An LPAR1 antagonist and its uses

Abstract

This invention relates to an LPAR1 antagonist and its use. In particular, this invention relates to compounds of general formula (I), methods for their preparation, pharmaceutical compositions thereof, and the use of compounds of general formula (I) or pharmaceutical compositions thereof, said compounds being used for the prevention and / or treatment of LPAR1-mediated diseases, wherein each substituent in general formula (I) is the same as defined in the specification.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, and particularly relates to a small molecule compound with LPAR1 antagonistic activity, its stereoisomer or pharmaceutically acceptable salt, and its use in the preparation of medicaments for treating related diseases. Background Technology

[0002] Lysophosphatidic acid (LPA) is a small-molecule glycerophosphate with a molecular weight of 430-480 D. LPA is widely distributed in the human body. After binding to receptors, it can activate multiple cell signaling pathways, participating in the regulation of cell proliferation, differentiation, apoptosis, neurotransmitter release, and other vital activities. It plays an important role in diseases such as cancer, fibrosis, neuronal dysfunction, and bone metabolism disorders. LPA is mainly generated by the hydrolysis of lysophosphatidylcholine (primarily lysophosphatidylcholine) by autocrine motor factors. In a bleomycin-induced pulmonary fibrosis model, LPA levels in bronchoalveolar lavage fluid were significantly elevated, leading to increased vascular permeability and pulmonary fibrosis. LPA can also mediate the production of various paracrine mediators by fibroblasts, acting on epithelial cells, leukocytes, and endothelial cells to regulate tissue remodeling, angiogenesis, inflammation, wound healing, and tumor progression. LPA can even induce extracellular shedding of epidermal growth factor (EGF) family ligands from fibroblasts, activating the release of soluble factors, and partially stimulating lung epithelial cells and amplifying local fibroblast responses through EGFR action. Recent studies have also found that the LPA-LPA1 signaling pathway can promote apoptosis of lung epithelial cells and inhibit fibroblast apoptosis in idiopathic pulmonary fibrosis (IPF), suggesting that this signaling pathway may regulate the development of fibrosis after lung injury. Research indicates that LPA is closely related to organ fibrosis, mainly mediated by lysophosphatidic acid receptor (LPAR) 1. Six types of LPARs have been identified, namely LPAR1 to LPAR6, with the function of LPAR1 being a hot research topic in recent years. Clinical studies have confirmed that LPAR antagonists have a therapeutic effect on idiopathic pulmonary fibrosis; it has also been found that the LPAR1 antagonist BMS-986020 can effectively improve lung function in patients with idiopathic pulmonary fibrosis. Summary of the Invention

[0003] This invention provides a compound of general formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, which antagonizes LPAR1, has good physicochemical properties such as high solubility, physical and / or chemical stability, improved pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, low toxicity, and advantages such as oral administration, rapid absorption and high clearance.

[0004] This invention relates to a compound represented by general formula (I), general formula (I-1), general formula (I-2), its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0005]

[0006] In some implementations, X is CH or N;

[0007] In some implementations, ring A is C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0008] In some implementations, ring A is C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0009] In some embodiments, ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexane, or pyridyl;

[0010] In some implementations, each R A Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0011] In some implementations, each R A Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0012] In some implementations, R1 is -COOH, -(CR a R b ) m COOH, -OS(O)2OH, -(CR a R b ) m OS(O)2OH, -S(O)2OH, -(CR a R b ) m S(O)₂OH, -P(O)(OH)₂ or -(CR) a R b ) m P(O)(OH)2;

[0013] In some implementations, R1 is -COOH or -(CH2). m COOH, -OS(O)2OH, -(CH2) m OS(O)2OH, -S(O)2OH, -(CH2) m S(O)₂OH, -P(O)(OH)₂, or -(CH₂) m P(O)(OH)2;

[0014] In some embodiments, R1 is -COOH, -(CH2)COOH, -OS(O)2OH, -(CH2)OS(O)2OH, -S(O)2OH, -(CH2)S(O)2OH, -P(O)(OH)2 or -(CH2)P(O)(OH)2;

[0015] In some implementations, R2 is -CR a R b OC(O)NR c R 2a or -CR a R b NR c C(O)OR 2a ;

[0016] In some implementations, R2 is -CH2OC(O)NR c R 2a or -CH2NR c C(O)OR 2a ;

[0017] In some implementations, R2 is -CH2OC(O)NRc R 2a or -CH2NHC(O)OR 2a ;

[0018] In some implementations, R2 is , , , , , , , , ;

[0019] In some implementations, R a and R b Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0020] In some implementations, R a and R b Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 3-5 cycloalkyl;

[0021] In some implementations, R c For hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0022] In some implementations, R c For hydrogen, deuterium, C 1-3 Alkyl, C 1-3Deuterated alkyl, C 1-3 Halogenated alkyl or C 1-3 Alkoxy;

[0023] In some implementations, R c For hydrogen, deuterium, C 1-3 Alkyl or C 1-3 Deuterated alkyl groups;

[0024] In some implementations, R c C 1-3 Alkyl or C 1-3 Deuterated alkyl groups;

[0025] In some implementations, R c The methyl, ethyl, deuterated methyl, and deuterated ethyl groups are used.

[0026] In some implementations, R 2a C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -(CH2) p (C 3-8 cycloalkyl), -(CH2) p (4-8 membered heterocyclic alkyl) or -(CH2) p (OC 3-8 (Cycloalkyl), wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S, and the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl may optionally be further substituted by 1-4 R;

[0027] In some implementations, R 2a C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) p (C 3-6 cycloalkyl), -(CH2) p (4-6 membered heterocyclic alkyl) or -(CH2) p (OC 3-6 (Cycloalkyl), wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S, and the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl may optionally be further substituted by 1-4 R;

[0028] In some implementations, R 2a For the following structures, which can be arbitrarily replaced by 1-3 R's: , ;

[0029] In some implementations, R 2a for , , , , , , ;

[0030] In some embodiments, R is deuterium, halogen, hydroxyl, cyano, amino, =O, =S, =NH, -SF5, -SCF3, -NHCOC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl, =CH2, =CF2, =CHF, =CH(C) 1-6 Alkyl), =CH(C) 1-6 Halogenated alkyl), =CF(C) 1-6 Alkyl), =CF(C) 1-6 Halogenated alkyl), =C(C 1-6 Alkyl)2、=C(C 1-6 Alkyl)(C 1-6 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl;

[0031] In some embodiments, R is deuterium, halogen, hydroxyl, cyano, amino, =O, =S, =NH, -SF5, -SCF3, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl), -C(O)C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 1-3 alkylamine group, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl;

[0032] In some implementations, R is =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Deuterated alkoxy groups;

[0033] In some embodiments, R3 is a halogen, hydroxyl, cyano, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0034] In some embodiments, R3 is a halogen, hydroxyl, cyano, amino, or C.1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 3-6 cycloalkyl;

[0035] In some embodiments, R3 is a halogen, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl;

[0036] In some embodiments, R3 is a halogen, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl;

[0037] In some embodiments, R3 is fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, vinyl, or cyclopropyl.

[0038] In some implementations, n is 0, 1, 2, 3, 4; in some implementations, n is 0, 1, 2, 3; in some implementations, n is 0, 1, 2; in some implementations, n is 0, 1; in some implementations, n is 0.

[0039] In some implementations, m is 1, 2, or 3; in some implementations, m is 1 or 2; in some implementations, m is 1.

[0040] In some implementations, p is 1, 2, or 3; in some implementations, p is 1 or 2; and in some implementations, p is 1.

[0041] The first specific technical solution involves a compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0042]

[0043] in:

[0044] X is CH or N;

[0045] Ring A is C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0046] Each R A Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0047] R1 is -COOH, -(CR) a R b ) m COOH, -OS(O)2OH, -(CR a R b ) m OS(O)2OH, -S(O)2OH, -(CR a R b ) m S(O)₂OH, -P(O)(OH)₂ or -(CR) a R b ) m P(O)(OH)2;

[0048] R2 is -CR a R b OC(O)NR c R 2a or -CR a R b NR c C(O)OR 2a ;

[0049] R a and R b Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0050] R c For hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0051] R 2a C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -(CH2) p (C 3-8 cycloalkyl), -(CH2) p (4-8 membered heterocyclic alkyl) or -(CH2) p (OC 3-8 (Cycloalkyl), wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S, and the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl may optionally be further substituted by 1-4 R;

[0052] R represents deuterium, halogen, hydroxyl, cyano, amino, =O, =S, =NH, -SF5, -SCF3, -NHCOC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl, =CH2, =CF2, =CHF, =CH(C) 1-6 Alkyl), =CH(C) 1-6 Halogenated alkyl), =CF(C) 1-6 Alkyl), =CF(C) 1-6 Halogenated alkyl), =C(C 1-6 Alkyl)2、=C(C 1-6 Alkyl)(C 1-6 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl;

[0053] R3 represents halogen, hydroxyl, cyano, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0054] n is 0, 1, 2, 3, or 4;

[0055] m is 1, 2, or 3;

[0056] p is 1, 2, or 3.

