LPAR1 antagonist of heteroaromatic ring derivative and application thereof

Abstract

Provided are an LPAR1 antagonist and a use thereof. Specifically provided are a compound represented by formula (I), or a stereoisomer, a deuterated compound, a solvate, a co-crystal or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, and a use thereof in the preparation of drugs for treating / preventing LPAR1-mediated diseases, each group in the formula (I) being as defined in the specification.

Description

LPAR1 antagonists of heteroaromatic ring derivatives and uses thereof Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a small molecule compound with LPAR1 antagonistic activity, its stereoisomers, deuterated products, solvates, cocrystals or pharmaceutically acceptable salts, and its use in preparing drugs for treating related diseases. Background Art

[0002] Lysophosphatidic acid (LPA) is a small glycerophosphodiester with a molecular weight of 430–480 Da. LPA is widely present in the human body. Upon binding to receptors, it activates multiple cellular signaling pathways, regulating cell proliferation, differentiation, apoptosis, neurotransmitter release, and other vital processes. It plays a crucial role in diseases such as cancer, fibrosis, neuronal dysfunction, and bone metabolic disorders. LPA is primarily produced by the hydrolysis of lysophospholipids (primarily lysophosphatidylcholine) by autocrine motility factor. In a bleomycin-induced pulmonary fibrosis model, LPA levels in bronchoalveolar lavage fluid are significantly elevated, leading to increased vascular permeability and pulmonary fibrosis. LPA also mediates the production of various paracrine mediators by fibroblasts, which act on epithelial cells, leukocytes, and endothelial cells, regulating tissue remodeling, angiogenesis, inflammation, wound healing, and tumor progression. LPA can even induce the extracellular shedding of epidermal growth factor (EGF) family ligands by fibroblasts, activating the release of soluble factors and, in part through EGFR, stimulating lung epithelial cells and amplifying the local fibroblast response. 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. Studies have shown that LPA is closely associated with organ fibrosis, primarily mediated through the lysophosphatidic acid receptor (LPAR) 1. Currently, six LPARs have been discovered, namely LPAR1 to LPAR6. The function of LPAR1 has been a hot topic of research in recent years. Clinical studies have confirmed that LPAR antagonists have therapeutic effects on idiopathic pulmonary fibrosis. Furthermore, the LPAR1 antagonist BMS-986020 has been found to effectively improve lung function in patients with idiopathic pulmonary fibrosis.

[0003] Summary of the Invention

[0004] The present invention provides a compound of formula (I), its stereoisomers, deuterated forms, solvates, cocrystals or pharmaceutically acceptable salts, wherein the compound has good activity, excellent physicochemical properties, convenient formulation, excellent pharmacokinetic properties, high bioavailability and low toxic and side effects.

[0005] The present invention is designed to provide the compound of formula (I) or (I-1), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt,

[0006] in,

[0007] Ring A is selected from 4-8 membered monocyclic carbocyclic group, 6-12 membered bicyclic carbocyclic group, 6-12 membered monocyclic heterocyclic group, 6-12 membered bicyclic heterocyclic group or none, wherein the carbocyclic group and heterocyclic group are optionally substituted by 1-4 R A In some embodiments, ring A is selected from 4-7 membered monocyclic carbocyclyl, 6-10 membered bicyclic carbocyclyl, 6-10 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; In some embodiments, ring A is selected from 4-7 membered monocyclic carbocyclyl; In some embodiments, ring A is selected from The ring A is substituted with 1 COOH;

[0008] In some embodiments, when Ring A is absent, L1 is selected from -OC substituted with one COOH. 1-6 Alkyl; In some embodiments, Ring A is selected from absent, L1 is selected from -OCH2C(CH3)2CH2COOH, -OCH2CH2C(CH3)2COOH;

[0009] Ring C is selected from 5-membered heteroaryl and 5-7-membered carbon ring, 5-membered heteroaryl and 5-7-membered hetero ring, C 3-6 Monocyclic carbocyclic ring, 5-6 membered monocyclic heterocyclic cycloalkyl, C 5-10 Bicyclic cycloalkyl, 5-10 membered bicyclic heterocyclic cycloalkyl, the heteroaryl, carbocyclic, heterocyclic, cycloalkyl, heterocycloalkyl are optionally substituted by 1-4 R C Replace; Indicates the connection site between ring C and pyridine ring, "*" indicates the connection site between ring C and L2; In some embodiments, ring C is selected from 5-membered heteroaryl and 5-7-membered cycloalkyl, 5-membered heteroaryl and aryl, 5-membered heteroaryl and 5-7-membered heterocycloalkyl, 5-membered heteroaryl and 5-7-membered heteroaryl, C 3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclic cycloalkyl, C 5-10 Bicyclic cycloalkyl, 5-10 membered bicyclic heterocyclic cycloalkyl, the heteroaryl, heterocyclic ring contains 1-3 heteroatoms selected from N, O, S; the heteroaryl, cycloalkyl, phenyl, heterocycloalkyl, heteroaryl are optionally substituted by 1-4 R C Replace; Indicates the connection site between ring C and pyridine ring, "*" indicates the connection site between ring C and L2; In some embodiments, ring C is selected from 5-membered heteroaryl and 5-6-membered cycloalkyl, 5-membered heteroaryl and 5-6-membered heterocycloalkyl, C 3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclic cycloalkyl, C 5-10 Bicyclic cycloalkyl, 5-10 membered bicyclic heterocyclic cycloalkyl, the heteroaryl, heterocyclic ring contains 1-3 heteroatoms selected from N, O, S; the heteroaryl, cycloalkyl, phenyl, heterocycloalkyl, heteroaryl are optionally substituted by 1-3 R C Substituted; In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from 5-membered heteroaryl and 5-7-membered carbocyclic ring, 5-membered heteroaryl and 5-7-membered heterocyclic ring, wherein the heteroaryl, carbocyclic ring, and heterocyclic ring are optionally replaced by 1-4 R C Replace; Indicates the connection site between ring C and pyridine ring, "*" indicates the connection site between ring C and L2; In some embodiments, ring C is selected from 5-membered heteroaryl and 5-7-membered cycloalkyl, 5-membered heteroaryl and aryl, 5-membered heteroaryl and 5-7-membered heterocycloalkyl, 5-membered heteroaryl and 5-7-membered heteroaryl, the heteroaryl and heterocycle contain 1-3 heteroatoms selected from N, O, and S; the heteroaryl, cycloalkyl, phenyl, heterocycloalkyl, heteroaryl are optionally substituted by 1-4 R C Replace; Indicates the connection site between ring C and pyridine ring, "*" indicates the connection site between ring C and L2; In some embodiments, ring C is selected from 5-membered heteroaryl and 5-6-membered cycloalkyl, 5-membered heteroaryl and 5-6-membered heterocycloalkyl, the heteroaryl and heterocycle contain 1-3 heteroatoms selected from N, O, and S; the heteroaryl, cycloalkyl, phenyl, heterocycloalkyl, heteroaryl are optionally substituted by 1-3 R C Substituted; In some embodiments, Ring C is selected from

[0010] R c1 、R c4 、R c5 are each independently selected from H, halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0011] R c3 Selected from H, C 1-4 alkyl;

[0012] Alternatively, R c1 With R BTogether they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;

[0013] Alternatively, R c3 With R B Together they form a 6-7 membered heterocyclic ring;

[0014] L1 is selected from a bond, -C 1-4 Alkyl-, -C=O, -OC(R L1a R L1b ) p -、-S-(CR L1a R L1b ) p -, -C(=O)NR L1 -、C 2-6 Alkenyl or C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1a Substitution; in some embodiments, L1 is selected from a bond, -O-, -O-CH2-, -C=O, -CH2-, -O-CH2-C(CH3)2-CH2-; in some embodiments, L1 is selected from a bond, -O-, -O-CH2-, -C=O, -CH2-; in some embodiments, L1 is selected from a bond, -O-, -O-CH2-, -C=O, -CH2-;

[0015] L2 is selected from (CR L2a1 R L2a2 ) p -OC(=O)N(R L2b )2、-C(=O)N(R L2b )2、-NR L2b -C(=O)OR L2c 、-(CR L2a1 R L2a2 ) p N(R L2b )2、-(CH2) p R L2d 、-(CR L2a1 R L2a2 ) p N(R L2b )S(O)2N(R L2b )2、(CR L2a1 R L2a2 ) p N(R L2b )C(=O)N(R L2b )2、-(CR L2a1 R L2a2 ) p N(R L2b )C(=O)OR L2b In some embodiments, L2 is selected from (CR L2a1 RL2a2 ) p -OC(=O)N(R L2b )2、-C(=O)N(R L2b )2、-NR L2b -C(=O)OR L2c 、-(CR L2a1 R L2a2 ) p N(R L2b )2、-(CH2) p R L2d 、-(CR L2a1 R L2a2 ) p N(R L2b )S(O)2N(R L2b )2、(CR L2a1 R L2a2 ) p N(R L2b )C(=O)N(R L2b )2; In some embodiments, L2 is selected from (CR L2a1 R L2a2 ) p -OC(=O)N(R L2b )2、-C(=O)N(R L2b )2、-NR L2b -C(=O)OR L2c In some embodiments, L2 is selected from (CR L2a1 R L2a2 ) p -OC(=O)N(R L2b )2、-C(=O)N(R L2b )2、-NR L2b -C(=O)OR L2c 、-(CR L2a1 R L2a2 ) p N(R L2b )C(=O)OR L2b In some embodiments, L2 is selected from -(CR L2a1 R L2a2 ) p -OC(=O)NHR L2b 、-(CR L2a1 R L2a2 ) p -OC(=O)N(C 1-4 alkyl)R L2b 、-C(=O)NHR L2b 、-C(=O)N(C 1-4 alkyl)R L2b 、-NHC(=O)ORL2c 、-N(C 1-4 alkyl)C(=O)OR L2c 、-(CR L2a1 R L2a2 ) p NHC(=O)OR L2b 、-(CR L2a1 R L2a2 ) p N(C 1-4 alkyl)C(=O)OR L2b In some embodiments, L2 is selected from -(CR L2a1 R L2a2 ) p -OC(=O)NHR L2b 、-(CR L2a1 R L2a2 ) p -OC(=O)N(CH3)R L2b 、-(CR L2a1 R L2a2 ) p NHC(=O)OR L2b 、-(CR L2a1 R L2a2 ) p N(CH3)C(=O)OR L2b ;

