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WO2025051266A1 - 杂芳环衍生物的lpar1拮抗剂及其用途 - Google Patents

杂芳环衍生物的lpar1拮抗剂及其用途 Download PDF

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WO2025051266A1
WO2025051266A1 PCT/CN2024/117602 CN2024117602W WO2025051266A1 WO 2025051266 A1 WO2025051266 A1 WO 2025051266A1 CN 2024117602 W CN2024117602 W CN 2024117602W WO 2025051266 A1 WO2025051266 A1 WO 2025051266A1
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alkyl
membered
cycloalkyl
alkynyl
ring
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French (fr)
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李瑶
陈雷
任磊
林潇
张晨
严庞科
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西藏海思科制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 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 substances, solvates, cocrystals or pharmaceutically acceptable salts, and use thereof in preparing medicines for treating related diseases.
  • Lysophosphatidic acid is a small molecule glycerophosphodiester with a molecular weight of 430-480D. LPA is widely present in the human body. After binding to receptors, it can activate multiple cell signaling pathways and participate in regulating cell proliferation, differentiation, apoptosis, neurotransmitter release and other life activities. It plays an important role in diseases such as cancer, fibrosis, neuronal dysfunction, and bone metabolic disorders. LPA is mainly produced by the hydrolysis of lysophospholipids (mainly lysophosphatidylcholine) by autocrine motility factor.
  • lysophospholipids mainly lysophosphatidylcholine
  • LPA in the bleomycin-induced pulmonary fibrosis model, the LPA level in bronchoalveolar lavage fluid increased significantly, leading to increased vascular permeability and pulmonary fibrosis; LPA can also mediate the production of a variety of paracrine mediators by fibroblasts, acting 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 of fibroblasts, activate the release of soluble factors, and stimulate lung epithelial cells and expand local fibroblast response partly through the action of EGFR.
  • EGF epidermal growth factor
  • LPA-LPA1 signaling pathway can promote apoptosis of lung tissue epithelial cells and inhibit apoptosis of fibroblasts in idiopathic pulmonary fibrosis (IPF), suggesting that this signaling pathway may regulate the development of fibrosis after lung injury.
  • LPA is closely related to organ fibrosis, mainly mediated by lysophosphatidic acid receptor (LPAR) 1.
  • LPAR lysophosphatidic acid receptor
  • LPAR antagonists have a therapeutic effect on idiopathic pulmonary fibrosis; it has also been found that the LPAR1 antagonist BMS-986020 can effectively improve the lung function of patients with idiopathic pulmonary fibrosis.
  • the present invention provides a compound of formula (I), its stereoisomers, deuterated products, solvates, cocrystals or pharmaceutically acceptable salts, wherein the compound has the excellent effects of good activity, excellent physicochemical properties, convenient preparation, excellent pharmacokinetic properties, high bioavailability and low toxic and side effects.
  • 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,
  • Ring A is selected from 4-8 membered monocyclic carbocyclyl, 6-12 membered bicyclic carbocyclyl, 6-12 membered monocyclic heterocyclyl, 6-12 membered bicyclic heterocyclyl or none, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1-4 RA ; in some embodiments, Ring A is selected from 4-7 membered monocyclic carbocyclyl, 6-10 membered bicyclic carbocyclic group, 6-10 membered monocyclic heterocyclic group, 6-10 membered bicyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; in some embodiments, ring A is selected from 4-7 membered monocyclic carbocyclic group; in some embodiments, ring A is selected from The ring A is substituted with 1 COOH;
  • Ring A when Ring A is selected from absent, L 1 is selected from -OC 1-6 alkyl substituted with one COOH; In some embodiments, Ring A is selected from absent, L 1 is selected from -OCH 2 C(CH 3 ) 2 CH 2 COOH, -OCH 2 CH 2 C(CH 3 ) 2 COOH;
  • 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, wherein the heteroaryl, carbocyclic ring, heterocyclic ring, cycloalkyl, heterocycloalkyl are optionally substituted by 1-4 R C ; wherein represents the connection site between ring C and the pyridine ring, and "*" represents 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
  • R c1 , R c4 , and R c5 are each independently selected from H, halogen, C 1-4 alkyl, and halogenated C 1-4 alkyl;
  • R c3 is selected from H, C 1-4 alkyl
  • R c1 and RB together form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;
  • R c3 and RB together form a 6-7 membered heterocyclic ring
  • L2 is selected from (CR L2a1 RL2a2 ) p -OC( ⁇ O)N( RL2b ) 2 , -C( ⁇ O)N( RL2b ) 2 , -NR L2b -C( ⁇ O)OR L2c , -(CR L2a1 RL2a2 ) p N( RL2b ) 2 , -(CH 2 ) p RL2d , -(CR L2a1 RL2a2 ) p N( RL2b )S(O) 2 N( RL2b ) 2 , (CR L2a1 RL2a2 ) p N( RL2b )C( ⁇ O)N( RL2b ) 2 , -(CR L2a1 RL2a2 ) p N( RL2b )C( ⁇ O)OR L2b ; in some embodiments, L2 is selected from (CR L2a1 RL2a
  • L2 is selected from In some embodiments, L2 is selected from In some embodiments, L2 is selected from
  • Ring C when Ring C is When L2 is selected from
  • R and B are independently selected from H;
  • Ra1 and Ra2 are each independently selected from H, C1-4 alkyl ;
  • R c2 is selected from -(CR L2a1 R L2a2 ) p -C 3-7 membered cycloalkyl, -(CR L2a1 R L2a2 ) p -(4-7 membered heterocycloalkyl), halogen, CN, OH, NO 2 , NH 2 , halogenated C 1-4 alkyl, -OC 1-4 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; in some embodiments, R c2 is selected from C 3-4 membered cycloalkyl, 4-5 membered heterocycloalkyl, -CH 2 -C 3-4 membered cycloalkyl, -CH 2 -(4-5 membered heterocycloalkyl), fluorinated C 1-2 alkyl; in some embodiments, R c2 is selected from cyclopropyl, cyclobutyl, oxetanyl, oxolanyl,
  • each R L2a1 , R L2a2 is independently is selected from H, C 1-2 alkyl, the alkyl is optionally further substituted by 1-4 groups selected from F, Cl, OH, NH 2 , CN; in some embodiments, each R L2a1 , R L2a2 is independently selected from H, methyl, ethyl;
  • Each RL2a1 and RL2a2 are independently selected from H, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, and the alkyl, alkenyl, alkynyl are optionally further substituted by 1-4 groups selected from halogen, OH, NH2 , CN, C1-4 alkoxy, halogenated C1-4 alkoxy; alternatively, RL2a1 and RB together form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;
  • Each RL2b is independently selected from H, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 alkoxy, 5-14 membered heterocyclyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl is optionally further substituted with 1-4 groups selected from halogen, OH, NH2 , CN, C1-4 alkoxy, halogenated C1-4 alkoxy, C3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; in some embodiments, each RL2b is independently selected from H, C1-4 alkyl, wherein the alkyl is optionally further substituted with 1-2 groups selected from F, Cl, OH, NH2 , CN, C1-4 alkyl, C1-4 alkyl subgroup, halogenated C1-4 alkyl sub
  • RL2c is selected from -C1-4 alkyl-(5-10 membered heteroaryl), wherein the heteroaryl is optionally further substituted with 1-3 substituents selected from halogen, CN, OH, NO2 , NH2 , halo-substituted C1-4 alkyl, -OC1-4 alkyl, C2-6 alkenyl or C2-6 alkynyl; in some embodiments, RL2c is selected from -C1-2 alkyl-(5-6 membered monocyclic heteroaryl), -C1-2 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 , halo-substituted C1-2 alkyl; in some embodiments, RL2c is selected from -C1-2 alkyl-(5-6 membered monocyclic heteroaryl), -C 1-2 -alky
  • 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;
  • heterocycle, heterocyclic group, heterocycloalkyl group and heteroaryl group contain 1, 2, 3 or 4 heteroatoms selected from N, O and S.