[0057] Specifically, in the second technical solution, the compound represented by the aforementioned general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0058] Ring A is C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0059] Each R A Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0060] R1 is -COOH or -(CH2) m COOH, -OS(O)2OH, -(CH2) mOS(O)2OH, -S(O)2OH, -(CH2) m S(O)₂OH, -P(O)(OH)₂, or -(CH₂) m P(O)(OH)2;

[0061] R a and R b Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 3-5 cycloalkyl;

[0062] R c For hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl or C 1-3 Alkoxy;

[0063] R 2a C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) p (C 3-6 cycloalkyl), -(CH2) p (4-6 membered heterocyclic alkyl) or -(CH2) p (OC 3-6 (Cycloalkyl), wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S, and the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl may optionally be further substituted by 1-4 R;

[0064] R represents deuterium, halogen, hydroxyl, cyano, amino, =O, =S, =NH, -SF5, -SCF3, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl), -C(O)C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl, =CH2, =CF2, =CHF, =CH(C) 1-3Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 1-3 alkylamine group, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl;

[0065] R3 represents halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 3-6 cycloalkyl;

[0066] The remaining definitions are the same as those in the specific first implementation scheme.

[0067] Specifically, in the third technical solution, the compound represented by the aforementioned general formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein:

[0068] Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexane, or pyridyl;

[0069] R2 is -CH2OC(O)NR c R 2a or -CH2NR c C(O)OR 2a ;

[0070] R c For hydrogen, deuterium, C 1-3 Alkyl or C 1-3 Deuterated alkyl groups;

[0071] R 2aFor the following structures, which can be arbitrarily replaced by 1-3 R's: , ;

[0072] Each R is independently of deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl), -C(O)C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 1-3 alkylamine group, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl;

[0073] R3 is a halogen, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl; in some preferred embodiments, R3 is fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, vinyl, or cyclopropyl;

[0074] The remaining definitions are the same as those in the specific first or second implementation scheme.

[0075] Specifically, the fourth technical solution refers to the compound represented by the aforementioned general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein R2 is... , , , , , , , , ;

[0076] The remaining definitions are the same as those in the specific first, second, or third implementation scheme.

[0077] Specifically, the fifth technical solution refers to the compound represented by the aforementioned general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the general formula (I) is further shown as general formula (I-1) and general formula (I-2):

[0078] or

[0079] in:

[0080] X is CH or N;

[0081] Ring A is C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl; in some preferred embodiments, ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexane, pyridyl;

[0082] Each R A Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0083] R1 is -COOH or -(CH2) m COOH, -OS(O)2OH, -(CH2) m OS(O)2OH, -S(O)2OH, -(CH2) m S(O)₂OH, -P(O)(OH)₂, or -(CH₂) m P(O)(OH)2;

[0084] R c C 1-3 Alkyl or C 1-3Deuterated alkyl; in some preferred embodiments, R c The methyl, ethyl, deuterated methyl, and deuterated ethyl groups are used.

[0085] R 2a For the following structures, which can be arbitrarily replaced by 1-3 R's: , ;

[0086] R is =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Deuterated alkoxy groups;

[0087] R3 is a halogen, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl; in some preferred embodiments, R3 is fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, vinyl, or cyclopropyl;

[0088] n is 0, 1, 2, or 3;

[0089] m is 1 or 2;

[0090] In some preferred embodiments, R 2a for , , , , , , .

[0091] In the specific sixth embodiment, the general formula (I) is selected from the compounds in Table 1 below:

[0092] Table 1:

[0093]

[0094]

[0095]

[0096]

[0097]

[0098] Secondly, the present invention also provides a pharmaceutical composition comprising any of the compounds described in any of the foregoing technical solutions, their stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0099] Furthermore, the pharmaceutical composition or pharmaceutical preparation comprises 1-1500 mg of the compound described in any of the foregoing technical solutions, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0100] Furthermore, the present invention also provides the use of the compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described in any of the foregoing embodiments in the preparation of a medicament, preferably a medicament for treating / preventing LPAR1-mediated diseases; in some embodiments, the LPAR1-mediated diseases are selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve injury, and neuralgia.

[0101] The present invention also provides a method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound described in any of the foregoing technical solutions, its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve injury, or neuralgia.

[0102] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the mammals described in the present invention include humans.

[0103] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound, conjugate, or pharmaceutically acceptable salt thereof disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0104] In some embodiments, the pharmaceutical composition or formulation of the present invention contains a therapeutically effective amount of any of the compounds shown above, their stereoisomers, or their pharmaceutically acceptable salts.

[0105] The present invention further relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of any of the compounds shown above, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 24 mg, etc. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, in any of the above amounts of 0 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0106] The present invention further relates to a method for treating a disease in mammals, the method comprising administering to a subject a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, at a daily dose of 1-1500 mg / day, wherein the daily dose may be a single dose or multiple doses, and in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, etc. 0 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day; in some embodiments, the daily dose includes, but is not limited to, 1 mg / day. g / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 300mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, 1500mg / day.

[0107] This invention relates to a kit that may comprise a single-dose or multi-dose composition comprising a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in any of the preceding claims of this invention, wherein the amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof is the same as that in the preceding pharmaceutical composition.

[0108] In this invention, the amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt is converted in each case as a free base.

[0109] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0110] Synthetic route

[0111] Those skilled in the art can prepare the compounds of this invention using known organic synthesis techniques, with starting materials being commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Energie Chemicals, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, among others.

[0112] Indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service can selectively identify specific and similar reactants. These indexes are available in most public and university libraries, as well as online. Known but not commercially available chemicals can optionally be prepared by custom chemical synthesis plants, many of which offer custom synthesis services, including those listed above.

[0113] the term

[0114] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0115] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C". 1-20 Alkyl group. The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 8 carbon atoms (i.e., C14-C ... 1-8 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups, most preferably alkyl groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point. When the alkyl group is substituted with a substituent, the substituent is no longer subject to further substitution.

[0116] The term "alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0117] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and even further such as 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl. The alkenyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable connection point. When the alkenyl group is substituted by a substituent, the substituent is not further substituted.

[0118] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically comprising 2 to 18 carbon atoms, further comprising 2 to 8 carbon atoms, further comprising 2 to 6 carbon atoms, and further comprising 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 3-octyynyl, 3-nonynyl, and 4-decynyl. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable linker. When the alkynyl group is substituted by a substituent, the substituent is not further substituted.

[0119] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C64. 3-20 Cycloalkyl group. The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C12). 3-12 cycloalkyl groups), more preferably cycloalkyl groups having 3 to 8 carbon atoms (i.e., C14-C2 ... 3-8 cycloalkyl groups), more preferably cycloalkyl groups having 3 to 6 carbon atoms (i.e., C14-C6 ... 3-6 cycloalkyl groups), most preferably cycloalkyl groups having 3 to 5 carbon atoms (i.e., C14-C5 ...3-5 (Cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl, etc. Non-limiting examples of polycyclic cycloalkyl groups include: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0120] The term "spirocycloalkyl" refers to a polycyclic group that shares a single carbon atom (called a spiro atom) between its monocyclic rings. It may contain one or more double bonds, but none of its rings has a fully conjugated π-electron system. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Spirocycloalkyl. The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., C14). 6-14 Spirocycloalkyl), more preferably spirocycloalkyl having 7 to 10 ring atoms (i.e., C 7-10 Spirocycloalkyl. Based on the number of spiroatoms shared between rings, spirocycloalkyl is classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 monospirocycloalkyl.