[0016] In some embodiments, L2 is selected from In some embodiments, L2 is selected from In some embodiments, L2 is selected from

[0017] In some embodiments, when Ring C is When L2 is selected

[0018] R A Each independently selected from H, halogen, CN, OH, -(CH2) p -COOR a1 、-(CH2) p -C(=O)NR a1 R a2 、-(CH2) p -C(=O)NHC(=O)R a1 、-(CH2) p -C(=O)NHS(O)2R a1 、-(CH2) p -C(=O)NHS(O)R a1、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHCOR a1 、-(CH2) p -P(O)(OH)2、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl or -(CH2) p -(5-10 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, heterocyclic group is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 In some embodiments, R A Each independently selected from halogen, CN, OH, COOH, -CH2COOH, C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -OC 1-2 Alkyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 In some embodiments, R A Each independently selected from COOH, -CH2COOH;

[0019] R B independently selected from H;

[0020] R C Each independently selected from halogen, CN, OH, NO2, NH2, =O, C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkoxy, alkyl, alkenyl, and alkynyl groups are optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN; in some embodiments, R C Each independently selected from H, halogen, CN, OH, =O, NH2, C 1-2 Alkyl, -OC 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R C Each independently selected from H, halogen, CN, OH, =O, NH2, C 1-2Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R C Each is independently selected from H, F, Cl, ═O, CH 3 , CH 2 CH 3 ; in some embodiments, R C Each independently selected from halogen, CN, OH, NO2, NH2, C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkoxy, alkyl, alkenyl, and alkynyl groups are optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN; in some embodiments, R C Each independently selected from H, halogen, CN, OH, NH2, C 1-2 Alkyl, -OC 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R C Each independently selected from H, halogen, CN, OH, NH2, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R C Each independently selected from H, F, Cl, CH3, CH2CH3;

[0021] R a1 、R a2 Each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 In some embodiments, R a1 、R a2 Each independently selected from H, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4Alkoxy, 5-10 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from F, Cl, =O, OH, NH2, CN, acetyl, C 1-2 Alkyl, C 1-2 Alkoxy, halogenated C 1-2 In some embodiments, R a1 、R a2 Each independently selected from H, C 1-4 alkyl;

[0022] R c2 Selected from -(CR L2a1 R L2a2 ) p -C 3-7 -(CR L2a1 R L2a2 ) p -(4-7 membered heterocycloalkyl), halogen, CN, OH, NO2, NH2, halogenated C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in some embodiments, R c2 Selected from C 3-4 cycloalkyl, 4-5 membered heterocycloalkyl, -CH2-C 3-4 -CH2-(4-5 membered heterocycloalkyl), fluoro-C 1-2 Alkyl; in some embodiments, R c2 is selected from cyclopropyl, cyclobutyl, oxetanyl, oxolanyl, azetidinyl, azetyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-azetidinyl, -CH2-azetyl, -CH2-azacyclopentyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3; in some embodiments, R c2 Selected from C 3-7 4-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, halogen, CN, OH, NO2, NH2, halogenated C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in some embodiments, R c2 Selected from C 3-4 4-membered cycloalkyl, 4-5-membered heterocycloalkyl, fluorinated C 1-2 Alkyl; in some embodiments, Rc2 Selected from cyclopropyl, cyclobutyl, oxetanyl, oxolanyl, azetidinyl, azopentyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3;

[0023] Each R L1a 、R L1b Each independently selected from H, halogen, CN, OH, NO2, NH2, =O, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -(CH2) p -COOR a1 The alkyl, alkenyl, alkynyl, cycloalkyl group may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 In some embodiments, each R L1a 、R L1b Each independently selected from H, halogen, CN, OH, NO2, NH2, =O, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 In some embodiments, each R L2a1 、R L2a2 Each independently selected from H, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from F, Cl, OH, NH2, CN; in some embodiments, each R L2a1 、R L2a2 Each is independently selected from H, methyl, ethyl;

[0024] R L1 Independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, acetyl, C1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0025] Each R L2a1 、R L2a2 Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substituted; alternatively, R L2a1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;

[0026] Each R L2b Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; In some embodiments, each R L2b Each independently selected from H, C 1-4 Alkyl, wherein the alkyl is optionally further substituted by 1-2 groups selected from F, Cl, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkyl subunit, halogenated C 1-4 Alkyl subunit, C 1-2 Alkoxy, fluorinated C 1-2 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; In some embodiments, each R L2b Each independently selected from H, C 1-4 Alkyl, C 4-6 Cycloalkyl, wherein the cycloalkyl is optionally further substituted by 1-2 groups selected from F, Cl, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkyl subunit, halogenated C 1-4 alkyl subunit; in some embodiments, each R L2bEach independently selected from H, C 1-4 alkyl;

[0027] Each R L2d Each independently selected from C 1-4 Alkyl, halogen, OH, NH2, CN, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)H, -C(=O)OH, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, N3, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; In some embodiments, each R L2d Each independently selected from C 1-4 Alkyl, wherein the alkyl is optionally further substituted by 1-2 groups selected from halogen, OH, NH2, CN, N3, C 1-2 Alkoxy, fluorinated C 1-2 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; In some embodiments, each R L2b Each independently selected from 1-2 C 1-4 Alkyl subunit, halogenated C 1-4 C substituted by alkyl subunit 3-10 Cycloalkyl; in some embodiments, each R L2b Each independently selected from 1-2 C 1-4 Alkyl subunit, halogenated C 1-4 C substituted by alkyl subunit 4-6 Cycloalkyl;

[0028] R L2c Selected from -C 1-4 Alkyl-(5-10 membered heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from halogen, CN, OH, NO2, NH2, halo 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 In some embodiments, R L2c Selected from -C 1-2 Alkyl-(5-6 membered monocyclic heteroaryl), -C 1-2Alkyl-(8-10 membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from F, Cl, CN, OH, NO2, NH2, halogenated C 1-2 In some embodiments, R L2c Selected from -C 1-2 Alkyl-(5-6 membered monocyclic heteroaryl), -C 1-2 Alkyl-(8-10 membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted with 1-3 substituents selected from F, Cl, CN, OH, NO2, NH2, -CH2F, -CHF2, -CF3;

[0029] p is selected from 0, 1, 2, 3, 4; in some embodiments, p is selected from 0, 1 or 2; in some embodiments, p is selected from 0 or 1;

[0030] Unless otherwise specified, the heterocycle, heterocyclic group, heterocycloalkyl group, and heteroaryl group contain 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0031] Specifically, in the first technical solution of the present invention, the compound of formula (I), its stereoisomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts,

[0032] Ring A is selected from 4-8 membered monocyclic carbocyclic group, 6-12 membered bicyclic carbocyclic group, 6-12 membered monocyclic heterocyclic group, 6-12 membered bicyclic heterocyclic group or none, wherein the carbocyclic group and heterocyclic group are optionally substituted by 1-4 R A replace;

[0033] Ring C is selected from 5-membered heteroaryl and 5-7-membered carbon ring, 5-membered heteroaryl and 5-7-membered hetero ring, C 3-6 Monocyclic carbocyclic ring, 5-6 membered monocyclic heterocyclic cycloalkyl, C 5-10 Bicyclic cycloalkyl, 5-10 membered bicyclic heterocyclic cycloalkyl, the heteroaryl, carbocyclic, heterocyclic, cycloalkyl, heterocycloalkyl are optionally substituted by 1-4 R C Replace; Indicates the connection site between ring C and pyridine ring, "*" indicates the connection site between ring C and L2;

[0034] R c1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;

[0035] R c3 With R B Together they form a 6-7 membered heterocyclic ring;

[0036] L1 is selected from a bond, -C 1-4 Alkyl-, -C=O, -OC(RL1a R L1b ) p -、-S-(CR L1a R L1b ) p -, -C(=O)NR L1 -、C 2-6 Alkenyl or C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1a replace;

[0037] In some embodiments, when Ring A is absent, L1 is selected from -OC substituted with one COOH. 1-6 Alkyl; In some embodiments, Ring A is selected from absent, L1 is selected from -OCH2C(CH3)2CH2COOH, -OCH2CH2C(CH3)2COOH;

[0038] L2 is selected from (CR L2a1 R L2a2 ) p -OC(=O)N(R L2b )2、-C(=O)N(R L2b )2、-NR L2b -C(=O)OR L2c 、-(CR L2a1 R L2a2 ) p N(R L2b )2、-(CH2) p R L2d 、-(CR L2a1 R L2a2 ) p N(R L2b )S(O)2N(R L2b )2、(CR L2a1 R L2a2 ) p N(R L2b )C(=O)N(R L2b )2 or -(CR L2a1 R L2a2 ) p N(R L2b )C(=O)OR L2b ;

[0039] R A Each independently selected from H, halogen, CN, OH, -(CH2) p -COOR a1 、-(CH2) p -C(=O)NR a1 R a2 、-(CH2)p -C(=O)NHC(=O)R a1 、-(CH2) p -C(=O)NHS(O)2R a1 、-(CH2) p -C(=O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHCOR a1 、-(CH2) p -P(O)(OH)2、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl or -(CH2) p -(5-10 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, heterocyclic group is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0040] R B independently selected from H;

[0041] R C Each independently selected from halogen, CN, OH, NO2, NH2, =O, C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkoxy, alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0042] R a1 、R a2 Each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0043] R c2 Selected from -(CR L2a1 R L2a2 ) p -C3-7 -(CR L2a1 R L2a2 ) p -(4-7 membered heterocycloalkyl), halogen, CN, OH, NO2, NH2, halogenated C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0044] Each R L1a 、R L1b Each independently selected from H, halogen, CN, OH, NO2, NH2, =O, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or -(CH2) p -COOR a1 The alkyl, alkenyl, alkynyl, cycloalkyl group may be further substituted by 1-4 halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0045] R L1 Independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0046] Each R L2a1 、R L2a2 Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0047] Alternatively, R L2a1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;

[0048] Each RL2b Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0049] Each R L2d Each independently selected from C 1-4 Alkyl, halogen, OH, NH2, CN, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)H, -C(=O)OH, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, N3, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0050] R L2c Selected from -C 1-4 Alkyl-(5-10 membered heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from halogen, CN, OH, NO2, NH2, halo 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Substitution of alkynyl groups by substituents;

[0051] p is selected from 0, 1, 2, 3, 4;

[0052] Unless otherwise specified, heterocycles, heterocyclic groups, heterocycloalkyl groups, and heteroaryl groups contain 1 to 4 heteroatoms selected from N, O, S, S(O), and S(O)2.