  • the compound of formula (I), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt is included in the first technical solution of the present invention.
  • Ring A is selected from 4-8 membered monocyclic carbocyclyl, 6-12 membered bicyclic carbocyclyl, 6-12 membered monocyclic heterocyclyl, 6-12 membered bicyclic heterocyclyl or none, and the carbocyclyl or heterocyclyl is optionally substituted by 1-4 RA ;
  • 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, wherein the heteroaryl, carbocyclic ring, heterocyclic ring, cycloalkyl, heterocycloalkyl are optionally substituted by 1-4 R C ; wherein " represents the connection site between ring C and pyridine ring, "*" represents the connection site between ring C and L2 ;
  • R c1 and RB together form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;
  • R c3 and RB together form a 6-7 membered heterocyclic ring
  • Ring A when Ring A is selected from absent, L 1 is selected from -OC 1-6 alkyl substituted with one COOH; In some embodiments, Ring A is selected from absent, L 1 is selected from -OCH 2 C(CH 3 ) 2 CH 2 COOH, -OCH 2 CH 2 C(CH 3 ) 2 COOH;
  • R and B are independently selected from H;
  • R c2 is selected from -(CR L2a1 R L2a2 ) p -C 3-7 membered cycloalkyl, -(CR L2a1 R L2a2 ) p -(4-7 membered heterocycloalkyl), halogen, CN, OH, NO 2 , NH 2 , halogenated C 1-4 alkyl, -OC 1-4 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • Each R L2a1 and R L2a2 is independently selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and the alkyl, alkenyl, and alkynyl are optionally further substituted with 1-4 groups selected from halogen, OH, NH 2 , CN, C 1-4 alkoxy, and halogenated C 1-4 alkoxy;
  • RL2a1 and RB together form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;
  • Each R L2b is 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 heterocyclyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl is optionally further substituted with 1-4 groups selected from halogen, OH, NH 2 , 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;
  • RL2c is selected from -C1-4alkyl- (5-10 membered heteroaryl), said heteroaryl being optionally further substituted with 1-3 substituents selected from halogen, CN, OH, NO2 , NH2 , halo-substituted C1-4alkyl , -OC1-4alkyl , C2-6alkenyl or C2-6alkynyl ;
  • p is selected from 0, 1, 2, 3, 4;
  • heterocycle, heterocyclyl, heterocycloalkyl and heteroaryl groups contain 1 to 4 heteroatoms selected from N, O, S, S(O) and S(O) 2 .
  • Ring A is selected from a 4-8 membered monocyclic carbocyclyl, a 6-12 membered bicyclic carbocyclyl, a 6-12 membered monocyclic heterocyclyl, a 6-12 membered bicyclic heterocyclyl, wherein the carbocyclyl and heterocyclyl are optionally substituted by 1-4 RA ;
  • 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, heterocyclic ring is optionally substituted by 1-4 R C ; wherein " represents the connection site between ring C and pyridine ring, “*" represents the connection site between ring C and L2 ;
  • R c1 and RB together form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;
  • R c3 and RB together form a 6-7 membered heterocyclic ring
  • R and B are independently selected from H;
  • R and C are each independently selected from halogen, CN, OH, NO 2 , NH 2 , C 1-4 alkyl, -OC 1-4 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, and the alkoxy, alkyl, alkenyl and alkynyl are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH 2 and CN;
  • R c2 is selected from C 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, halogen, CN, OH, NO 2 , NH 2 , halogenated C 1-4 alkyl, -OC 1-4 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R c1 and RB together form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;
  • R c3 and RB together form a 6-7 membered heterocyclic ring
  • Each R L2a1 and R L2a2 is independently selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and the alkyl, alkenyl, and alkynyl are optionally further substituted with 1-4 groups selected from halogen, OH, NH 2 , CN, C 1-4 alkoxy, and halogenated C 1-4 alkoxy;
  • RL2a1 and RB together form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;
  • Each R L2b is 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 heterocyclyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl is optionally further substituted with 1-4 groups selected from halogen, OH, NH 2 , 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;
  • RL2c is selected from -C1-4alkyl- (5-10 membered heteroaryl), said heteroaryl being optionally further substituted with 1-3 substituents selected from halogen, CN, OH, NO2 , NH2 , halo-substituted C1-4alkyl , -OC1-4alkyl , C2-6alkenyl or C2-6alkynyl ;
  • p is selected from 0, 1, 2, 3, 4;
  • heterocycle, heterocyclic group, heterocycloalkyl group and heteroaryl group contain 1 to 4 heteroatoms selected from N, O and S.
  • the second technical solution of the present invention is the compound of formula (I), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein:
  • Ring A is selected from 4-7 membered monocyclic carbocyclic groups, 6-10 membered bicyclic carbocyclic groups, 6-10 membered monocyclic heterocyclic groups, 6-10 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; in some embodiments, Ring A is selected from 4-7 membered monocyclic carbocyclic groups In some embodiments, ring A is selected from The ring A is substituted by 1 COOH; and/or
  • RA is independently selected from halogen, CN, OH, COOH, -CH2COOH, C1-2 alkyl, C2-4 alkenyl, C2-4 alkynyl or -OC1-2 alkyl, wherein the alkyl, alkenyl or alkynyl is optionally further substituted with 1-4 groups selected from halogen, OH, NH2 , CN or -O-halogenated C1-2 alkyl.
  • RA is independently selected from COOH or -CH2COOH .
  • the third technical solution of the present invention is that the compound of formula (I) or (I-1), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt,
  • 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 heterocycloalkyl, C 5-10 bicyclic cycloalkyl, 5-10-membered bicyclic heterocycloalkyl, the heteroaryl and heterocycle contain 1-3 heteroatoms selected from N, O, and S; the heteroaryl, cycloalkyl, phenyl, heterocycloalkyl, and heteroaryl are optionally substituted by 1-4 R C ; wherein represents the connection site between ring C and the pyridine ring, and "*" represents the connection site between ring C and L2 ; in some embodiments, ring C is selected from 5-membered heteroaryl and 5-6-
  • R c2 is selected from C 3-4 membered cycloalkyl, 4-5 membered heterocycloalkyl, -CH 2 -C 3-4 membered cycloalkyl, -CH 2 -(4-5 membered heterocycloalkyl), fluorinated C 1-2 alkyl; in some embodiments, R c2 is selected from cyclopropyl, cyclobutyl, oxetanyl, oxolanyl, azetidinyl, azetidinyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -oxetanyl, -CH 2 -oxolanyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -azetidinyl, -CH 2 -aze
  • R c1 , R c4 , and R c5 are each independently selected from H, F, Cl, methyl, ethyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -CHFCF 3 , -CF 2 CH 2 F, -CF 2 CHF 2 , -CF 2 CF 3 ;
  • R c3 is selected from H, methyl, ethyl
  • R c1 and RB together form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;
  • R c3 and RB are taken together to form a 6-7 membered heterocyclic ring.
