplerenone, renin inhibitors, Rho kinase inhibitors, soluble guanylate cyclase (sGC) activators, and sGC... Sensitizers, PDE inhibitors, PDE5 inhibitors, NO donors, digitalis drugs, ACE / NEP inhibitors, inhibin, bile acid reabsorption inhibitors, PDGF antagonists, vasopressin antagonists, diuretics, NHE1 inhibitors, factor Xa antagonists, factor XIIIa antagonists, anticoagulants, antithrombotic agents, platelet inhibitors, profibrotic agents, thrombin-activated fibrinolysis inhibitors (TAFI), PAI-1 inhibitors, coumarin, heparin, thrombin antagonists, serotonin antagonists, COX inhibitors, aspirin, therapeutic antibodies, GPIIb / IIIa antagonists, ER antagonists, SERM, tyrosine kinase inhibitors, RAF kinase inhibitors, p38 MAPK inhibitors, pirfenidone, multiple kinase inhibitors, nintedanib, sorafenib.

[0468] In some embodiments, one or more other therapeutically active agents other than the compound of formula (I) or a pharmaceutically acceptable salt thereof are selected from Gremlin-1 mAb, PA1-1 mAb, Promedior (PRM-151; recombinant human pentamericin-2); FGF21, TGFβ antagonists, αvβ6 and αvβpan antagonists; FAK inhibitors, TG2 inhibitors, LOXL2 inhibitors, NOX4 inhibitors, MGAT2 inhibitors, and GPR120 agonists.

[0469] The pharmaceutical formulations described herein can be administered to subjects in a variety of ways via various routes of administration, including (but not limited to) oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, local, or transdermal routes. The pharmaceutical formulations described herein include (but are not limited to) aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate-release formulations, controlled-release formulations, rapidly melting formulations, tablets, capsules, pills, delayed-release formulations, sustained-release formulations, pulsatile-release formulations, multi-microparticle formulations, and mixed immediate-release and controlled-release formulations.

[0470] In some implementations, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

[0471] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered topically. In such embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is formulated into a variety of topically applicable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, ointments, plasters, 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 a pharmaceutically acceptable salt thereof is administered topically to the skin.

[0472] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered by inhalation. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered by inhalation directly targeting the pulmonary system.

[0473] In another aspect, compounds of formula (I) or pharmaceutically acceptable salts thereof are formulated for intranasal administration. Such formulations include nasal sprays, nasal atomizers, and the like.

[0474] In another aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is formulated as an eye drop.

[0475] Another aspect is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease, symptom, or condition, wherein the activity of at least one LPA receptor results in the pathology and / or symptoms of the disease or condition. In one embodiment of this aspect, the LPA is selected from LPA1, LPA2, LPA3, LPA4, LPA5, and LPA6. In one aspect, the LPA receptor is LPA1. In one aspect, the disease or condition is any disease or condition specified herein.

[0476] Any of the foregoing aspects are other embodiments, wherein: (a) an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered systemically to a mammal; and / or (b) an effective amount of the compound is administered orally to a mammal; and / or (c) an effective amount of the compound is administered intravenously to a mammal; and / or (d) an effective amount of the compound is administered by inhalation; and / or (e) an effective amount of the compound is administered by nasal administration; or and / or (f) an effective amount of the compound is administered by injection to a mammal; 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 neither systemically nor topically to a mammal.

[0477] Any of the foregoing aspects are other embodiments of the compound comprising a single-dose effective amount, including other embodiments in which (i) the compound is administered once; (ii) the compound is administered to a mammal multiple times during a day; (iii) continuously; or (iv) the compound is administered continuously.

[0478] Any of the foregoing aspects constitutes other embodiments of a compound comprising multiple doses of an effective amount, including wherein (i) the compound is administered continuously or intermittently, such as by 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; and (v) other embodiments of administering the compound to a mammal every 24 hours. In other or alternative embodiments, the method includes a withdrawal period, wherein administration of the compound is suspended or the dose of the administered compound is temporarily reduced; at the end of the withdrawal period, administration of the compound is resumed. In one embodiment, the length of the withdrawal period ranges from 2 days to 1 year.

[0479] A method for inhibiting the physiological activity of LPA in mammals is also provided, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need of doing so.

[0480] In one aspect, a medicament is provided for treating LPA-dependent or LPA-mediated diseases or conditions in mammals, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0481] In some cases, this document discloses the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of an agent for the treatment of LPA-dependent or LPA-mediated diseases or conditions.

[0482] In some cases, the compound of formula (I) disclosed herein, or a pharmaceutically acceptable salt thereof, may be used for the treatment or prevention of LPA-dependent or LPA-mediated diseases or conditions.

[0483] In one aspect, a method for treating or preventing LPA-dependent or LPA-mediated diseases or conditions in mammals includes administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0484] 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 disease or condition, inflammation, gastrointestinal disease, kidney disease, urinary tract-related diseases, inflammation of the lower urinary tract, dysuria, urinary frequency, pancreatic disease, arterial obstruction, cerebral infarction, cerebral hemorrhage, pain, peripheral neuropathy, and myofibromyalgia.

[0485] In one aspect, the LPA-dependent or LPA-mediated disease or condition is a respiratory disease or condition. In some implementations, the respiratory disease or condition is asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, or acute respiratory distress syndrome.

[0486] In some implementations, LPA-dependent or LPA-mediated diseases or conditions are selected from idiopathic pulmonary fibrosis; cystic fibrosis; other diffuse solid lung diseases of various etiologies, including iatrogenic drug-induced fibrosis, occupational and / or environmental induced fibrosis, granulomatous diseases (sarcomatoid diseases, hypersensitivity pneumonitis), collagen vascular diseases, pulmonary alveolar proteinosis, Langerhans cell granulomatosis, pulmonary lymphangiomyopathy, and genetic diseases (Hermansky-Pudlak syndrome). Syndrome, tuberous sclerosis, neurofibroma, metabolic storage disease, 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; liver fibrosis; cirrhosis; alcohol-induced liver fibrosis; toxic / drug-induced liver fibrosis; hemochromatosis; non-alcoholic steatosis (NASH); biliary tract injury; primary biliary cirrhosis; infection-induced liver fibrosis; virus-induced liver fibrosis; and autoimmune hepatitis; corneal scars; hypertrophic scars; Dupuytren's disease. Diseases, keloids, cutaneous fibrosis; scleroderma; spinal cord injury / fibrosis; myelofibrosis; restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Pelony's disease; chronic lymphocytic leukemia; tumor metastasis; transplant rejection; endometriosis; neonatal respiratory distress syndrome; and neuralgia.

[0487] In one aspect, this article describes diseases or conditions that are LPA dependent or LPA-mediated.

[0488] In one aspect, a method for treating or preventing organ fibrosis in mammals is provided, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0489] In one aspect, the organ fibrosis includes pulmonary fibrosis, renal fibrosis, or liver fibrosis.

[0490] In one aspect, a method for improving lung function in a mammal is provided, comprising administering to the mammal in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the mammal has been diagnosed with pulmonary fibrosis.

[0491] In one aspect, the compounds disclosed herein are used to treat idiopathic pulmonary fibrosis (common interstitial pneumonia) in mammals.

[0492] In some embodiments, the compounds disclosed herein are used to treat diffuse interstitial lung diseases in mammals: iatrogenic drug-induced, occupational / environmental (farmer's lung), granulomatous diseases (sarcomatoid diseases, hypersensitivity pneumonia), collagen vascular diseases (scleroderma and others), pulmonary alveolar proteinosis, Langerhans cell granulomatosis, pulmonary lymphangiomyopathy, Hermansky-Praque syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, and familial interstitial lung disease.

[0493] In some implementations, the compounds disclosed herein are used to treat post-transplant fibrosis associated with chronic rejection in mammals: obstructive bronchiolitis following lung transplantation.

[0494] In some embodiments, the compounds disclosed herein are used to treat skin fibrosis in mammals: scleroderma, Depietrohen's disease, and keloids.

[0495] In one aspect, the compounds disclosed herein are intended for the treatment of liver fibrosis in mammals with or without cirrhosis: 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.

[0496] In one aspect, the compounds disclosed herein are used to treat renal fibrosis in mammals: tubulointerstitial fibrosis, glomerulosclerosis.

[0497] In any of the foregoing aspects relating to the treatment of LPA-dependent diseases or conditions, there are other embodiments comprising administering at least one other agent in addition to administering a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof. In various embodiments, the agents are administered in any order (including simultaneously).

[0498] In any of the embodiments disclosed herein, the mammal is a human.

[0499] In some implementations, the compounds provided herein are administered to humans.

[0500] In some implementations, the compounds provided herein are administered orally.

[0501] 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 diseases or conditions that would benefit from inhibiting the activity of at least one LPA receptor. In one aspect, the LPA receptor is LPA1.

[0502] In other embodiments, the compounds provided herein are used as formulations of a drug for inhibiting LPA1 activity.

[0503] Articles comprising packaging material, a compound of formula (I) or a pharmaceutically acceptable salt thereof within the packaging material, and a label indicating that the compound or composition or a pharmaceutically acceptable salt thereof, 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 the inhibition of at least one LPA receptor activity.

[0504] VI. General synthesis, including process

[0505] The compounds of this invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of this invention can be synthesized using the methods described below, as well as synthetic methods known in organic synthetic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include (but are not limited to) the methods described below. The reaction is carried out in a solvent or solvent mixture suitable for the reagents and substances used and suitable for achieving the transformation. Those skilled in the art of organic synthesis will understand 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 choose a particular method flow instead of another to obtain the desired compound of this invention.

[0506] It will also be recognized that another major consideration in the planning of any synthetic route in the art is the careful selection of protecting groups for protecting the reactive functional groups present in the compounds described in this invention. An authoritative description of the various alternatives to trained practitioners is provided by Greene et al. (Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience (2006)).

[0507] Compounds of formula (I) can be prepared by the exemplary methods described in the following processes and working examples, as well as by relevant published procedures used by those skilled in the art. Exemplary reagents and procedures used for these reactions are presented below and in the working examples. Protecting and deprotecting 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 transformation can be 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 their references.

[0508] Procedure 1 describes the synthesis of N-carbamoyl-triazole-aryloxycyclohexyl acids 16 and 17. A dihalogen (preferably dibromo)phenyl or azazine (e.g., pyridine) derivative 1 is coupled with a suitably protected (e.g., in the form of a tetrahydropyranyl ether) propargyl alcohol 2 under Sonogashira conditions (e.g., Alper, P. et al., WO 2008097428) to give propargyl alcohol 3 protected with the corresponding bromo-aryl or bromo-heteroaryl group. The thermal reaction of alkyne 3 with alkyl azide 4 (with or without a suitable catalyst; Qian, Y. et al., J. Med. Chem. 2012, 55, 7920-7939 or Boren, BC et al., J. Am. Chem. Soc. 2008, 130, 8923-8930) yields the corresponding protected hydroxymethyl-triazole regioisomer, from which the desired triazole regioisomer 5 can be isolated. The reaction of bromoaryl- or bromoheteroaryl-triazole 5 with dipinalyl diboronate in the presence of a suitable palladium catalyst (e.g., Ishiyama, T. et al., J. Org. Chem. 1995, 60, 7508-7510) yields the corresponding pinalyl borate 6, which is then oxidized by peroxide to give the corresponding phenol or hydroxyheteroaryl 7 (Fukumoto, S. et al., WO 2012137982). Phenol / hydroxyheteroaryl 7 reacts with 3-hydroxycycloalkyl (e.g., cyclohexyl) ester 8 under Mitsunobu reaction conditions (Kumara Swamy, KC, Chem. Rev., 2009, 109, 2551-2651) to give the corresponding triazole cycloalkyl ether ester 9. Hydroxytriazole 9 is deprotected to give triazole alcohol 10, which then reacts with a brominating agent (e.g., PBr3 or CBr4 / Ph3P) to give triazole bromide 11. Substituting bromide 11 with NaN3 (or an equivalent azide reagent) gives triazole azide 12, which is then reduced (e.g., by Staudinger reduction with Ph3P / H2O) to give triazole amine 13. Amine 13 is then reacted with an acylating agent 14 (e.g., chloroformate or 4-nitrobenzene carbonate) in the presence of a suitable base to give the corresponding NH-carbamate 15. The ester protecting group of triazole 15 is removed to obtain the desired triazole-carbamate cycloalkyl acid 16. This is achieved by using a suitable base (e.g., NaH or NaN(TMS)2) and a halide R. 3 Triazole NH-carbamate 16 was treated with X to obtain the corresponding N-alkylated carbamate-cycloalkyl ester, which was then protected by base-mediated hydrolysis to obtain triazole N-carbamoylcycloalkyl acid 17.

[0509] Process 1

[0510]

[0511] In a specific embodiment of analog 20, where R2 = CH3 (procedure 1A), a trimethylsilyl azide is a viable alternative (Qian, Y. et al., J. Med. Chem., 2012, 55, 7920-7939), which can be used under thermal or transition metal catalytic conditions (Boren, BC et al., J. Am. Chem. Soc., 2008, 130, 8923-8930), instead of using an alkyl azide to cycloaddition with the protected hydroxyalkyl alkyne 3. Under these conditions, the desired triazole regioisomer 18 is obtained as the major product of the 1,3-dipolar cycloaddition reaction. Removal of the trimethylsilyl group from 18 under standard desilylation conditions (e.g., Bu4NF, as Qian, Y. et al., J. Med. Chem., 2012, 55, 7920-7939) yields N-methyltriazole 19 (corresponding to 5, where R... 5 =CH3), and then converted to N-carbamoyltriazole cyclohexyl acid 20 according to the synthesis sequence described in process 1 (i.e., 5→16 and 17).

[0512] Process 1A

[0513]

[0514] Procedure 2 describes an alternative synthetic route for N-carbamoyltriazole-aryloxycyclohexyl acid 16 or 17. A dihalogen (preferably dibromo)phenyl or azazine (e.g., pyridine) derivative 1 is coupled with propargyl alcohol under Sonogashira conditions (Alper, P. et al., WO 2008097428) to give the corresponding bromo-aryl or bromo-heteroaryl propargyl alcohol 21. The thermal reaction of alkyne 21 with alkyl azide 4 (with or without a suitable catalyst, Qian, Y. et al., J. Med. Chem., 2012, 55, 7920-7939; Boren, BC et al., J. Am. Chem. Soc., 2008, 130, 8923-8930) yields the corresponding regioisomer hydroxymethyl-triazole, from which the desired triazole regioisomer 22 can be isolated. Triazol 18 is then reacted with a brominating agent (e.g., PBr3 or CBr4 / Ph3P) to give the corresponding bromide 23. Substituting bromide 23 with NaN3 (or other suitable azide reagent) gives azide 24, which is then reduced (e.g., by Staudinger reduction with Ph3P / H2O) to give triazolamine 25. Protecting triazolamine 25 gives intermediate 26. Then, using the same two-step sequence as described in Procedure 1 [boronization with a B2(pin)2 / Pd catalyst, followed by H2O2-mediated oxidation of the borate ester], bromo-aryl / heteroaryl triazole 26 is converted to the corresponding hydroxy-aryl / heteroaryl triazole 27 via the corresponding borate ester. The hydroxyaryl triazole 27 is then reacted with 3-hydroxycycloalkyl ester 8 via a Mitsunobu reaction to give the corresponding triazole cycloalkyl ether ester 28. Amine 28 is deprotected to obtain the key triazole amine intermediate 13, which is then converted to N-carbamate acid 16 or 17 via the synthetic sequence described in process 1.

[0515] Process 2

[0516]

[0517] Procedure 3 describes an alternative synthetic route for triazole N-carbamate cyclohexyl acids 16 and 17. Triazoleamine 25 reacts with acylation reagent 14 in the presence of a base to give triazole N-carbamate 29. Using a two-step sequence as described in Procedure 1 [B2(pin)2 / Pd catalyst, followed by oxidation with H2O2], bromo-aryl / heteroaryl triazole 29 is converted to the corresponding hydroxyaryl / heteroaryl triazole 30 via the corresponding borate ester. The hydroxyaryl / heteroaryl triazole 30 is then reacted with 3-hydroxycycloalkyl ester 8 via Mitsunobu reaction to give the corresponding triazole N-carbamate cycloalkyl ester 15. This key triazole N-carbamate intermediate 15 is then converted to N-carbamate acids 16 and 17 as described in Procedure 1.

[0518] Process 3

[0519]

[0520] Procedure 4 describes alternative synthetic routes for triazole N-carbamate cyclohexyl acids 16 and 17. An alkoxyphenyl or azazine (e.g., pyridine or pyrazine) derivative 31 is reacted with trimethylsilylacetylene under Sonogashira conditions (Alper, P. et al., WO 2008097428) to give the corresponding alkoxy-aryl or heteroarylsilylacetylene, which is then desilylated under standard conditions (e.g., Bu4NF) to give alkyne 32. Alkyne 32 is thermally reacted with sodium azide to give the corresponding triazole (Roehrig, U. et al., WO 2009127669), which is then alkylated with alkyl iodide 25 in the presence of a base to give a mixture of regioisomers of alkylated triazoles from which the desired triazole regioisomer 33 can be isolated. Triazole 33 is metallized with a suitable lithiumizing agent (e.g., Hernandez, M. et al., US 20120115844), followed by formylation (e.g., using dimethylformamide) to give triazole aldehyde 34. The alkoxy group of the aromatic / heteroaromatic 34 is deprotected, and then the phenol / hydroxy-heteroaromatic is reprotected with a less stable protecting group (e.g., tert-butyldimethylsilyl ether) to give the protected aryl / heteroaromatic triazole aldehyde 35, which is then reduced to the corresponding triazole alcohol 36 by a standard method (e.g., NaBH4). Triazole alcohol 36 is converted to triazole amine 37 by the same three-step sequence (10→13) as described in Procedure 1. Triazole amine 37 is then reacted with acylation agent 14 in the presence of a base, followed by deprotection to give triazole N-carbamate 30. Next, as described in process 3, the key hydroxyaryl / heteroaryl triazole intermediate 30 is converted into N-carbamate acids 16 and 17.