[0121] The term "fused-cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, and which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Fused cyclic alkyl groups. They may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the fused cyclic alkyl group has 6 to 14 ring atoms (i.e., C14). 6-14 Fused cycloalkyl groups), more preferably fused cycloalkyl groups having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Fused cyclic alkyl groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused cyclic alkyl groups based on the number of constituent rings. Bicyclic or tricyclic fused cyclic alkyl groups are preferred, and ternary / quadrivalent, ternary / quinary, ternary / sixary, quadrivalent / quadrivalent, quadrivalent / quinary, quadrivalent / sixary, quinary / trivalent, quinary / quadrivalent, quinary / quinary, quinary / sixary, quinary / sevenary, quinary / trivalent, quinary / quadrivalent, quinary / quadrivalent, quinary / sixary, quinary / sevenary, quinary / trivalent, quinary / quadrivalent, quinary / sixary, quinary / sevenary, quinary / trivalent, or quinary / sixary bicyclic fused cyclic alkyl groups are more preferred.

[0122] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Bridged cycloalkyl groups. They contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, the bridged cycloalkyl group has 6 to 14 ring atoms (i.e., C14). 6-14 Bridged cycloalkyl groups), more preferably bridged cycloalkyl groups having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Bridged cycloalkyl groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups based on the number of rings, with bicyclic or tricyclic bridged cycloalkyl groups being preferred.

[0123] The cycloalkyl group includes polycyclic cycloalkyl groups that can be fused to an aryl, heteroaryl, or heterocyclic alkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group, for example including C 5-6 cycloalkylphenyl, C 5-6 cycloalkyl 5-6-membered heteroaryl, C 5-6 The cycloalkyl group is preferably a 5-6 membered heterocycloalkyl group, such as cyclopentyl 5-membered heterocycloalkyl, cyclopentyl 6-membered heterocycloalkyl, cyclopentyl 5-membered heteroaryl, cyclopentyl 6-membered heteroaryl, cyclohexyl 5-membered heterocycloalkyl, cyclohexyl 6-membered heterocycloalkyl, cyclohexyl 5-membered heteroaryl, or cyclohexyl 6-membered heteroaryl. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point. When the cycloalkyl group is substituted by a substituent, the substituent is not further substituted.

[0124] The term "heterocycle" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, which, unless otherwise specified, contains 1 to 3 heteroatoms selected from N, O, Se, or S, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spirocyclic heterocycles, etc., and, unless otherwise specified, is a 3- to 12-membered heterocycle, more preferably a 4- to 12-membered heterocycle, more preferably a 4- to 10-membered heterocycle, and even more preferably a 4- to 7-membered heterocycle. Its definition includes heterocyclic alkyl groups and heteroaryl groups. The N and S in the heterocyclic group ring can be oxidized to various oxidation states. Heterocyclic groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazoleyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, and dioxinyl. Hydrofuranyl, dihydropyranyl, dithiapentylcycloyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazoyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazoyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl, etc.

[0125] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclic alkyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclic alkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, selenium, and phosphorus (P(O)). m and S(O) nThe heterocyclic alkyl group (where m and n are integers from 0 to 2) contains heteroatoms, but excludes the ring portions of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heterocyclic alkyl group preferably has 3 to 10 ring atoms (i.e., 3-10 membered heterocyclic alkyl groups), containing 1-4 heteroatoms selected from N, O, and S atoms; more preferably, it has 3 to 8 ring atoms (i.e., 3-8 membered heterocyclic alkyl groups), containing 1-4, 1-3, or 1-2 heteroatoms selected from N, O, Se, and S atoms; even more preferably, it has 3 to 6 ring atoms (i.e., 3-6 membered heterocyclic alkyl groups), containing 1-4, 1-3, or 1-2 heteroatoms selected from N, O, and S atoms; or even more preferably, it has 4 to 6 ring atoms (i.e., 4-6 membered heterocyclic alkyl groups), containing 1-4, 1-3, or 1-2 heteroatoms selected from N, O, and S atoms. Non-limiting examples of the monocyclic heterocyclic alkyl groups include: azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxocyclopentyl, 2,2-difluoro-1,3-dioxocyclopentyl, cyclopentanone, 2,2-difluorocyclopentanone, acrylonitrile, oxacyclopentyl, or azirropentyl. Non-limiting examples of the polycyclic heterocyclic alkyl groups include: spiroheterocyclic alkyl, fused heterocyclic alkyl, and bridged heterocyclic alkyl.

[0126] The term "spiroheteroalkyl" refers to a polycyclic heterocyclic alkyl group that shares a single atom (called a spiro atom) between monocyclic rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20-membered spiroheteroalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, Se, P(O)m, and S(O)n (where m and n are integers from 0 to 2), but excluding the -OO-, -OS-, or -SS- ring portions, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. The spiroheteroalkyl is preferably a spiroheteroalkyl having 6 to 14 ring atoms (i.e., 6-14-membered spiroheteroalkyl), more preferably a spiroheteroalkyl having 7 to 10 ring atoms (i.e., 7-10-membered spiroheteroalkyl). The spiroheterocyclic alkyl groups are classified into monospirocyclic alkyl groups, bispirocyclic alkyl groups, or polyspirocyclic alkyl groups based on the number of shared spiroatoms between the rings. Monospirocyclic alkyl groups or bispirocyclic alkyl groups are preferred, and more preferably, they are 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic alkyl groups. Non-limiting examples include: , , wait.

[0127] The term "fused heterocyclic alkyl" or "heterocyclic alkyl" refers to a polycyclic heterocyclic alkyl group in which each ring shares an adjacent pair of atoms with the other rings in the system. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered fused heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, Se, P(O)m, and S(O)n (where m and n are integers from 0 to 2), but excludes the -OO-, -OS-, or -SS- ring portions. The remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. The fused heterocyclic alkyl group is preferably a fused heterocyclic alkyl group having 6 to 14 ring atoms (i.e., 6-14-membered fused heterocyclic alkyl group), more preferably a fused heterocyclic alkyl group having 7 to 10 ring atoms (i.e., 7-10-membered fused heterocyclic alkyl group). It is classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl group according to the number of constituent rings, preferably bicyclic or tricyclic fused heterocyclic alkyl groups, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 3-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 5 / 7-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, 6 / 6-membered, 6 / 7-membered, 7 / 5-membered, or 7 / 6-membered bicyclic fused heterocyclic alkyl groups. Non-limiting examples include: , , The term "bridged heterocyclic alkyl" refers to a polycyclic heterocyclic alkyl group in which any two rings share two non-directly bonded atoms. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered bridged heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, Se, P(O)m, and S(O)n (where m and n are integers from 0 to 2), but excludes the -OO-, -OS-, or -SS- ring portions. The remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The bridged heterocyclic alkyl group is preferably a bridged heterocyclic alkyl group having 6 to 14 ring atoms (i.e., 6-14 membered bridged heterocyclic alkyl group), more preferably a bridged heterocyclic alkyl group having 7 to 10 ring atoms (i.e., 7-10 membered bridged heterocyclic alkyl group). Depending on the number of constituent rings, it is classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic alkyl groups, with bicyclic or tricyclic bridged heterocyclic alkyl groups being preferred. Non-limiting examples include: , wait.

[0128] The heterocyclic alkyl group includes polycyclic heterocyclic alkyl groups that can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic alkyl group, such as 5-6 membered heterocyclic alkyl phenyl, 5-6 membered heterocyclic alkyl 5-6 membered heteroaryl, 5-6 membered heterocyclic alkyl 5-6 membered heteroaryl, and 5-6 membered heterocyclic alkyl 5-6 membered C 5-6 Cycloalkyl groups, etc., preferably 5-membered heterocycloalkyl with 5-membered heterocycloalkyl, 5-membered heterocycloalkyl with 6-membered heterocycloalkyl, 5-membered heterocycloalkyl with 5-membered heteroaryl, 5-membered heterocycloalkyl with 6-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heterocycloalkyl, 6-membered heterocycloalkyl with 5-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heteroaryl, etc. The heterocycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable connection point. When the heterocycloalkyl group is substituted by a substituent, the substituent is not further substituted.

[0129] The term "aryl" refers to a monocyclic group with a conjugated π-electron system (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl), having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., C atoms). 6-14 Aryl group). The aryl group is preferably an aryl group having 6 to 12 carbon atoms (i.e., C64). 6-12 Aryl), more preferably aryl having 6 to 10 carbon atoms (i.e., C). 6-10 Aryl), further preferably phenyl or naphthyl, most preferably phenyl. The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracene, phenanthrene, etc.