[0053] Furthermore, the compound of formula (I), its stereoisomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts,

[0054] Ring A is selected from 4-8 membered monocyclic carbocyclic groups, 6-12 membered bicyclic carbocyclic groups, 6-12 membered monocyclic heterocyclic groups, 6-12 membered bicyclic heterocyclic groups, wherein the carbocyclic groups and heterocyclic groups are optionally substituted by 1-4 R A replace;

[0055] Ring C is selected from 5-membered heteroaryl and 5-7-membered carbocyclic ring, 5-membered heteroaryl and 5-7-membered heterocyclic ring, wherein the heteroaryl, carbocyclic ring, and heterocyclic ring are optionally replaced by 1-4 R C Replace; Indicates the connection site between ring C and pyridine ring, "*" indicates the connection site between ring C and L2;

[0056] L1 is selected from a bond, -C 1-4 Alkyl-, -C=O, -OC(R L1a R L1b ) p -、-S-(CR L1a R L1b ) p -, -C(=O)NR L1 -、C 2-6 Alkenyl or C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1a replace;

[0057] R c1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;

[0058] R c3 With R B Together they form a 6-7 membered heterocyclic ring;

[0059] L2 is selected from (CR L2a1 R L2a2 ) p -OC(=O)N(R L2b )2、-C(=O)N(R L2b )2、-NR L2b -C(=O)OR L2c 、-(CR L2a1 R L2a2 ) p N(R L2b )2、-(CH2) p R L2d 、-(CR L2a1 R L2a2 ) p N(R L2b )S(O)2N(R L2b )2、(CR L2a1 R L2a2 )p N(R L2b )C(=O)N(R L2b )2;

[0060] R A Each independently selected from H, halogen, CN, OH, -(CH2) p -COOR a1 、-(CH2) p -C(=O)NR a1 R a2 、-(CH2) p -C(=O)NHC(=O)R a1 、-(CH2) p -C(=O)NHS(O)2R a1 、-(CH2) p -C(=O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHCOR a1 、-(CH2) p -P(O)(OH)2、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl or -(CH2) p -(5-10 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, heterocyclic group is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0061] R B independently selected from H;

[0062] R C Each independently selected from halogen, CN, OH, NO2, NH2, C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkoxy, alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0063] R a1 、R a2 Each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0064] R c2 Selected from C 3-7 4-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, halogen, CN, OH, NO2, NH2, halogenated C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0065] R c1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;

[0066] R c3 With R B Together they form a 6-7 membered heterocyclic ring;

[0067] Each R L1a 、R L1b Each independently selected from H, halogen, CN, OH, NO2, NH2, =O, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0068] R L1 Independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0069] Each R L2a1 、R L2a2 Each independently selected from H, C 1-4 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0070] Alternatively, R L2a1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;

[0071] Each R L2b Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0072] Each R L2d Each independently selected from C 1-4 Alkyl, halogen, OH, NH2, CN, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)H, -C(=O)OH, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, N3, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0073] R L2c Selected from -C 1-4 Alkyl-(5-10 membered heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from halogen, CN, OH, NO2, NH2, halo 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Substitution of alkynyl groups by substituents;

[0074] p is selected from 0, 1, 2, 3, 4;

[0075] Unless otherwise specified, the heterocycle, heterocyclic group, heterocycloalkyl group, and heteroaryl group contain 1 to 4 heteroatoms selected from N, O, and S.

[0076] The second technical solution of the present invention is the compound of formula (I), its stereoisomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein:

[0077] Ring A is selected from 4-7 membered monocyclic carbocyclyl, 6-10 membered bicyclic carbocyclyl, 6-10 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; in some embodiments, ring A is selected from 4-7 membered monocyclic carbocyclyl; in some embodiments, ring A is selected from The ring A is substituted with 1 COOH; and / or

[0078] R A Each independently selected from halogen, CN, OH, COOH, -CH2COOH, C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -OC 1-2 Alkyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 In some embodiments, R A Each is independently selected from COOH, -CH2COOH.

[0079] The third technical solution of the present invention is the compound of formula (I) or (I-1), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt,

[0080] Ring C is selected from 5-membered heteroaryl and 5-7-membered cycloalkyl, 5-membered heteroaryl and aryl, 5-membered heteroaryl and 5-7-membered heterocycloalkyl, 5-membered heteroaryl and 5-7-membered heteroaryl, C 3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclic cycloalkyl, C 5-10 Bicyclic cycloalkyl, 5-10 membered bicyclic heterocyclic cycloalkyl, the heteroaryl, heterocyclic ring contains 1-3 heteroatoms selected from N, O, S; the heteroaryl, cycloalkyl, phenyl, heterocycloalkyl, heteroaryl are optionally substituted by 1-4 R C Replace; Indicates the connection site between ring C and pyridine ring, "*" indicates the connection site between ring C and L2; In some embodiments, ring C is selected from 5-membered heteroaryl and 5-6-membered cycloalkyl, 5-membered heteroaryl and 5-6-membered heterocycloalkyl, C 3-6Monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclic cycloalkyl, C 5-10 Bicyclic cycloalkyl, 5-10 membered bicyclic heterocyclic cycloalkyl, the heteroaryl, heterocyclic ring contains 1-3 heteroatoms selected from N, O, S; the heteroaryl, cycloalkyl, phenyl, heterocycloalkyl, heteroaryl are optionally substituted by 1-3 R C Substituted; In some embodiments, Ring C is selected from and / or

[0081] R C Each independently selected from H, halogen, CN, OH, =O, NH2, C 1-2 Alkyl, -OC 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R C Each independently selected from H, halogen, CN, OH, =O, NH2, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R C Each independently selected from H, F, Cl, ═O, CH 3 , CH 2 CH 3 ; and / or

[0082] R c2 Selected from C 3-4 cycloalkyl, 4-5 membered heterocycloalkyl, -CH2-C 3-4 -CH2-(4-5 membered heterocycloalkyl), fluoro-C 1-2 Alkyl; in some embodiments, R c2 Selected from cyclopropyl, cyclobutyl, oxetanyl, oxolanyl, azetidinyl, azetyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3;

[0083] R c1 、R c4 、R c5Each is independently selected from H, F, Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3;

[0084] R c3 Selected from H, methyl, ethyl;

[0085] Alternatively, R c1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;

[0086] Alternatively, R c3 With R B Together they form a 6-7 membered heterocyclic ring.

[0087] Furthermore, the compound of formula (I) or (I-1), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt,

[0088] Ring C is selected from 5-membered heteroaryl and 5-7-membered cycloalkyl, 5-membered heteroaryl and aryl, 5-membered heteroaryl and 5-7-membered heterocycloalkyl, 5-membered heteroaryl and 5-7-membered heteroaryl, the heteroaryl and heterocycle contain 1-3 heteroatoms selected from N, O, and S; the heteroaryl, cycloalkyl, phenyl, heterocycloalkyl, heteroaryl are optionally substituted by 1-4 R C Replace; Indicates the connection site between ring C and pyridine ring, "*" indicates the connection site between ring C and L2; In some embodiments, ring C is selected from 5-membered heteroaryl and 5-6-membered cycloalkyl, 5-membered heteroaryl and 5-6-membered heterocycloalkyl, the heteroaryl and heterocycle contain 1-3 heteroatoms selected from N, O, and S; the heteroaryl, cycloalkyl, phenyl, heterocycloalkyl, heteroaryl are optionally substituted by 1-3 R C Substituted; In some embodiments, Ring C is selected from and / or

[0089] R C Each independently selected from H, halogen, CN, OH, NH2, C 1-2 Alkyl, -OC 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R CEach independently selected from H, halogen, CN, OH, NH2, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R C Each independently selected from H, F, Cl, CH3, CH2CH3; and / or

[0090] R c2 Selected from C 3-4 4-membered cycloalkyl, 4-5-membered heterocycloalkyl, fluorinated C 1-2 Alkyl; in some embodiments, R c2 Selected from cyclopropyl, cyclobutyl, oxetanyl, oxolanyl, azetidinyl, azopentyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3;

[0091] R c1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;

[0092] R c3 With R B Together they form a 6-7 membered heterocyclic ring.

[0093] Furthermore, the compound of formula (I), its stereoisomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein:

[0094] Ring C is selected from in Indicates the connection site between ring C and pyridine ring, "*" indicates the connection site between ring C and L2;

[0095] L1 is selected from -O-; and / or

[0096] L2 is selected from -(CR L2a1 R L2a2 ) p -OC(=O)NHR L2b 、-(CR L2a1 R L2a2 ) p -OC(=O)N(C 1-4 alkyl)R L2b 、-C(=O)NHR L2b 、-C(=O)N(C 1-4 alkyl)R L2b 、-NHC(=O)OR L2c 、-N(C 1-4alkyl)C(=O)OR L2c 、-(CR L2a1 R L2a2 ) p NHC(=O)OR L2b 、-(CR L2a1 R L2a2 ) p N(C 1-4 alkyl)C(=O)OR L2b ;

[0097] Each R L2a1 、R L2a2 Each independently selected from H, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from F, Cl, OH, NH2, and CN;

[0098] Alternatively, R L2a1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;

[0099] Each R L2b Each independently selected from 1-2 C 1-4 Alkyl subunit, halogenated C 1-4 C substituted by alkyl subunit 3-10 Cycloalkyl;

[0100] R L2c Selected from -C 1-2 Alkyl-(5-6 membered monocyclic heteroaryl), -C 1-2 Alkyl-(8-10 membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from F, Cl, CN, OH, NO2, NH2, halogenated C 1-2 The substituent of the alkyl group is substituted; preferably, R L2c Selected from -C 1-2 Alkyl-(5-6 membered monocyclic heteroaryl), -C 1-2 Alkyl-(8-10 membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted with 1-3 substituents selected from F, Cl, CN, OH, NO2, NH2, -CH2F, -CHF2, -CF3;

[0101] p is selected from 0, 1 or 2.