[0521] Process 4

[0522]

[0523] Procedure 5 describes the synthesis of N-carbamoyltriazole-aryloxy α-fluorocyclohexyl acids 44 and 45. 1,3-Butadiene is reacted with a suitably protected 2-fluoroacrylate via a Diels-Alder reaction (e.g., Kotikyan et al., Bull. Acad. Sci. USSR, Division of Chemical Science (Engl.), 1971, 20, 292) to give α-fluorocyclohexyl ester 38. Ester 38 is deprotected (e.g., by hydrolysis) to give acid 39. The olefin is then reacted with the carboxylic acid of 38 via iodolactoneation (e.g., by...). JMJ et al. (Eur. J. Org. Chem., 2014, 3051-3065) yielded iodolactone 39. Radical-mediated deiodination (e.g., AIBN / (TMS)3SiH, see Chatgilialoglu, C. et al., Molecules, 2012, 17, 527-555) or hydrogenolysis conditions gave lactone 41. Lactone 41 underwent acid-mediated ring-opening in the presence of an alcohol to give protected α-fluoro-cyclohexyl ester 42. Following the procedure described in step 1, hydroxy-ester 42 was then reacted with hydroxyaryl / hydroxy-heteroaryl-triazole 7 via a Mitsunobu reaction to give the corresponding cyclohexyl ether triazole ester 43. Following the general synthetic procedure described in step 1, N-carbamoylmethyltriazole-aryloxyα-fluoro-cyclohexyl acids 44 and 45 were synthesized from α-fluoro-cyclohexyl triazole ester 43.

[0524] Process 5

[0525]

[0526] Procedure 6 describes the synthesis of N-carbamoylmethyltriazole-aryloxycyclohexyl acids 44 and 45. It involves using alkyl organometallic reagents (e.g., R...) 7a Li or R 7a MgX) is added to aldehyde 35 to give triazole alcohol 46, which is then protected to 47. The hydroxy-aromatic / hydroxy-heteroaromatic hydrocarbon is deprotected, followed by a Mitsunobu reaction with 8 to give cyclohexyl ether triazole 48. Deprotection of 48 yields alcohol 49, which can be converted to cyclohexyl N-carbamate-triazole acid 50 and 51 via the general synthetic procedure described in step 1.

[0527] Process 6

[0528]

[0529] Procedure 7 describes the synthesis of directly linked N-carbamoyltriazole acids 54 and 55. Cyclohexyl ether triazole-alcohol 10 is oxidized to carboxylic acid 52 (e.g., directly oxidized to the acid using pyridinium dichromate, or via a two-step procedure, via an aldehyde [Swern oxidation or Dess-Martin periodoyl alkane, followed by oxidation to the acid with NaClO2, e.g., Lindgren, BO, Acta Chem. Scand. 1973, 27, 888]). 52 is then added to alcohol R. 4 A Curtius rearrangement occurs in the presence of -OH to give triazole NH-carbamate 53. Deprotection of triazole NH-carbamate 53 yields triazole NH-carbamate acid 54. Alternatively, NH-carbamate cyclohexyl ester 53 is deprotonated with a suitable base and then alkylated with an R... 3- Halogenation (as in process 1) yields triazole N-alkylcarbamate acid 55.

[0530] Process 7

[0531]

[0532] Procedure 8 describes the synthesis of N-carbamoyltriazole-aryloxycyclohexyl acids 59 and 60. Triazole alcohol 10 is oxidized to the corresponding aldehyde (e.g., Des Martin periodoyl alkyl or Sven oxidation), followed by olefination (e.g., Wittig or Peterson olefination) to give terminal olefin 56. Olefin 56 is hydrobored at the terminal carbon (e.g., using 9-BBN), followed by oxidation to give the corresponding triazole ethanol 57. Triazole ethanol 57 is subjected to the three-step procedure described in Procedure 1 (bromination, azide substitution, azide reduction) to give the critical intermediate triazole-ethylamine 58. Triazole-ethylamine 58 is then converted to triazole-ethyl-N-carbamoyl cyclohexyl acids 59 and 60 using the same synthetic procedure described in Procedure 1 for the conversion of amine 13 to triazole carbamate acids 16 and 17.

[0533] Process 8

[0534]

[0535] Procedure 9 describes the synthesis of N-ureido-triazole-aryloxycyclohexyl acids 63 and 65. Triazoleamine cyclohexyl ester 13 is reacted with carbamoyl chloride 62 (e.g., prepared by reacting secondary amine 61 with triphosgene) to give the corresponding ureido-triazole cyclohexyl ester, followed by deprotection to give N,N′-dialkyl-ureido-triazole-aryloxycyclohexyl acid 63. In a supplementary synthetic route, triazoleamine cyclohexyl ester 13 is reacted directly with triphosgene to give carbamoyl chloride 64 (CDI, to give the corresponding intermediate), which is then reacted with primary amine R... 3 -NH2 (or reacts with secondary amine 61) to give (after ester deprotection) the corresponding N-alkyl-ureido-triazole aryloxycyclohexyl acid 65 (when using secondary amine, the product is N,N′-dialkylureido-triazole acid 63).

[0536] Process 9

[0537]

[0538] Procedure 10 describes the synthesis of triazole-N-linked ureacyclohexyl acids 67 and 68. Cyclohexyl ether triazole alcohol 10 is oxidized to triazole carboxylic acid 66 (e.g., directly oxidized to the acid using pyridinium dichromate, or via a two-step procedure, via an aldehyde [Sven oxidation or Dess-Martin periodane followed by oxidation to the acid with NaClO2, e.g., Lindgren, BO, Acta Chem. Scand. 1973, 27, 888]). Triazole acid 66 undergoes a Coulters rearrangement (e.g., with (PhO)₂PON₃) to give the corresponding intermediate triazole isocyanate, which is then reacted with a primary amine R. 3 NH2 or secondary amine R 3 R 4 The NH reaction, after ester deprotection, yields triazole-ureo-NH-alkyl-cyclohexyl acid 67 or triazole-ureo-N,N-dialkyl-cyclohexyl acid 68.

[0539] Process 10

[0540]

[0541] Procedure 11 describes the synthesis of triazole-sulfonylurea-cyclohexyl acid 70. Triazole amine cyclohexyl ester 13 is reacted with dialkylamine sulfonyl chloride 69 (prepared by reacting secondary amine 61 with thioyl chloride) to give the corresponding sulfonylurea-triazole cyclohexyl ester, which is then deprotected to give sulfonylurea-triazole-aryloxycyclohexyl acid 70.

[0542] Process 11

[0543]

[0544] VII. Examples

[0545] The following examples are provided as illustrative examples, as part of the scope of the invention, and as specific embodiments, and are not intended to limit the scope of the invention. Unless otherwise specified, abbreviations and chemical symbols have their common and conventional meanings. Unless otherwise specified, the compounds described herein have been prepared, isolated, and characterized using the processes and other methods disclosed herein, or can be prepared using such methods.

[0546] When appropriate, the reaction is carried out under a dry nitrogen (or argon) atmosphere. Anhydrous reactions are performed using reagents obtained from EM. Solvents. Reagent-grade or HPLC-grade solvents should be used for other reactions. Unless otherwise specified, all commercially available reagents should be used exactly as is.

[0547] Microwave reactions were conducted in a microwave reaction vessel using a 400W Biotage Initiator instrument under microwave (2.5 GHz) irradiation.

[0548] The HPLC / MS and preparative / analytical HPLC methods used in the characterization or purification examples

[0549] Typically, NMR (nuclear magnetic resonance) spectra are obtained in specified solvents using Bruker or JEOL 400MHz and 500MHz instruments. Solvent resonance is used as an internal standard, and all chemical shifts (ppm) are reported relative to tetramethylsilane. 1 HNMR spectral data are typically reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, sep = septet, m = multiplet, app = apparent), coupling constant (Hz), and integral.

[0550] Collection in d6-DMSO 1 In examples of H NMR spectroscopy, a water suppression procedure is typically employed. This procedure effectively suppresses the water signal and any proton peaks in the same range (typically between 3.30 and 3.65 ppm) that would affect the overall proton integral.

[0551] The term HPLC refers to Shimadzu high-performance liquid chromatography instruments that use one of the following methods:

[0552] HPLC-1: Sunfire C18 column (4.6×150mm) 3.5μm, gradient 10 to 100% B: A for 12 minutes, followed by a stop at 100% B for 3 minutes.

[0553] Mobile phase A: Water containing 0.05% TFA: CH3CN (95:5)

[0554] Mobile phase B: CH3CN:water (95:5) containing 0.05% TFA

[0555] TFA buffer pH = 2.5; flow rate: 1 mL / min; wavelength: 254 nm, 220 nm.

[0556] HPLC-2: XBridge Phenyl (4.6 × 150 mm) 3.5 μm, gradient 10 to 100% B: A for 12 min, followed by 3 min at 100% B.

[0557] Mobile phase A: Water containing 0.05% TFA: CH3CN (95:5)

[0558] Mobile phase B: CH3CN:water (95:5) containing 0.05% TFA

[0559] TFA buffer pH = 2.5; flow rate: 1 mL / min; wavelength: 254 nm, 220 nm.

[0560] HPLC-3: Chiralpak AD-H, 4.6×250mm, 5μm.

[0561] Mobile phase: 30% EtOH-heptane (1:1) / 70% CO2

[0562] Flow rate = 40 mL / min, 100 bar, 35℃; Wavelength: 220 nm

[0563] HPLC-4: Waters Acquity UPLC BEH C18, 2.1×50mm, 1.7μm particles;

[0564] Mobile phase A: 5:95 CH3CN: water containing 10 mM NH4OAc;

[0565] Mobile phase B: 95:5 CH3CN: water containing 10 mM NH4OAc;

[0566] Temperature: 50℃; Gradient: 0-100%B for 3 minutes, followed by 0.75 minutes at 100%B; Flow rate: 1.11 mL / min; Detection: UV at 220 nm.

[0567] HPLC-5: Waters Acquity UPLC BEH C18, 2.1×50mm, 1.7μm particles;

[0568] Mobile phase A: 5:95 CH3CN: water containing 0.1% TFA;

[0569] Mobile phase B: 95:5 CH3CN: water containing 0.1% TFA;

[0570] Temperature: 50℃; Gradient: 0-100%B for 3 minutes, followed by 0.75 minutes at 100%B; Flow rate: 1.11 mL / min; Detection: UV at 220 nm.

[0571] Intermediate 1: (±)-cis-1-fluoro-3-hydroxycyclohexanecarboxylate isopropyl ester

[0572]

[0573] Intermediate 1A: (±)-1-fluorocyclohexyl-3-encarboxylic acid ethyl ester

[0574]

[0575] A mixture of 20% but-1,3-diene in toluene (13.8 mL, 41.1 mmol) and ethyl 2-fluoroacrylate (3.07 mL, 27.4 mmol) was heated at 120 °C for 7 days in a sealed tube, followed by cooling to room temperature and vacuum concentration. The residue was separated by chromatography (80 g SiO2; continuous gradient from 0% to 10% EtOAc / hexane over 20 min) to give intermediate 1A (3.80 g, 22.1 mmol, 80% yield) as a clear oil. 1 H NMR (500MHz, CDCl3) δ5.79 (ddd, J=9.9, 4.7, 2.2Hz, 1H ) , 5.64-5.58 (m, 1H), 4.26 (q, J=7.2Hz, 2H), 2.73-2.57 (m, 1H), 2.45-2.23 (m, 2H), 2.20-1.91 (m, 3H), 1.32 (t, J=7.2Hz, 3H); 19 F NMR (471MHz, CDCl3) δ-162.69 (s, 1F).

[0576] Intermediate 1B: (±)-1-fluorocyclohexyl-3-encarboxylic acid

[0577]

[0578] The mixture of intermediate 1A (3.80 g, 22.1 mmol) and LiOH aqueous solution (55.2 mL 2.0 M solution, 110 mmol) in THF (50 mL) was stirred at room temperature for 18 hours. The reaction mixture was acidified to pH 2 with concentrated HCl (9.19 mL, 110 mmol) and then extracted with EtOAc (3 × 25 mL). The combined organic extracts were washed with water and concentrated under vacuum to give intermediate 1B (3.0 g, 20.8 mmol, 94% yield) as a pale yellow oil. 1 H NMR (500MHz, CDCl3) δ5.81 (ddd, J=9.8, 4.6, 2.1Hz, 1H), 5.66-5.58 (m, 1H), 2.76-2.59(m, 1H), 2.49-2.37(m, 1H), 2.35-2.23(m, 1H), 2.22-1.92(m, 3H); 19 F NMR (471MHz, CDCl3) δ-163.02 (s, 1F).

[0579] Intermediate 1C: (±)-1-fluoro-4-iodo-6-oxabicyclo[3.2.1]oct-7-one

[0580]

[0581] NaHCO3 (5.25 g, 62.4 mmol) was added fractionally to a mixture of intermediate 1B (3.0 g, 20.8 mmol) and water (20 mL), and the mixture was stirred until homogeneous. An aqueous solution of I2 (prepared by dissolving I2 (5.81 g, 22.0 mmol) and KI (20.7 g, 125 mmol) in 20 mL of water) was added, and the reaction mixture was stirred overnight in the dark at room temperature. Water (100 mL) was then added, and the mixture was extracted with DCM (3 × 25 mL), washed with 10% Na2S2O3 aqueous solution (20 mL × 2) and water, dried (MgSO4), and concentrated under vacuum. The residual crude oil was separated by chromatography (80 g SiO2; continuous gradient 0% to 50% EtOAc / hexane for 20 min) to give intermediate 1C (3.53 g, 13.1 mmol, 62.8% yield) as a white solid. 1 H NMR (500MHz, CDCl3) δ4.89 (dt, J=6.5, 3.5Hz, 1H), 4.44 (q, J=4.6Hz, 1H), 3.08 (dd, J=11.6, 1.9Hz, 1H ), 2.75 (tddd, J=11.3, 6.5, 3.3, 1.1Hz, 1H), 2.50-2.38 (m, 1H), 2.34-2.17 (m, 2H), 2.11-1.99 (m, 1H); 13 C NMR (126MHz, CDCl3) δ172.2, 172.0, 93.6, 91.9, 78.4, 78.3, 39.2, 39.0, 29.7, 29.6, 28.4, 28.2, 20.2; 19 F NMR (471MHz, CDCl3) δ-167.97 (s, 1F).

[0582] Intermediate 1D: (±)-1-fluoro-6-oxabicyclo[3.2.1]oct-7-one

[0583]

[0584] Tris(trimethylsilyl)silane (0.60 mL, 1.94 mmol) was added fractionally to a solution of intermediate 1C (350 mg, 1.30 mmol) and AIBN (21 mg, 0.130 mmol) in benzene (5 mL) over 10 minutes at 60 °C. The reaction mixture was stirred at 70 °C for 2 hours, cooled to room temperature, and then concentrated under vacuum. The residue was dissolved in EtOAc, washed with saturated aqueous NH4Cl solution, dried (MgSO4), and concentrated under vacuum. The crude oil was separated by chromatography (12 g SiO2; continuous gradient 0% to 30% EtOAc / hexane over 10 minutes) to give intermediate 1D as a white solid (124 mg, 0.860 mmol, 66.4% yield). 19 FNMR (471MHz, CDCl3) δ-167.01 (s, 1F); 1 H NMR (500MHz, CDCl3) δ4.98-4.81 (m, 1H), 2.75 (dtdd, J=15.9, 6.8, 3.3, 1.7Hz, 1H), 2.24-1.89 (m, 5H), 1.82-1.65 (m, 1H), 1.60-1.46 (m, 1H); 13 C NMR (126MHz, CDCl3) δ173.2, 173.0, 93.9, 92.3, 75.6, 75.5, 42.0, 41.9, 31.3, 31.1, 26.7, 17.7, 17.6.

[0585] Intermediate 1

[0586] Acetyl chloride (0.061 mL, 0.860 mmol) was added fractionally to isopropanol (3 mL) at 0 °C, followed by stirring at room temperature for 30 min. Intermediate 1D (124 mg, 0.860 mmol) was added, and the reaction mixture was stirred at room temperature overnight, followed by vacuum concentration. The residual crude oil was separated by chromatography (4 g SiO2; continuous gradient from 0% to 50% EtOAc / hexane over 10 min) to give intermediate 1 (140 mg, 0.685 mmol, 80% yield) as a clear oil. 1 H NMR (500MHz, CDCl3) δ5.08 (spt, J=6.3Hz, 1H), 3.91 (tt, J=10.9, 4.4Hz, 1H), 2.68 (br.s., 1H), 2.28 (dddt, J=13.5, 9.0, 4.6, 2.1Hz, 1H), 2.06-1.98 (m, 1H), 1.96-1.87 (m, 1H), 1.82-1.62 (m, 4H), 1.37-1.22 (m, 7H); 19FNMR (471MHz, CDCl3) δ-162.93 (s, 1F); 13 C NMR (126MHz, CDCl3) δ170.9, 170.7, 95.7, 94.2, 69.3, 66.1, 40.7, 40.5, 33.9, 31.6, 31.4, 21.5, 19.1.