[0130] The aryl group includes polycyclic systems that can be fused to a heteroaryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to benzo[a]C[b]. 3-8 Cycloalkyl, benzo3-8 heterocycloalkyl, benzo5-6 heteroaryl, preferably benzoC 4-6 The aryl group comprises cycloalkyl, benzo4-6-membered heterocycloalkyl, and benzo5-6-membered heteroaryl groups, with further preferred groups being benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzoazacyclobutyl, benzooxacyclobutyl, benzooxacyclopentyl, benzoazacyclopentyl, benzooxacyclohexyl, benzozacyclohexyl, benzothiophene, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzopyridyl, benzopyrimidinyl, benzopyridonel, benzopyrazinyl, and benzopyridazinyl. The aryl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable connection point. When the aryl group is substituted by a substituent, the substituent is not further substituted.

[0131] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, selenium, and phosphorus (P(O)). m and S(O) n The heteroatom (where m and n are integers from 0 to 2) is preferably selected from nitrogen, oxygen, or sulfur, but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl group). The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 8 ring atoms (i.e., a 5-8 membered heteroaryl group), and more preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group). Non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyridazinyl, etc. The polycyclic heteroaryl group is preferably a 5-6 member heteroaryl-5-6 member heteroaryl or a 5-10 member heteroaryl-C 6-10 Aryl or C 6-10 The compounds are aryl 5-10-membered heteroaryl groups, more preferably 5-6-membered heteroaryl 5-6-membered heteroaryl, 5-6-membered heteroaryl phenyl, or phenyl 5-6-membered heteroaryl. Non-limiting examples include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, thiophene-phenyl, quinazolinyl, benzothiazolyl, carbazole, thiophene-pyridyl, pyridothiophene, pyridopyrrole, benzo-γ-pyranone, pyrido-γ-pyranone. , wait.

[0132] The heteroaryl group includes a polycyclic system fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to 5-6 membered heteroaryl rings with C positrons. 3-8 Cycloalkyl, 5-6-membered heteroaryl, 3-8-membered heterocycloalkyl, 5-6-membered heteroarylphenyl, preferably 5-6-membered heteroaryl-C 4-6 Cycloalkyl, 5-6-membered heteroaryl, and 4-6-membered heterocycloalkyl, 5-6-membered heteroarylphenyl. The heteroaryl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linker. When the heteroaryl group is substituted by a substituent, the substituent is not further substituted. Non-limiting examples include: , wait.

[0133] The term "alkoxy" refers to -O- (alkyl) or -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C2). 1-10 Alkoxy group). The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkoxy groups), more preferably alkoxy groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkoxy groups), preferably alkoxy groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3 Alkoxy groups. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable linking point. When the alkoxy group is substituted by a substituent, the substituent is not further substituted.

[0134] The term "alkylamine" refers to -NH- (alkyl) or -N- (alkyl)2, wherein the alkyl group is defined as described above and has 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkylamine group). The alkylamine group is preferably an alkylamine group having 1 to 8 carbon atoms (i.e., C12). 1-8 Alkylamine group), more preferably alkylamine group having 1 to 6 carbon atoms (i.e., C14). 1-6 Alkylamine group), preferably alkylamine group with 1 to 3 carbon atoms (i.e., C). 1-3 (Alkylamine group). Non-limiting examples include: dimethylamino, monomethylamino, diethylamino, monoethylamino, etc. The alkylamine group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linker. When the alkylamine group is substituted by a substituent, the substituent is no longer further substituted.

[0135] The term "alkathioyl" refers to -S- (alkyl) or -S- (unsubstituted cycloalkyl), wherein the alkyl and cycloalkyl groups are defined as described above and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkylthio group). The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkylthioyl), more preferably alkylthioyl groups having 1 to 6 carbon atoms (i.e., C14-C ... 1-6 Alkylthio group), preferably alkylthio group with 1 to 3 carbon atoms (i.e., C12). 1-3Alkylthioyl groups. Non-limiting examples include: methylthioyl, ethylthioyl, propylthioyl, butylthioyl, cyclopropylthioyl, cyclobutylthioyl, cyclopentylthioyl, cyclohexylthioyl, etc. The alkylthioyl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linker. When the alkylthioyl group is substituted by a substituent, the substituent is not further substituted.

[0136] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0137] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2 2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0138] The term "haloalkoxy" refers to an alkoxy group that is substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2 -Chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0139] The term "thiol" refers to -SH.

[0140] The term "hydroxyl group" refers to -OH.

[0141] The term "nitro" refers to -NO2.

[0142] The term "amino" refers to -NH2.

[0143] The term "cyano" refers to -CN.

[0144] The term "carboxyl group" refers to -C(O)OH.

[0145] The term "aldehyde group" refers to -CHO.

[0146] The term "oxo" or "oxo group" refers to =O.

[0147] The term "carbonyl" refers to C=O.

[0148] The term "aminoacyl" refers to -C(O)NH2.

[0149] The term "sulfonyl" refers to -S(O)2.

[0150] The term “deuterated alkyl” refers to an alkyl group that is substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

[0151] The term “deuterated alkoxy” refers to an alkoxy group that is substituted with one or more deuterium groups, wherein the alkoxy group is as defined above.

[0152] The term "haloalkoxy" refers to an alkoxy group that is substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0153] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0154] The term "alkenyl" refers to divalent straight-chain and branched alkenyl groups.

[0155] The term "ethynyl" refers to divalent straight-chain and branched ethynyl groups.

[0156] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0157] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0158] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0159] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0160] The expression "mn" used in this paper refers to the range from m to n, the subrange consisting of the individual point values ​​within it, and the individual point values ​​themselves. For example, the expression "C2-C8" or "C 2-8 "Covering a range of 2-8 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C..." 10 "or "C 3-10 "It should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C..." 10 C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C10 For example, stating "C1-C6" or "C..." 1-6 "The term 'covers' the range of 1-6 carbon atoms and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, and C1, C2, C3, C4, C5, C6, etc. Similarly, the expression 'ternary to decaary' should be understood to include any subrange within this range and each point value, such as ternary to pentary, ternary to hexaary, ternary to octary, quaternary to pentary, quaternary to hexaary, quaternary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, octary to octary, quinary to decaary, etc., and tri-, quadri-, quinary, quinary, quinary, quinary, octary, quinary, octary, quinary, decaary, etc. Other similar expressions in this text should also be understood in a similar manner."

[0161] The different expressions used in this article, such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C", all express the same meaning, that is, X can be any one or more of A, B, and C.

[0162] The terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally (al) alkyl-substituted cycloalkyl” means that an alkyl group may but is not required to be present, and this description includes both cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0163] The terms "substitution" and "substituted" refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Furthermore, when a structural unit is substituted, even if the structural unit is marked with a hydrogen atom, it does not mean that the hydrogen atom cannot be substituted, but rather that any position in the structural unit including the hydrogen atom can be substituted. For example, structural unit... Substitution means that any position, including the hydrogen atom on the nitrogen atom, can be substituted. Combinations of substituents and / or variables are only permitted if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing each carbon atom in a group as optionally being replaced by a heteroatom, the condition is that it does not exceed the normal valence of all atoms in the group under the current condition, and a stable compound is formed. Exemplary substituents include, but are not limited to: C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 5-12 Aryl, 5-12 heteroaryl, -CO-(C 3-8 cycloalkyl), -CO- (3-8 membered heterocycloalkyl), -CO- (C 5-12 aryl), -CO- (5-12 membered heteroaryl), hydroxyl, C 1-6 Alkoxy, C 5-12 aryloxy groups, thiol groups, C 1-6 Alkylthio, cyano, halogen, oxo, aldehyde, SF5, SCF3, -N3, C 1-6 alkylthiocarbonyl, C 1-6 Alkyl carbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, carboxyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, phosphonic acid, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-HC(=O)NH(C 1-6 Alkyl groups), -NHC(=O)NH2, -CH=N(C 1-6 Alkyl group), -CH=NO(C 1-6 alkyl), -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl groups, etc.

[0164] If a substituent is described as "optionally...substituted", then the substituent may be unsubstituted or may be substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogen atoms on that atom or group may be substituted by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. When the substituent is a subunit (e.g., ... When the substituent is hydrogen, it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this can also indicate that the corresponding group is "unsubstituted" or "unreplaced". Unless otherwise specified, as used herein, the connection point of the substituent can come from any suitable position of the substituent.