  • 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, wherein the heteroaryl and heterocycle contain 1-3 heteroatoms selected from N, O, and S; the heteroaryl, cycloalkyl, phenyl, heterocycloalkyl, and heteroaryl are optionally substituted with 1-4 R C ; wherein represents the connection site between ring C and the pyridine ring, and "*" represents 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 heteroary
  • R C are each independently selected from H, halogen, CN, OH, NH 2 , C 1-2 alkyl, -OC 1-2 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, and the alkyl, alkenyl, alkynyl, cycloalkyl are optionally further substituted with 1-4 groups selected from halogen, OH, NH 2 , CN; in some embodiments, R C are each independently selected from H, halogen, CN, OH, NH 2 , C 1-2 alkyl, and the alkyl is optionally further substituted with 1-4 groups selected from halogen, OH, NH 2 , CN; in some embodiments, R C are each independently selected from H, F, Cl, CH 3 , CH 2 CH 3 ; and/or
  • R c2 is selected from C 3-4 membered cycloalkyl, 4-5 membered heterocycloalkyl, fluorinated C 1-2 alkyl; in some embodiments, R c2 is selected from cyclopropyl, cyclobutyl, oxetanyl, oxolyl, azetidinyl, azopentyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -CHFCF 3 , -CF 2 CH 2 F, -CF 2 CHF 2 , -CF 2 CF 3 ;
  • R c1 and RB together form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;
  • R c3 and RB together form a 6-7 membered heterocyclic ring.
  • 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-;
  • Each R L2a1 and R L2a2 is independently selected from H, C 1-2 alkyl, and the alkyl is optionally further substituted with 1-4 groups selected from F, Cl, OH, NH 2 , and CN;
  • RL2a1 and RB together form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;
  • Each R L2b is independently selected from a C 3-10 cycloalkyl group substituted with 1-2 C 1-4 alkyl substituents or halogenated C 1-4 alkyl substituents;
  • RL2c is selected from -C1-2 alkyl-(5-6-membered monocyclic heteroaryl), -C1-2 alkyl-(8-10-membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 substituents selected from F, Cl, CN, OH, NO2 , NH2 , halogenated C1-2 alkyl; preferably, RL2c is selected from -C1-2 alkyl-(5-6-membered monocyclic heteroaryl), -C1-2 alkyl-(8-10-membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 substituents selected from F, Cl, CN, OH , NO2 , NH2, -CH2F , -CHF2 , -CF3 ;
  • p is selected from 0, 1 or 2.
  • the fourth technical solution of the present invention is the compound of formula (I), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein:
  • Each R L2a1 and R L2a2 is independently selected from H, C 1-2 alkyl, and the alkyl is optionally further substituted with 1-4 groups selected from F, Cl, OH, NH 2 , and CN; in some embodiments, each R L2a1 and R L2a2 is independently selected from H, methyl, and ethyl;
  • RL2a1 and RB together form a 6-7 membered heterocyclic ring or a 6-7 membered carbocyclic ring;
  • Each RL2b is independently selected from H, C1-4 alkyl, C3-10 cycloalkyl, and the alkyl and cycloalkyl groups are optionally further substituted by 1-2 groups selected from F, Cl, OH, NH2 , CN, C1-4 alkyl, C1-4 alkyl subunit, halogenated C1-4 alkyl subunit, C1-2 alkoxy, fluorinated C1-2 alkoxy, C3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; preferably, each RL2b is independently selected from H, C1-4 alkyl, C4-6 cycloalkyl, and the cycloalkyl groups are optionally further substituted by 1-2 groups selected from F, Cl, OH, NH2 , CN, C1-4 alkyl, C1-4 alkyl subunit, halogenated C1-4 alkyl subunit; or in some embodiments, each RL2b is independently selected
  • RL2c is selected from -C1-2 alkyl-(5-6 membered monocyclic heteroaryl), -C1-2 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 , halogenated C1-2 alkyl; in some embodiments, RL2c is selected from -C1-2 alkyl-(5-6 membered monocyclic heteroaryl), -C1-2 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.
  • R L2a1 and R L2a2 are independently selected from H, C 1-2 alkyl;
  • Each R L2b is independently selected from C 4-6 cycloalkyl substituted by 1-2 C 1-4 alkyl substituents or halogenated C 1-4 alkyl substituents;
  • p is selected from 0 or 1.
  • L 2 and RB are as described in any of the above technical solutions.
  • 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.
  • composition or pharmaceutical preparation of the present invention contains 1-1500 mg of the compound described in any one of the preceding schemes, its stereoisomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and/or excipients.
  • the present invention also provides the use of the compound described in any one of the above schemes, its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt in the preparation of a drug for treating/preventing a disease mediated by LPAR1.
  • the disease mediated by LPAR1 is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve damage, neuralgia, preferably idiopathic pulmonary fibrosis and progressive pulmonary fibrosis.
  • the present invention also provides a method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of a compound, a stereoisomer, a deuterated substance, a solvate, a cocrystal or a pharmaceutically acceptable salt thereof, or a composition of the present invention, the disease being selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve damage, neuralgia, and preferably the therapeutically effective amount is 1-1500 mg.
  • the mammals in the present invention do not include humans.
  • an "effective amount” or “therapeutically effective amount” refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition being treated to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system.
  • an "effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • 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, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 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, 10-1 500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt and a carrier and/or excipient.
  • the pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
  • 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 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg
  • 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 stereoisomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and/or excipient, the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably idiopathic pulmonary fibrosis or progressive pulmonary fibrosis.
  • a method for treating a disease in a mammal or a human comprising administering a pharmaceutical compound of the present invention, a stereoisomer, a deuterated substance, a solvate, a cocrystal or a 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
  • 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
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or a stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt thereof is the same as that in the above-mentioned pharmaceutical composition.
  • 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 as the free base.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • Halogen herein refers to F, Cl, Br, I, or isotopes thereof.
  • Halo or halogen substituted means that a hydrogen atom is replaced by one or more halogens selected from F, Cl, Br, I, or isotopes thereof, and 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 substituted by the same or different halogens.
  • Deuterated or “deuterated substance” refers to the situation where the hydrogen atoms on the alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, alkynyl and other groups are replaced by at least one isotope of deuterium, and the upper limit of the number of deuterated groups 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 deuterated groups is any integer between 1 and the upper limit, preferably 1-20 deuterium atoms.
  • the deuterium atoms are preferably substituted by 1 to 10 deuterium atoms, more preferably substituted by 1 to 6 deuterium atoms, and further preferably substituted by 1 to 3 deuterium atoms.
  • Alkyl refers to a monovalent straight or branched saturated aliphatic hydrocarbon group, and unless otherwise specified, is an alkyl group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further preferably an alkyl group of 1 to 4 carbon atoms, and further preferably an alkyl group of 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 isomers thereof.
  • Alkylene refers to a divalent straight chain or branched chain saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.