[0587] Example 1

[0588] (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((((S)-2-methylbutoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid

[0589]

[0590] 1A: 3-Bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine

[0591]

[0592] Et3N (8.83 mL, 63.3 mmol) was added to a solution of 2,5-dibromo-6-methylpyridine (5 g, 21.11 mmol) and 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (4.44 g, 31.7 mmol) in MeCN (42.2 mL). The solution was degassed under N2, followed by the addition of (Ph3P)2PdCl2 (0.74 g, 1.06 mmol) and CuI (0.20 g, 1.06 mmol). The reaction mixture was stirred at room temperature for 14 hours, and the reaction mixture was then passed through... The plunger was filtered and the plunger was washed with EtOAc (2 × 10 mL). The combined filtrates were concentrated under vacuum and the residues were separated by chromatography (SiO2; continuous gradient from 0% to 100% EtOAc / hexane over 20 min) to give the title compound as a white solid (6.0 g, 20.3 mmol, 96% yield). 1 H NMR (400MHz, CDCl3) δ8.65 (d, J=2.0Hz, 1H), 7.80 (dd, J=8.3, 2.3Hz, 1H), 7.35 (dd, J=8.4, 0.4Hz, 1H), 4.91 (t, J=3.3Hz, 1 H), 4.61-4.45 (m, 2H), 3.98-3.81 (m, 1H), 3.66-3.44 (m, 1H), 1.92-1.73 (m, 2H), 1.72-1.52 (m, 2H). LCMS, [M+H]+=298.0.

[0593] 1B: 3-Bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine

[0594]

[0595] A solution of Example 1A (6.0 g, 20.3 mmol) in toluene (20 mL) and TMSCH2N3 (7.85 g, 60.8 mmol) was heated at 90 °C for 15 hours under Ar conditions, followed by cooling to room temperature. Volatiles were removed under vacuum, and the residue was dissolved in THF (20 mL). At 0 °C, TBAF (20.3 mL of 1 M solution in THF, 20.3 mmol) was added to the mixture. After stirring for 10 minutes, the reaction was complete, as determined by analytical HPLC. Volatiles were removed under vacuum, and the residue was separated chromatographically (SiO2; continuous gradient 0% to 100% EtOAc / hexane over 20 minutes) to give the title compound (2.1 g, 29% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.85 (d, J=8.4Hz, 1H), 7.13 (d, J=8.4Hz, 1H), 6.03 (br.s., 1H), 5.39-5.23 (m, 4H), 4.81-4.76 (m, 1H ), 4.17 (s, 3H), 3.91 (ddd, J=11.3, 7.9, 3.3Hz, 1H), 3.65-3.48 (m, 1H), 2.54 (s, 3H), 1.88-1.68 (m, 2H), 1.56 (br.s., 2H).

[0596] 1C: 2-Methyl-6-(1-Methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-ol

[0597]

[0598] Pd(dppf)Cl2 (22 mg, 0.03 mmol) was added to a degassed solution of bis(pinacol)diboron (230 mg, 0.91 mmol) and KOAc (178 mg, 1.81 mmol) in THF (bubbled three times with Ar). The reaction mixture was heated at 80°C for 16 hours in a sealed tube, then cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated under vacuum. The crude borate ester product was used in the next step without further purification. H₂O₂ (0.19 mL 30% aqueous solution, 6.0 mmol) was added to a solution of crude product 2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (241 mg, 0.603 mmol) in EtOAc (2 mL). The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0 °C and quenched by slow addition of a saturated aqueous solution of Na₂S₂O₃. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine, dried (MgSO₄), filtered, and concentrated under vacuum. Chromatographic separation (SiO2 ISCO column, continuous gradient 0% to 100% EtOAc / hexane for 20 minutes) of the residue yielded the title compound (150 mg, 86%) as a white solid. 1 H NMR(400M Hz, CDCl3) δ8.27 (d, J=2.6Hz, 1H), 8.06 (d, J=8.6Hz, 1H), 7.29-7.21 (m, 1H), 5.33 (s, 1H), 5.28 (d, J=2.4Hz, 2H), 4.76 (s, 1H), 4.18 (s, 3H), 3.90 (s, 1H), 3.63-3.48 (m, 1H), 1.72 (s, 2H), 1.65-1.51 (m, 2H). LCMS, [M+H]+=291.2.

[0599] 1D: (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester

[0600]

[0601] Bu3P (3.17 mL, 12.2 mmol) was added to a solution of (1S,3R)-3-hydroxycyclohexanecarboxylate (synthesized according to the procedure described in US2007 / 0197788A1, 1.51 g, 8.13 mmol) in toluene (81 mL). (E)-diazepine-1,2-dimethylbis(piperidin-1-yl-methyl ketone) (3.08 g, 12.2 mmol) was added fractionally to the stirred mixture, and the reaction mixture was heated at 50 °C for 120 min, followed by cooling to room temperature. At this point, the LC-MS spectrum of the reaction mixture showed the presence of the desired product. The mixture was filtered and the filtrate was concentrated under vacuum. Chromatographic separation (SiO2; continuous gradient 0% to 100% EtOAc / hexane, 20 min) of the residue yielded the title compound as a white foam (1.2 g, 2.62 mmol, 64.4% yield). 1 H NMR (400MHz, CDCl3) δ7.95 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 5.45-5.24 (m, 2H), 5.04 (dt, J=12.5, 6.3Hz, 1H), 4.83-4.64 (m, 2H), 4.16 (s , 3H), 3.91 (ddd, J=11.2, 7.9, 3.1Hz, 1H), 3.64-3.48 (m, 1H), 2.93-2.71 (m, 1H), 2.52 (s, 3H), 2.23-1.45 (m, 14H), 1.26 (dd, J=6.4, 2.0Hz, 6H).

[0602] 1E: (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester

[0603]

[0604] PPTS (0.932 g, 3.71 mmol) was added to a solution of Example 1D (1.7 g, 3.71 mmol) in MeOH (37 mL). The reaction mixture was heated to 60 °C and maintained for 2 hours, then cooled to room temperature, diluted with water and a saturated aqueous solution of NaHCO3, and then extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried (Na2SO4), concentrated under vacuum, and chromatographically separated (SiO2; continuous gradient 0% to 100% EtOAc / hexane for 20 min) to give the title compound (1.36 g, 3.63 mmol, 98% yield) as a white foam. 1H NMR (400MHz, CDCl3) δ8.01 (d, J=8.6Hz, 1H), 7.46 (d, J=5.1Hz, 1H), 7.27-7.15 (m, 1H), 4.96 (dt, J=12.5, 6.3Hz, 1H), 4.74 (s, 2H), 4.66-4.59 (m, 1H), 4.00 (s, 3H), 2.80-2.64 (m, 1H), 2.46 (s, 3H), 2.07-1.50 (m, 8H), 1.18 (dd, J=6.4, 2.2Hz, 6H).

[0605] 1F: (1S,3S)-3-((6-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid isopropyl ester

[0606]

[0607] At 0°C, PBr3 (0.17 mL, 1.80 mmol) was added to a solution of Example 1E (0.28 g, 0.721 mmol) in DME (7 mL). The reaction mixture was stirred overnight at room temperature, then cooled to 0°C and neutralized to pH 7 with a saturated aqueous solution of NaHCO3. The mixture was partitioned between EtOAc (50 mL) and water (5 mL), and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried (MgSO4) and concentrated under vacuum. The residue was separated chromatographically (12 g SiO2; continuous gradient 0% to 50% EtOAc / hexane, 25 min) to give the title compound as a white solid (300 mg, 0.665 mmol, 92% yield). LCMS, [M+H] + =451.2. 1 H NMR (500MHz, CDCl3) δ7.99 (d, J=8.5Hz, 1H), 7.22 (d, J=8.5Hz, 1H), 5.26 (d, J=1.4Hz, 2H), 5.03 (spt, J=6.3Hz, 1H), 4.75-4.63 (m , 1H), 4.12(s, 3H), 2.82-2.74(m, 1H), 2.54(s, 3H), 2.14-2.07(m, 1H), 1.99-1.88(m, 3H), 1.81-1.59(m, 4H), 1.27-1.24(m, 6H).

[0608] 1G: (1S,3S)-3-((6-(5-(azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid isopropyl ester

[0609]

[0610] NaN3 (36 mg, 0.554 mmol) was added to a solution of Example 1F (100 mg, 0.222 mmol) in DMF (1.5 mL), and the reaction mixture was stirred at 80 °C for 1 hour, followed by cooling to room temperature. LCMS analysis indicated the reaction was complete. The reaction mixture was partitioned between EtOAc and water, and the mixture was stirred at room temperature for 15 minutes. The organic layer was dried (Na2SO4) and concentrated under vacuum to give the crude title compound, which was used in the next step without further purification. LCMS, [M+H] + =414.3.

[0611] 1H: (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)isopropylcyclohexanecarboxylate

[0612]

[0613] Ph3P (58 mg, 0.22 mmol) was added to a solution of Example 1G (92 mg, 0.22 mmol) in THF (1 mL) and H2O (0.3 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between EtOAc and water, and the resulting mixture was stirred at room temperature for 15 min. The organic layer was dried (Na2SO4) and concentrated under vacuum. The residue was separated by chromatography (12 g SiO2; 100% EtOAc, 10 min, followed by a gradient of 0% to 10% MeOH / CH2Cl2 for 20 min; flow rate = 30 mL / min) to give the title compound (81 mg, 0.21 mmol, 94% yield) as a beige oil. LCMS, [M+H] + =388.3.

[0614] Example 1

[0615] N-ethyl-N-isopropylpropyl-2-amine (11 μL, 0.062 mmol) was added to a solution of Example 1H (8 mg, 0.021 mmol) and (4-nitrophenyl) carbonate·(S)-2-methylbutyl ester (7 mg, 0.027 mmol) in THF (0.4 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of THF (0.8 mL) / H2O (0.4 mL) / MeOH (0.4 mL) and LiOH·H2O (5 mg, 0.105 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated under vacuum and diluted with H2O (5 mL). The pH of the mixture was adjusted to approximately 5 with 1 N HCl aqueous solution and extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine (2 mL), dried (MgSO4), and concentrated under vacuum. The residual crude product was purified by preparative LC / MS. Column: Waters XBridge C18, 19 × 200 mm, 5 μm particles; Guard column: Waters XBridge C18, 19 × 10 mm, 5 μm particles; Mobile phase A: 5:95 MeCN: H₂O with 0.1% TFA; Mobile phase B: 95:5 MeCN: H₂O with 0.1% TFA; Gradient: 50-90% B for 20 min, followed by 5 min at 100% B; Flow rate: 20 mL / min. The fraction containing the desired product was concentrated under vacuum by centrifugation to give the title compound (6.6 mg, 0.014 mmol, 68% yield). LCMS, [M+H] + =460.3. 1 H NMR (500MHz, DMSO-d6) δ7.80 (d, J=8.2Hz, 1H), 7.55 (br.s., 1H), 7.46 (d, J=8.7Hz, 1H), 4.80-4.62 (m, 3H) , 4.02 (s, 3H), 3.76-3.67 (m, 2H), 2.62-2.55 (m, 1H), 2.42 (s, 3H), 2.04-0.93 (m, 11H), 0.83-0.72 (m, 6H). hLPA1 IC 50 =18nM.

[0616] Example 2

[0617] (1S,3S)-3-((2-methyl-6-(1-methyl-5-((methyl(((S)-2-methylbutoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid

[0618]

[0619] Under N2, NaH (0.5 mg of a 60% dispersion in mineral oil; 0.011 mmol) was added to a mixture of compound 1 (1.7 mg, 3.70 μmol) in DMF (0.2 mL) at 0°C, and the mixture was stirred at 0°C for 30 min. Then, MeI (0.7 μL, 0.011 mmol) was added, and the mixture was stirred at room temperature for 1 h, followed by vacuum concentration. The residue was dissolved in THF (0.8 mL) / MeOH (0.4 mL) / water (0.4 mL), and LiOH·H2O (1 mg, 18.5 μmol) was added at room temperature. The reaction mixture was stirred overnight at room temperature, followed by vacuum concentration and dilution with H2O (5 mL). The pH of the mixture was adjusted to approximately 5 with 1N HCl aqueous solution, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine (2 mL), dried (MgSO4), and concentrated under vacuum. The crude product was purified by preparative LC / MS: Column: Waters XBridge C18, 19×200 mm, 5 μm particles; Guard column: Waters XBridge C18, 19×10 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: 50-90% B for 20 min, followed by 100% B for 5 min; Flow rate: 20 mL / min. The fraction containing the desired product was concentrated under vacuum by centrifugation to give the title compound (1 mg, 2.1 μmol, 56.5% yield). LCMS, [M+H] = 474.0. 1 H NMR (500MHz, DMSO-d6) δ7.82 (d, J=8.2Hz, 1H), 7.48 (d, J=8.5Hz, 1H), 5.09 (br.s., 2H), 4.78-4.68 (m, 1H ), 4.04-3.76 (m, 5H), 2.73 (s, 3H), 2.65-2.56 (m, 1H), 2.40 (s, 3H), 1.98-1.02 (m, 11H), 0.82 (br.s., 6H). hLPA1IC 50 =29nM.

[0620] Example 3

[0621] (1S,3S)-3-((6-(5-(((butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0622]

[0623] 3A: (1S,3S)-3-((6-(5-(((butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester

[0624]

[0625] At room temperature, butyl chloroformate (0.017 mL, 0.129 mmol) was added to a solution of Example 1H (10 mg, 0.026 mmol) in EtOAc (0.3 mL) and a saturated aqueous solution of NaHCO3 (0.3 mL). The reaction mixture was stirred overnight and then concentrated under vacuum. This crude product was used in the next step without further purification. LCMS, [M+H] + =488.3.

[0626] Example 3

[0627] At room temperature, LiOH·H2O (6 mg, 0.13 mmol) was added to a solution of crude Example 3A (12.7 mg, 0.026 mmol) in THF (0.8 mL) / H2O (0.400 mL) / MeOH (0.400 mL). The mixture was stirred overnight at room temperature, followed by vacuum concentration; the residue was diluted with H2O (5 mL) and the pH was adjusted to approximately 5 with 1N HCl aqueous solution. The mixture was extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine (2 mL), dried (MgSO4), and concentrated under vacuum. The crude product was purified by preparative HPLC (Phenomenex Luna Axia 5μC18 30×100mm; 10 min gradient 85% A:15% B to 0% A:100% B (A = 90% H2O / 10% ACN + 0.1% TFA); (B = 90% ACN / 10% H2O + 0.1% TFA); detection at 220 nm) to give the title compound (11.3 mg, 0.025 mmol, 98% yield). 1 H NMR (500MHz, CDCl3) δ8.14 (d, J=8.8Hz, 1H), 7.92 (d, J=9.1Hz, 1H), 4.90-4.81 (m, 1H), 4.59 (s, 2H), 4.20 (s, 3H), 4.08 (t, J=6.6Hz, 2H), 2.9 5-2.83 (m, 1H), 2.75 (s, 3H), 2.23-2.13 (m, 1H), 2.03-1.76 (m, 6H), 1.73-1.55 (m, 3H), 1.42-1.31 (m, 2H), 0.92 (t, J=7.4Hz, 3H). LCMS, [M+H] +=446.3. hLPA1IC 50 =14nM.

[0628] Example 4

[0629] (±)-(trans)-3-(4-(5-(((((isopentyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid

[0630]

[0631] 4A: 2-((3-(4-bromophenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran

[0632]

[0633] A solution of 1-bromo-4-iodobenzene (10.0 g, 35.3 mmol) in DMF (50 mL) was supplemented with TEA (25 mL, 177 mmol), CuI (0.40 g, 2.12 mmol), Pd(Ph3P)4 (0.82 g, 0.71 mmol), and 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (6.44 g, 46.0 mmol). The reaction mixture was stirred under N2 at room temperature for 16 hours, followed by vacuum concentration. The residue was separated by chromatography (120 g SiO2; isohexane / EtOAc = 95:5) to give the title compound (10.0 g, 33.9 mmol, 96% yield) as a colorless oil. LCMS, [M+Na] + =319.0. 1 H NMR (500MHz, CDCl3) δ7.46-7.42 (m, 2H), 7.33-7.29 (m, 2H), 4.89 (t, J=3.4Hz, 1H), 4.54 -4.40 (m, 2H), 3.89 (ddd, J=11.5, 9.0, 2.9Hz, 1H), 3.61-3.54 (m, 1H), 1.92-1.51 (m, 6H).

[0634] 4B: 4-(4-bromophenyl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole

[0635]

[0636] TMSCH2N3 (1.8 mL, 12.2 mmol) was added to a solution of 4A (3.0 g, 10.2 mmol) in toluene (10 mL). The mixture was refluxed under Ar for 15 hours, then cooled to room temperature and concentrated under vacuum. The crude residue was separated by chromatography (120 SiO2; continuous gradient from 0 to 20% EtOAc / hexane for 25 min, followed by holding at 20% EtOAc for 20 min) to give the title compound as a beige solid (667 mg, 1.57 mmol, 15% yield). LCMS, [M+H] + =424.1. 1 H NMR (500MHz, CDCl3) δ7.73-7.69 (m, 2H), 7.60-7.56 (m, 2H), 4.84 (d, J=12.9Hz, 1H), 4. 70-4.64(m, 2H), 3.87-3.79(m, 3H), 3.58-3.49(m, 1H), 1.88-1.51(m, 6H), 0.23(s, 9H).