[0165] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0166] When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of a compound, their definition is independent for each occurrence in each case. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the option of each R substituent in each case is independent of each other.

[0167] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of linking in the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes the cases of AMWB and AWMB, with AMWB being preferred.

[0168] The compounds of this invention can exist in specific geometric or stereoisomeric forms. Stereoisomers are isomers that exist in molecules with the same order of interconnection of atoms or groups of atoms, but different spatial arrangements. All such compounds of this invention include cis-trans isomers, optical isomers, and racemic mixtures and other mixtures thereof, such as cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched with enantiomers or diastereomers; all such mixtures are within the scope of this invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of this invention. All such isomers and mixtures thereof are included within the scope of this invention. In some embodiments, the preferred compounds are those isomers that exhibit superior biological activity. The purified or partially purified isomers and stereoisomers of the compounds of this invention, or racemic mixtures or diastereomer mixtures, are also included within the scope of this invention. The purification and separation of such substances can be achieved using standard techniques known in the art.

[0169] The compounds of this invention also include their tautomer forms. Tautomers refer to compounds that can interconvert through a reversible chemical reaction known as tautomerization, typically caused by the associated migration of hydrogen atoms and π bonds (double or triple bonds), resulting in a transformation of one functional group into another. Examples include the following paired compounds: aldehyde / ketone–enol, imine–enamine.

[0170] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0171] The compounds of this invention include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, respectively. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0172] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0173] In the compounds of this invention, when a position is specifically designated as deuterium D, that position should be understood as having a deuterium abundance at least 1000 times greater than the native abundance (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0174] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0175] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is safe and effective when used in mammals and has the intended biological activity.

[0176] The term "pharmaceutical composition" refers to a composition containing one or more compounds described in this invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0177] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0178] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0179] As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the symptom of a disease or symptom to cease; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0180] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom. The term "neuropsychiatric disorders" is a collective term for neurological and psychiatric disorders, encompassing both neurological and / or psychiatric conditions.

[0181] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0182] As used herein, “individual” includes humans or non-human animals. Exemplary human individuals include individuals with a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0183] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0184] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, with the basic raw material used in each step as a reference (1 equivalent).

[0185] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application. Detailed Implementation

[0186] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0187] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0188] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0189] The HPLC determination was performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C). 18 100 × 4.6mm, 3.5 μM);

[0190] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used for thin-layer chromatography (TLC) are 0.15 mm-0.20 mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4 mm-0.5 mm in diameter.

[0191] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0192] Example

[0193] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products. Unless otherwise specified, all proportions or percentages used herein are by weight.

[0194] Intermediate 1

[0195]

[0196] Step 1: Potassium tert-butoxide (9.53 g, 85.13 mmol) was added to a three-necked flask and dissolved in DMF (100 ml). The mixture was purged with nitrogen three times and cooled to -45°C. Then, 1a (10 g, 56.75 mmol) in 25 ml DMF solution and 2-(difluoromethanesulfonyl)pyridine (9.86 g, 51.08 mmol) in 25 ml DMF solution were slowly added dropwise. After the addition was complete, the mixture was reacted at this temperature for one hour. Then, a saturated ammonium chloride solution (30 mL) and hydrochloric acid aqueous solution (1N, 50 mL) were added, and the mixture was slowly heated to room temperature and reacted for 16 hours. After the reaction was completed by TLC monitoring, the mixture was diluted with water (100 ml) and extracted twice with methyl tert-butyl ether (100 ml × 2). The organic phases were combined and dried, then concentrated under reduced pressure at 30°C. The residue was purified by silica gel column chromatography to give compound 1b (4 g, yield: 33.53%).

[0197] 1 H NMR (400 MHz, CDCl3) δ7.29–7.20 (m, 5H), 4.36 (s, 2H), 4.11–4.03 (m, 1H), 2.86–2.79 (m, 2H), 2.64–2.55 (m, 2H).

[0198] Step 2: Compound 1b (4 g, 19.05 mmol) was added to a reaction flask, dissolved in dichloromethane (100 ml), purged with nitrogen three times, cooled to -78°C, and then boron tribromide (9.52 g, 38.10 mmol) was added dropwise. The reaction was maintained at this temperature for one hour. After the reaction was completed by TLC monitoring, the reaction solution was slowly added dropwise to a saturated sodium carbonate solution (200 ml) at 0°C, the pH was adjusted to be greater than 7, and the mixture was extracted twice with dichloromethane (50 ml × 2). The organic phases were combined and dried, concentrated at 20°C, and the residue was purified by silica gel column chromatography to give compound 1c (1.63 g, yield: 71.33%).

[0199] Step 3: Compound 1c (1.63 g, 13.58 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (20 ml). Then, pyridine (5.37 g, 67.90 mmol) and p-nitrophenyl chloroformate (8.2 g, 40.74 mmol) were added, and the mixture was reacted at room temperature for one hour. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give intermediate 1 (2.4 g, yield: 62.02%).

[0200] 1H NMR (400 MHz, CDCl3) δ 8.32–8.26 (m, 2H), 7.43–7.36 (m, 2H), 5.23–5.10 (m, 1H), 3.25–3.14 (m, 2H), 3.01–2.88 (m, 2H).

[0201] Intermediate 1C

[0202]

[0203] Step 1: Compound 1A (500 mg, 2.73 mmol) was added to a reaction flask and dissolved in DMF (10 ml). NaH (160 mg, 4.10 mmol) was added at 0 °C, and the reaction was maintained at this temperature for 30 min. Then, methyl iodoform (775 mg, 5.46 mmol) was added, and the reaction was brought to room temperature for 3 h. After the reaction was completed by TLC monitoring, the mixture was diluted with water (50 ml) and extracted twice with ethyl acetate (50 ml × 2). The organic phases were combined, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 1B (475 mg, yield: 88.29%).

[0204] 1 H NMR (400 MHz, DMSO-d6) δ 4.84–4.80 (m, 2H), 4.50–4.24 (m, 1H), 2.90–2.80 (m, 2H), 2.78–2.70 (m, 5H), 1.39 (s, 9H).

[0205] Step 2: Compound 1B (470 mg, 2.38 mmol) was added to a reaction flask, dissolved in dichloromethane (10 ml), and then trifluoroacetic acid (0.5 ml) was added. The reaction was carried out at room temperature for 1 h. After the reaction was completed by TLC monitoring, the solution was concentrated under reduced pressure to obtain crude intermediate 1C (250 mg, TFA salt), which was used directly in the next step.

[0206] Intermediate 3

[0207]

[0208] Step 1: Dissolve potassium tert-butoxide (5.0 g, 44.56 mmol) in DMF (50 ml) in a three-necked flask, purge with nitrogen three times, cool to -45°C, and slowly add 3a (5.0 g, 27.00 mmol) in DMF (25 ml) and difluoromethyl (2-pyridyl) sulfone (4.35 g, 22.95 mmol) in DMF (25 ml). After the addition is complete, slowly raise the temperature to room temperature and react for 16 hours. After the reaction is complete as monitored by TLC, add saturated ammonium chloride solution (50 ml) and 3M hydrochloric acid aqueous solution (15 ml) to the reaction solution and stir at room temperature for 1 hour. Then dilute with water (100 ml), extract twice with ethyl acetate (100 ml × 2), combine the organic phases, dry, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (PE:EA = 20:1) to give compound 3b (360 mg, yield: 6.08%).

[0209] 1 H NMR (400 MHz, DMSO-d6) δ7.40–7.30 (m, 1H), 4.13–4.00 (m, 1H), 2.95–2.84 (m, 2H), 2.65–2.54 (m, 2H), 1.38 (s, 9H).

[0210] Step 2: Compound 3b (360 mg, 1.64 mmol) was added to a reaction flask, dissolved in DMF (10 ml), cooled to 0°C, and then NaH (100 mg, 2.46 mmol) was added. The reaction was maintained at this temperature for 20 min. Finally, iodomethane (450 mg, 3.28 mmol) was added, and the reaction was moved to room temperature for two hours. After the reaction was completed by TLC monitoring, saturated ammonium chloride solution (50 ml) was added to quench the reaction, and the mixture was extracted twice with ethyl acetate (50 ml × 2). The organic phases were combined, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 20:1) to give compound 3c (340 mg, yield: 88.89%).