  • Alkylene refers to a divalent free valence alkyl structure formed by the loss of two hydrogen atoms, wherein alkyl is as defined above.
  • Non-limiting examples include: Ethyl subunit 1-Methylethylidene
  • Haloalkylene refers to an alkylene group substituted with one or more halogens, wherein alkylene group is as defined above.
  • Non-limiting examples include: fluoromethylene group Difluoromethylidene
  • 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 (eg, a bicyclic cycloalkyl group or a tricyclic cycloalkyl group).
  • Cycloalkylene refers to a divalent radical of “cycloalkyl”, and non-limiting examples include cyclopropylene, cyclobutylene, and the like.
  • Heterocycle or “heterocyclic group” refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, which contains 1 to 3 heteroatoms selected from N, O or S, when not specifically limited, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles and bicyclic spiro heterocycles, etc., and when not specifically limited, is a 3-12-membered heterocycle, more preferably a 4-12-membered heterocycle, more preferably a 4-10-membered heterocycle, and further preferably a 4-7-membered heterocycle. Its definition includes heterocycloalkyl and heteroaryl.
  • N and S in the heterocyclic 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-dioxhexacyclyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dithio ...
  • Heterocyclylene is a divalent group corresponding to “heterocyclyl”, and non-limiting examples include imidazolylene, piperidinylene, aziridinylene, and the like.
  • Carbocycle or “carbocyclyl” refers to substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic groups, including monocyclic Cyclic carbocycles, bicyclic bridged rings, bicyclic fused rings and bicyclic spirocycles, etc., when not otherwise specified, have 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms.
  • the definition includes cycloalkyl and aryl.
  • 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.
  • Aryl refers to a carbon ring having aromatic properties. Non-limiting examples include phenyl, naphthyl, and the like.
  • 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.
  • 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 are ethenyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.
  • Alkoxy or “alkyloxy” refers to -O-alkyl, and when not specifically limited, is -OC 1-8 alkyl, preferably -OC 1-6 alkyl, more preferably -OC 1-4 alkyl, and further preferably -OC 1-2 alkyl.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy.
  • Haloalkoxy refers to -O-haloalkyl, and when not specifically limited, is -O-halo C 1-8 alkyl, preferably -O-halo C 1-6 alkyl, more preferably -O-halo C 1-4 alkyl, and further preferably -O-halo C 1-2 alkyl.
  • Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.
  • C 1-4 alkylacyl refers to C 1-4 alkyl-C(O)-.
  • Non-limiting examples include formyl, acetyl, propionyl.
  • C 1-4 alkylsulfonyl refers to C 1-4 alkyl-S(O) 2 -.
  • Non-limiting examples include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
  • Heteroaromatic ring or “heteroaryl” refers to a heterocyclic ring having aromatic properties.
  • Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridinyl, furanyl, and the like.
  • 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.
  • 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.
  • 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, and the like.
  • alkyl optionally substituted with F means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.
  • “Pharmaceutically acceptable salts” refer to compounds of the invention that retain the biological effectiveness and properties of the free acid or free base, and the The free acid is reacted with a non-toxic inorganic base or organic base, and the free base is reacted with a non-toxic inorganic acid or organic acid to obtain a salt.
  • 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.
  • 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 targeted organ.
  • Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.
  • Excipient refers to a substance that is not a therapeutic agent in itself but is used as a diluent, adjuvant, binder and/or vehicle and 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.
  • pharmaceutical excipients can serve a variety of 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., cross-linked sodium 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 starch, etc.
  • sugars such as lactose, glucose, and sucrose
  • starches such as corn starch and potato starch
  • cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate,
  • glycols such as propylene glycol
  • polyols such as glycerol, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • agar such as agar
  • buffers such as magnesium hydroxide and aluminum hydroxide
  • Steps refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
  • Solvate refers to a substance formed by a stoichiometric or non-stoichiometric amount of a solvent that is bound to the compound or salt of the present invention by non-covalent forces between molecules.
  • the solvent is water, it is a hydrate.
  • Co-crystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C 18 100 ⁇ 4.6 mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • Step 1 At room temperature, 1A (7.0 g, 37.2 mmol) was dissolved in dry toluene (300 mL), and (1S, 3R)-3-hydroxycyclohexane-1-carboxylic acid isopropyl ester (20.8 g, 111.6 mmol) and tri-n-butylphosphine (37.6 g, 186.0 mmol) were added thereto, stirred evenly, and then azodicarbonyl dipiperidine (28.1 g, 111.6 mmol) was added, and the mixture was reacted at 80°C for 16 hours under a nitrogen atmosphere.
  • Step 2 1B (3.0 g, 8.5 mmol), (3-formylthiophene-2-yl)boric acid (2.7 g, 17.0 mmol) and potassium fluoride (3.0 g, 51.0 mmol) were added to tetrahydrofuran (60 mL), and then bis(tri-tert-butylphosphine)palladium (436 mg, 0.85 mmol) was added. The mixture was reacted overnight at room temperature under a nitrogen atmosphere.
  • 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 the reaction is completed, concentrate under reduced pressure and separate and purify by silica gel column chromatography to obtain the target compound 1D (2.9 g, 99%).
  • Step 4 1D (2.9 g, 7.45 mmol) was dissolved in N,N-dimethylformamide (30 mL), N-chlorosuccinimide (1.1 g, 8.19 mmol) was added, and the mixture was reacted at 45°C for 16 hours. After the reaction was completed, ethyl acetate (100 mL) was added to the reaction solution, and the organic phase was washed with water (100 mL ⁇ 3), washed with saturated brine (100 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound 1E (3.0 g, 95%).
  • Step 5 Pyridine (2.8 g, 35.35 mmol) was added to 1E (3.0 g, 7.07 mmol) and 4-nitrophenyl chloroformate (4.3 g, 21.21 mmol) in dichloromethane (60 mL) at room temperature, and the mixture was reacted for 2 hours at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure and the target compound 1F (2.2 g, 53%) was obtained by silica gel column chromatography.
  • Step 6 Add N,N-diisopropylethylamine (0.66 g, 5.1 mmol) to 1F (1.0 g, 1.7 mmol) and 3-methylenecyclobutane-1-amine trifluoroacetate (0.31 g, 1.7 mmol) in tetrahydrofuran (20 mL) at room temperature and react for 2 hours at room temperature. After the reaction is completed, concentrate under reduced pressure and obtain the target compound 1G (0.7 g, 77%) by silica gel column chromatography.
  • Step 7 Sodium hydride (68 mg, 1.7 mmol, 60%) was added to 1G (0.3 g, 0.56 mmol) and iodomethane (0.24 g, 1.7 mmol) in N,N-dimethylformamide (5 mL) at room temperature, and the mixture was reacted at room temperature for 2 hours.
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Step 1 Compound 2A (500 mg, 2.73 mmol) was added to a reaction bottle, dissolved in N,N-dimethylformamide (10 ml), sodium hydride (160 mg, 4.10 mmol, purity 60%) was added at 0°C, the temperature was maintained for 30 min, and then iodomethane (775 mg, 5.46 mmol) was added, and the mixture was heated to room temperature for 3 hours.