[0637] 4C: 4-(4-bromophenyl)-1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole

[0638]

[0639] H₂O (0.06 mL, 3.1 mmol) was added to a solution of Example 4B (660 mg, 1.56 mmol) in THF (10 mL), and the reaction mixture was cooled to 0 °C. TBAF (1.87 mL of 1.0 M solution in THF; 1.87 mmol) was added, and the reaction mixture was stirred at 0 °C for 10 min. Volatiles were removed under vacuum, and the mixture was separated chromatographically (40 g SiO₂; continuous gradient from 100% hexane to 50:50 hexane:EtOAc for 30 min, followed by a 10 min hold in 50% hexane:EtOAc) to give the title compound as a beige oil (510 mg, 1.49 mmol, 93% yield). LCMS, [M+H] + =352.0. 1 H NMR (500MHz, CDCl3) δ7.70-7.66 (m, 2H), 7.61-7.57 (m, 2H), 4.87 (d, J=12.9Hz, 1H), 4.74-4.65 (m, 2H), 4.15 (s, 3H), 3.82 (ddd, J=11.3, 8.1, 3.2Hz, 1H), 3.58-3.49 (m, 1H), 1.88-1.50 (m, 6H).

[0640] 4D: 4-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenol

[0641]

[0642] A mixture of Pd2(dba)3 (44 mg, 0.048 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (81 mg, 0.191 mmol), KOH (268 mg, 4.77 mmol), and Example 4C (281 mg, 0.80 mmol) in 1,4-dioxane (3 mL) and water (3 mL) was rapidly evacuated under vacuum and recharged with Ar (repeated 3 times). The mixture was stirred at 85 °C for 16 hours, then cooled to room temperature and carefully acidified with a 1N dilute HCl aqueous solution. The mixture was extracted with EtOAc (4 × 5 mL). The combined organic extracts were dried (MgSO4) and concentrated under vacuum to give a crude product as a brown solid. This substance was separated by chromatography (SiO2; EtOAc / hexane) to give the title compound as a white solid (210 mg, 0.726 mmol, 91% yield). LCMS, [M+H] + =290.1.

[0643] 4E: (±)-trans-3-(4-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic acid 1,3-isopropyl (a mixture of diastereomers of tetrahydropyranyl ether)

[0644]

[0645] DIAD (0.22 mL, 1.15 mmol) was added dropwise to a mixture of 4D (0.19 g, 0.64 mmol), (±)-cis-3-hydroxycyclohexane-1-carboxylic acid isopropyl ester (0.21 g, 1.15 mmol), Et3N (0.16 mL, 1.15 mmol), and Ph3P (0.30 g, 1.15 mmol) in THF (4 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature. Water (4 mL) was added, and the reaction mixture was acidified with 1 N HCl aqueous solution and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated under vacuum. The crude product was separated by chromatography (40 g SiO2; continuous gradient from 0% to 80% EtOAc / hexane for 30 min, followed by a 20 min maintenance in 80% EtOAc / hexane) to give the title compound (0.12 g, 0.257 mmol, 40% yield) as a beige oil. LCMS, [M+H]+ =458.1.

[0646] 4F: (±)-trans-3-(4-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic acid 1,3-isopropyl ester

[0647]

[0648] PPTS (6 mg, 0.025 mmol) was added to a solution of Example 4E (115 mg, 0.251 mmol) in MeOH (2.5 mL). The reaction mixture was stirred overnight at room temperature. LCMS showed that the reaction was still incomplete, so the mixture was heated again at 60 °C for 6 hours, followed by cooling to room temperature. The mixture was concentrated under vacuum and chromatographically separated (12 g SiO2; continuous gradient 80-100% EtOAc / hexane, 10 min) of the residue to give the title compound (84 mg, 90% yield) as a brown oil. LCMS, [M+H] + =374.2.

[0649] 4G.(±)-trans-3-(4-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic acid 1,3-isopropyl ester

[0650]

[0651] Ph3P (65 mg, 0.247 mmol) was added fractionally to a mixture of Example 4F (84 mg, 0.225 mmol) and CBr4 (82 mg, 0.247 mmol) in DCM (1.2 mL) at 0 °C. The reaction mixture was slowly heated to room temperature overnight, followed by vacuum concentration. The residue was separated by chromatography (12 g SiO2; 25 min continuous gradient 0% to 70% EtOAc / hexane; flow rate = 30 mL / min). The pure fraction was concentrated under vacuum to give the title compound (66 mg, 0.151 mmol, 67% yield) as a colorless oil. LCMS, [M+H] + =436.0.

[0652] 4H: (±)-trans-3-(4-(5-(azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic acid 1,3-isopropyl ester

[0653]

[0654] NaN3 (24 mg, 0.37 mmol) was added to a solution of Example 4G (65 mg, 0.149 mmol) in DMF (1 mL), and the reaction mixture was stirred at 80 °C for 1 hour, followed by cooling to room temperature. LCMS analysis indicated that the reaction was complete. The reaction mixture was partitioned between EtOAc and water (5 mL each), and the resulting mixture was stirred at room temperature. After 15 minutes, the organic layer was dried (Na2SO4) and concentrated under vacuum. The crude azide product was used in the next step without further purification.

[0655] 4I: (±)-trans-3-(4-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic acid 1,3-isopropyl ester

[0656]

[0657] Ph3P (39 mg, 0.149 mmol) was added to a solution of Example 4H (59 mg, 0.149 mmol) in THF (0.6 mL) and H2O (0.2 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between EtOAc and water (5 mL each), and the resulting mixture was stirred at room temperature. After 15 minutes, the organic layer was dried (Na2SO4) and concentrated under vacuum. The residue was separated chromatographically (8 g SiO2; 100% EtOAc, 10 min, followed by a continuous gradient of 0% to 10% MeOH / CH2Cl2, 15 min; flow rate = 30 mL / min) to give the title compound (47 mg, 0.126 mmol, 84% yield) as a beige oil. LCMS, [M+H] + =373.1.

[0658] Example 4

[0659] A solution of 3-methylbut-1-ol (6 mg, 0.064 mmol), CDI (11 mg, 0.064 mmol), and LiOH·H₂O (3 mg, 0.11 mmol) in toluene (0.5 mL) was stirred at 60 °C for 2 hours. Example 4I (8 mg, 0.021 mmol) was added to this mixture, and the reaction mixture was stirred overnight at 60 °C, followed by cooling to room temperature. The mixture was partitioned between EtOAc and water; the aqueous phase was extracted with EtOAc (3 times), and the combined organic extracts were dried (MgSO₄) and concentrated under vacuum. At room temperature, LiOH·H₂O (7 mg, 0.168 mmol) was added to this crude product in a solution of THF (0.8 mL), H₂O (0.40 mL), and MeOH (0.40 mL). The reaction mixture was stirred overnight at room temperature, followed by vacuum concentration and dilution with H₂O (5 mL). The mixture was adjusted to pH approximately 3 with 1N HCl aqueous solution and extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine (2 mL), dried (MgSO4), and concentrated under vacuum. The crude product was purified by preparative LC / MS: column: Waters XBridge C18, 19 × 200 mm, 5 μm particles; guard column: Waters XBridge C18, 19 × 10 mm, 5 μm particles; mobile phase A: 5:95 MeCN: H2O with 0.1% TFA; mobile phase B: 95:5 MeCN: H2O with 0.1% TFA; gradient: 50–90% B for 20 min, followed by 100% B for 5 min; flow rate: 20 mL / min, to give the title compound (1.4 mg, 3.15 μmol, 15% yield). LCMS, [M+H] + =445.1. 1 H NMR (500MHz, DMSO-d6) δ7.77 (br.s., 1H), 7.63 (d, J=7.6Hz, 2H), 7.02 (d, J=8.5Hz, 2H), 4.72-4.64 (m, 1H) , 4.41 (d, J=5.2Hz, 2H), 4.06-3.94 (m, 5H), 2.70-2.59 (m, 1H), 1.98-1.34 (m, 11H), 0.86 (d, J=6.1Hz, 6H). hLPA1 IC 50 =148nM.

[0660] Example 5

[0661] (1S,3S)-3-((6-(5-(((butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0662]

[0663] 5A: 3-(5-bromopyridin-2-yl)prop-2-yn-1-ol

[0664]

[0665] Et3N (33.2 mL, 240 mmol) was added to a solution of 3,6-dibromopyridine (25.0 g, 100 mmol) and propane-2-yn-1-ol (8.70 mL, 149 mmol) in MeCN (141 mL). The solution was degassed under Ar (bubbling with Ar three times), followed by the addition of (Ph3P)2PdCl2 (2.96 g, 4.22 mmol) and CuI (0.804 g, 4.22 mmol). The reaction mixture was stirred under Ar at room temperature for 14 hours; subsequently, the reaction was carried out by... The mixture was filtered through a plunger and washed with EtOAc (3 × 50 mL). The combined filtrates were concentrated under vacuum. The residue was separated by chromatography (SiO2; continuous gradient 0% to 100% EtOAc / hexane for 20 min) to give the title compound as a white solid (16.6 g, 74% yield). 1 H NMR (400MHz, CD3OD) δ 8.60 (d, J=2.2Hz, 1H), 7.99 (dd, J=8.4, 2.2Hz, 1H), 7.44 (d, J=8.4Hz, 1H), 4.41 (s, 2H).

[0666] 5B: (4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

[0667]

[0668] Add 0.402 g, 0.504 mmol of chloro(pentamethylcyclopentadienyl)bis(triphenylphosphine)ruthenium(II) to a degassed (bubbled three times with Ar) solution of 5A (1.9 g, 8.40 mmol) in dioxane (42.0 mL). Degassed the mixture three times with Ar, then added TMSCH2N3 (1.87 mL, 12.6 mmol). The reaction mixture was stirred at 50 °C under Ar for 15 h, then cooled to room temperature and concentrated under vacuum. The oily crude product was dissolved in THF (90 mL) and cooled to 0 °C. Added TBAF (5.40 mL of 1.0 M solution in THF; 5.40 mmol) and stirred the reaction mixture at 0 °C for 10 min, then added solid NaHCO3 (4 g). The reaction mixture was stirred at room temperature for 30 min and then filtered. The filtrate was concentrated under vacuum. Chromatographic separation (SiO2; continuous gradient 0% to 100% EtOAc / hexane, 20 min) of the residue yielded the title compound as a white solid (1.30 g, 4.59 mmol, 102% yield). 1 H NMR (500MHz, CDCl3) δ8.49 (dd, J=2.3, 0.7Hz, 1H), 8.08 (dd, J=8.5, 0.6Hz, 1H), 7.8 3 (dd, J=8.5, 2.2Hz, 1H), 6.16 (t, J=6.9Hz, 1H), 4.68 (d, J=6.9Hz, 2H), 3.95 (s, 3H).

[0669] 5C: 5-Bromo-2-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine

[0670]

[0671] PBr3 (0.21 mL, 2.23 mmol) was added to a stirred solution of Example 5B (300 mg, 1.15 mmol) in anhydrous CH2Cl2 (8 mL), and the solution was stirred at 0 °C for 45 min. The reaction mixture was then quenched with water (20 mL), extracted with EtOAc (2 × 20 mL), and the combined organic extracts were washed with brine (25 mL), dried (Na2SO4), and concentrated under vacuum to give the title compound (250 mg, 67%) as a yellow, oily liquid. LCMS, [M+H] + =329.9. 1 H NMR (300MHz, CDCl3) δ 8.64 (d, J=2.10Hz, 1H), 8.14 (dd, J=0.90, 8.56Hz, 1H), 7.90 (dd, J=2.40, 5.70Hz, 1H), 5.18 (s, 2H), 4.13 (s, 3H).

[0672] 5D: 2-(5-(azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-5-bromopyridine

[0673]

[0674] NaN3 (86 mg, 1.33 mmol) was added to the solution of Example 5C (220 mg, 0.66 mmol) in anhydrous DMF (2.5 mL), and the resulting solution was stirred at 70 °C for 16 hours, then cooled to room temperature and poured into water (25 mL). The precipitated solid product was filtered, washed with water (5 mL), and dried under vacuum to give the title compound (162 mg, 82%) as a white solid. LCMS, [M+H] + =296.0. 1 H NMR (400MHz, DMSO-d6) δ 8.76 (dd, J=0.8, 2.4Hz, 1H), 8.18 (dd, J=2.4, 8.4Hz, 1H), 8.06 (dd, J=0.8, 8.6Hz, 1H), 5.10 (s, 2H), 4.11 (s, 3H).

[0675] 5E: ((4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)tert-butyl carbamate

[0676]

[0677] Under N2 conditions, Ph3P (178 mg, 0.680 mmol) and water (1 mL) were added to a solution of Example 5D (100 mg, 0.34 mmol) in THF (3 mL), and the resulting solution was stirred at room temperature for 16 hours. NaOH (34 mg, 0.85 mmol) was added to this reaction mixture, followed by (Boc)2O (0.10 mL, 0.48 mmol), and the reaction mixture was stirred again at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (25 mL), dried over (Na2SO4), and concentrated under vacuum to give the title compound (100 mg, 80%) as a white solid. LCMS, [M+H] + =368.2. 1H NMR (300MHz, CDCl3) δ8.67 (d, J=2.1Hz, 1H), 8.15 (d, J=8.7Hz, 1H), 7.92 (dd, J=2. 4, 8.4Hz, 1H), 5.98-5.99 (m, 1H), 4.60 (d, J=6.0Hz, 2H), 4.21 (s, 3H), 1.41 (s, 9H).

[0678] 5F: ((1-Methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)methyl)tert-butyl carbamate

[0679]

[0680] A solution of Example 5E (50 mg, 0.136 mmol) in dioxane (5 mL) was supplemented with bis(pinacol)diboron (51.7 mg, 0.204 mmol) and KOAc (27 mg, 0.27 mmol). The reaction mixture was washed with N2 for 5 min, followed by the addition of the 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride DCM complex (6 mg, 0.006 mmol). The reaction mixture was stirred at 90 °C for 16 h, then cooled to room temperature. The mixture was filtered and the filtrate was concentrated under vacuum to give a crude, brown liquid containing the title compound (70 mg). LCMS: [M+H] + =416.0. This crude product is used in the next reaction without further purification.

[0681] 5G: ((4-(5-hydroxypyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)tert-butyl carbamate

[0682]

[0683] Sodium perborate monohydrate (41 mg, 0.407 mmol) was added to a stirred solution of Example 5F (70 mg, 0.722 mmol) in THF (5 mL) and water (1.5 mL). The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (20 mL). This mixture was extracted once with CHCl3 (2 × 10 mL) containing 10% MeOH. The combined organic extracts were dried (Na2SO4) and concentrated under vacuum. The crude product was chromatographically analyzed (12 g). SiO2 column chromatography (eluted with 3% MeOH / CHCl3) yielded the title compound (40 mg, 96%) as a pale yellow liquid. LCMS, [M+H] + =306.2. This crude substance is used in the next reaction without further purification.

[0684] 5H: (1S,3S)-3-((6-(5-(((tert-butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid ethyl ester

[0685]

[0686] Under N2 atmosphere, di-tert-butyl azodicarbonate (4.07 g, 17.7 mmol), Ph3P (4.64 g, 17.7 mmol), and (1S,3R)-3-hydroxycyclohexanecarboxylate (synthesized according to a similar procedure as described in US2007 / 0197788A1, 1.52 g, 8.84 mmol) were added sequentially to a solution of Example 5G (1.80 g, 5.90 mmol) in THF (35 mL). The reaction solution was stirred at 60 °C for 16 hours, then cooled to room temperature and concentrated under vacuum. The crude product was chromatographically separated (24 g SiO2, 40% EtOAc / hexane) to give the title compound (1.9 g, 70%) as a pale yellow solid. LCMS, [M+H] + =460.1. 1 H NMR (300MHz, CDCl3) δ8.30 (d, J=2.1Hz, 1H), 8.15 (d, J=5.4Hz, 1H), 7.34 (dd, J=2.4, 6.5Hz, 1H), 6.13 (s, 1H), 4.71 (s, 1H), 4.58 (d, J=1.5Hz, 2H), 4 .20(s, 3H), 4.12(q, J=3.0Hz, 2H), 2.80-2.82(m, 1H), 2.02-2.05(m, 1H), 1.84-1.99 (m, 3H), 1.56-1.79 (m, 4H), 1.41 (s, 9H), 1.26 (t, J=1.2Hz, 3H).

[0687] 5I: (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)ethyl cyclohexanecarboxylate

[0688]

[0689] A solution of dioxane containing HCl (10.3 mL of 4M solution, 41.3 mmol) in CH₂Cl₂ (50 mL) was added to a stirred solution of Example 5H (1.90 g, 4.13 mmol) and stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum to give the title compound (1.25 g, 84%) as a pale yellow solid. LCMS, [M+H]+ =360.0. This crude product is used in the next reaction without further purification.

[0690] 5J: (1S,3S)-3-((6-(5-(((butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid ethyl ester

[0691]

[0692] Under N2 conditions, 78 μL (0.83 mmol) of n-butyl chloroformate was added to a stirred solution of Example 5I (30 mg, 0.083 mmol) in CH2Cl2 (5 mL), and the solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum and the crude product (12 g SiO2, isogradient 27% EtOAc / hexane) was separated chromatographically to give the title compound (30 mg, 82%) as a pale yellow liquid. LCMS, [M+H] + =432.2.