[0211] 1 H NMR (400 MHz, DMSO-d6) δ 4.65–4.40 (m, 1H), 2.95–2.79 (m, 4H), 2.77 (s, 3H), 1.40 (s, 9H).

[0212] Step 3: Compound 3c (340 mg, 1.45 mmol) was added to a reaction flask, dissolved in DCM (5 ml), and then TFA (1 ml) was added. The reaction was carried out at room temperature for 3 hours. After the reaction was completed by TLC monitoring, the solution was concentrated under reduced pressure to obtain compound 3 (200 mg, TFA salt), and proceeded directly to the next step.

[0213] LC-MS(ESI): m / z=134.1[M+H] + .

[0214] Example 1

[0215] Typical operating procedures, taking the preparation process of compound 1 as an example:

[0216]

[0217] Step 1: Compound 1F (1 eq, synthesized according to the method of patent WO2021018237) was dissolved in anhydrous methanol, and K2CO3 (2 eq) was added. Dimethyl (1-diazo-2-oxopropyl)phosphonate (1.5 eq) was slowly added dropwise under ice bath conditions. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 h. After the reaction was complete by TLC, the mixture was diluted with water, extracted with EA, dried and concentrated by column chromatography to obtain compound 1G.

[0218] Step 2: Compound 1A (1 eq) was added to a reaction flask, dissolved in DMF, and NaH (1.5 eq) was added at 0°C. The reaction was maintained at this temperature for 30 min, followed by the addition of iodomethane (2 eq), and the reaction was brought to room temperature for 3 hours. After the reaction was completed by TLC monitoring, the mixture was diluted with water, extracted with ethyl acetate, dried over reduced pressure, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 1B.

[0219] Step 3: Compound 1B was added to a reaction flask, dissolved in DCM, and then TFA was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure to obtain compound 1C.

[0220] Step 4: Compound 1D (1 eq, synthesized according to the method of patent WO2020257139) and compound 1C (1.2 eq) were added to a reaction flask, dissolved in DCM, and then DIPEA (5 eq) was added. The reaction was carried out at room temperature until the reaction was completed by TLC monitoring. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 1E.

[0221] LC-MS (ESI): m / z = 406.2 [M+H] + .

[0222] Step 5: Add compound 1E (1 eq) and compound 1G (2.0 eq) to the reaction flask, dissolve them in DMF and TEA (5:1), then add Pd(PPh3)2Cl2 (0.1 eq), Pd(PPh3)4 (0.1 eq) and CuI. (0.2 eq), reacted at 90 °C until the reaction was complete as monitored by TLC, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 1H.

[0223] LC-MS (ESI): m / z = 464.2 [M+H] + .

[0224] Step 6: Add compound 1H (1 eq) to the reaction flask and dissolve it with THF:MeOH:H2O=3:1:1. Then add anhydrous lithium hydroxide (4 eq) and react at room temperature until the reaction is complete as monitored by TLC. Concentrate under reduced pressure and purify the residue by HPLC to obtain compound 1.

[0225] LC-MS (ESI): m / z = 450.2 [M+H] + .

[0226] Some embodiments can also be synthesized according to the following route:

[0227] Example 1

[0228]

[0229] Step 1: Compound 1I (150 mg, 0.30 mmol, synthetic method reference: WO2025026266) was dissolved in tetrahydrofuran (10 ml), then triethylamine (91 mg, 0.90 mmol) and intermediate 1C (58 mg, 0.60 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the mixture was diluted with water (20 ml), extracted with ethyl acetate (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 1J (100 mg, yield: 72.8%).

[0230] LC-MS (ESI): m / z = 454.2 [M+H] + .

[0231] Step 2: Compound 1J (100 mg, 0.22 mmol) and Compound 1K (93 mg, 0.44 mmol, synthetic method reference: WO2025026266) were dissolved in 10 mL of 1,4-dioxane. Then, potassium carbonate (85 mg, 0.66 mmol), triethylamine (75 mg, 0.66 mmol), bis(triphenylphosphine)palladium dichloride (30 mg, 0.044 mmol), cuprous iodide (8 mg, 0.044 mmol), and cesium fluoride (65 mg, 0.44 mmol) were added. Under nitrogen protection, the mixture was stirred at 80 °C for 16 hours. After the reaction was completed by TLC monitoring, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 1L (80 mg, yield: 62.6%).

[0232] LC-MS (ESI): m / z = 464.2 [M+H] + .

[0233] Step 3: 1 L of compound (80 mg, 0.16 mmol) was dissolved in methanol (10 ml), then lithium hydroxide monohydrate (20 mg, 0.48 mmol) and water (5 ml) were added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the pH was adjusted to about 5 with 1M HCl, and the mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography and HPLC to obtain compound 1 (30 mg, yield: 38.7%).

[0234] LC-MS (ESI): m / z = 450.2 [M+H] +

[0235] 1 H NMR (400 MHz, DMSO-d6) δ7.84 (d, 1H), 7.73(d, 1H), 5.66 (s, 2H), 4.83–4.75 (m, 2H), 4.11(s, 3H), 2.88–2.62 (m,7H), 2.53(s, 3H), 2.52–2.51 (m,1H), 2.43 (s, 2H), 1.07–1.02 (m, 2H), 0.97–0.94 (m, 2H).

[0236] Example 2

[0237]

[0238] Step 1: Compound 2A (600 mg, 1.82 mmol, synthetic method reference: WO2025026266) was dissolved in tetrahydrofuran (10 ml), then triethylamine (370 mg, 3.64 mmol) and intermediate 1 (620 mg, 2.18 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the mixture was diluted with water (20 ml), extracted with ethyl acetate (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 2B (400 mg, yield: 46.2%).

[0239] LC-MS (ESI): m / z = 476.2 [M+H] + .

[0240] Step 2: Compound 2B (400 mg, 0.84 mmol) was added to 10 mL of 1,4-dioxane, followed by compound 2C (310 mg, 1.68 mmol, synthetic method reference: WO2025026266), potassium carbonate (350 mg, 2.52 mmol), triethylamine (420 mg, 4.20 mmol), bis(triphenylphosphine) palladium dichloride (120 mg, 0.17 mmol), and cuprous iodide (23 mg, 0.17 mmol). Under nitrogen protection, the mixture was stirred at 80 °C for 16 hours. After the reaction was completed by TLC monitoring, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 2D (200 mg, yield: 44.9%).

[0241] LC-MS (ESI): m / z = 530.2 [M+H] + .

[0242] Step 3: Compound 2D (200 mg, 0.38 mmol) was dissolved in methanol (10 ml), then lithium hydroxide monohydrate (48 mg, 1.14 mmol) and water (5 ml) were added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the pH was adjusted to about 5 with 1M HCl, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the crude compound, which was then chirally resolved to obtain compounds 2-1 (SFC retention time: 1.688 min, 12 mg) and 2-2 (SFC retention time: 1.774 min, 26 mg). SFC analysis method: Instrument: CAS-05-ANA-SFC-D, column: OX column; mobile phase: A: CO2, B: 0.05% NH3.H2O in MeOH; flow rate: 3 mL / min; column temperature: 35℃; wavelength: 220 nm. SFC preparation method: Instrument: C CAS-05-Prep-SFC-E, column: OX column; mobile phase: A: CO2, B: 0.1%NH3.H2O in MeOH; flow rate: 130 mL / min, column temperature: 25℃, wavelength: 220nm; sample preparation: sample concentration 3 mg / mL, ethanol and acetonitrile mixed solution injection.

[0243] Compound 2-1 (SFC analysis retention time: 1.688 min): 1 H NMR (400 MHz, DMSO-d6) δ12.25 (s, 1H), 7.85 (d, 1H), 7.75(d, 1H), 7.72–7.66 (m, 1H), 4.97–4.89 (m,1H), 4.84–4.78 (m, 2H), 4.06(s, 3H), 4.02–3.96 (m, 1H), 3.15(s, 3H), 3.06–2.97 (m, 2H), 2.71–2.63 (m, 6H), 2.58(s, 3H), 2.28–2.23 (m, 2H); LC-MS (ESI):m / z =516.2 [M+H] + .

[0244] Compound 2-2 (SFC analysis retention time: 1.774 min): 1H NMR (400 MHz, DMSO-d6) δ12.21 (s, 1H), 7.85 (d, 1H), 7.77(d, 1H), 7.72–7.66 (m, 1H), 4.97–4.88 (m,1H), 4.84–4.77 (m, 2H), LC-MS (ESI):m / z =516.2 [M+H] + .