  • Step 2 Add compound 2B (470 mg, 2.38 mmol) to a reaction flask, dissolve it in dichloromethane (10 ml), then add trifluoroacetic acid (0.5 ml), and react at room temperature for 1 h. After the reaction is completed as monitored by TLC, concentrate under reduced pressure to obtain a crude compound 2C (250 mg, TFA salt), which is used directly in the next step.
  • Step 3 Add compound 2D (0.30 g, 0.77 mmol, synthesized according to the method of patent WO2019126085A1) to dichloromethane (15 mL), and then add pyridine (0.24 g, 3.08 mmol) and 4-nitrophenyl chloroformate (0.23 g, 1.16 mmol) in turn, react at room temperature for 3 hours, and concentrate under reduced pressure after the reaction is completed by TLC monitoring. The residue is dissolved in tetrahydrofuran (15 mL), and then triethylamine (0.39 g, 3.85 mmol) and compound 2C (250 mg, TFA salt) are added in turn. The reaction is continued at room temperature for 3 hours. After the reaction is completed by TLC monitoring, it is concentrated under reduced pressure. The residue is purified by normal phase column to obtain compound 2E (0.32 g, yield: 81%).
  • Step 4 Compound 2E (0.32 g, 0.63 mmol) was dissolved in methanol (5 mL), tetrahydrofuran (5 mL) and water (5 mL), and then lithium hydroxide (112 mg, 2.71 mmol) was added and reacted at room temperature for 15 hours. After the reaction was completed, 1 M dilute hydrochloric acid was directly added to adjust the pH to weak acidity, and then a small amount of water was added, and ethyl acetate (20 mL) was extracted 3 times, and the organic phases were combined, concentrated, and sent to HPLC for preparation and purification to obtain compound 2 (0.15 g, 51%).
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Step 1 Add potassium tert-butoxide (9.53 g, 85.13 mmol) to a three-necked flask, dissolve it with DMF (100 ml), replace it with nitrogen three times, cool it to -45 ° C, slowly drop 3A (10 g, 56.75 mmol) in DMF (25 ml) solution and 2-(difluoromethanesulfonyl)pyridine (9.86 g, 51.08 mmol) in DMF (25 ml) solution, and react at this temperature for one hour after the addition is completed. Then add saturated ammonium chloride solution (30 mL) and hydrochloric acid aqueous solution (1N, 50 mL), slowly warm to room temperature and react for 16 hours.
  • Step 2 Add compound 3B (4 g, 19.05 mmol) to a reaction flask, dissolve it with dichloromethane (100 ml), replace it with nitrogen three times, cool it to -78 ° C, then drop boron tribromide (9.52 g, 38.10 mmol), and maintain this temperature for half an hour. After the reaction is completed by TLC monitoring, add saturated sodium bicarbonate solution (200 ml) to adjust the pH to greater than 7, extract it with dichloromethane twice (50 ml ⁇ 2), combine the organic phases, dry and filter them, and obtain a crude solution of compound 3C, which is directly used in the next step.
  • dichloromethane 100 ml
  • boron tribromide 9.52 g, 38.10 mmol
  • Step 5 Compound 3F (210 mg, 0.39 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (2 mL) and water (2 mL), and then lithium hydroxide (81 mg, 1.97 mmol) was added and reacted at room temperature for 15 hours. After the reaction was completed, 1 M dilute hydrochloric acid was directly added to adjust the pH to 5-6, and the mixture was concentrated and sent to HPLC for preparation and purification to obtain compound 3 (30 mg, 15.1%).
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Step 1 Dissolve compound 4A (15.00 g, 102.64 mmol) in methanol (150 mL), cool to 0-5°C, slowly add concentrated sulfuric acid (2 mL), return to room temperature and stir for 17 hours. After the reaction is completed, pressurize and concentrate, then add saturated sodium bicarbonate aqueous solution (150 mL) in batches and extract impurities twice with petroleum ether (100 mL). Cool the aqueous phase to 0°C, adjust pH to 3-4 with 6N hydrochloric acid aqueous solution, and extract the product twice with ethyl acetate (100 mL). Dry the combined organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 4B (9.20 g, yield: 56%).
  • Step 2 Dissolve compound 4B (5.00 g, 31.22 mmol) in dry tetrahydrofuran (50 mL), replace with nitrogen three times, and reduce The mixture was warmed to 0-5°C, and a borane tetrahydrofuran solution (62.44 mL, 62.44 mmol, 1.0 mol/L tetrahydrofuran solution) was slowly added dropwise. After the addition was completed, the temperature was slowly returned to room temperature and reacted for 3 hours. After the reaction was completed under TLC monitoring, the temperature was lowered to 0°C, and methanol (100 mL) was slowly added dropwise to quench the reaction. After the quenching was complete, the reaction was concentrated under reduced pressure. The residue was purified by normal phase column to give compound 4C (2.60 g, yield: 57%).
  • Step 3 Add compound 4C (2 g, 13.68 mmol) to a dichloromethane (20 mL) solution, then add triethylamine (4.15 g, 41.04 mmol), cool to 0-5°C, add methanesulfonic anhydride (4.77 g, 27.36 mmol) in batches, react at room temperature for 16 hours, and after the reaction is completed as monitored by TLC, concentrate under reduced pressure, and purify the residue by normal phase column to obtain compound 4D (3 g, yield: 97%).
  • 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), and cesium carbonate (13.08 g, 40.13 mmol) and sodium iodide (200.5 mg, 1.34 mmol) were added in sequence. After addition, the temperature was raised to 100 ° C and reacted for 16 hours. After the reaction was completed, it was cooled to room temperature, water (50 mL) was added, and the product was extracted twice with ethyl acetate (50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and the obtained residue was purified by normal phase column to obtain compound 4E (400 mg, yield: 9.5%).
  • Step 5 Dissolve compound 4F (500 mg, 1.82 mmol, synthesized according to the method of patent WO2019126085A1) and tetrahydroxydiboron (326 mg, 3.63 mmol) in anhydrous ethanol (10 mL), add 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), replace with nitrogen and stir 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, followed by addition of compound 4E (400 mg, 1.27 mmol), additional XPhos (7 mg, 0.02 mmol) and XPhos Pd G2 (14 mg, 0.02 mmol), and replaced with nitrogen again, heated to 80 °C and stirred for 16 h. After the reaction was completed as monitored by TLC,
  • Step 6 Compound 4G (100 mg, 0.23 mmol) was added to methanol (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was completed as monitored by TLC, it was concentrated under reduced pressure, and dichloromethane (10 mL) was added to dissolve the mixture. The mixture was washed twice with saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was concentrated to obtain compound 4H (80 mg, yield: 99.4%).
  • Step 7 Compound 4H (80 mg, 0.23 mmol) was added to dichloromethane (5 mL), and then pyridine (91 mg, 1.15 mmol) and 4-nitrophenyl chloroformate (139 mg, 0.69 mmol) were added in sequence. The mixture was reacted at room temperature for 3 hours. After the reaction was completed under TLC monitoring, the mixture was concentrated under reduced pressure. The residue was purified by normal phase column to obtain compound 4I (100 mg, yield: 84.7%).
  • Step 8 Compound 4I (100 mg, 0.20 mmol) was dissolved in tetrahydrofuran (2 mL), and then 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 starting material disappeared after TLC monitoring. 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%).