[0693] Example 5

[0694] A solution of LiOH·H₂O (2 mg, 0.093 mmol) in water (1.5 mL) was added to a stirred solution of Example 5J (30 mg, 0.046 mmol) in THF (4 mL) and MeOH (1 mL), and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and washed with Et₂O (20 mL). The aqueous layer was neutralized with 1.5 N HCl aqueous solution (2 mL) and extracted with CHCl₃ containing 5% MeOH (25 mL). The organic layer was washed with brine (25 mL), dried (Na₂SO₄), and concentrated under vacuum. The crude product was purified by preparative reversed-phase HPLC (Sunfire C18 (150×19) mm; 5 μm; mobile phase A: 10 mM NH4OAc aqueous solution (pH: 4.5); mobile phase B: MeCN, flow rate: 15 mL / min; time (min) / %B: 0 / 20, 25 / 60; retention time: 15.19 min) to give the title compound (6 mg, 32%) as a white solid. LCMS, [M+H + =432.0. 1H NMR (400MHz, CD3OD) δ8.40 (br.s., 1H) 8.00 (d, J=8.8Hz, 1H) 7.53 (dd, J=8.8, 2.7Hz, 1H), 4.70-4.80 (m, 1H) 4.58 (s, 3H) 4.20 (s, 3H) 4.03 (t, J=6.6Hz, 2H) 2.77-2.88 (m, 1H) 1.87-2.15 (m, 3H) 1.45-1.86 (m, 6H) 1.23-1.44 (m, 2H) 0.92 (t, J=7.3Hz, 3H). hLPA1 IC 50 =96nM.

[0695] Table 1 below lists other examples prepared by the same synthesis method described herein.

[0696] Table 1

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713] Table 2 below lists other examples of synthesis using the intermediates described below.

[0714] Intermediate 2

[0715] 4-Nitrophenyl carbonate·((1-propylcyclopropyl)methyl) ester

[0716]

[0717] Intermediate 2A: 1-Propylcyclopropane-1-tert-butyl carboxylate

[0718]

[0719] tert-butyl cyclopropanecarboxylate (3.78 g, 26.6 mmol) was added dropwise to a solution of LDA in THF (40 mL of 0.8 M solution; 33.2 mmol) over 10 minutes at -78 °C. The solution was stirred at -78 °C for 2 hours, followed by dropwise addition of 1-bromopropane (4.84 mL, 53.2 mmol) over 20 minutes at -78 °C. The reaction mixture was slowly heated to room temperature and stirred overnight at room temperature, then quenched with a saturated aqueous NH4Cl solution and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was distilled under reduced pressure (20 Torr, BP = 95 °C) to give the title compound as an oil (2.99 g, 61% yield). 1 H NMR (500MHz, CDCl3) δ1.48 (m, 4H), 1.45 (s, 9H), 1.12 (m, 2H), 0.92 (m, 3H), 0.61 (m, 2H).

[0720] Intermediate 2B: (1-propylcyclopropyl)methanol

[0721]

[0722] At room temperature, LiAlH4 (103 mg, 2.71 mmol) was added fractionally to a solution of intermediate 2A (250 mg, 1.36 mmol) in Et2O (5 mL); the reaction mixture was stirred overnight at room temperature. The mixture was then treated sequentially with water (0.1 mL), 15% NaOH aqueous solution (0.1 mL), and water (0.3 mL), followed by stirring at room temperature for 1 hour, drying (MgSO4), and concentrating under vacuum. The residue was distilled under reduced pressure to give a slightly impure title compound (186 mg) in an oily form. 1 H NMR (500MHz, CDCl3) δ3.44 (br s, 2H), 1.48-1.36 (m, 4H), 0.93 (t, J = 7.0Hz, 3H), 0.44-0.27 (m, 4H).

[0723] Intermediate 2

[0724] Pyridine (0.44 mL, 5.43 mmol) and 4-nitrobenzene chloroformate (410 mg, 2.04 mmol) were added to a room-temperature solution of intermediate 2B (155 mg, 1.36 mmol) in CH2Cl2 (10 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under vacuum and chromatographically separated (SiO2; continuous gradient 0-25% EtOAc / hexane) to give intermediate 2 (226 mg, 60% yield) as a white solid. 1 H NMR (500MHz, CDCl3) δ8.31 (d, J=9.1Hz, 2H), 7.42 (d, J=9.1Hz, 2H), 4.15 (s, 2H), 1.45 (m, 4H), 0.96 (t, J=7.0Hz, 3H), 0.58 (m, 2H), 0.51 (m, 2H).

[0725] The following intermediates were prepared using the same synthetic procedure as intermediate 2, starting with tert-butyl cyclopropanecarboxylate or tert-butyl cyclobutanecarboxylate and then alkylated with the desired alkyl iodide or bromide.

[0726] Intermediate 3: (1-methylcyclopropyl)methyl carbonate·(4-nitrophenyl) ester

[0727]

[0728] 1 H NMR (400MHz, CDCl3) δ8.28 (d, J=9.2Hz, 2H), 7.40 (d, J=9.2Hz, 2H), 4.10 (s, 2H), 1.22 (s, 3H), 0.60 (m, 2H), 0.47 (m, 2H).

[0729] Intermediate 4: (1-Ethylcyclopropyl)methyl carbonate·(4-nitrophenyl) ester

[0730]

[0731] 1 H NMR (400MHz, CDCl3) δ8.28 (d, J=9.2Hz, 2H), 7.39 (d, J=9.2Hz, 2H), 4.14 (s, 2H), 1.48 (q, J=7.3Hz, 2H), 0.98 (t, J=7.4Hz, 3H), 0.54 (m, 4H).

[0732] Intermediate 5: (1-Ethylcyclobutyl)methyl carbonate·(4-nitrophenyl) ester

[0733]

[0734] 1 H NMR (500MHz, CDCl3) δ8.31 (d, J=9.4Hz, 2H), 7.42 (d, J=9.4Hz, 2H), 4.27 (s, 2H), 1.99-1.83 (m, 6H), 1.63 (q, J=7.4Hz, 2H), 0.90 (t, J=7.4Hz, 3H).

[0735] Intermediate 6: 4-Nitrophenyl carbonate·((1-propylcyclobutyl)methyl) ester

[0736]

[0737] 1 H NMR (500MHz, CDCl3) δ8.31 (d, J=9.4Hz, 2H), 7.42 (d, J=9.4Hz, 2H), 4.26 (s, 2H), 1.99-1.85 (m, 6H), 1.56 (m, 2H), 1.32 (m, 2H), 0.97 (t, J=7.3Hz, 3H).

[0738] Table 2

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746] Example 64: (1S,3S)-3-((6-(5-((tert-butoxycarbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0747]

[0748] 64A: (1S,3S)-3-((6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0749]

[0750] Methyl (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (similar to the synthesis of the corresponding isopropyl ester in Example 1E; 3.28 g, 9.10 mmol) in a stirred solution of (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (3.28 g, 9.10 mmol) in CH2Cl2 (45.5 ml) was mixed with NaHCO3 (3.82 g, 45.5 mmol) and Desmond-Martin periodane (4.63 g, 10.9 mmol) and stirred at room temperature for 1 hour. A white solid was obtained by... Filter and rinse with EtOAc. Wash the combined filtrate with saturated NaHCO3 aqueous solution, water, and brine, dry (Na2SO4), and concentrate under vacuum. Separate by chromatography (120g). SiO2 column chromatography; crude product (EtOAc) in 60% hexane with isogradients yielded the title compound (3.10 g, 95%) as a clear, colorless oil. LC-MS, [M+H] + =359.1. 1 H NMR (500MHz, CDCl3) δ10.96 (s, 1H), 8.09 (d, J = 8.5Hz, 1H), 7.24 (d, J = 8.5Hz, 1H), 4.77-4.72 (m, 1H), 4.36 (s , 3H), 3.70 (s, 3H), 2.87-2.80 (m, 1H), 2.51 (s, 3H), 2.20-2.08 (m, 1H), 2.02-1.91 (m, 3H), 1.80-1.59 (m, 4H).

[0751] 64B: 4-(5-(((1S,3S)-3-(methoxycarbonyl)cyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-carboxylic acid

[0752]

[0753] At room temperature, NaClO2 (131 mg, 1.45 mmol) was added to a mixture of 64A (260 mg, 0.725 mmol), NaH2PO4 (435 mg, 3.63 mmol), 2-methyl-2-butene (0.617 mL of 2.0 M solution in THF; 5.80 mmol), water (0.2 mL), and t-BuOH (2 mL). The reaction mixture was stirred at room temperature for 3 hours, then poured into brine and extracted (3 times) with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated under vacuum to give the title compound. This crude acid was used in the next reaction without further purification. 1H NMR (500MHz, CDCl3) δ8.52-8.19 (m, 1H), 7.67-7.40 (m, 1H), 4.85-4.75 (m, 1H), 4.52-4.40 (m, 3H) , 3.78-3.63(m, 3H), 2.90-2.77(m, 1H), 2.67-2.53(m, 3H), 1.99-1.83(m, 3H), 1.80-1.62(m, 5H).

[0754] 64C: (1S,3S)-3-((6-(5-((tert-butoxycarbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0755]

[0756] A mixture of 64B (60 mg, 0.160 mmol), diphenylphosphoazide (63 μL, 0.288 mmol), 2-methylprop-2-ol (36 mg, 0.240 mmol), and TEA (89 μL, 0.641 mmol) in toluene (1 mL) was stirred at 80 °C for 1 hour, then cooled to room temperature and concentrated under vacuum. LC / MS indicated the formation of the desired product. The crude product was separated by chromatography (12 g SiO2; continuous gradient from 0% to 80% EtOAc / hexane for 30 min and 80% EtOAc / hexane for 20 min) to give the title compound (60 mg, 0.135 mmol, 84% yield). 1 H NMR (400MHz, CDCl3) δ8.00-7.81 (m, 1H), 7.28-7.15 (m, 1H), 4.84-4.62 (m, 1H), 4.14-4.06 (m, 3H), 3.76-3. 67 (m, 3H), 2.92-2.77 (m, 1H), 2.57-2.49 (m, 3H), 2.25-2.09 (m, 1H), 2.05-1.60 (m, 8H), 1.58-1.48 (m, 9H).

[0757] Example 64

[0758] At room temperature, 2.0 M LiOH aqueous solution (0.101 mL, 0.202 mmol) was added to a stirred solution of 64C (30 mg, 0.067 mmol) in THF (1.5 mL), MeOH (0.100 mL), and water (0.15 mL). The mixture was stirred at 50 °C for 1 hour, then cooled to room temperature and acidified to pH 2.3 by dropwise addition of 1 M HCl aqueous solution. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Sunfire C18 (150 x 19) mm; 5 μm; mobile phase A: 10 mM NH4OAc / water (pH: 4.5); mobile phase B: MeCN, flow rate: 15 mL / min; time (min) / %B: 0 / 20, 25 / 60; retention time: 15.19 min) to give the title compound (15 mg, 0.031 mmol, 46.5% yield). LCMS, [M+H] + =460.2. 1 H NMR (400MHz, CDCl3) δ8.03-7.85 (m, 1H), 7.26-7.22 (m, 1H), 4.77-4.66 (m, 1H), 4.15-4.05 (m, 3H), 2.92-2.75 (m, 1H), 2.56-2.43(m, 3H), 2.23-2.08(m, 1H), 2.05-1.85(m, 3H), 1.82-1.61(m, 4H), 1.60-1.48(m, 9H).LCMS, [M+H] + =446.2. hLPA1 IC 50 =54nM.

[0759] Table 3 below lists other examples. Some of these examples (103 to 107) are synthesized using triazole-ethanol intermediate 7 (shown below). Specifically, intermediate alcohol 7 is converted into the following examples using the same method and procedure as shown in process 1 and illustrated by converting intermediate 1E into Example 1 in 5 steps.

[0760] Intermediate 7: (1S,3S)-3-((6-(5-(2-hydroxyethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0761]

[0762] 7A: (1S,3S)-3-((2-methyl-6-(1-methyl-5-vinyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0763]

[0764] KOtBu (0.947 g, 8.44 mmol) was added to a suspension of Ph3PCH3Br (3.77 g, 10.6 mmol) in THF (70 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. A solution of Example 241A (2.52 g, 7.03 mmol) in THF (10 mL) was added to the reaction mixture, and the mixture was stirred at 0 °C for 30 min, then heated to room temperature. The reaction mixture was stirred at room temperature for 1 h, then quenched with a saturated aqueous solution of NH4Cl and diluted with EtOAc. The aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated under vacuum. Chromatographic separation (220 g) was performed. SiO2 column chromatography; crude product (EtOAc) in a continuous gradient of 0-60% hexane was obtained to give the title compound (2.2 g, 88%) as a white gel. LC-MS, [M+H] + =357.0. 1 H NMR (500MHz, CDCl3) δ7.91 (d, J=8.5Hz, 1H), 7.42 (dd, J=18.3, 12.0Hz, 1H), 7.20 (d, J=8.5Hz, 1H), 5.93-5.88 (m, 1H), 5.70-5.66 (m, 1H), 4.71 (br s, 1H), 4.15 (s, 3H), 3.70 (s, 3H), 2.84 (tt, J=10.5, 3.9Hz, 1H), 2.53 (s, 3H), 2.16 (br d, J=13.8Hz, 1H), 2.02-1.87 (m, 3H), 1.87-1.71 (m, 1H), 1.71-1.54 (m, 3H).

[0765] Intermediate 7

[0766] 9-BBN (17.9 mL of 0.5 M solution in THF; 8.95 mmol) was added dropwise to a solution of intermediate 7A (1.45 g, 4.07 mmol) in 13.6 mL of THF at 0 °C. The ice bath was removed, and the reaction mixture was heated at 65 °C for 4 hours, followed by cooling to 0 °C. A solution of sodium perborate tetrahydrate (2.50 g, 16.3 mmol) in water (10 mL) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 18 hours; then water was added. The aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated under vacuum. Chromatographic separation (120 g) was performed. SiO2 column chromatography; crude product (EtOAc) in a continuous gradient of 0-100% hexane was obtained to give the title compound (0.37 g, 24%) as a colorless oil. LC-MS, [M+H] + =375.1. 1 H NMR (400MHz, CDCl3) δ7.92 (d, J=8.6Hz, 1H), 7.30-7.25 (m, 1H), 6.71-6.42 (m, 1H), 4.74-4.68 (m, 1H), 4.06-3.98 (m, 5H), 3.70 (s, 3H), 3. 26 (td, J=5.6, 1.4Hz, 2H), 2.83 (tt, J=10.3, 3.9Hz, 1H), 2.51 (s, 3H), 2.14 (dt, J=13.9, 4.3Hz, 1H), 2.02-1.87 (m, 3H), 1.82-1.56 (m, 4H).

[0767] Table 3

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783] Example 108: (1S,3S)-3-((6-(5-((3-(cyclobutylmethyl)-3-methylurea)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid

[0784]

[0785] 108A: (Cyclobutylmethyl)(methyl)carbamate chloride

[0786]

[0787] A solution of 1-cyclobutyl-N-methylmethylamine (150 mg, 1.51 mmol) and pyridine (183 μL, 2.27 mmol) in CH2Cl2 (3 mL) was added dropwise to a solution of triphosgene (269 mg, 0.91 mmol) in CH2Cl2 (5 mL) at 0 °C. The reaction mixture was heated to room temperature over 30 minutes, and then quenched by careful addition of 0.1 N HCl aqueous solution (5 mL). The aqueous phase was extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were dried (MgSO4) and concentrated under vacuum to give the title compound (239 mg, 1.48 mmol, 98% yield) as a yellow oil, which was used in the next step without further purification. 1 H NMR (500MHz, CDCl3) δ 3.57-3.44 (m, 2H), 3.14-3.00 (m, 3H), 2.66 (dt, J = 15.7, 7.8Hz, 1H), 2.17-2.04 (m, 2H), 2.02-1.73 (m, 4H).

[0788] 108B: (1S,3S)-3-((6-(5-((3-(cyclobutylmethyl)-3-methylurea)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid isopropyl ester

[0789]

[0790] At 0 °C, 108A (18 mg, 0.11 mmol) was added to a solution of Example 1H (28 mg, 0.072 mmol) and TEA (12 μL, 0.087 mmol) in CH2Cl2 (1 mL), followed by the addition of DMAP (1 mg, 7 μmol). After 10 minutes at 0 °C, the reaction mixture was heated to room temperature and stirred at room temperature for 2 hours, followed by vacuum concentration. The crude product was separated by chromatography (4 g SiO2; continuous gradient from 0% to 100% EtOAc / hexane over 10 minutes) to give the title compound (35 mg, 0.068 mmol, 94% yield) as a clear oil. 1 H NMR (500MHz, CDCl3) δ8.07 (d, J=8.5Hz, 1H), 7.32-7.27 (m, 1H), 6.92 (br t, J=6.1Hz, 1H), 5.05 (quin, J=6.3Hz, 1H), 4.75-4.69 (m, 1H), 4.60 (d, J=6.3Hz, 2H), 4.28 (s, 3H), 3.24 (d, J=7.2Hz, 2H), 2.87-2.74 (m, 4H), 2.55 (s, 3H), 2.48 (dt, J=15.5, 7.9Hz, 1H), 2.14-2.07 (m, 1H), 2.03-1.58 (m, 13H), 1.29-1.24 (m, 6H).