[0102] The fourth technical solution of the present invention is the compound of formula (I), its stereoisomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein:

[0103] L1 is selected from a bond, -O-, -O-CH2-, -C=O, -CH2-, or -O-CH2-C(CH3)2-CH2-; in some embodiments, L1 is selected from -O-; and / or

[0104] L2 is selected from (CR L2a1 R L2a2 ) p -OC(=O)N(R L2b )2、-C(=O)N(R L2b )2、-NR L2b -C(=O)OR L2c or -(CR L2a1 R L2a2 ) p N(R L2b )C(=O)OR L2b ;

[0105] Each R L2a1 、R L2a2 Each independently selected from H, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from F, Cl, OH, NH2, CN; in some embodiments, each R L2a1 、R L2a2 Each is independently selected from H, methyl, ethyl;

[0106] Alternatively, R L2a1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;

[0107] Each R L2b Each independently selected from H, C 1-4 Alkyl, C 3-10 Cycloalkyl, the alkyl, cycloalkyl optionally further 1-2 selected from F, Cl, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkyl subunit, halogenated C 1-4 Alkyl subunit, C 1-2 Alkoxy, fluorinated C 1-2 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; preferably, each R L2b Each independently selected from H, C 1-4 Alkyl, C 4-6 Cycloalkyl, wherein the cycloalkyl is optionally further substituted by 1-2 groups selected from F, Cl, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkyl subunit, halogenated C 1-4alkyl subunit; or in some embodiments, each R L2b Each independently selected from H, C 1-4 Alkyl, wherein the alkyl is optionally further substituted by 1-2 groups selected from F, Cl, OH, NH2, CN, C 1-2 Alkoxy, fluorinated C 1-2 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; In some embodiments, each R L2b Each independently selected from H, C 1-4 alkyl;

[0108] R L2c Selected from -C 1-2 Alkyl-(5-6 membered monocyclic heteroaryl), -C 1-2 Alkyl-(8-10 membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from F, Cl, CN, OH, NO2, NH2, halogenated C 1-2 In some embodiments, R L2c Selected from -C 1-2 Alkyl-(5-6 membered monocyclic heteroaryl), -C 1-2 Alkyl-(8-10 membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted with 1-3 substituents selected from F, Cl, CN, OH, NO2, NH2, -CH2F, -CHF2, -CF3;

[0109] p is selected from 0, 1 or 2.

[0110] Furthermore, the compound of formula (I), its stereoisomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein:

[0111] L2 is selected from -(CR L2a1 R L2a2 ) p -OC(=O)NHR L2b 、-(CR L2a1 R L2a2 ) p -OC(=O)N(CH3)R L2b 、-(CR L2a1 R L2a2 ) p NHC(=O)OR L2b 、-(CR L2a1 R L2a2 ) p N(CH3)C(=O)OR L2b ;

[0112] Each R L2a1、R L2a2 Each independently selected from H, C 1-2 alkyl;

[0113] Each R L2b Each independently selected from 1-2 C 1-4 Alkyl subunit, halogenated C 1-4 C substituted by alkyl subunit 4-6 Cycloalkyl;

[0114] p is selected from 0 or 1.

[0115] In the fifth technical solution of the present invention, the general formula (I) is further represented by the general formula (I-1):

[0116] Among them, L2, R B As described in any of the above technical solutions.

[0117] Furthermore, the compounds of formula (I) and (I-1) of the present invention, their stereoisomers, deuterated forms, solvates, cocrystals or pharmaceutically acceptable salts are selected from but not limited to the structures in Table 1 below:

[0118] Table 1:

[0119] Secondly, the present invention also provides a pharmaceutical composition, which contains the compound described in any one of the aforementioned schemes, its stereoisomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0120] Furthermore, the pharmaceutical composition or pharmaceutical preparation of the present invention contains 1-1500 mg of the compound described in any of the aforementioned schemes, its stereoisomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0121] Furthermore, the present invention also provides the use of a compound according to any of the aforementioned embodiments, or a stereoisomer, deuterated form, solvate, cocrystal, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating / preventing an LPAR1-mediated disease. Furthermore, the LPAR1-mediated disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve damage, and neuralgia, preferably idiopathic pulmonary fibrosis and progressive pulmonary fibrosis.

[0122] The present invention also provides a method for treating a disease in a mammal or human, comprising administering to a subject a therapeutically effective amount of a compound as described in any of the foregoing schemes, its stereoisomers, deuterated forms, solvates, cocrystals, or pharmaceutically acceptable salts, or a composition as described herein, wherein the disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve damage, and neuralgia. Preferably, the therapeutically effective amount is 1-1500 mg. In some embodiments, the mammal described herein does not include humans.

[0123] As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein to 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 alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts 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. ;

[0124] The present invention relates to a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, cocrystal, or pharmaceutically acceptable salt thereof, and a carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength"). In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 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 1500 mg, 1500 mg of a compound of the present invention or a stereoisomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt thereof.

[0125] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, its stereoisomers, deuterated forms, solvates, cocrystals or pharmaceutically acceptable salts, 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 or progressive pulmonary fibrosis.

[0126] A method for treating a disease in a mammal or a human, comprising administering a compound of the present invention, a stereoisomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient to a subject at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or divided doses. 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 In some embodiments, the daily dose includes but is not limited to 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day.

[0127] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.

[0128] The amount of the compound of the invention or its stereoisomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt in the present invention is in each case calculated based on the free base form.

[0129] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0130] Synthesis route

[0131] Those skilled in the art can prepare the compounds of the present invention by combining this document with known organic synthesis techniques, using commercially available chemicals and / or compounds described in the chemical literature as starting materials. "Commercially available chemicals" are obtained from reputable commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0132] The ACS Chemical Abstracts Service index of known chemical substances allows for the selective identification of specific and similar

[0133] Reactants are indexed to a wide variety of reagents, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis facilities, many of which (e.g., those listed above) offer custom synthesis services.

[0134] the term

[0135] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0136] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0137] "Halo" or "halogen substitution" means that a hydrogen atom is replaced by one or more halogens selected from F, Cl, Br, I, or isotopes thereof. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they may be the same or different halogens.

[0138] "Deuterated" or "deuterated compound" refers to a situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl or other group is replaced by at least one isotope, deuterium. The upper limit of the number of deuterated groups is equal to the sum of the number of replaceable hydrogen atoms in the substituted group. Unless otherwise specified, the number of deuterated groups is any integer between 1 and the upper limit, preferably 1-20 deuterium atoms, more preferably 1-10 deuterium atoms, more preferably 1-6 deuterium atoms, and even more preferably 1-3 deuterium atoms.

[0139] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group. Unless otherwise specified, it is an alkyl group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, further preferably an alkyl group having 1 to 4 carbon atoms, and further preferably an alkyl group having 1-2 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof.

[0140] "Alkylene" refers to a divalent straight-chain or branched saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0141] "Alkylene" refers to a divalent free valence alkyl structure formed by losing two hydrogen atoms, wherein alkyl is as defined above. Non-limiting examples include: ethyl subunit 1-Methylethylidene

[0142] "Haloalkylene" refers to an alkylene group substituted with one or more halogens, wherein alkylene is as defined above. Non-limiting examples include: fluoromethylene difluoromethylidene

[0143] "Cycloalkyl" refers to a monovalent non-aromatic, partially unsaturated or fully saturated, substituted or unsubstituted carbocyclic hydrocarbon group, which, unless otherwise specified, usually has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and further preferably 3 to 4 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, etc. The cycloalkyl group may be a monocyclic cycloalkyl group or a polycyclic cycloalkyl group (such as a bicyclic cycloalkyl group or a tricyclic cycloalkyl group).

[0144] "Cycloalkylene" refers to a divalent radical of "cycloalkyl", non-limiting examples of which include cyclopropylene, cyclobutylene, and the like.

[0145] "Heterocycle" or "heterocyclyl" 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 nitrogen, oxygen, or sulfur, and includes monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles, and bicyclic spiro heterocycles. Unless otherwise specified, it 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. This definition includes heterocycloalkyl and heteroaryl groups. The nitrogen and sulfur atoms in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxane, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dithio ... hydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, wait.

[0146] "Heterocyclylene" is a divalent group corresponding to "heterocyclyl", and non-limiting examples include imidazolyl, piperidinyl, aziridinyl, and the like.

[0147] "Carbocycle" or "carbocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic group, including monocyclic carbocycles, bicyclic bridged rings, bicyclic cyclic rings and bicyclic spirocycles, etc., unless otherwise specified, and has 3 to 12 carbon atoms, preferably 3-10 carbon atoms, and more preferably 3-6 carbon atoms. Its definition includes cycloalkyl and aryl. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, etc., the bicyclic bridge ring includes etc., double ring and ring include etc., bicyclic spiro ring includes wait.

[0148] "Aryl" refers to a carbon ring having aromatic properties. Non-limiting examples include phenyl, naphthyl, and the like.

[0149] "Alkynyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, propargyl, etc.

[0150] "Alkenyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include ethenyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0151] "Alkoxy" or "alkyloxy" refers to -O-alkyl, and unless otherwise specified, -OC 1-8 Alkyl, preferably -OC 1-6 Alkyl, more preferably -OC 1-4 Alkyl, more preferably -OC 1-2 Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, cyclobutyloxy, and the like.

[0152] "Haloalkoxy" refers to -O-haloalkyl, unless otherwise specified, -O-haloC 1-8 Alkyl, preferably -O-halogenated C 1-6 Alkyl, more preferably -O-halogenated C 1-4 Alkyl, more preferably -O-halogenated C 1-2 Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0153] “C 1-4 "Alkyl acyl" refers to C 1-4 Alkyl-C(O)-. Non-limiting examples include formyl, acetyl, propionyl.

[0154] “C 1-4 "Alkylsulfonyl" refers to C 1-4 Alkyl-S(O)2-. Non-limiting examples include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.

[0155] "Heteroaromatic ring" or "heteroaryl" refers to a heterocyclic ring having aromatic properties. Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridinyl, furyl, and the like.