  • Step 9 Compound 4J (70 mg, 0.15 mmol) was dissolved in methanol (1.5 mL) and water (1.5 mL), and then lithium hydroxide (18 mg, 0.74 mmol) was added, and the reaction was carried out at room temperature for 15 hours. After the reaction was completed, 1 M dilute hydrochloric acid was directly added to adjust the pH to weak acidity, and then water (10 mL) was added, and ethyl acetate (10 mL) was extracted three times, and the organic phases were combined and concentrated, and then purified by HPLC to obtain compound 4 (40 mg, 58.9%).
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • Step 1 Add compound 5A (15.0 g, 115.26 mmol) to a reaction flask, dissolve it in dichloromethane (200 ml), add triethylamine (34.99 g, 345.78 mmol), replace it with nitrogen three times, cool it to 0°C, slowly add tert-butyldiphenylsilyl chloride (38.02 g, 138.31 mmol), and react at this temperature for 4 hours after the addition is completed.
  • dichloromethane 200 ml
  • triethylamine 34.99 g, 345.78 mmol
  • tert-butyldiphenylsilyl chloride 38.02 g, 138.31 mmol
  • Step 3 Add compound 5C (2.0 g, 5.87 mmol) to a reaction bottle, dissolve it with tetrahydrofuran (20 ml), add 2-nitrophenyl seryl cyanate (4.00 g, 17.61 mmol) and tri-n-butylphosphine (3.56 g, 17.61 mmol), and react at room temperature for one hour.
  • Step 4 Compound 5D (2.0 g, 6.20 mmol) was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (12.4 mL, 12.4 mmol) was added and reacted at room temperature for 16 h. After the raw material disappeared completely, the mixture was concentrated to obtain the target compound 5E (2 g, crude product), which was directly used in the next step.
  • 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 raw material disappeared completely, 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%).
  • Step 7 Compound 5G (72 mg, 0.14 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL), and then lithium hydroxide (30 mg, 0.72 mmol) was added, and the mixture was reacted at room temperature for 16 hours. After the reaction was completed, 1 M dilute hydrochloric acid was directly added to adjust the pH to 5-6, and the mixture was concentrated and sent to HPLC for preparation and purification to obtain compound 5 (35 mg, 53.1%).
  • the synthetic routes of Examples 6-19 refer to the synthetic routes of Examples 1-5, as shown in the following table.
  • CHO-LPA1 cells were cultured using F12 medium (10% FBS).
  • the compounds of the present invention have a significant antagonistic effect on LPAR 1 enzyme activity in vitro, and the IC 50 value of the example compounds on LPAR 1 enzyme activity is less than 100 ⁇ M.
  • the IC 50 value is expressed in A, B, C, and D grades, A means 0 ⁇ IC 50 ⁇ 10 nM, B means 10nM ⁇ IC 50 ⁇ 50nM, C represents 50nM ⁇ IC 50 ⁇ 100nM, and D represents IC 50 >100nM.
  • the test results of some embodiments are shown in Table 1.
  • mice Male C57 mice, 20-25 g, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic characteristics in mice.
  • mice Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats per compound. Purchased from Chengdu Dashuo Experimental Animal Center Ltd.
  • Example Compound 3 have good pharmacokinetic characteristics in rats.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic characteristics in monkeys.
  • Cell line Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
  • CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature.
  • the glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller.
  • the tip resistance after perfusion of the electrode liquid was about 2-5M ⁇ .
  • the glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier.
  • the clamping voltage and data recording were controlled and recorded by pClamp 10 software through a computer, with a sampling frequency of 10kHz and a filter frequency of 2kHz.
  • the cell was clamped at -80mV, and the step voltage to induce the hERG potassium current (I hERG) was given a 2s depolarization voltage from -80mV to +20mV, then repolarized to -50mV, and returned to -80mV after 1s.
  • This voltage stimulation was given every 10s, and the drug administration process was started after the hERG potassium current was determined to be stable (at least 1 minute).
  • Compounds were administered for at least 1 min at each tested concentration, and at least 2 cells (n ⁇ 2) were tested at each concentration.
  • Inhibition% represents the inhibition percentage of the compound on hERG potassium current
  • I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.
  • the IC50 of the compounds was calculated using GraphPad Prism 5 software by fitting the following equation:
  • X is the Log value of the test sample detection concentration
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum inhibition percentages, respectively.
  • Example Compound 3 have no inhibitory effect on hERG.
  • the purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system.
  • Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction.
  • NADPH nicotinamide adenine dinucleotide phosphate
  • the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC50 values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype. Under the test conditions, the incubation concentration was 0-30 ⁇ M.
  • the compounds of the present invention have no inhibitory effect on CYP enzymes.
  • 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.
  • test substance was incubated with microsomal proteins and coenzyme NADPH. After a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS. T 1/2 was calculated by the ln value of the drug residual rate in the incubation system and the incubation time, and the liver microsomal intrinsic clearance CL int(mic) and liver intrinsic clearance CL int(Liver) were further calculated.
  • the compounds of the present invention such as the compounds in the examples, have good liver microsomal stability.
  • the experiment used a monolayer of Caco-2 cells and was incubated in triplicate in a 96-well Transwell plate.
  • a transport buffer solution (HBSS, 10 mM HEPES, pH 7.4 ⁇ 0.05) containing the compound of the present invention (2 ⁇ M) or the control compounds digoxin (10 ⁇ M), nadolol (2 ⁇ M) and metoprolol (2 ⁇ M) was added to the dosing port well on the apical side or the basolateral side.
  • a transport buffer solution containing DMSO was added to the corresponding receiving port well. After incubation at 37 ⁇ 1 ° C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate.
  • acetonitrile containing an internal standard was added to precipitate the protein.
  • the samples were analyzed using LC MS/MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical side to the basolateral side of the monolayer cells and from the basolateral side to the apical side, thereby calculating the efflux rate.
  • the integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.
  • the compounds of the present invention such as the compounds in the examples, have good permeability.
  • mice in the model group were injected intratracheally (i.t.) with bleomycin at a dose of 0.66 mg/kg (1 U/kg) in a volume of 50 ⁇ L on the first day.
  • mice in each experimental group were given the test compound by gavage twice a day; the control group was given nintedanib at a dose of 60 mg/kg, with a dosing volume of 10 mL/kg body weight, by gavage once a day.
  • the sham operation group 1 and the model group 2 were given the vehicle at a volume of 10 mL/kg body weight by oral gavage twice a day.