[0791] Example 108

[0792] A mixture of 108B (32 mg, 0.062 mmol) and 1.0 M NaOH aqueous solution (0.31 mL, 0.31 mmol) in THF (1 mL) was stirred at 45 °C for 18 hours, then cooled to room temperature and acidified with TFA to pH 4 and concentrated under vacuum. The crude product was purified by preparative HPLC (Sunrire C18 30 × 100 mm column; detection at 220 nm; flow rate = 40 mL / min; continuous gradient from 30% B to 100% B for 10 min + hold time at 100% B for 2 min, where A = 90:10:0.1 H2O:MeCN:TFA and B = 90:10:0.1 MeCN:H2O:TFA) to give the title compound (TFA salt; 35 mg, 0.059 mmol, 94% yield) as a clear oil. 1H NMR (500MHz, CDCl3) δ8.21 (d, J=8.8Hz, 1H), 8.00 (d, J=8.8Hz, 1H), 4.91 (br.s., 1H), 4.55 (s, 2H), 4.21 (s, 3H), 3.34 (d, J =7.2Hz, 2H), 3.00-2.85(m, 4H), 2.80(s, 3H), 2.56(dt, J=15.2, 7.7Hz, 1H), 2.26-2.12(m, 1H), 2.09-1.62(m, 14H); [M+H] + =471.1; hLPA1 IC 50 =82nM.

[0793] The examples in Table 4 below are synthesized according to the procedure described for the preparation of Example 108.

[0794] Table 4

[0795]

[0796]

[0797] Example 112: (1S,3S)-3-((6-(5-(((3-benzylureo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, TFA salt

[0798]

[0799] 112A: (1S,3S)-3-((6-(5-(((3-benzylureo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0800]

[0801] To a solution of (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (similar to the synthesis in Example 1H of the corresponding isopropyl ester, 30 mg, 0.083 mmol), in a DCE (1.7 mL) solution, Et3N (29 μL, 0.21 mmol) was added, followed by CDI (27.1 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 1 h, followed by the addition of benzylamine (23 μL, 0.21 mmol). The reaction mixture was stirred at room temperature for 30 min and then heated at 80 °C for 30 min, followed by cooling to room temperature. Water was added to the reaction mixture, and the mixture was neutralized to pH 7 with 1 M HCl aqueous solution, followed by extraction with EtOAc (3 times). The combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated under vacuum to give the title compound (41 mg, 100%) as a colorless, transparent residue. This substance was used in the next step without further purification. LCMS, [M+H] + =493.4.

[0802] Example 112

[0803] A solution of 112A (41 mg, 0.083 mmol) in THF (0.56 mL) was added to a 1.0 M LiOH aqueous solution (0.42 mL, 0.42 mmol). The reaction mixture was stirred at room temperature for 23 hours, followed by vacuum concentration. The residue was dissolved in a 1:1 MeCN:H₂O (1.5 mL) solution, and TFA was added to adjust the pH to 3. This substance was purified by preparative HPLC (column: Sunrire PrepC18 OBD, 30 × 100 mm, 5 μm particles; mobile phase A: 10:90 MeCN:H₂O with 0.1% TFA; mobile phase B: 90:10 MeCN:H₂O with 0.1% TFA; gradient: 10–100% B for 10 min, followed by 2 min at 100% B; flow rate: 40 mL / min) to give the title compound (10 mg, 20%) as a white solid. LCMS, [M+H] + =479.4. 1H NMR (500MHz, DMSO-d6 and D2O) δ7.90 (d, J=8.5Hz, 1H), 7.59 (br d, J=8.5Hz, 1H), 7.30-7.25 (m, 2H), 7.23-7.16 (m, 3H), 4.81 (br s, 1H), 4.64 (s, 2H), 4.18 (s, 2H), 4.13 (s, 3H), 2.67-2.59 (m, 1H), 2.49 (s, 3H), 2.07-1.98 (m, 1H), 1.91-1.74 (m, 3H), 1.68-1.44 (m, 4H). hLPA1 IC 50 =63nM.

[0804] Example 113: (1S,3S)-3-((6-(5-(((3-benzyl-1-methylurea)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, TFA salt.

[0805]

[0806] 113A: (1S,3S)-3-((2-methyl-6-(1-methyl-5-((methylamino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0807]

[0808] MeNH2·HCl (92 mg, 1.36 mmol) was added to a room-temperature solution of aldehyde Example 64A (325 mg, 0.91 mmol) in MeOH (3.6 mL). The reaction mixture was stirred at room temperature for 20 min, followed by the addition of NaBH3CN (85 mg, 1.36 mmol). The reaction mixture was stirred at room temperature for 2 h, followed by partitioning between EtOAc and a 1.0 M K2HPO4 aqueous solution. The aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated under vacuum to give a viscous yellow oil. The residue was separated by chromatography (SiO2; continuous gradient 0-10% MeOH / CH2Cl2) to give the title compound (180 mg, 53%) as a colorless, transparent oil. LCMS, [M+H] + =374.2. 1H NMR (500MHz, CD3OD) δ7.89 (d, J=8.8Hz, 1H), 7.47 (d, J=8.5Hz, 1H), 4.84-4.79 (m, 1H), 4.16 (s, 3H), 4.09 (s, 2H), 3 .70 (s, 3H), 2.89-2.82 (m, 1H), 2.53 (s, 3H), 2.46 (s, 3H), 2.19-2.09 (m, 1H), 2.01-1.90 (m, 3H), 1.82-1.61 (m, 4H).

[0809] 113B: (1S,3S)-3-((6-(5-(((3-benzyl-1-methylurea)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0810]

[0811] Et3N (52 μL, 0.38 mmol) was added to a solution of 113A (20 mg, 0.054 mmol) in DCE (1.1 mL) at 0 °C, followed by triphosgene (24 mg, 0.080 mmol). The reaction mixture was stirred at 0 °C for 30 min; then benzylamine (35 μL, 0.32 mmol) was added. The mixture was heated to room temperature (a white precipitate formed over time) and stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc and a 0.5 M HCl aqueous solution. The aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with 1.0 M K2HPO4 aqueous solution and brine, dried (Na2SO4), and concentrated under vacuum to give the title compound (27 mg, 100%) as a pale yellow, transparent oil. This substance was used in the next step without further purification. LCMS, [M+H] + =507.4.

[0812] Example 113

[0813] Add 1.0 M LiOH aqueous solution (0.27 mL, 0.27 mmol) to a solution of 113B (27 mg, 0.053 mmol) in THF (0.36 mL). Stir the reaction mixture at room temperature for 18.5 h, then partition it between water and EtOAc. Extract the aqueous layer twice with EtOAc, and discard the combined organic extracts. Acidify the aqueous layer to pH 5 with 1 N HCl aqueous solution, then extract three times with EtOAc. Wash the combined organic extracts with brine, dry (Na₂SO₄), and concentrate under vacuum. The title compound (8 mg, 25%) was purified by preparative HPLC (column: Sunrire Prep C18 OBD, 30 × 100 mm, 5 μm particles; mobile phase A: 10:90 MeCN: H₂O with 0.1% TFA; mobile phase B: 90:10 MeCN: H₂O with 0.1% TFA; gradient: 15–100% B for 10 min, followed by a 2-minute hold at 100% B; flow rate: 40 mL / min). LCMS, [M+H] + =493.3. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.86 (d, J = 8.6Hz, 1H), 7.52 (d, J = 8.8Hz, 1H), 7.33–7.26 (m, 2H), 7.26–7.13 (m, 4H), 5.13 (s, 2H), 4.82–4.74 (m, 1H), 4.27 (d, J = 5.5Hz, 2H), 3.99 (s, 3H), 2.83 (s, 3H), 2.71–2.58 (m, 1H), 2.43 (s, 3H), 2.09–1.97 (m, 1H), 1.92–1.74 (m, 3H), 1.70–1.44 (m, 4H). 31 out of 32 protons were found, indicating the absence of acid protons. hLPA1 IC 50 =218nM.

[0814] The embodiments in Table 5 below were synthesized according to the procedures described in respect of the preparation of embodiments 112 and 113.

[0815] Table 5

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826] Example 135: (1S,3S)-3-((6-(5-(3-benzylureido)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, 1TFA.

[0827]

[0828] 135A: (1S,3S)-3-((6-(5-(3-benzylureido)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester, 1TFA

[0829]

[0830] Add Et3N (67 μL, 0.48 mmol) and (PhO)2PON3 (43 μL, 0.20 mmol) to a microwave-safe vial containing a suspension of Example 64B (30 mg, 0.080 mmol) in toluene (0.80 mL). Heat the reaction mixture in a microwave reactor at 100 °C for 1 hour, then cool to room temperature. Add benzoylamine (22 μL, 0.20 mmol) and heat the reaction mixture in a microwave reactor at 100 °C for 10 minutes, then cool to room temperature. Partition the reaction mixture between EtOAc and a 1.0 M K2HPO4 aqueous solution. Extract the aqueous layer twice with EtOAc. Dry the combined organic extracts (Na2SO4) and concentrate under vacuum. The colorless, transparent residue was purified by preparative HPLC (column: Sunrire Prep C18 OBD, 30 × 100 mm, 5 μm particles; mobile phase A: 10:90 MeOH: H₂O with 0.1% TFA; mobile phase B: 90:10 MeOH: H₂O with 0.1% TFA; gradient: 25–100% B for 10 min, followed by a 2-min hold at 100% B; flow rate: 40 mL / min) to give the title compound (22 mg, 46%) as a colorless, transparent oil. LCMS, [M+H] + =479.3.

[0831] Example 135

[0832] A solution of 135A (22 mg, 0.037 mmol) in THF (0.24 mL) was added to a 1.0 M LiOH aqueous solution (0.22 mL, 0.22 mmol). The reaction mixture was stirred at room temperature for 20 hours, followed by vacuum concentration. The residue was dissolved in a 1:1 MeCN:H₂O (1.5 mL); TFA was added to adjust the pH to 3. This substance was purified by preparative HPLC (column: Sunrire PrepC18 OBD, 30 × 100 mm, 5 μm particles; mobile phase A: 10:90 MeCN:H₂O with 0.1% TFA; mobile phase B: 90:10 MeCN:H₂O with 0.1% TFA; gradient: 10–100% B for 10 min, followed by 2 min at 100% B; flow rate: 40 mL / min) to give the title compound (13 mg, 61%) as a white solid. LCMS, [M+H] + =465.3. 1 H NMR (500MHz, CDCl3) δ11.59-11.45 (m, 1H), 9.76-9.66 (m, 1H), 8.16 (d, J=8.8Hz, 1H), 7.92 (d, J= 9.1Hz, 1H), 7.42-7.38(m, 2H), 7.38-7.32(m, 2H), 7.31-7.26(m, 1H), 4.76-4.67(m, 1H), 4.53(br d, J = 5.0 Hz, 2H), 4.11 (s, 3H), 2.89–2.82 (m, 1H), 2.26 (s, 3H), 2.23–2.15 (m, 1H), 2.06–1.93 (m, 2H), 1.86–1.63 (m, 4H), 1.63–1.52 (m, 1H). 27 out of 28 protons were found to be missing acid protons. hLPA1 IC 50 =329nM.

[0833] Example 136: (1S,3S)-3-((2-methyl-6-(1-methyl-5-(3-((R)-1-phenylethyl)ureo)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, 1TFA

[0834]

[0835] Example 136 was synthesized according to the procedure described in Example 135. LCMS, [M+H] + =479.1; 1HNMR (500MHz, DMSO-d6) δ8.48 (s, 1H), 7.80 (br d, J=7.9Hz, 1H), 7.73 (br d, J=8.5Hz, 1H), 7.51 (br d, J=8.5Hz, 1H), 7.39-7.26 (m, 4H), 7.25-7.19 (m, 1H), 4.86-4.73 (m, 2H), 3.84 (s, 3H), 2.69 -2.59(m, 1H), 2.54(s, 3H), 2.11-1.95(m, 1H), 1.92-1.72(m, 3H), 1.70-1.44(m, 4H), 1.39(br (d, J = 7.0 Hz, 3H); carboxylic acid protons were not observed. hLPA1 IC 50 =103nM.

[0836] Example 137: (1S,3S)-3-((6-(5-(((N-(cyclopentylmethyl)-N-methylaminosulfonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0837]

[0838] 137A: (cyclopentylmethyl)(methyl)aminosulfonyl chloride

[0839]

[0840] A mixture of 1-cyclopentyl-N-methylmethylamine-HCl salt (77 mg, 0.51 mmol) and TEA (179 μL, 1.29 mmol) in CH2Cl2 (1 mL) was added to a 0 °C solution of 1.0 M thioyl chloride in CH2Cl2 (514 μL, 0.51 mmol) in CH2Cl2 (1 mL). The reaction mixture was heated to room temperature and stirred at room temperature for 2 hours to give the crude title compound, which was used in the next reaction without further purification.

[0841] 137B: (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid tert-butyl ester

[0842]

[0843] A mixture of (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (obtained by LiOH-mediated 1E hydrolysis; 500 mg, 1.44 mmol) and (Z)-N,N′-2-isopropyliminocarbamate tert-butyl ester (867 mg, 4.33 mmol) in tert-butanol (1 mL) / THF (1 mL) was stirred at room temperature for 18 hours. The reaction mixture was filtered; the filtrate was concentrated under vacuum. The crude oily product was purified by preparative HPLC (Sunfire C1830 × 100 mm-regenerated column; detection at 220 nm; flow rate = 40 mL / min; continuous gradient from 20% B to 100% B for 10 min + hold time at 100% B for 2 min, wherein A = 90:10 H₂O:MeCN and B = 90:10 MeCN:H₂O) to give the title compound (300 mg, 0.745 mmol, 51.6% yield) as a clear oil. [M+H] + =403.2.

[0844] 137C: (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid tert-butyl ester

[0845]

[0846] A mixture of 137B (300 mg, 0.75 mmol), DBU (0.23 mL, 1.49 mmol), and (PhO)₂PON₃ (0.24 mL, 1.12 mmol) in THF (5 mL) was stirred overnight at room temperature. Ph₃P (391 mg, 1.49 mmol) and H₂O (1 mL) were added, and the reaction mixture was stirred at room temperature for 2 hours, followed by partitioning between EtOAc and water. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated under vacuum. Chromatographic separation (24 g SiO₂; continuous gradient 0–10% EtOAc / hexane for 10 min) of the crude oil yielded the title compound as a clear oil (280 mg, 0.697 mmol, 94% yield). [M+H] + =402.2.

[0847] Example 137

[0848] At 0°C, 137A (21 mg, 0.10 mmol) was added to a solution of 137C (20 mg, 0.050 mmol) and iPr2NEt (0.026 mL, 0.149 mmol) in 1 mL of DCM over 5 minutes. The reaction mixture was stirred at room temperature for 20 hours, followed by the addition of TFA (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours, followed by vacuum concentration. The crude product was purified by preparative HPLC (Sunrire C18 30×100mm-regenerated column; detection at 220 nm; flow rate = 40 mL / min; continuous gradient from 30% B to 100% B for 10 min + hold time at 100% B for 2 min, wherein A = 90:10:0.1 H2O:MeCN:TFA and B = 90:10:0.1 MeCN:H2O:TFA) to give the title compound (TFA salt; 4 mg, 6.0 μmol, 12% yield) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ8.00 (d, J=8.8Hz, 1H), 7.53 (d, J=8.8Hz, 1H), 4.77 (br d, J=1.3Hz, 1H), 4.42 (s, 2H), 4.15 (s, 3H), 3.01 (d, J=7.7Hz, 2H), 2.93-2.82 (m, 1 H), 2.75(s, 3H), 2.62(s, 3H), 2.15-1.49(m, 16H), 1.24-1.15(m, 2H); LCMS, [M+H] + =521.3; hLPA1 IC 50 =167nM.

[0849] The following examples in Table 6 were synthesized according to the procedure described for the preparation of Example 136.

[0850] Table 6

[0851]

[0852]

[0853] The following examples in Table 7 are synthesized according to the procedure described for the preparation of Example 64.

[0854] Table 7

[0855]

[0856]

[0857] The following embodiments are synthesized according to the procedure described above.

[0858] Table 8

[0859]

[0860]

[0861]

[0862]

[0863] Intermediate 8: 4-Nitrophenyl carbonate (4-oxopentyl) ester

[0864]

[0865] Pyridine (0.95 mL, 11.8 mmol) was added to a solution of 5-hydroxypentan-2-one (400 mg, 3.92 mmol) and 4-nitrobenzene chloroformate (947 mg, 4.70 mmol) in THF (8 mL) at room temperature. The reaction mixture was stirred at room temperature for 48 hours; the solid was filtered off and the filtrate was concentrated under vacuum to give the crude product. This substance was separated by chromatography (40 g SiO2; continuous gradient from 0% to 50% EtOAc / hexane for 12 min, followed by 10 min in 50% EtOAc / hexane) to give the title compound as a colorless oil (500 mg, 1.871 mmol, 47.8% yield). 1 H NMR (400MHz, CDCl3) δ8.34-8.21 (m, 2H), 7.40-7.33 (m, 2H), 4.31 (t, J=6.3Hz, 2H), 2.62 (t, J=7.0Hz, 2H), 2.19 (s, 3H), 2.10-1.96 (m, 2H).LC-MS, [M+H] + =268.1.

[0866] The required 4-nitrobenzene carbonate intermediate for the preparation of the following examples is synthesized from the corresponding alcohol according to the procedure described for the preparation of intermediate 2.