[0156] " Heterocycloalkyl " refers to a non-aromatic, partially unsaturated or fully saturated heterocycle, which generally has 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, further preferably 5 or 6 ring members. In addition to carbon atoms, heterocycloalkyl also includes 1-3 heteroatoms selected from N, S, O, Si, P as ring members. Non-limiting examples include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl etc. Heterocycloalkyl can be monocyclic heterocyclic cycloalkyl, polycyclic heterocyclic cycloalkyl (such as bicyclic heterocyclic cycloalkyl, tricyclic heterocyclic cycloalkyl). At least one ring in the ring system of polycyclic heterocyclic cycloalkyl contains heteroatoms.

[0157] "Alkylamino" or "alkylamino" refers to an amino group substituted with a single or double alkyl group, also written as -N-(alkyl)2 or -NH-alkyl, the latter also written as monoalkylamino. Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino, etc.

[0158] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0159] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that retain the biological effectiveness and properties of the free acids or free bases, and the free acids are reacted with non-toxic inorganic or organic bases, or the free bases are reacted with non-toxic inorganic or organic acids.

[0160] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0161] "Carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0162] "Excipient" refers to a substance that is not itself a therapeutic agent and is used as a diluent, adjuvant, binder, and / or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can provide various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., sodium cross-linked carboxymethylcellulose); (4) tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other nontoxic compatible substances used in pharmaceutical preparations.

[0163] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0164] "Solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric amount of a solvent bound to the compound or salt thereof by non-covalent forces between the molecules. When the solvent is water, the solvate is a hydrate.

[0165] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate. DETAILED DESCRIPTION

[0166] The present invention will be described in detail below through examples. Where specific conditions are not specified in the examples, the experimental methods are carried out according to conventional conditions. The examples are provided to better illustrate the present invention, but it should not be understood that the present invention is limited to the examples. Any non-essential improvements and adjustments made by those skilled in the art to the embodiments based on the above invention are still within the scope of protection of the present invention.

[0167] Test Method

[0168] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (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).

[0169] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0170] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C 18 100 × 4.6 mm, 3.5 μM);

[0171] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0172] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0173] Example 1

[0174] Step 1: Dissolve 1A (7.0 g, 37.2 mmol) in dry toluene (300 mL) at room temperature. Add isopropyl (1S,3R)-3-hydroxycyclohexane-1-carboxylate (20.8 g, 111.6 mmol) and tri-n-butylphosphine (37.6 g, 186.0 mmol). Stir thoroughly. Add diazopyridine (28.1 g, 111.6 mmol). Under a nitrogen atmosphere, react at 80°C for 16 hours. Cool to room temperature, add ethyl acetate (300 mL), and wash the organic phase with water (100 mL × 3) and saturated brine (100 mL × 2). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The residue is purified by silica gel column chromatography to obtain the target compound 1B (3.0 g, 22%).

[0175] LC-MS (ESI): m / z = 356.2 [M+H] + .

[0176] Step 2: 1B (3.0 g, 8.5 mmol), (3-formylthiophen-2-yl)boronic acid (2.7 g, 17.0 mmol), and potassium fluoride (3.0 g, 51.0 mmol) were added to tetrahydrofuran (60 mL), followed by bis(tri-tert-butylphosphine)palladium (436 mg, 0.85 mmol). The mixture was reacted overnight at room temperature under a nitrogen atmosphere. Ethyl acetate (100 mL) was added to the reaction solution, and the organic phase was washed with water (100 mL × 3) and saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain the target compound 1C (2.9 g, 87%).

[0177] LC-MS (ESI): m / z = 388.2 [M+H] + .

[0178] Step 3: Dissolve 1C (2.9 g, 7.49 mmol) and sodium borohydride (570 mg, 15.0 mmol) in anhydrous ethanol (30 mL) and react at room temperature for 1 hour. After completion of the reaction, concentrate under reduced pressure and purify by silica gel column chromatography to obtain the target compound 1D (2.9 g, 99%).

[0179] LC-MS (ESI): m / z = 390.1 [M+H] + .

[0180] Step 4: Dissolve 1D (2.9 g, 7.45 mmol) in N,N-dimethylformamide (30 mL), add N-chlorosuccinimide (1.1 g, 8.19 mmol), and react at 45°C for 16 hours. After completion of the reaction, add ethyl acetate (100 mL). The organic phase is washed with water (100 mL × 3) and saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain the target compound 1E (3.0 g, 95%).

[0181] LC-MS (ESI): m / z = 424.2 [M+H] + .

[0182] Step 5: To a solution of 1E (3.0 g, 7.07 mmol) and phenyl 4-nitrochloroformate (4.3 g, 21.21 mmol) in dichloromethane (60 mL) was added pyridine (2.8 g, 35.35 mmol) and allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford the target compound 1F (2.2 g, 53%).

[0183] LC-MS (ESI): m / z = 589.1 [M+H] + .

[0184] Step 6: To a solution of 1F (1.0 g, 1.7 mmol) and 3-methylenecyclobutane-1-amine trifluoroacetate (0.31 g, 1.7 mmol) in tetrahydrofuran (20 mL) was added N,N-diisopropylethylamine (0.66 g, 5.1 mmol) and allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford the target compound 1G (0.7 g, 77%).

[0185] LC-MS (ESI): m / z = 533.1 [M+H] + .

[0186] Step 7: To a solution of 1G (0.3 g, 0.56 mmol) and iodomethane (0.24 g, 1.7 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (68 mg, 1.7 mmol, 60%) at room temperature for 2 hours. Ethyl acetate (20 mL) was added to the reaction solution, and the organic phase was washed with water (20 mL × 3) and saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to afford the target compound 1H (0.25 g, 82%).

[0187] LC-MS (ESI): m / z = 547.1 [M+H] + .

[0188] Step 8: Compound 1H (250 mg, 0.46 mmol) was dissolved in tetrahydrofuran:methanol:water = 1:1:1 (6 ml), and then anhydrous lithium hydroxide (55 mg, 2.3 mmol) was added. The reaction was allowed to react at 50°C for 1 hour. After completion of the reaction, the pH was adjusted to 5-6 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3), washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative HPLC to obtain compound 1 (100 mg, yield: 43%).

[0189] LC-MS (ESI): m / z = 505.2 [M+H] + .

[0190] 1 H NMR(400MHz,DMSO-d6)δ7.53-7.44(m,1H),7.44-7.35(m,1H),7.11(s,1H),5.19(s,2H),4.89-4.61(m,3H),4.61-4.17(m,1H ),2.91-2.83(m,2H),2.82(s,3H),2.78-2.57(m,3H),2.40(s,3H),2.10-1.93(m,1H),1.90-1.72(m,3H),1.67-1.41(m,4H).

[0191] Example 2:

[0192] Step 1: Compound 2A (500 mg, 2.73 mmol) was added to a reaction flask and dissolved in N,N-dimethylformamide (10 ml). Sodium hydride (160 mg, 4.10 mmol, 60% purity) was added at 0°C and maintained at this temperature for 30 min. Then, iodomethane (775 mg, 5.46 mmol) was added and the mixture was allowed to warm to room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (50 ml) and extracted twice with ethyl acetate (50 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified on a normal phase column to afford compound 2B (475 mg, 88.29% yield).

[0193] 1 H NMR (400MHz, DMSO-d6) δ4.84-4.80(m,2H),4.50-4.24(m,1H),2.90-2.80(m,2H),2.78-2.70(m,2H),1.39(s,9H).

[0194] Step 2: Compound 2B (470 mg, 2.38 mmol) was added to a reaction flask and dissolved in dichloromethane (10 ml). Trifluoroacetic acid (0.5 ml) was then added and allowed to react at room temperature for 1 h. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure to afford crude compound 2C (250 mg, TFA salt), which was used directly in the next step.

[0195] LC-MS (ESI): m / z = 98.1 [M+H] + .

[0196] Step 3: Compound 2D (0.30 g, 0.77 mmol, synthesized according to the method of patent WO2019126085A1) was added to dichloromethane (15 mL), and pyridine (0.24 g, 3.08 mmol) and 4-nitrophenyl chloroformate (0.23 g, 1.16 mmol) were added in sequence. The reaction was continued at room temperature for 3 hours. After the reaction was completed by TLC monitoring, it was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), and triethylamine (0.39 g, 3.85 mmol) and compound 2C (250 mg, TFA salt) were added in sequence. The reaction was continued at room temperature for 3 hours. After the reaction was completed by TLC monitoring, it was concentrated under reduced pressure. The residue was purified by normal phase column to obtain compound 2E (0.32 g, yield: 81%).

[0197] LC-MS (ESI): m / z = 511.2 [M+H] + .

[0198] Step 4: Compound 2E (0.32 g, 0.63 mmol) was dissolved in methanol (5 mL), tetrahydrofuran (5 mL), and water (5 mL), followed by the addition of lithium hydroxide (112 mg, 2.71 mmol). The reaction was allowed to react at room temperature for 15 hours. After completion of the reaction, 1 M dilute hydrochloric acid was added to adjust the pH to a weakly acidic state. A small amount of water was then added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were concentrated and purified by HPLC to afford compound 2 (0.15 g, 51%).

[0199] LC-MS (ESI): m / z = 469.2 [M+H] + .

[0200] 1H NMR(400MHz,CD3OD)δ8.06(d,1H),7.87(s,1H),7.82(d,1H),5.42(s,2H),4.97-4.94(m,1H),4.86-4.85(m,2H),4.52 -4.49(m,1H),4.03(s,3H),2.98-2.91(m,5H),2.86-2.78(m,3H),2.71(s,3H),2.13-1.93(m,4H),1.81-1.68(m,4H).

[0201] Example 3:

[0202] 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 atmosphere was purged with nitrogen three times and cooled to -45°C. A solution of 3A (10 g, 56.75 mmol) in DMF (25 ml) and a solution of 2-(difluoromethanesulfonyl)pyridine (9.86 g, 51.08 mmol) in DMF (25 ml) were slowly added dropwise. The mixture was allowed to react at this temperature for one hour. Saturated ammonium chloride solution (30 mL) and aqueous hydrochloric acid (1 N, 50 mL) were then added, and the temperature was slowly warmed to room temperature for 16 hours. After completion of the reaction, the mixture was diluted with water (100 ml) and extracted twice with methyl tert-butyl ether (100 ml x 2). The organic phases were combined, dried, and concentrated under reduced pressure at 30°C. The resulting residue was purified by silica gel column chromatography (PE:EA = 10:1) to yield compound 3B (4 g, 33.5%).

[0203] 1 H NMR (400MHz, CDCl3-d) 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).