[0245] Example 3

[0246]

[0247] Step 1: Compound 2B (200 mg, 0.42 mmol) was added to 10 mL of 1,4-dioxane, followed by compound 1K (180 mg, 0.84 mmol), potassium carbonate (170 mg, 1.26 mmol), triethylamine (130 mg, 1.26 mmol), bis(triphenylphosphine) palladium dichloride (59 mg, 0.084 mmol), cuprous iodide (16 mg, 0.084 mmol), and cesium fluoride (130 mg, 0.84 mmol). Under nitrogen protection, the mixture was stirred at 80 °C for 16 hours. After the reaction was completed by TLC monitoring, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 3A (80 mg, yield: 39.2%).

[0248] LC-MS (ESI): m / z = 486.2 [M+H] + .

[0249] Step 2: Compound 3A (80 mg, 0.16 mmol) was dissolved in methanol (10 ml), then lithium hydroxide monohydrate (20 mg, 0.48 mmol) and water (5 ml) were added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the pH was adjusted to about 5 with 1M HCl, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography and HPLC to obtain compound 3 (12 mg, yield: 15.5%).

[0250] LC-MS (ESI): m / z = 472.1 [M+H] + .

[0251] 1 H NMR (400 MHz, DMSO-d6) δ7.82 (d, 1H), 7.72(d, 1H), 7.72–7.66 (m,1H), 4.97–4.87 (m, 1H), 4.84–4.76 (m, 2H), 4.06(s, 3H), 3.07–2.96 (m, 2H), 2.72–2.61 (m, 2H), 2.57 (s, 3H), 2.39 (s, 2H), 1.04–0.99 (m, 2H), 0.97–0.93 (m, 2H).

[0252] Example 4

[0253]

[0254] Step 1: Compound 1I (200 mg, 0.40 mmol) was dissolved in tetrahydrofuran (10 ml), then triethylamine (120 mg, 1.20 mmol) and intermediate 3 (80 mg, 0.60 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the mixture was diluted with water (20 ml), extracted with ethyl acetate (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 4A (170 mg, yield: 86.1%).

[0255] LC-MS (ESI): m / z=490.1[M+H] + .

[0256] Step 2: Compound 4B (100 mg, yield: 57.6%) was obtained by using compound 4A (170 mg, 0.35 mmol) and compound 1K (150 mg, 0.70 mmol) according to the method in Step 2 of Example 1.

[0257] LC-MS (ESI): m / z = 500.2 [M+H] + .

[0258] Step 3: Compound 4B (100 mg, 0.20 mmol) was dissolved in methanol (10 ml), then lithium hydroxide monohydrate (25 mg, 0.60 mmol) and water (5 ml) were added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the pH was adjusted to about 5 with 1M HCl, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography and HPLC to obtain compound 4 (30 mg, yield: 15.5%).

[0259] LC-MS (ESI): m / z = 486.2 [M+H] +

[0260] 1 H NMR (400 MHz, DMSO-d6) δ12.19 (s, 1H), 7.85 (d, 1H), 7.73(d, 1H), 5.67 (s, 2H), 4.11(s, 3H), 2.90–2.70 (m,7H), 2.54–2.52 (m,4H), 2.46 (s, 2H), 1.08–1.04 (m, 2H), 0.97–0.94 (m, 2H).

[0261] Biological test evaluation

[0262] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0263] 1. Cellular calcium flow experiment

[0264] 1) Dilute the test compound to a 400X stock solution with DMSO in a 384-well plate.

[0265] 2) Transfer 1 μl of the compound solution from step 1 to 39 μl of assay buffer and prepare a 10X working solution in a 384-well plate using the Bravo automated liquid handling platform.

[0266] 3) CHO-LPA1 cells were cultured in F12 medium (10% FBS).

[0267] 4) When the cells reach 80% confluence, dissociate the cells with 0.25% trypsin-EDTA.

[0268] 5) Measure cell density and dilute cells to 4 x 10e5 / ml with F12 (10% FBS).

[0269] 6) Using a multidrop autodispenser, dispense 30 μl of cells into 384-well plates (corning 3764#), 12 cells per well. Incubate at 37°C and 5% CO2 for 18-20 hours.

[0270] 7) Replace with 25 μL of serum-free culture medium and incubate overnight.

[0271] 8) Add 10 μL of 3.5X loading dye to each well of the cell plate. Incubate at 37°C and 5% CO2 in the dark for 0.5–1 hour.

[0272] 9) After incubation, transfer 5 μl of the 10X working solution from step 2 into the cell plate.

[0273] 10) Incubate the cell plate at 25°C in the dark for 15 minutes, and then read the calcium signal.

[0274] 11) Prepare at least 20 μl / well of a 5X agonist (LPA) working solution in a 384-well assay plate (greiner 784075#), with LPA added to 1X HBSS + 20 mM HEPES + 0.1% BSA. The agonist concentration used in this assay was determined by the dose-response pattern in a previous agonist assay. EC80 is used as the final agonist concentration in the assay.

[0275] 12) Use FLIPR to read and save data at room temperature with the specified settings.

[0276] 13) Plot the signal values ​​against compound concentrations, and use GraphPad Prism software to perform curve fitting and IC50 analysis using nonlinear regression. 50 calculate.

[0277] Experimental conclusions: The compounds of the present invention, such as the compounds in the examples, exhibit high antagonistic activity against the LPAR1 receptor. The IC50 values ​​of the compounds in the examples against LPAR1 enzyme activity are [not specified in the original text]. 50 Value less than 100 μM. IC 50 Values ​​are represented by grades A, B, C, and D, with A representing 0. <IC 50 ≤10nM, B represents 10nM <IC 50 ≤50nM, where C represents 50nM <IC 50 ≤100nM, D represents IC 50 >100nM. The test results for some embodiments are shown in Table 1.

[0278] Table 1. Antagonistic activity of the compounds of the present invention against LPAR 1

[0279]

[0280] 2. Pharmacokinetics test in mice

[0281] 2.1 Experimental animals: Male C57 mice, 20-25 g, 6 mice / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0282] 2.2 Experimental Design: On the day of the experiment, C57 mice were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0283] Before and after administration of isoflurane anesthesia, 0.06 mL of blood was collected via the orbital cavity and placed in an EDTAK2 centrifuge tube. The centrifuge was then incubated at 5000 rpm for 4 hours. o Plasma was collected after centrifugation at C for 10 min. Blood samples were collected at the following time points for both the intravenous and gavage groups: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. All samples were stored at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0284] Conclusion: The compounds of the present invention, such as those in the examples, exhibit favorable pharmacokinetic characteristics in mice.

[0285] 3. Rat pharmacokinetic test

[0286] 3.1 Experimental animals: Male SD rats, approximately 220 g in size, 6-8 weeks old, 6 rats per compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0287] 3.2 Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before drug administration but allowed free access to water. They were fed 4 hours after drug administration.

[0288] Before and after administration of isoflurane anesthesia, 0.15 mL of blood was drawn via the orbital cavity and placed in an EDTAK2 centrifuge tube. The centrifuge was then incubated at 5000 rpm for 4 hours. o Centrifuge at 1°C for 10 min and collect plasma. Store all samples at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0289] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in rats.

[0290] 4. Pharmacokinetics of Beagle Dogs

[0291] 4.1 Experimental animals: Male beagle dogs, weighing approximately 8-11 kg, 6 dogs per compound, purchased from Beijing Mars Biotechnology Co., Ltd.

[0292] 4.2 Experimental Methods: On the day of the experiment, beagle dogs were randomly grouped according to their weight. They were fasted for 12-14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0293] Blood samples of 1 mL were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. The plasma was collected by centrifugation at 5000 rpm and 4 °C for 10 min. All samples were stored at -80 °C before analysis and quantitative analysis was performed using LC-MS / MS.

[0294] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in beagle dogs.

[0295] 5. Pharmacokinetics test in monkeys

[0296] 5.1 Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0297] 5.2 Experimental Methods: On the day of the experiment, monkeys were randomly divided into groups according to their body weight. They were fasted for 14-18 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0298] Before and after drug administration, 1.0 mL of blood was collected via venous sampling from each of the four limbs and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm for 4 hours. o Centrifuge at 1°C for 10 min and collect plasma. Store all samples at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0299] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in monkeys.