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Abstract

提供一种LPAR1 拮抗剂及其用途。具体提供了一种式(I)所示的化合物，或其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐和它们的药物组合物，及其在制备治疗/预防LPAR1介导的疾病的药物中的用途，式（I）中各基团如说明书之定义。

Description

杂芳环衍生物的LPAR1拮抗剂及其用途 技术领域
本发明属于药物领域，尤其涉及一种具有LPAR1拮抗活性的小分子化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，及其在制备治疗相关疾病的药物中的用途。
背景技术
溶血磷脂酸(lysophosphatidic acid,LPA)是一种小分子甘油磷酸，分子量在430～480D。LPA广泛存在于人体内，与受体结合后可以激活多条细胞信号通路，参与调控细胞的增殖、分化、凋亡、神经递质释放等生命活动，在癌症、纤维化、神经元功能障碍、骨代谢障碍等疾病中发挥重要的作用。LPA主要由自分泌运动因子水解溶血磷脂(主要为溶血磷脂酰胆碱)生成。在博来霉素致肺纤维化模型中，支气管肺泡灌洗液的LPA水平明显升高，并导致血管渗透性增加和肺纤维化；LPA还可介导成纤维细胞产生多种旁分泌的介质，作用于上皮细胞、白细胞和内皮细胞，调节组织重塑、血管形成、炎症、伤口愈合和肿瘤进展；LPA甚至可诱导成纤维细胞的表皮生长因子(EGF)家族配体细胞外脱落，激活可溶性因子释放，并部分通过EGFR作用，刺激肺上皮细胞，扩大局部成纤维细胞反应。最新研究还发现，LPA-LPA1信号途径可促进特发性肺纤维化(IPF)中肺组织上皮细胞凋亡，抑制成纤维细胞凋亡，提示该信号途径可能调控肺损伤后纤维化的发展。研究表明，LPA与器官纤维化密切相关，主要通过溶血磷脂酸受体(lysophosphatidic acid receptor,LPAR)1介导。目前已发现6种LPAR，即LPAR1～LPAR6，其中LPAR1的功能是近年来研究的热点。临床研究证实，LPAR拮抗剂对特发性肺纤维化具有治疗作用；还发现LPAR1拮抗剂BMS-986020可有效改善特发性肺纤维化患者的肺功能。
发明内容
本发明提供了一种式(I)的化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，所述化合物具有活性好、理化性质优异、便于制剂、药代动力学性质优异、生物利用度高、毒副作用低的优异效果。
本发明设计提供所述式(I)、(I-1)的化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，
其中，
环A选自4-8元单环碳环基、6-12元双环碳环基、6-12元单环杂环基、6-12元双环杂环基或无，所述的碳环基、杂环基任选被1-4个RA取代；在一些实施方案中，环A选自4-7元单环碳 环基、6-10元双环碳环基、6-10元单环杂环基、6-10元双环杂环基，所述杂环基含有1-3个选自N、O、S的杂原子；在一些实施方案中，环A选自4-7元单环碳环基；在一些实施方案中，环A选自所述环A被1个COOH取代；
在一些实施方案中，当环A选自不存在时，L1选自被一个COOH取代的-OC1-6烷基；在一些实施方案中，环A选自不存在，L1选自-OCH2C(CH3)2CH2COOH、-OCH2CH2C(CH3)2COOH；
环C选自5元杂芳基并5-7元碳环、5元杂芳基并5-7元杂环、C3-6单环碳环、5-6元单环杂环环烷基、C5-10双环环烷基、5-10元双环杂环环烷基，所述的杂芳基、碳环、杂环、环烷基、杂环烷基任选被1-4个RC取代；其中表示环C与吡啶环的连接位点，“*”表示环C与L2连接位点；在一些实施方案中，环C选自5元杂芳基并5-7元环烷基、5元杂芳基并芳基、5元杂芳基并5-7元杂环烷基、5元杂芳基并5-7元杂芳基、C3-6单环环烷基、5-6元单环杂环环烷基、C5-10双环环烷基、5-10元双环杂环环烷基，所述杂芳基、杂环含有1-3个选自N、O、S的杂原子；所述的杂芳基、环烷基、苯基、杂环烷基、杂芳基任选被1-4个RC取代；其中表示环C与吡啶环的连接位点，“*”表示环C与L2连接位点；在一些实施方案中，环C选自 5元杂芳基并5-6元环烷基、5元杂芳基并5-6元杂环烷基、C3-6单环环烷基、5-6元单环杂环环烷基、C5-10双环环烷基、5-10元双环杂环环烷基，所述杂芳基、杂环含有1-3个选自N、O、S的杂原子；所述的杂芳基、环烷基、苯基、杂环烷基、杂芳基任选被1-3个RC取代；在一些实施方案中，环C选自
在一些实施方案中，环C选自5元杂芳基并5-7元碳环、5元杂芳基并5-7元杂环，所述的杂芳基、碳环、杂环任选被1-4个RC取代；其中表示环C与吡啶环的连接位点，“*”表示环C与L2连接位点；在一些实施方案中，环C选自 5元杂芳基并5-7元环烷基、5元杂芳基并芳基、5元杂芳基并5-7元杂环烷基、5元杂芳基并5-7元杂芳基，所述杂芳基、杂环含有1-3个选自N、O、S的杂原子；所述的杂芳基、环烷基、苯基、杂环烷基、杂芳基任选被1-4个RC取代；其中表示环C与吡啶环的连接位点，“*”表示环C与L2连接位点；在一些实施方案中，环C选自 5元杂芳基并5-6元环烷基、5元杂芳基并5-6元杂环烷基，所述杂芳基、杂环含有1-3个选自N、O、S的杂原子；所述的杂芳基、环烷基、苯基、杂环烷基、杂芳基任选被1-3个RC取代；在一些实施方案中，环C选自
Rc1、Rc4、Rc5各自独立地选自H、卤素、C1-4烷基、卤代C1-4烷基；
Rc3选自H、C1-4烷基；
作为选择，Rc1与RB一起形成6-7元杂环或者6-7元碳环；
作为选择，Rc3与RB一起形成6-7元杂环；
L1选自键、-C1-4烷基-、-C＝O、-O-C(RL1aRL1b)p-、-S-(CRL1aRL1b)p-、-C(＝O)NRL1-、C2-6烯基 或C2-6炔基，所述烷基、烯基、炔基任选进一步的被1-4个RL1a取代；在一些实施方案中，L1选自键、-O-、-O-CH2-、-C＝O、-CH2-、-O-CH2-C(CH3)2-CH2-；在一些实施方案中，L1选自键、-O-、-O-CH2-、-C＝O、-CH2-；在一些实施方案中，L1选自-O-；
L2选自(CRL2a1RL2a2)p-OC(＝O)N(RL2b)2、-C(＝O)N(RL2b)2、-NRL2b-C(＝O)ORL2c、-(CRL2a1RL2a2)pN(RL2b)2、-(CH2)pRL2d、-(CRL2a1RL2a2)pN(RL2b)S(O)2N(RL2b)2、(CRL2a1RL2a2)pN(RL2b)C(＝O)N(RL2b)2、-(CRL2a1RL2a2)pN(RL2b)C(＝O)ORL2b；在一些实施方案中，L2选自(CRL2a1RL2a2)p-OC(＝O)N(RL2b)2、-C(＝O)N(RL2b)2、-NRL2b-C(＝O)ORL2c、-(CRL2a1RL2a2)pN(RL2b)2、-(CH2)pRL2d、-(CRL2a1RL2a2)pN(RL2b)S(O)2N(RL2b)2、(CRL2a1RL2a2)pN(RL2b)C(＝O)N(RL2b)2；在一些实施方案中，L2选自(CRL2a1RL2a2)p-OC(＝O)N(RL2b)2、-C(＝O)N(RL2b)2、-NRL2b-C(＝O)ORL2c；在一些实施方案中，L2选自(CRL2a1RL2a2)p-OC(＝O)N(RL2b)2、-C(＝O)N(RL2b)2、-NRL2b-C(＝O)ORL2c、-(CRL2a1RL2a2)pN(RL2b)C(＝O)ORL2b；在一些实施方案中，L2选自-(CRL2a1RL2a2)p-OC(＝O)NHRL2b、-(CRL2a1RL2a2)p-OC(＝O)N(C1-4烷基)RL2b、-C(＝O)NHRL2b、-C(＝O)N(C1-4烷基)RL2b、-NHC(＝O)ORL2c、-N(C1-4烷基)C(＝O)ORL2c、-(CRL2a1RL2a2)pNHC(＝O)ORL2b、-(CRL2a1RL2a2)pN(C1-4烷基)C(＝O)ORL2b；在一些实施方案中，L2选自-(CRL2a1RL2a2)p-OC(＝O)NHRL2b、-(CRL2a1RL2a2)p-OC(＝O)N(CH3)RL2b、-(CRL2a1RL2a2)pNHC(＝O)ORL2b、-(CRL2a1RL2a2)pN(CH3)C(＝O)ORL2b；
在一些实施方案中，L2选自 在一些实施方案中，L2选自在一些实施方案中，L2选自
在一些实施方案中，当环C为时，L2选自