[0204] Step 2: Compound 3B (4 g, 19.05 mmol) was added to a reaction flask and dissolved in dichloromethane (100 ml). The atmosphere was replaced with nitrogen three times and cooled to -78°C. Boron tribromide (9.52 g, 38.10 mmol) was then added dropwise and maintained at this temperature for half an hour. After completion of the reaction, saturated sodium bicarbonate solution (200 ml) was added to adjust the pH to greater than 7 using TLC. The mixture was extracted with dichloromethane twice (50 ml x 2). The organic phases were combined, dried, and filtered to obtain a crude solution of compound 3C, which was used directly in the next step.

[0205] Step 3: Compound 3C was added to a reaction flask and dissolved in tetrahydrofuran (20 ml). Pyridine (4.52 g, 57.2 mmol) and p-nitrophenyl chloroformate (7.67 g, 38.1 mmol) were then added and allowed to react at room temperature for 1 hour. After completion of the reaction, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford compound 3D (2.5 g, two-step yield: 46.0%).

[0206] 1 H NMR (400MHz, CDCl3-d) δ8.32-8.26(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).

[0207] Step 4: Compound 3E (330 mg, 0.86 mmol, synthesized according to the method of patent WO2019126085A1) was dissolved in tetrahydrofuran (20 mL), and compound 3D (368 mg, 1.29 mmol) and N,N-diisopropylethylamine (333 mg, 2.58 mmol) were added. The mixture was reacted at room temperature for 1 h. After the raw material completely disappeared, the mixture was concentrated and the crude product was separated by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain the target compound 3F (210 mg, 46.2%).

[0208] LC-MS (ESI): m / z = 533.1 [M+H] +

[0209] Step 5: Compound 3F (210 mg, 0.39 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (81 mg, 1.97 mmol) was then added and allowed to react at room temperature for 15 hours. After completion of the reaction, 1 M dilute hydrochloric acid was added to adjust the pH to 5-6. The mixture was concentrated and purified by HPLC to yield compound 3 (30 mg, 15.1%).

[0210] LC-MS (ESI): m / z = 491.3 [M+H] + .

[0211] 1H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.67-7.60(m,1H),7.47-7.35(m,2H),4.99-4.91(m,1H),4.72(s,1H),4.61(d,2H ),3.85(s,3H),3.01(s,2H),2.73-2.57(m,3H),2.41(s,3H),2.03-1.94(m,1H),1.89-1.74(m,3H),1.69-1.44(m,4H).

[0212] Example 4:

[0213] Step 1: Dissolve compound 4A (15.00 g, 102.64 mmol) in methanol (150 mL), cool to 0-5°C, and slowly add concentrated sulfuric acid (2 mL) dropwise. Return to room temperature and stir for 17 hours. After completion of the reaction, concentrate under pressure, then add saturated aqueous sodium bicarbonate (150 mL) in portions and extract the impurities twice with petroleum ether (100 mL). The aqueous phase is cooled to 0°C, adjusted to pH 3-4 with 6N aqueous hydrochloric acid, and the product is extracted twice with ethyl acetate (100 mL). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to provide compound 4B (9.20 g, 56% yield).

[0214] Step 2: Compound 4B (5.00 g, 31.22 mmol) was dissolved in dry tetrahydrofuran (50 mL), replaced with nitrogen three times, cooled to 0-5°C, and borane tetrahydrofuran solution (62.44 mL, 62.44 mmol, 1.0 mol / L tetrahydrofuran solution) was slowly added dropwise. After the addition was complete, the temperature was slowly returned to room temperature and reacted for 3 hours. After the reaction was completed, the temperature was lowered to 0°C and methanol (100 mL) was slowly added dropwise to quench the reaction. After quenching was complete, the reaction was concentrated under reduced pressure. The residue was purified by normal phase column to obtain compound 4C (2.60 g, yield: 57%).

[0215] Step 3: Compound 4C (2 g, 13.68 mmol) was added to a dichloromethane (20 mL) solution, followed by the addition of triethylamine (4.15 g, 41.04 mmol). After the addition, the temperature was lowered to 0-5°C and methanesulfonic anhydride (4.77 g, 27.36 mmol) was added in batches. The mixture was reacted at room temperature for 16 hours. After the completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure and the residue was purified by normal phase column to give compound 4D (3 g, yield: 97%).

[0216] LC-MS (ESI): m / z = 225.1 [M+H] + .

[0217] Step 4: Compound 4D (3 g, 13.38 mmol) and 6-bromo-3-hydroxy-2-methylpyridine (2.5 g, 13.38 mmol) were dissolved in N,N-dimethylformamide (10 mL). Cesium carbonate (13.08 g, 40.13 mmol) and sodium iodide (200.5 mg, 1.34 mmol) were added sequentially. The temperature was raised to 100°C and the reaction was allowed to proceed for 16 hours. After completion of the reaction, the reaction was cooled to room temperature, water (50 mL) was added, and the product was extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase column chromatography to afford compound 4E (400 mg, 9.5% yield).

[0218] LC-MS(ESI):m / z=316.1&318.1[M+H] + .

[0219] Step 5: Compound 4F (500 mg, 1.82 mmol, synthesized according to the method of patent WO2019126085A1) and tetrahydroxydiboron (326 mg, 3.63 mmol) were dissolved in anhydrous ethanol (10 mL), and potassium acetate (357 mg, 3.63 mmol), ethylene glycol (338 mg, 5.45 mmol), XPhos (7 mg, 0.02 mmol) and XPhos Pd G2 (14 mg, 0.02 mmol) were added. After nitrogen replacement, the mixture was stirred at 80 ° C for 1 h, then cooled to room temperature, potassium phosphate (773 mg, 3.64 mmol) was added and stirred for 30 min, and then compound 4E (400 mg, 1.27 mmol) was added, and XPhos (7 mg, 0.02 mmol) and XPhos Pd G2 (14 mg, 0.02 mmol) was replaced with nitrogen again, and the temperature was raised to 80°C and stirred for 16 h. After the reaction was completed as monitored by TLC, the solid was filtered out and the reaction was concentrated under reduced pressure. The residue was purified by normal phase column to give compound 4G (450 mg, yield: 57.4%).

[0220] LC-MS (ESI): m / z = 432.2 [M+H] + .

[0221] Step 6: Compound 4G (100 mg, 0.23 mmol) was added to methanol (3 mL), followed by trifluoroacetic acid (1 mL). The mixture was reacted at room temperature for 16 hours. After completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure and dissolved in dichloromethane (10 mL). The mixture was washed twice with saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was concentrated to give compound 4H (80 mg, yield: 99.4%).

[0222] LC-MS (ESI): m / z = 348.2 [M+H] + .

[0223] Step 7: Compound 4H (80 mg, 0.23 mmol) was added to dichloromethane (5 mL), followed by pyridine (91 mg, 1.15 mmol) and 4-nitrophenyl chloroformate (139 mg, 0.69 mmol). The mixture was reacted at room temperature for 3 hours. After completion of the reaction, the reaction was monitored by TLC and concentrated under reduced pressure. The residue was purified by normal phase column chromatography to give compound 4I (100 mg, yield: 84.7%).

[0224] LC-MS (ESI): m / z = 513.2 [M+H] + .

[0225] Step 8: Compound 4I (100 mg, 0.20 mmol) was dissolved in tetrahydrofuran (2 mL), and triethylamine (60 mg, 0.59 mmol) and compound 2C (57 mg, 0.29 mmol, TFA salt) were added. The reaction was carried out at room temperature for 1 h. The disappearance of the starting material was monitored by TLC. Water (10 mL) was added and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was concentrated and purified using a forward column to obtain compound 4J (70 mg, 76.2%).

[0226] LC-MS (ESI): m / z = 471.2 [M+H] + .

[0227] Step 9: Compound 4J (70 mg, 0.15 mmol) was dissolved in methanol (1.5 mL) and water (1.5 mL), followed by the addition of lithium hydroxide (18 mg, 0.74 mmol) and the reaction was allowed to react at room temperature for 15 hours. After completion of the reaction, 1 M dilute hydrochloric acid was added to adjust the pH to a weakly acidic state. Water (10 mL) was then added and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were concentrated and purified by HPLC to afford compound 4 (40 mg, 58.9%).

[0228] LC-MS (ESI): m / z = 457.3 [M+H] + .

[0229] 1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.58-7.47(m,2H),5.48(d,2H),4.80(s,2H),4.60-4.20(m,2H),4.15-4.06 (m,1H),3.90(s,3H),3.87(s,3H),2.90-2.80(m,2H),2.78(s,3H),2.74-2.61(m,2H),2.44(s,2H),1.16(d,6H).

[0230] Example 5:

[0231] Step 1: Compound 5A (15.0 g, 115.26 mmol) was added to a reaction flask and dissolved in dichloromethane (200 ml). Triethylamine (34.99 g, 345.78 mmol) was added and the atmosphere was replaced with nitrogen three times. The mixture was cooled to 0°C and tert-butyldiphenylsilyl chloride (38.02 g, 138.31 mmol) was slowly added. The mixture was reacted at this temperature for 4 hours. After completion of the reaction, the mixture was diluted with water (500 ml) and extracted twice with methyl tert-butyl ether (300 ml x 2). The organic phases were combined, dried, and concentrated under reduced pressure at 40°C. The resulting residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 5B (40 g, 94.2%).

[0232] LC-MS (ESI): m / z = 369.3 [M+H] + .

[0233] Step 2: Compound 5B (10 g, 27.13 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (50 ml). The atmosphere was replaced with nitrogen three times, cooled to 0°C, and lithium borohydride (1.18 g, 54.26 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction as monitored by TLC, saturated ammonium chloride solution (100 ml) was added and extracted twice with ethyl acetate (50 ml x 2). The organic phases were combined, dried, and concentrated at 45°C. The resulting residue was purified by silica gel column chromatography (PE:EA = 2:1) to afford compound 5C (4.0 g, 43.3%).

[0234] LC-MS (ESI): m / z = 341.2 [M+H] + .