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873] The examples in the table below were synthesized using the above-described 4-nitrobenzene carbonate intermediate, according to the preparation procedures described for Examples 1 and 2.

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891] Example 206: (1S,3S)-3-((6-(5-((((((4,4-difluoropentyl)oxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0892]

[0893] 206A: (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((((4-oxopentyl)oxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0894]

[0895] To a solution of (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (synthesized as in Example 1H, but using (1S,3R)-3-hydroxycyclohexanecarboxylate instead of isopropyl ester; 25 mg, 0.070 mmol) and 4-nitrobenzene carbonate·(4-oxopentyl) ester (22 mg, 0.083 mmol) in THF (0.2 mL), iPr2NEt (0.036 mL, 0.209 mmol) was added. The mixture was stirred at room temperature for 52 hours, followed by vacuum concentration. Chromatographic separation (12 g SiO2; continuous gradient 0% to 100% EtOAc / hexane for 19 min, hold for 5 min) of the residue yielded the title compound as a colorless oil (31 mg, 0.064 mmol, 91% yield). 1 HNMR (500MHz, CDCl3) δ8.05 (d, J=8.6Hz, 1H), 7.27 (s, 1H), 7.07 (br s, 1H), 4.75 (dq, J=5.0, 2.6Hz, 1H), 4.63 (d, J=5.4Hz, 2H), 4.23 (s, 3H), 4.07 (t, J=6.3Hz, 2H), 3.73 (s, 3H), 2.86 (tt, J=10.3, 3.9Hz, 1H), 2.57 (s, 3H), 2.50 (t, J=7.2Hz, 2H), 2.19-1.61 (m, 13H).LCMS, [M+H] + =488.1.

[0896] Example 206

[0897] At 0°C, DAST (0.027 mL, 0.205 mmol) was added to a solution of Example 206A (25 mg, 0.051 mmol) in DCM (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours, then quenched with water (0.5 mL) and concentrated under vacuum. The residue was dissolved in THF (1 mL) and water (0.5 mL) and LiOH·H2O (22 mg, 0.51 mmol) was added. The reaction mixture was stirred overnight at room temperature, then adjusted to pH approximately 5 with 1 N HCl aqueous solution and extracted with EtOAc (3 × 2 mL). The combined organic extracts were dried (MgSO4) and concentrated under vacuum. The crude material was purified by preparative LC / MS (column: XBridge C18, 19 × 200 mm, 5 μm particles; mobile phase A: 5:95 MeCN: H₂O with 0.1% TFA; mobile phase B: 95:5 MeCN: H₂O with 0.1% TFA; gradient: 10–55% B for 19 min, followed by a 5 min hold at 100% B; flow rate: 20 mL / min). Fractions containing the desired product were combined and dried by centrifugation and evaporation to give the title compound (17.2 mg, 0.027 mmol, 53% yield; LCMS purity = 97%). LCMS [M+H] + =496.3; 1 H NMR (500MHz, DMSO-d6) δ7.96 (s, 1H), 7.50 (d, J = 8.4Hz, 2H), 4.77 (d, J = 5.5Hz, 3H), 4. 07 (s, 3H), 3.99 (t, J=6.5Hz, 2H), 2.70-2.61 (m, 1H), 2.42 (s, 3H), 2.06-1.47 (m, 15H). hLPA1 IC 50 =71nM.

[0898] Example 207: (1S,3S)-3-((6-(5-(((((((R)-2,2-difluorocyclopropyl)methoxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid diethylammonium salt (first eluting isomer; stereochemical configuration of any specified cyclopropyl chiral center)

[0899]

[0900] Example 208: (1S,3S)-3-((6-(5-((((((S)-2,2-difluorocyclopropyl)methoxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid diethylammonium salt (second eluting isomer; stereochemical configuration of any specified cyclopropyl chiral center)

[0901]

[0902] Individual diastereomers of Example 180 were separated by SFC (column: Chiralpak AD-H, 21 × 250 mm, 5 μm; flow rate: 45 mL / min; oven temperature: 40 °C; BPR setting: 150 bar; UV wavelength: 255 nm; mobile phase: 90% CO2 / 10% MeOH-0.1% DEA (isogradient); injection: 0.5 mL, approximately 14 mg / mL, in MeOH:MeCN), yielding two diastereomers. The chiral purity of both compounds was determined to be >93% ee under these analytical conditions: column: Chiralpak AD-H, 4.6 × 250 mm, 5 μm (analytical); flow rate: 2 mL / min; oven temperature: 40 °C; BPR setting: 150 bar; UV wavelength: 254 nm; mobile phase: 10% MeOH-0.1% DEA / 85% CO2 (isogradient).

[0903] Example 207: First eluted enantiomer: LCMS, [M+H] + =480.2.hLPA1 IC 50 =44nM.

[0904] Example 208: Second eluted enantiomer: LCMS, [M+H] + =480.2.hLPA1 IC 50 =57nM.

[0905] Example 209: (±)-cis-3-((6-(5-(((((benzyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexanecarboxylic acid

[0906]

[0907] 209A: (±)-cis-1-fluoro-3-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid isopropyl ester

[0908]

[0909] Ph3P (0.317 mL, 1.268 mmol) and (E)-diazepine-1,2-dimethylbis(piperidin-1-ylmethyl ketone) (0.320 g, 1.268 mmol) were added to a solution of Example 1C (0.193 g, 0.634 mmol) and Intermediate 1 (0.194 g, 0.951 mmol) in toluene (18 mL). The reaction mixture was stirred at 50 °C for 5 hours, then cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The crude oil was separated by chromatography (24 g SiO2; continuous gradient 0% to 50% EtOAc / hexane for 10 min) to give the title compound (0.06 g, 0.122 mmol, 19.29% yield) as a clear oil. 1 H NMR (500MHz, CDCl3) δ7.86 (d, J=8.5Hz, 1H), 7.10 (d, J=8.8Hz, 1H), 5.31-5.17 (m, 2H), 5.04 (dt, J=12.4, 6.3Hz, 1H), 4.72-4.66 (m, 1H), 4.6 4-4.57 (m, 1H), 4.07 (s, 3H), 3.82 (tt, J=8.5, 2.5Hz, 1H), 3.49-3.42 (m, 1H), 2.42 (s, 4H), 2.08-1.39 (m, 13H), 1.24 (dd, J=6.2, 2.6Hz, 6H).

[0910] 209B: (±)-cis-1-fluoro-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid isopropyl ester

[0911]

[0912] The mixture of Example 209A (0.18 g, 0.367 mmol) and p-TsOH (0.021 g, 0.110 mmol) in MeOH (10 mL) was stirred at 60 °C for 3 hours, then cooled to room temperature and NaHCO3 (0.031 g, 0.367 mmol) was added. The mixture was stirred at room temperature for 1 hour, then DCM (10 mL) was added. The mixture was filtered; the filtrate was concentrated under vacuum. The crude oil was separated by chromatography (12 g SiO2; continuous gradient 0% to 100% EtOAc / hexane for 14 min) to give the title compound (0.133 g, 0.327 mmol, 89% yield) as a clear oil. 1H NMR (500MHz, CDCl3) δ7.22-7.18 (m, 1H), 5.03 (spt, J=6.3Hz, 1H), 4.74 (d, J=1.1Hz, 2H), 4.65 (quin, J=5.0Hz, 1H) , 3.99 (s, 3H), 2.44 (s, 3H), 2.40-2.28 (m, 1H), 2.12-1.76 (m, 6H), 1.52-1.41 (m, 1H), 1.23 (dd, J=6.3, 2.8Hz, 6H); 19 FNMR (471MHz, CDCl3) δ-153.01 (s, 1F).

[0913] 209C: (±)-cis-3-((6-(5-(((((benzyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexanecarboxylic acid isopropyl ester

[0914]

[0915] A solution of Example 209B (33 mg, 0.081 mmol), N-[(tert-butoxy)carbonyl]carbamate benzyl ester (30.6 mg, 0.122 mmol), n-Bu3P (0.030 mL, 0.122 mmol), and 1,1′-(azadicarbonyl)piperidine (31 mg, 0.122 mmol) in toluene (2 mL) was stirred at 50 °C for 3 hours, then cooled to room temperature. TFA (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour, followed by vacuum concentration. The crude oily substance was purified by preparative HPLC (Sunrire C18 30×100 mm column; detection at 220 nm; flow rate = 40 mL / min; continuous gradient from 20% B to 100% B for 10 min + hold time at 100% B for 2 min, where A = 90:10:0.1 H2O:MeCN:TFA and B = 90:10:0.1 MeCN:H2O:TFA) to give the title compound (40 mg, 0.074 mmol, 91% yield) as a clear oil. [M+H] + =540.3.

[0916] Example 209

[0917] A mixture of Example 209C (40 mg, 0.074 mmol) and 2.0 M LiOH aqueous solution (1.86 mL, 3.71 mmol) in THF (3 mL) was stirred at room temperature for 3 hours. The product was purified by preparative HPLC (Sunrire C18 30 × 100 mm column; detection at 220 nm; flow rate = 40 mL / min; continuous gradient from 20% B to 100% B for 10 minutes + hold time at 100% B for 2 minutes, wherein A = 90:10:0.1 H2O:MeCN:TFA and B = 90:10:0.1 MeCN:H2O:TFA) to give the title compound (37.1 mg, 0.058 mmol, 79% yield) as a clear oil. [M+H] + =498.2; 1 H NMR (400MHz, CDCl3) δ8.06 (d, J=8.4Hz, 1H), 7.76 (d, J=8.8Hz, 1H), 7.39-7.28 (m, 5H), 5.10 (s, 2H), 4.93 (b r.s., 1H), 4.59(s, 2H), 4.16(s, 3H), 2.68(s, 3H), 2.45-2.29(m, 1H), 2.25-1.87(m, 7H), 1.68(br.s., 1H); 19 F NMR (377MHz, CDCl3) δ-154.52 (s, 1F). hLPA1 IC 50 =12nM.

[0918] Example 210: (1R,3S)-3-((6-(5-(((((benzyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylic acid

[0919]

[0920] Example 211: (1S,3R)-3-((6-(5-(((((benzyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylic acid

[0921]

[0922] The absolute stereochemical configurations of Examples 210 and 211 were not determined – the stereochemical configurations of the structures shown were drawn arbitrarily. Two separate enantiomers (32 mg, 0.064 mmol) of Example 209 were obtained by separation using a chiral SFC: Instrument: Berger MGII-SFC; Column: Chiralpak IC, 21 × 250 mm, 5 μm; Mobile phase: 20% MeOH / 80% CO2; Flow conditions: 45 mL / min, 150 bar, 40 °C; Detector wavelength: 254 nm; Injection: 0.5 mL of an 8 mg / mL solution in MeOH:MeCN (1:1).

[0923] Example 210 - First eluted enantiomer (8.4 mg, 0.017 mmol, 25.7% yield); [M+H] + =498.1; 1 H NMR (400MHz, CDCl3) δ8.06 (br.s., 1H), 7.32 (br.s., 6H), 5.08 (br.s., 2H), 4.92-4.50 (m, 3H), 4.21 (br.s., 2H), 2.52 (br.s., 4H), 2.32-1.27 (m, 8H); 19 F NMR (377MHz, CDCl3) δ-149.29 (s, 1F); hLPA1 IC 50 =5nM.

[0924] Example 211 - Second eluted enantiomer (11 mg, 0.022 mmol, 33.7% yield); [M+H] + =498.1; 1 H NMR (400MHz, CDCl3) δ8.06 (br.s., 1H), 7.32 (br.s., 6H), 5.08 (br.s., 2H), 4.92-4.50 (m, 3H), 4.21 (br.s., 2H), 2.52 (br.s., 4H), 2.32-1.27 (m, 8H); 19 F NMR (377MHz, CDCl3) δ-150.17 (s, 1F); hLPA1 IC 50 =192nM.

[0925] Intermediate 40: 2,5-Dibromo-3-fluoro-6-methylpyridine

[0926]

[0927] Intermediate 40A: 3-Fluoro-6-methylpyridin-2-amine

[0928]

[0929] Cu₂O (0.19 g, 1.32 mmol), K₂CO₃ (0.73 g, 5.26 mmol), and N₁,N₁-dimethylethane-1,2-diamine (0.29 mL, 2.63 mmol) were added to a solution of 2-bromo-3-fluoro-6-methylpyridine (5.0 g, 26.3 mmol) in ethylene glycol (50 mL) and 28% NH₄OH aqueous solution (63 mL, 450 mmol). The reaction mixture was washed with N₂, then heated overnight at 80 °C in a sealed tube, followed by cooling to room temperature and extraction with CH₂Cl₂ (3 times). The combined organic extracts were dried (Na₂SO₄) and concentrated under vacuum. The residue was separated by chromatography (SiO₂; continuous gradient 0–100% EtOAc / hexane) to give the title compound (2.81 g, 85% yield). 1 H NMR (500MHz, CDCl3) δ7.11 (dd, J=10.6, 8.1Hz, 1H), 6.47 (dd, J=8.0, 3.0Hz, 1H), 4.55 (br s, 2H), 2.38 (s, 3H).

[0930] Intermediate 40B: 5-bromo-3-fluoro-6-methylpyridin-2-amine

[0931]

[0932] NBS (5.52 g, 31.0 mmol) was added fractionally to a solution of intermediate 34A (3.91 g, 31.0 mmol) in CH3CN (100 mL) at 0 °C, while maintaining the reaction temperature ≤5 °C. The reaction mixture was stirred at room temperature for 30 min, followed by vacuum concentration. The residue was separated by chromatography (SiO2; isocratic 30% EtOAc / hexane) to give the title compound (6.14 g, 97% yield). 1 HNMR (500MHz, CDCl3) δ7.37 (d, J=9.6Hz, 1H), 4.59 (br s, 2H), 2.48 (d, J=1.1Hz, 3H).

[0933] Intermediate 40

[0934] Intermediate 34B (6.14 g, 29.9 mmol) was slowly added fractionally to a 48% HBr aqueous solution (23.7 mL, 210 mmol, 48%) at 0 °C. Br2 (3.09 mL, 59.9 mmol) was added dropwise while maintaining the reaction temperature ≤5 °C. The reaction mixture was stirred at 0 °C for 30 min, followed by the dropwise addition of NaNO2 (5.17 g, 74.9 mmol) in water (10 mL) while maintaining the reaction temperature ≤5 °C. The reaction mixture was stirred at 0 °C for 30 min, then poured into ice water, alkalized with 50% NaOH aqueous solution, and extracted (twice) with EtOAc. The combined organic extracts were washed with 10% Na2S2O3 aqueous solution and brine, dried (Na2SO4), and concentrated under vacuum. The residue was separated chromatographically (SiO2; continuous gradient 0–25% EtOAc / hexane) to give the title compound (3.90 g, 48% yield). 1 H NMR (500MHz, CDCl3) δ7.60 (d, J=6.6Hz, 1H), 2.64 (d, J=1.4Hz, 3H).

[0935] Intermediate 41: (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-5-fluoro-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester

[0936]

[0937] Intermediate 41 was prepared using the same synthetic procedure as in Example 1E, but intermediate 40 was used instead of 2,5-dibromo-6-methylpyridine used in the synthesis of Example 1A. LCMS, [M+H] + =407. 1 H NMR (400MHz, CDCl3) δ7.16 (d, J=11.9Hz, 1H), 5.05 (quin, J=12.5Hz, 1H), 4.76 (s, 2H), 4.66 (m, 1H), 4.13 (s, 3H), 2.77 (m, 1H), 2.50 (d, J=1.1Hz, 3H), 2.07-2.02 (m, 2H), 1.97-1.86 (m, 2H), 1.81-1.62 (m, 4H), 1.27 (dd, J=6.2, 3.7Hz, 6H).

[0938] Intermediate 42: 4-(3-fluoro-5-(((1S,3S)-3-(isopropoxycarbonyl)cyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-carboxylic acid

[0939]

[0940] Intermediate 42 was prepared using the same synthetic procedure as that used in Preparation Example 64B. In the synthetic procedure, intermediate 40 was used instead of 2,5-dibromo-6-methylpyridine.

[0941] The examples in the table below use the general procedures described for the preparation of Examples 1 and 64 and use intermediates 41 and 42; or Example 137 to synthesize.

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951] Example 234: (1S,3S)-3-((2-methyl-6-(1-methyl-5-((2-methyl-2-phenoxypropionylamino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0952]

[0953] 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (3 μL, 0.023 mmol) was added to a solution of 2-methyl-2-phenoxypropionic acid (4.2 mg, 0.023 mmol) in DCM (0.3 mL). The mixture was stirred at room temperature for 10 min, followed by concentration under vacuum. THF (0.3 mL), Example 1H (6 mg, 0.015 mmol), and iPr2NEt (5 μL, 0.03 mmol) were added to the residue. The reaction mixture was stirred at room temperature for 1 h, followed by the addition of MeOH (0.2 mL), THF / water (0.5 mL each), and LiOH·H2O (4 mg, 0.1 mmol). The reaction mixture was stirred overnight at room temperature; the pH was adjusted to approximately 5 with 1N HCl aqueous solution. The mixture was extracted with EtOAc (3 × 2 mL). The combined organic fractions were dried (MgSO4) and concentrated under vacuum. The crude product was purified by preparative LC / MS (column: XBridge C18, 19×200mm, 5μm particles; mobile phase A: 5:95 MeCN: H2O containing 0.1% TFA; mobile phase B: 95:5 MeCN: H2O containing 0.1% TFA; gradient: 21-61% B for 20 min, followed by 4 min at 100% B; flow rate: 20 mL / min). The fractions containing the desired product were separated and dried by centrifugation and evaporation.