[0300] 6. hERG potassium ion channel function test

[0301] Experimental platform: Electrophysiological manual patch-clamp system

[0302] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0303] Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamping voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV. The step voltage to induce hERG potassium current (IhERG) was applied from -80 mV with a 2-second depolarization voltage to +20 mV, followed by repolarization to -50 mV, held for 1 second, and then returned to -80 mV. This voltage stimulation is applied every 10 seconds. Once the hERG potassium current has stabilized (at least 1 minute), the dosing process begins. Each test concentration of the compound is administered for at least 1 minute, and at least 2 cells are tested for each concentration (n≥2).

[0304] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0305]

[0306] Where Inhibition % represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0307] The IC50 of the compound was calculated using GraphPad Prism 5 software by fitting the following equation:

[0308]

[0309] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0310] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not inhibit hERG.

[0311] 7. CYP enzyme inhibition test

[0312] The aim of this study was to evaluate the effects of test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro assay system. Specific probe substrates for CYP450 isoenzymes were co-incubated with human liver microsomes and different concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing, and the changes in CYP enzyme activity were measured. The IC50 values ​​were calculated. 50 The value was used to evaluate the inhibitory potential of the test substance against each CYP enzyme subtype. Under the test conditions, the incubation concentration ranged from 0 to 30 μM.

[0313] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not inhibit CYP enzymes.

[0314] 8. Liver microsomal stability test

[0315] This experiment used liver microsomes from five genera—human, canine, monkey, rat, and mouse—as in vitro models to evaluate the metabolic stability of the test substance.

[0316] At 37°C, 1 µM of the test substance was co-incubated with microsomal protein and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after certain time intervals (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. T was calculated using the ln value of the drug residue in the incubation system and the incubation time. 1 / 2 Furthermore, the intrinsic clearance rate of liver microsomes (CL) was calculated. int(mic) and hepatic intrinsic clearance rate CL int(Liver) .

[0317] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good liver microsomal stability.

[0318] 9. Caco2 permeability test

[0319] The experiment used monolayers of Caco-2 cells, incubated in triple parallel in 96-well Transwell plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. After incubation at 37±1°C for 2 hours, the cell plate was removed, and a suitable amount of sample was transferred from both the apical and basal sides to a new 96-well plate. Acetonitrile containing an internal standard was then added to precipitate the protein. The samples were analyzed using LC MS / MS to determine the concentrations of the compound of the present invention and the control compound. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells, and from the basal side to the apical side, thereby calculating the efflux rate. The integrity of the monolayer cells after 2 hours of incubation was evaluated by the leakage of fluorescein.

[0320] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

[0321] 10. Bleomycin (BLM)-induced mouse model of idiopathic pulmonary fibrosis (IPF)

[0322] 1) Screening and Grouping: This project used male C57BL / 6j mice for a total of 9 weeks. Before the start of the experiment, the animals were divided into a sham-operated group and a model group according to their weight. One week after modeling, the model group was randomly divided into subgroups according to the animals' weight.

[0323] 2) Animal modeling: On day 1 of the experiment, animals were anesthetized with sulfadiazine (50 mg / kg) and xylazine (10 mg / kg). Mice in the model group received an intratracheal injection of bleomycin at a dose of 0.66 mg / kg (1 U / kg) in a volume of 50 μL on day 1. Mice in the sham-operated group (n=10) received an intratracheal injection of physiological saline in a volume of 50 μL.

[0324] 3) Experimental methods: Starting from day 7 of the experiment, mice in each experimental group were administered the test compound by gavage twice daily. The control group was given nintedanib at a dose of 60 mg / kg, administered by gavage at a volume of 10 mL / kg body weight once daily. The sham-operated group 1 and the model group 2 were given the solvent by gavage at a volume of 10 mL / kg body weight twice daily.

[0325] 4) Detection indicators: Lung tissue was collected for pathological examination at the end of the study.

[0326] Results: Bleomycin (0.66 mg / kg, it) injection for 21 days significantly increased the Modified Ashcroft score and pulmonary fibrosis area in the lung tissue of model mice. Compared with the model group given solvent, the compound administered by gavage twice daily for 14 days significantly reduced the Modified Ashcroft score and pulmonary fibrosis area in the lung tissue of model mice at the study endpoint.

Claims

1. A compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: X is CH or N; Ring A is C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl or 5-10 membered heteroaryl; Each R A Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R1 is -COOH, -(CR a R b ) m COOH, -OS(O)2OH, -(CR a R b ) m OS(O)2OH, -S(O)2OH, -(CR a R b ) m S(O)2OH, -P(O)(OH)2 or -(CR a R b ) m P(O)(OH)2; R2 is -CR a R b OC(O)NR c R 2a or -CR a R b NR c C(O)OR 2a ; R a and R b Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl; R c For hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy; R 2a C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -(CH2) p (C 3-8 cycloalkyl), -(CH2) p (4-8 membered heterocyclic alkyl) or -(CH2) p (OC 3-8 (Cycloalkyl), wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S, and the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl may optionally be further substituted by 1-4 R; R represents deuterium, halogen, hydroxyl, cyano, amino, =O, =S, =NH, -SF5, -SCF3, -NHCOC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl, =CH2, =CF2, =CHF, =CH(C) 1-6 Alkyl), =CH(C) 1-6 Halogenated alkyl), =CF(C) 1-6 Alkyl), =CF(C) 1-6 Halogenated alkyl), =C(C 1-6 Alkyl)2、=C(C 1-6 Alkyl)(C 1-6 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl; R3 represents halogen, hydroxyl, cyano, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl; n is 0, 1, 2, 3, or 4; m is 1, 2, or 3; p is 1, 2, or 3.

2. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, Ring A is C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl; Each R A Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups; R1 is -COOH or -(CH2) m COOH, -OS(O)2OH, -(CH2) m OS(O)2OH, -S(O)2OH, -(CH2) m S(O)₂OH, -P(O)(OH)₂, or -(CH₂) m P(O)(OH)2; R a and R b Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 3-5 cycloalkyl; R c For hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl or C 1-3 Alkoxy; R 2a C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) p (C 3-6 cycloalkyl), -(CH2) p (4-6 membered heterocyclic alkyl) or -(CH2) p (OC 3-6 (Cycloalkyl), wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S, and the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl may optionally be further substituted by 1-4 R; R represents deuterium, halogen, hydroxyl, cyano, amino, =O, =S, =NH, -SF5, -SCF3, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl), -C(O)C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 1-3 alkylamine group, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl; R3 represents halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 3-6 Cycloalkyl.

3. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexane, or pyridyl; R2 is -CH2OC(O)NR c R 2a or -CH2NR c C(O)OR 2a ; R c For hydrogen, deuterium, C 1-3 Alkyl or C 1-3 Deuterated alkyl groups; R 2a For the following structures, which can be arbitrarily replaced by 1-3 R's: , ; Each R is independently of deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl), -C(O)C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 1-3 alkylamine group, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl; R3 is a halogen, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl.

4. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R2 is , , , , , , , , .

5. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, General formula (I) is further shown in general formula (I-1) and general formula (I-2): or in: X is CH or N; Ring A is C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl or 5-6-membered heteroaryl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexane, pyridyl; Each R A Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups; R1 is -COOH or -(CH2) m COOH, -OS(O)2OH, -(CH2) m OS(O)2OH, -S(O)2OH, -(CH2) m S(O)₂OH, -P(O)(OH)₂, or -(CH₂) m P(O)(OH)2; R c C 1-3 Alkyl or C 1-3 Deuterated alkyl groups; R 2a The following structures are replaced by 1-3 R's: , ; R is =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Deuterated alkoxy groups; R3 is a halogen, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl groups, preferably fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, vinyl, or cyclopropyl; n is 0, 1, 2, or 3; m is 1 or 2.

6. The compound according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound is selected from one of the structures in Table 1.

7. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1-6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

8. The pharmaceutical composition according to claim 7, comprising 1-1500 mg of the compound of any one of claims 1-6, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

9. Use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-6, or the pharmaceutical composition according to claim 7 or 8, in the preparation of a medicament for treating / preventing LPAR1-mediated diseases.

10. The use according to claim 9, wherein the LPAR1-mediated disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve injury, and neuralgia.

11. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-6, its stereoisomers or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7 or 8, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve injury, or neuralgia.

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