[0235] Step 3: Compound 5C (2.0 g, 5.87 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (20 ml). 2-Nitrophenyl seryl cyanate (4.00 g, 17.61 mmol) and tri-n-butylphosphine (3.56 g, 17.61 mmol) were added and reacted at room temperature for one hour. The mixture was concentrated under reduced pressure, dissolved in dichloromethane (20 ml), cooled to 0°C, and m-chloroperbenzoic acid (3.04 g, 17.61 mmol) was added. The mixture was stirred for one hour and concentrated under reduced pressure. The mixture was dissolved in toluene (20 ml), and diisopropylamine (1.78 g, 17.61 mmol) was added. The mixture was stirred at 90°C for 16 hours. After completion of the reaction, water (50 ml) was added, and the mixture was extracted with ethyl acetate (50 ml). The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 10:1) to yield compound 5D (1.2 g, 63.4%).

[0236] 1 H NMR (400MHz, CDCl3-d) δ7.64-7.66(m,4H),7.34-7.44(m,6H),4.74-4.76(m,2H),4.27-4.34(m,1H),2.72-2.82(m,4H),1.04(s,9H).

[0237] Step 4: Compound 5D (2.0 g, 6.20 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (12.4 mL, 12.4 mmol) was added and reacted at room temperature for 16 h. After the starting material completely disappeared, the mixture was concentrated to obtain the target compound 5E (2 g, crude product), which was directly used in the next reaction.

[0238] Step 5: Compound 5E (500 mg, 5.94 mmol) was added to a reaction flask and dissolved in dichloromethane (15 ml). Triethylamine (1.80 g, 17.82 mmol) and p-nitrophenyl chloroformate (1.44 g, 7.13 mmol) were added and allowed to react at room temperature for 16 hours. After completion of the reaction, as monitored by TLC, water (20 ml) was added and extracted with dichloromethane (20 ml). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford compound 5F (0.2 g, 13.2%).

[0239] LC-MS (ESI): m / z = 250.1 [M+H] + .

[0240] Step 6: Compound 3E (110 mg, 0.28 mmol) was dissolved in tetrahydrofuran (5 mL), and compound 5F (106 mg, 0.43 mmol) and N,N-diisopropylethylamine (92 mg, 0.71 mmol) were added. The mixture was reacted at room temperature for 1 h. After the starting material completely disappeared, the mixture was concentrated and the crude product was separated by silica gel column chromatography to obtain the target compound 5G (72 mg, 50.9%).

[0241] LC-MS (ESI): m / z = 497.2 [M+H] +

[0242] Step 7: Compound 5G (72 mg, 0.14 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide (30 mg, 0.72 mmol) was then added and allowed to react at room temperature for 16 hours. After completion of the reaction, 1 M dilute hydrochloric acid was added to adjust the pH to 5-6. The mixture was concentrated and purified by HPLC to yield compound 5 (35 mg, 53.1%).

[0243] LC-MS (ESI): m / z = 455.2 [M+H] + .

[0244] 1 H NMR (400MHz, DMSO) δ7.78(s,1H),7.56(s,1H),7.47-7.34(m,2H),4.86(s,3H),4.72(s,1H),4.63-457(m,2H),3.85( s,3H),3.01-2.89(m,2H),2.70-2.57(m,3H),2.41(s,3H),2.03-1.94(m,1H),1.88-1.72(m,3H),1.68-1.46(m,4H).

[0245] Examples 6-19

[0246] The synthetic routes of Examples 6-19 refer to the synthetic routes of Examples 1-5, as shown in the following table.

[0247] Biological test evaluation

[0248] 1. Cellular calcium flux experiment

[0249] Experimental Method: 1) Dilute the test compound to 400X stock solution with DMSO in a 384-well plate.

[0250] 2) Transfer 1 μl of 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.

[0251] 3) CHO-LPA1 cells were cultured using F12 medium (10% FBS).

[0252] 4) When the cells reached 80% confluency, 0.25% trypsin-EDTA was used to dissociate the cells.

[0253] 5) Measure the cell density and dilute the cells to 4 x 10e5 / ml with F12 (10% FBS).

[0254] 6) Use a multidrop automatic dispenser to dispense 30 μl of cells into a 384-well plate (Corning 3764#), with 12K cells per well. Incubate at 37°C, 5% CO2 for 18-20 hours.

[0255] 7) Replace with 25uL serum-free medium overnight.

[0256] 8) Add 10 μl of 3.5X loading dye to each well of the cell plate and incubate at 37°C, 5% CO2 in the dark for 0.5-1 hour.

[0257] 9) After incubation, transfer 5 μl of the 10X working solution from step 2 to the cell plate.

[0258] 10) Incubate the cell plate in the dark at 25°C for 15 minutes and then read the calcium signal.

[0259] 11) Prepare at least 20 μl / well of a 5X agonist (LPA) working solution in 1X HBSS + 20 mM HEPES + 0.1% BSA in a 384-well assay plate (Greiner #784075). The agonist concentration used in this assay is determined by the dose-response model previously tested. The EC80 is used as the final agonist concentration in the assay.

[0260] 12) Read and save the data using the FLIPR at room temperature using the specified settings.

[0261] 13) The signal value was plotted against the compound concentration, and the curve fitting and IC were performed using the nonlinear regression method of GraphPad Prism software. 50 calculate.

[0262] Experimental results: The compounds of the present invention have a significant antagonistic effect on LPAR 1 enzyme activity in vitro. The IC values ​​of the compounds of the examples on LPAR 1 enzyme activity are 50 The value is less than 100 μM. IC 50 The value is expressed as A, B, C, D, with A representing 0 <IC 50 ≤10nM, B means 10nM <IC 50≤50nM, C represents 50nM <IC 50 ≤100nM, D represents IC 50 The test results of some examples are shown in Table 1.

[0263] Table 1 Antagonistic activity of the compounds of the present invention against LPAR 1

[0264] Experimental conclusion: The compounds of the present invention, such as the compounds in the examples, show high antagonistic activity against LPAR1 receptor.

[0265] 2. Pharmacokinetic test in mice

[0266] 2.1 Experimental Animals: Male C57 mice, 20-25 g, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0267] 2.2 Experimental Design: On the day of the experiment, C57 mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0268] Table 2. Dosing Information

[0269] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 10% Cremophor-EL + 40% PEG400 + 50% 1XPBS (pH = 7.4)

[0270] Before and after drug administration, 0.06 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0271] Table 3. Pharmacokinetic parameters of test compounds in mouse plasma

[0272] -:not applicable.

[0273] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in mice.

[0274] 3. Pharmacokinetic test in rats

[0275] 3.1. Experimental Animals: Male SD rats, approximately 220 g, 6-8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0276] 3.2 Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0277] Table 4. Dosing Information

[0278] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 10% Cremophor-EL + 40% PEG400 + 50% 1XPBS (pH = 7.4)

[0279] Before and after drug administration, 0.15 mL of blood was collected from the eye socket under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0280] Table 5. Pharmacokinetic parameters of test compounds in rat plasma

[0281] -:not applicable.

[0282] Conclusion: The compounds of the present invention, such as Example Compound 3, have good pharmacokinetic characteristics in rats.

[0283] 4. Beagle dog pharmacokinetic test

[0284] 4.1. Experimental Animals: Male beagle dogs, weighing approximately 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0285] 4.2 Experimental Methods: On the day of the experiment, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0286] Table 6. Dosing Information

[0287] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 10% Cremophor-EL + 40% PEG400 + 50% 1XPBS (pH = 7.4)

[0288] Before and after dosing, 1 mL of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 minutes. All samples were stored at -80°C prior to analysis and quantitative analysis by LC-MS / MS.

[0289] Table 7. Pharmacokinetic parameters of test compounds in dog plasma

[0290] -:not applicable.

[0291] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.

[0292] 5. Monkey pharmacokinetic test

[0293] 5.1. Experimental Animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0294] 5.2 Experimental Methods: On the day of the experiment, monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0295] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 minutes. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0296] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in monkeys.

[0297] 6. hERG potassium channel effect test

[0298] Experimental platform: electrophysiology manual patch clamp system

[0299] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0300] Experimental Methods: hERG potassium channel currents were recorded using the whole-cell patch-clamp technique at room temperature in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch-clamp amplifier by inserting them into the amplifier headstage. Clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -80 mV. To elicit hERG potassium currents (I hERG ), a 2-second depolarization step from -80 mV to +20 mV was applied, followed by repolarization to -50 mV, which was maintained for 1 second before returning to -80 mV. This voltage stimulus was applied every 10 seconds, and drug administration was initiated after confirming the stability of the hERG potassium current (at least 1 minute). Compounds were administered for at least 1 minute at each tested concentration, and at least two cells were tested at each concentration (n≥2).

[0301] Data processing: Data analysis was 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:

[0302] Inhibition%=[1-(I / Io)]×100%

[0303] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0304] The IC50 of the compounds was calculated using GraphPad Prism 5 software by fitting the following equation:

[0305] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0306] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0307] Experimental results: IC of the test compound's inhibitory effect on hERG potassium channel current 50 The values ​​are shown in Table 8 below:

[0308] Table 8 hERG potassium channel current inhibition test results

[0309] Conclusion: The compounds of the present invention, such as Example Compound 3, have no inhibitory effect on hERG.

[0310] 7. CYP enzyme inhibition test

[0311] The purpose of this study was to evaluate the effects of test compounds on the activities of five cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) in human liver microsomes using an in vitro assay system. Specific probe substrates for each CYP450 isoform were incubated with human liver microsomes and varying concentrations of the test compounds. The reaction was initiated by the addition of reduced nicotinamide adenine dinucleotide phosphate (NADPH). Following the reaction, the samples were processed and metabolites generated by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and IC50 values ​​were calculated to evaluate the inhibitory potential of the test compounds against each CYP enzyme isoform. Under the assay conditions, the incubation concentration ranged from 0 to 30 μM.

[0312] Experimental results: IC of the test compound against CYP enzyme inhibition 50 The values ​​are shown in Table 9 below:

[0313] Table 9 CYP enzyme inhibition test results

[0314] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no inhibitory effect on CYP enzymes.

[0315] 8. Liver microsome stability test

[0316] In this study, liver microsomes from five species, including humans, dogs, rats, and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.

[0317] At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. The T value was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CL int(mic) and hepatic intrinsic clearance CL int(Liver) .

[0318] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good liver microsomal stability.