[0954] The substance was further purified using preparative LC / MS (column: XBridge C18, 19 × 200 mm, 5 μm particles; mobile phase A: 5:95 MeCN: H2O with 10 mM NH4OAc aqueous solution; mobile phase B: 95:5 MeCN: H2O with 10 mM NH4OAc; gradient: 16-56% B for 25 min, followed by a 5 min hold at 100% B; flow rate: 20 mL / min). Fractions containing the desired product were combined and dried by centrifugation and evaporation to give the title compound (3.9 mg; 47% yield; purity = 95% according to LCMS). LCMS, [M+H] + =508.2; 1 H NMR (500MHz, DMSO-d6) δ8.64 (s, 1H), 7.78 (d, J = 8.5Hz, 1H), 7.43 (d, J = 8.6Hz, 1H), 7.02 (t, J = 7.8Hz, 2H), 6.86 (t, J = 7.3Hz, 1H), 6. 60 (d, J=8.0Hz, 2H), 4.73-4.66 (m, 3H), 4.10 (s, 3H), 2.49-2.43 (m, 1H), 2.31 (s, 3H), 1.91-1.46 (m, 8H), 1.36 (s, 3H), 1.35 (s, 3H). hLPA1 IC 50=392nM.

[0955] Example 235: (1S,3S)-3-((6-(5-((2-cyclopentylacetamido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid

[0956]

[0957] 235A: (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid ethyl ester

[0958]

[0959] Under N2, 2-cyclopentylacetyl chloride (9.4 mg, 0.064 mmol) was added to a solution of (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexanecarboxylate (20 mg, 0.054 mmol; prepared in the same manner as intermediate 1H) and Et3N (7.5 μL, 0.054 mmol) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, followed by vacuum concentration. The crude title compound was used in the next reaction without further purification.

[0960] Example 235

[0961] LiOH·H₂O (3 mg, 0.124 mmol) was added to a solution of 235A (20 mg, 0.041 mmol) in THF / MeOH (1.5 mL each). The reaction mixture was stirred at room temperature for 14 hours, then diluted with water (20 mL), washed with Et₂O (10 mL), and neutralized with 1.5 N HCl aqueous solution (1.5 mL). The mixture was stirred with MeOH in 5% CHCl₃ (20 mL) for 2 minutes. The organic phase was washed with brine, dried (Na₂SO₄), and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Ascentis Express C18 (50 × 2.1 mm), 2.7 μm; mobile phase A: 5:95 MeCN: water with 10 mM NH4OAc aqueous solution; mobile phase B: 95:5 MeCN: water with 10 mM NH4OAc aqueous solution; temperature: 50 °C; gradient: 0-100% B for 3 min; flow rate: 1.1 mL / min) to give the title compound as a clear oil (8.7 mg, 0.019 mmol, 46.2% yield). [M+H] +=456.2; 1 H NMR (400MHz, CD3OD): δ7.84 (d, J=8.40Hz, 1H), 7.47 (d, J=8.80Hz, 1H), 4.89 (s, 2H), 4.74-4.78 (m, 1H), 4.16 (s, 3H), hLPA1 IC 50 =105nM.

[0962] The embodiments in the table below are synthesized according to the procedure described for the synthesis of embodiment 235.

[0963]

[0964]

[0965] Example 238: (1S,3S)-3-((2-methyl-6-(1-methyl-5-(2-(2-phenylacetamido)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0966]

[0967] 238A: (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0968]

[0969] The title compound was synthesized using the same procedure as intermediate 1E, but with the use of methyl (1S,3R)-3-hydroxycyclohexanecarboxylate. 1 H NMR (400MHz, CDCl3) δ8.09 (d, J=8.7Hz, 1H), 7.29 (d, J=8.6Hz, 1H), 4.81 (s, 2H), 4.72 (dp, J=5.1, 2 .7Hz, 1H), 4.07 (s, 3H), 3.69 (s, 3H), 2.82 (tt, J=10.2, 3.9Hz, 1H), 2.53 (s, 3H), 2.19-1.54 (m, 8H). LC-MS, [M+H]+=361.2.

[0970] 238B: (1S,3S)-3-((6-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0971]

[0972] PBr3 (0.26 mL, 2.8 mmol) was added to a solution of 238A (1.0 g, 2.77 mmol) in DCM (25 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, followed by neutralization by slow addition of a saturated aqueous solution of NaHCO3; the mixture was extracted with EtOAc (3 × 25 mL). The combined organic extracts were washed with water and brine (15 mL each), dried (MgSO4), and concentrated under vacuum. The crude product was separated by chromatography (SiO2; continuous gradient 0% to 100% EtOAc / hexane for 20 min) to give the title compound (1.10 g, 2.6 mmol, 92% yield) as a white, frothy substance, MS (ESI) m / z: 425.1 (M+2+H). + .

[0973] 238C: (1S,3S)-3-((6-(5-(cyanomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)methyl cyclohexane-1-carboxylate

[0974]

[0975] To a solution of 238B (1.10 g, 2.60 mmol) in MeCN (10 mL), NaCN (0.127 g, 2.60 mmol) in DMSO (10 mL) was added fractionally. The reaction mixture was stirred at 0 °C for 30 min, followed by partitioning between EtOAc and water. The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic extracts were concentrated under vacuum. The crude product was separated chromatographically (SiO2; continuous gradient 0% to 100% EtOAc / hexane for 20 min) to give the title compound (0.864 g, 2.34 mmol, 90% yield) as a white solid. MS(+)MS = 370.2 1 H NMR (400MHz, CDCl3) δ8.28-7.77(m, 1H), 7.23(d, J=8.8Hz, 1H), 4.79-4.55(m, 3H), 4.20(s , 3H), 3.72(s, 3H), 3.06-2.72(m, 1H), 2.53(s, 3H), 2.25-2.08(m, 1H), 2.03-1.59(m, 7H).

[0976] 238D: (1S,3S)-3-((6-(5-(2-aminoethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0977]

[0978] Add NiCl₂·6H₂O (10 mg, 0.042 mmol) and NaBH₄ (32 mg, 0.84 mmol) to a 0°C solution of 238°C (155 mg, 0.42 mmol) in MeOH (5 mL). Stir the reaction mixture at 0°C for 1 hour; add water and extract the mixture with EtOAc (3 × 10 mL). Dry the combined organic extracts (Na₂SO₄) and concentrate under vacuum. The crude product was purified by preparative LC / MS: Column: Waters XBridge C18, 19×200 mm, 5 μm particles; Guard column: Waters XBridge C18, 19×10 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: 50-90% B for 20 min, followed by 100% B for 5 min; Flow rate: 20 mL / min. Fractions containing the desired product were combined and concentrated under vacuum by centrifugation to give the title compound (130 mg; 0.35 mmol, 83% yield). 1 H NMR (400MHz, CDCl3) δ8.99 (br s, 1H), 8.63 (br s, 1H), 7.83-7.70 (m, 1H), 7.62 (d, J = 9.0Hz, 1H), 4.79 (br s, 1H), 4.08 (s, 3H), 3.72 (s, 3H), 3.37 (br d, J=5.1Hz, 4H), 2.84 (br d, J=4.6Hz, 1H), 2.56 (s, 3H), 2.16-2.02 (m, 2H), 2.00-1.84 (m, 2H), 1.82-1.56 (m, 4H).

[0979] Example 238

[0980] 2-Phenylacetyl chloride (3.3 mg, 0.021 mmol) was added to a solution of 238D (8 mg, 0.021 mmol) in 1 mL of saturated THF / NaHCO3 aqueous solution. The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of EtOAc (2 mL). The aqueous layer was extracted with EtOAc (2 × 1 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated under vacuum to give crude 2-phenylacetamide ester (LCMS[M+H)). + =492.3), which was used in the next step without further purification. The crude product was dissolved in THF (1 mL) and 2M LiOH aqueous solution (60 μL, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, followed by vacuum concentration. The residue was dissolved in H2O (1 mL); the pH was adjusted to approximately 3 with 1N HCl aqueous solution, and the mixture was extracted with EtOAc (2 × 1 mL). The combined organic extracts were washed with brine (1 mL), dried (MgSO4), and concentrated under vacuum. The crude product was purified by preparative LC / MS: Column: Waters XBridge C18, 19×200 mm, 5 μm particles; Guard column: Waters XBridge C18, 19×10 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: 50-90% B for 20 min, followed by 100% B for 5 min; Flow rate: 20 mL / min. Fractions containing the desired product were combined and concentrated under vacuum by centrifugation to obtain the title compound as a colorless oil (6.9 mg, 0.012 mmol, 54.1% yield). LCMS, [M+H] + =478.1; 1 H NMR (DMSO-d6) δ: 8.10 (br s, 1H), 7.82 (d, J = 8.5Hz, 1H), 7.46 (br d, J = 8.6Hz, 1H), 7.22-7.29 (m, 2H), 7.13-7.22 (m, 3H), 4.74 (br s, 1H), 3.89 (s, 3H), 3.21-3.65 (m, 2H), 2.60 (brs, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 1.97 (br d, J=13.5Hz, 1H), 1.75-1.92(m, 4H), 1.60-1.71(m, 2H), 1.49-1.60(m, 2H); hLPA1 IC 50 =138nM.

[0981] The examples in the table below are synthesized according to the procedure described for the preparation of Example 238.

[0982]

[0983]

[0984] Other features of the invention will become apparent during the above description of exemplary embodiments, which are provided for illustrative purposes and are not intended to limit the invention. The invention may be practiced in other specific forms without departing from its spirit or essential characteristics. The invention encompasses all combinations of the preferred aspects mentioned herein. It should be understood that any and all embodiments of the invention may be combined with any other embodiments to describe further embodiments. It should also be understood that the various individual elements of the embodiments are independent embodiments in themselves. Furthermore, any element of an embodiment is intended to be combined with any and all other elements of any embodiment to describe another embodiment.

Claims

1. According to the compound of formula (IIa), Or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: X 1 X 2 X 3 and X 4 Each independently for CR 6 Or N; its constraint is X 1 X 2 X 3 or X 4 The two numbers in the middle do not exceed N; R 1 It is CO2H; R 2 Each is an independent halogen; n is an integer, either 0 or 1; R 3 It is hydrogen or C 1-6 alkyl; R 4 C 1-10 Alkyl, C 1-10 Halogenated, C 3-8 cycloalkyl, 6- to 10-membered aryl, -(C 1-6 alkylene)-(C 3-8 cycloalkyl) or -(C 1-6 Alkylene (6- to 10-aryl); wherein each of the alkyl, cycloalkyl, and aryl groups is independently bound by 0 to 3 R groups, either individually or as part of other portions. 8 replace; R 5 C 1-6 alkyl; R 6 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated, or C 1-6 Alkoxy C 1-6 alkyl; Each R 7a Independently hydrogen; f is an integer 0, 1, or 2; R 8 Each independently constitutes a halogen, C 1-6 Alkyl or C 1-6 Alkyl group.

2. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R 5 C 1-4 alkyl.

3. The compound according to claim 1 or 2, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein... R 4 C 1-10 Alkyl, C 1-10 Halogenated, C 3-6 cycloalkyl, -(C 1-4 alkylene)-(C 3-6 cycloalkyl) or -(C 1-4 Alkylene-phenyl; wherein each of the alkylene, cycloalkylene, and phenyl groups is independently bound by 0 to 3 R groups, either alone or as part of another group. 8 Replace; and R 8 Each independently constitutes a halogen, C 1-6 Alkyl or C 1-6 Alkyl group.

4. The compound according to claim 1 or 2, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: R 3 It is hydrogen or C 1-4 alkyl; R 4 C 1-10 Alkyl, C 3-8 cycloalkyl, 6- to 10-membered aryl, -(C 1-6 alkylene)-(C 3-8 cycloalkyl), or -(C 1-6 Alkylene (6- to 10-aryl); wherein each of the alkyl, cycloalkyl, and aryl groups is independently bound by 0 to 3 R groups, either individually or as part of other portions. 8 Replace; and n is 0 or 1.

5. The compound according to claim 4, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein X 1 For CR 6 , where R 6 For hydrogen, C 1-4 Alkyl, C 1-4 Halogenated groups, or C 1-4 Alkoxy C 1-6 alkyl.

6. The compound according to claim 4, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein X 3 Let N be the number of elements in the array.

7. The compound according to claim 4, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein... The Partially selected from R 6a Each independently constitutes a halogen, C 1-6 Alkyl, C 1-6 Halogenated or C 1-6 Alkoxy C 1-6 Alkyl groups; and d is an integer, 0, 1, or 2.

8. The compound according to claim 7, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein... The Partially selected from and R 6 Each is independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated or C 1-6 Alkoxy C 1-6 alkyl.

9. The compound according to claim 4, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein f is 0 or 1.

10. The compound according to claim 1 or 2, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, represented by formula (IIIa) or (IIIb): Or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: R 2a It can be hydrogen, chlorine, or fluorine; R 3 It is hydrogen or C 1-6 Alkyl groups; and R 1 R 4 X 1 X 2 X 3 and X 4 Same as defined in claim 1 or 2.

11. The compound of claim 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein... Partially selected from 12. The compound according to claim 10, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein... The Partially selected from R 6 Each can be independently hydrogen, CH3, CH2CH3, CH2OCH3, CHF2, or CF3.

13. The compound according to claim 10, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein... R 4 C 3-10 Alkyl, C 3-10 Halogenated, C 3-6 Cycloalkyl, phenyl, -(C 1-4 alkylene)-(C 3-6 cycloalkyl), or benzyl; wherein the alkyl, alkylene, cycloalkyl, and benzyl groups are each independently marked with 0 to 3 R groups. 8 Replace; and R 8 Each independently constitutes a halogen, C 1-6 Alkyl or C 1-6 Alkyl group.

14. The compound according to claim 10, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein... R 4 C 3-10 Alkyl, C 3-10 Halogenated groups, cyclobutyl groups, cyclopentyl groups, -(CH2) 1-2 -(C 1-3 alkoxy), -(CHR) 8a ) 1-2 -Cyclopropyl, -(CHR) 8a ) 1-2 -Cyclobutyl, or -(CHR 8a ) 1-2 -Phenyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl and phenyl groups are each independently separated by 0 to 3 R groups. 8 replace; R 8a Each is independently hydrogen or methyl; and R 8 Each is independently halogen or C 1-4 alkyl.

15. The compound according to claim 10, represented by formula (VI): Or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: R 2a It can be hydrogen, chlorine, or fluorine; R 3 It is hydrogen or C 1-6 alkyl; R 4 C 1-10 Alkyl, -(C 1-6 Alkylene) 0-1 -phenyl, or -(C 1-6 Alkylene) 0-1 -(C 3-8 cycloalkyl); and R 6 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated or C 1-6 Alkoxy C 1-6 alkyl.

16. The compound according to claim 15, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: R 4 C 1-6 Alkyl group, -(CH2) 0-2 -(C 3-6 cycloalkyl), -(CHCH3)-(C 3-6 cycloalkyl), -(CH2) 1-2 -phenyl, or -(CHCH3)-phenyl; and R 6 It can be methyl or ethyl.

17. A compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein said compound is selected from the following table:

18. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 17, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier or diluent.

19. The pharmaceutical composition according to claim 18, wherein it is an oral pharmaceutical composition.

20. Use of the compound of any one of claims 1 to 17, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 18 or 19, in the preparation of a medicament for treating a disease, condition, or illness associated with abnormal regulation of lysophosphatidylcholine receptor 1 (LPA1).

21. The use according to claim 20, wherein the disease, symptom, or condition is pathological fibrosis, transplant rejection, cancer, osteoporosis, or inflammation.

22. The use according to claim 20, wherein the pathological fibrosis is fibrosis of the lungs, liver, kidneys, heart, skin, eyes, or pancreas.

23. The use according to claim 20, wherein the disease, condition or illness is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, and systemic sclerosis.

24. The use according to claim 21, wherein the cancer is a cancer of the bladder, blood, bones, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitals, genitourinary tract, head, kidney, larynx, liver, lungs, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testis, or thyroid gland.

25. Use of the compound of any one of claims 1 to 17, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 18 or 19, in the preparation of a medicament for treating fibrosis in mammals with this need.

26. The use according to claim 25, wherein the fibrosis is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatosis hepatitis (NASH), chronic kidney disease, diabetic nephropathy, and systemic sclerosis.

27. Use of the compound of any one of claims 1 to 17, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 18 or 19, in the preparation of a medicament for treating the following diseases in mammals in need: pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis, skin fibrosis, intestinal fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, intestinal cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant rejection, scleroderma, ocular fibrosis, age-related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenon, or neuralgia.

28. Use of the compound according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 18 or 19 in the preparation of a medicament for the treatment or prevention of organ fibrosis in mammals in need of such treatment.

29. Use of the compound according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 18 or 19 in the preparation of a medicament for the treatment or prevention of liver fibrosis in mammals in need of such treatment.

30. Use of the compound according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 18 or 19 in the preparation of a medicament for the treatment or prevention of non-alcoholic steatosis hepatitis in mammals with such need.

31. Use of the compound according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 18 or 19 in the preparation of a medicament for the treatment or prevention of pulmonary fibrosis in mammals in need of such treatment.

32. Use of the compound according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 18 or 19 in the preparation of a medicament for the treatment or prevention of idiopathic pulmonary fibrosis in mammals with such need.

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