[0319] 9. Caco2 permeability test

[0320] The experiment used Caco-2 cell monolayers in 96-well Transwell plates, incubated in triplicate. Transport buffer (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM), and metoprolol (2 μM) was added to the apical or basolateral wells of the cell monolayer. Transport buffer containing DMSO was added to the corresponding receiving wells. After incubation at 37 ± 1°C for 2 hours, the cell plate was removed and appropriate samples were taken from the apical and basolateral wells to a new 96-well plate. Proteins were then precipitated by adding acetonitrile containing an internal standard. Samples were analyzed using LC-MS / MS to determine the concentrations of the compound of the invention and the control compound. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to basolateral side of the cell monolayer and from the basolateral to apical side, thereby calculating the efflux rate. The integrity of the cell monolayer after 2 hours of incubation was assessed by leakage of Lucifer Yellow.

[0321] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

[0322] 10. Bleomycin (BLM)-induced idiopathic pulmonary fibrosis (IPF) mouse model

[0323] 1) Screening and Grouping: This study used 9-week-old male C57BL / 6j mice. Before the start of the experiment, animals were divided into a sham-operated group and a model group based on their body weight. One week after modeling, the model group was randomly divided into groups based on their body weight.

[0324] 2) Animal Modeling: On day 1 of the experiment, animals were anesthetized with Zotadine (50 mg / kg) and Xylazine (10 mg / kg). Mice in the model group received an intratracheal (it) injection of bleomycin at a dose of 0.66 mg / kg (1 U / kg) in a volume of 50 μL. Sham-operated group 1 (n=10) received an intratracheal injection of normal saline in a volume of 50 μL.

[0325] 3) Experimental Methods: Starting on day 7, mice in each experimental group were administered the test compound by oral gavage twice daily. The control group was given nintedanib at a dose of 60 mg / kg in a volume of 10 mL / kg body weight, once daily by oral gavage. Sham-operated group 1 and model group 2 were given vehicle in a volume of 10 mL / kg body weight, twice daily by oral gavage.

[0326] 4) Detection indicators: Lung tissue was collected for pathological examination at the end of the study.

[0327] Results: Bleomycin (0.66 mg / kg, intravenously) administered for 21 days significantly increased the Modified Ashcroft score and pulmonary fibrosis area in the model mice's lung tissue. Compared to the vehicle-administered model group, oral administration of the example compound twice daily for 14 days significantly reduced the Modified Ashcroft score and pulmonary fibrosis area in the model mice's lung tissue at the study endpoint.

Claims

1. A compound represented by formula (I), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, Ring A is selected from a 4-8 membered monocyclic carbocyclic group, a 6-12 membered bicyclic carbocyclic group, a 6-12 membered monocyclic heterocyclic group, a 6-12 membered bicyclic heterocyclic group or none, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1-4 R A replace; Ring C is selected from 5-membered heteroaryl and 5-7-membered carbocyclic ring, 5-membered heteroaryl and 5-7-membered heterocyclic ring, C 3-6 Monocyclic carbocyclic ring, 5-6 membered monocyclic heterocyclic cycloalkyl, C 5-10 Bicyclic cycloalkyl, 5-10 membered bicyclic heterocyclic cycloalkyl, the heteroaryl, carbocyclic, heterocyclic, cycloalkyl, heterocycloalkyl are optionally substituted by 1-4 R C Replace; " represents the connection site between ring C and pyridine ring, "*" represents the connection site between ring C and L2; R B Selected from H; R c1 , R c4 , R c5 are each independently selected from H, halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl; R c3 Selected from H, C 1-4 alkyl; Alternatively, R c1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring; Alternatively, R c3 With R B Together they form a 6-7 membered heterocyclic ring; L1 is selected from a bond, -C 1-4 Alkyl-, -C=O, -OC(R L1a R L1b ) p -、-S-(CR L1a R L1b ) p -、-C(=O)NR L1 -、C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl, alkynyl is optionally further substituted by 1-4 R L1a replace; When ring A is absent, L1 is selected from -OC substituted with one COOH 1-6 alkyl; L2 is selected from (CR L2a1 R L2a2 ) p -OC(=O)N(R L2b )2, -C(=O)N(R L2b )2, -NR L2b -C(=O)OR L2c 、-(CR L2a1 R L2a2 ) p N(R L2b )2, -(CH2) p R L2d 、-(CR L2a1 R L2a2 ) p N(R L2b )S(O)2N(R L2b )2, -(CR L2a1 R L2a2 ) p N(R L2b )C(=O)N(R L2b )2, -(CR L2a1 R L2a2 ) p N(R L2b )C(=O)OR L2b ; R A Each independently selected from H, halogen, CN, OH, -(CH2) p -COOR a1 、-(CH2) p -C(=O)NR a1 R a2 、-(CH2) p -C(=O)NHC(=O)R a1 、-(CH2) p -C(=O)NHS(O)2R a1 、-(CH2) p -C(=O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHCOR a1 、-(CH2) p -P(O)(OH)2、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl or -(CH2) p -(5-10 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, heterocyclic group is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution; R C Each independently selected from halogen, CN, OH, NO2, NH2, =O, C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkoxy, alkyl, alkenyl, and alkynyl are optionally further substituted by 1 to 4 groups selected from halogen, OH, NH2, and CN; R a1 , R a2 Each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution; R c2 Selected from -(CR L2a1 R L2a2 ) p -C 3-7 Cycloalkyl, -(CR L2a1 R L2a2 ) p -(4-7 membered heterocycloalkyl), halogen, CN, OH, NO2, NH2, halogenated C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; Each R L1a , R L1b Each independently selected from H, halogen, CN, OH, NO2, NH2, =O, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -(CH2) p -COOR a1 The alkyl, alkenyl, alkynyl, cycloalkyl group may be further substituted by 1-4 halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution; R L1 Independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution; Each R L2a1 , R L2a2 Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl, and alkynyl are optionally further substituted by 1 to 4 groups selected from halogen, OH, NH2, CN, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution; Alternatively, R L2a1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring; Each R L2b Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkyl subunit, halogenated C 1-4 Alkyl subunit, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; Each R L2d Each independently selected from C 1-4 Alkyl, halogen, OH, NH2, CN, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)H, -C(=O)OH, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 halogen, OH, NH2, CN, N3, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; R L2c Selected from -C 1-4 Alkyl-(5-10 membered heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from halogen, CN, OH, NO2, NH2, halo 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Substitution of alkynyl groups by substituents; p is selected from 0, 1, 2, 3, 4; Unless otherwise specified, the heterocycle, heterocyclic group, heterocycloalkyl group and heteroaryl group contain 1 to 4 heteroatoms selected from N, O, S, S(O) and S(O)2.

2. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein: Ring A is selected from 4-7 membered monocyclic carbocyclic group, 6-10 membered bicyclic carbocyclic group, 6-10 membered monocyclic heterocyclic group, 6-10 membered bicyclic heterocyclic group or none, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; preferably, ring A is selected from 4-7 membered monocyclic carbocyclic group; preferably, ring A is selected from The ring A is substituted by 1 COOH; and / or R A Each independently selected from halogen, CN, OH, COOH, -CH2COOH, C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -OC 1-2 Alkyl, wherein the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Preferably, R A Each is independently selected from COOH, -CH2COOH.

3. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, Ring C is selected from in " represents the connection site between ring C and pyridine ring, "*" represents the connection site between ring C and L2; L1 is selected from -O-; and / or L2 is selected from -(CR L2a1 R L2a2 ) p -OC(=O)NHR L2b 、-(CR L2a1 R L2a2 ) p -OC(=O)N(C 1-4 Alkyl)R L2b ,-C(=O)NHR L2b 、-C(=O)N(C 1-4 Alkyl)R L2b 、-NHC(=O)OR L2c 、-N(C 1-4 alkyl)C(=O)OR L2c 、-(CR L2a1 R L2a2 ) p NHC(=O)OR L2b 、-(CR L2a1 R L2a2 ) p N(C 1-4 alkyl)C(=O)OR L2b ; Each R L2a1 , R L2a2 Each independently selected from H, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from F, Cl, OH, NH2, CN; Alternatively, R L2a1 With R B Together they form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring; Each R L2b Each independently selected from 1-2 C 1-4 Alkyl subunit, halogenated C 1-4 C substituted by alkyl subunit 3-10 Cycloalkyl; R L2c Selected from -C 1-2 Alkyl-(5-6 membered monocyclic heteroaryl), -C 1-2 Alkyl-(8-10 membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from F, Cl, CN, OH, NO2, NH2, halogenated C 1-2 The alkyl group is substituted with a substituent; preferably, R L2c Selected from -C 1-2 Alkyl-(5-6 membered monocyclic heteroaryl), -C 1-2 Alkyl-(8-10 membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted with 1-3 substituents selected from F, Cl, CN, OH, NO2, NH2, -CH2F, -CHF2, -CF3; p is selected from 0, 1 or 2.

4. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein: L2 is selected from -(CR L2a1 R L2a2 ) p -OC(=O)NHR L2b 、-(CR L2a1 R L2a2 ) p -OC(=O)N(CH3)R L2b 、-(CR L2a1 R L2a2 ) p NHC(=O)OR L2b 、-(CR L2a1 R L2a2 ) p N(CH3)C(=O)OR L2b ; Each R L2a1 , R L2a2 Each independently selected from H, C 1-2 alkyl; Each R L2b Each independently selected from 1-2 C 1-4 Alkyl subunit, halogenated C 1-4 C substituted by alkyl subunit 4-6 Cycloalkyl; p is selected from 0 or 1.

5. The compound according to any one of claims 1 to 4, its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein the general formula (I) is further represented by the general formula (I-1):

6. The compound according to claim 1, its stereoisomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures in Table 1.

7. A pharmaceutical composition or pharmaceutical preparation comprising the compound according to any one of claims 1 to 6, or a stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

8. The pharmaceutical composition or pharmaceutical preparation according to claim 7, comprising 1-1500 mg of the compound according to any one of claims 1-6 or its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt and a carrier and / or excipient.

9. Use of the compound according to any one of claims 1 to 6, its stereoisomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt, or the composition according to claims 7 to 8 in the preparation of a medicament for treating / preventing a disease mediated by LPAR 1.

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 damage, and neuralgia.

11. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a stereoisomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt thereof, or a composition according to claims 7 to 8, the therapeutically effective amount preferably being 1 to 1500 mg, wherein the disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve damage, and neuralgia.

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