RA各自独立的选自H、卤素、CN、OH、-(CH2)p-COORa1、-(CH2)p-C(＝O)NRa1Ra2、-(CH2)p-C(＝O)NHC(＝O)Ra1、-(CH2)p-C(＝O)NHS(O)2Ra1、-(CH2)p-C(＝O)NHS(O)Ra1、-(CH2)p-S(O)2OH、-(CH2)p-S(O)2NHCORa1、-(CH2)p-P(O)(OH)2、C1-4烷基、C2-6烯基、C2-6炔基、-OC1-4烷基或-(CH2)p-(5-10元杂环基)，所述的烷基、烯基、炔基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、-O-卤代C1-4烷基的基团取代；在一些实施方案中，RA各自独立的选自卤素、CN、OH、COOH、-CH2COOH、C1-2烷基、C2-4烯基、C2-4炔基或-OC1-2烷基，所述的烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN、-O-卤代C1-2烷基的基团取代；在一些实施方案中，RA各自独立的选自COOH、-CH2COOH；
RB独立的选自H；
RC各自独立的选自卤素、CN、OH、NO2、NH2、＝O、C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基，所述的烷氧基、烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；在一些实施方案，RC各自独立的选自H、卤素、CN、OH、＝O、NH2、C1-2烷基、-OC1-2烷基、C2-4烯基、C2-4炔基、C3-6环烷基，所述的烷基、烯基、炔基、环烷基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；在一些实施方案中，RC各自独立的选自H、卤素、CN、OH、＝O、NH2、C1-2烷基，所述的烷基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；在一些实施方案中，RC各自独立的选自H、F、Cl、＝O、CH3、CH2CH3；在一些实施方案中，RC各自独立的选自卤素、CN、OH、NO2、NH2、C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基，所述的烷氧基、烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；在一些实施方案中，RC各自独立的选自H、卤素、CN、OH、NH2、C1-2烷基、-OC1-2烷基、C2-4烯基、C2-4炔基、C3-6环烷基，所述的烷基、烯基、炔基、环烷基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；在一些实施方案中，RC各自独立的选自H、卤素、CN、OH、NH2、C1-2烷基，所述的烷基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；在一些实施方案中，RC各自独立的选自H、F、Cl、CH3、CH2CH3；
Ra1、Ra2各自独立的选自H、卤素、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、＝O、OH、NH2、CN、乙酰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基的基团取代；在一些实施方案中，Ra1、Ra2各自独立的选自H、C1-4烷基、C3-5环烷基、C1-4烷氧基、5-10元杂环基，所述的烷基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自F、Cl、＝O、OH、NH2、CN、乙酰基、C1-2烷基、C1-2烷氧基、卤代C1-2烷氧基的基团取代；在一些实施方案中，Ra1、Ra2各自独立的选自H、C1-4烷基；
Rc2选自-(CRL2a1RL2a2)p-C3-7元环烷基、-(CRL2a1RL2a2)p-(4-7元杂环烷基)、卤素、CN、OH、NO2、NH2、卤代C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基；在一些实施方案中，Rc2选自C3-4元环烷基、4-5元杂环烷基、-CH2-C3-4元环烷基、-CH2-(4-5元杂环烷基)、氟代C1-2烷基；在一些实施方案中，Rc2选自环丙基、环丁基、氧杂环丁基、氧杂环戊基、氮杂环丁基、氮杂环戊基、-CH2-环丙基、-CH2-环丁基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH2F、-CHFCHF2、-CHFCF3、-CF2CH2F、-CF2CHF2、-CF2CF3；在一些实施方案中，Rc2选自C3-7元环烷基、4-7元杂环烷基、卤素、CN、OH、NO2、NH2、卤代C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基；在一些实施方案中，Rc2选自C3-4元环烷基、4-5元杂环烷基、氟代C1-2烷基；在一些实施方案中，Rc2选自环丙基、环丁基、氧杂环丁基、氧杂环戊基、氮杂环丁基、氮杂环戊基、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH2F、-CHFCHF2、-CHFCF3、-CF2CH2F、-CF2CHF2、-CF2CF3；
每个RL1a、RL1b各自独立的选自H、卤素、CN、OH、NO2、NH2、＝O、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、-(CH2)p-COORa1，所述的烷基、烯基、炔基、环烷基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基的基团取代；在一些实施方案中，每个RL1a、RL1b各自独立的选自H、卤素、CN、OH、NO2、NH2、＝O、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基，所述的烷基、烯基、炔基、环烷基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基的基团取代；在一些实施方案中，每个RL2a1、RL2a2各自独立 的选自H、C1-2烷基，所述的烷基任选进一步被1-4个选自F、Cl、OH、NH2、CN的基团取代；在一些实施方案中，每个RL2a1、RL2a2各自独立的选自H、甲基、乙基；
RL1独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、＝O、OH、NH2、CN、乙酰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
每个RL2a1、RL2a2各自独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基，所述的烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基的基团取代；作为选择，RL2a1与RB一起形成6-7元杂环或6-7元碳环；
每个RL2b各自独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；在一些实施方案中，每个RL2b各自独立的选自H、C1-4烷基，所述的烷基任选进一步被1-2个选自F、Cl、OH、NH2、CN、C1-4烷基、C1-4烷基亚基、卤代C1-4烷基亚基、C1-2烷氧基、氟代C1-2烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；在一些实施方案中，每个RL2b各自独立的选自H、C1-4烷基、C4-6环烷基，所述的环烷基任选进一步被1-2个选自F、Cl、OH、NH2、CN、C1-4烷基、C1-4烷基亚基、卤代C1-4烷基亚基；在一些实施方案中，每个RL2b各自独立的选自H、C1-4烷基；
每个RL2d各自独立的选自C1-4烷基、卤素、OH、NH2、CN、C2-6烯基、C2-6炔基、-C(＝O)H、-C(＝O)OH、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、N3、C1-4烷氧基、卤代C1-4烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；在一些实施方案中，每个RL2d各自独立的选自C1-4烷基，所述的烷基任选进一步被1-2个选自卤素、OH、NH2、CN、N3、C1-2烷氧基、氟代C1-2烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；在一些实施方案中，每个RL2b各自独立的选自被1-2个C1-4烷基亚基、卤代C1-4烷基亚基所取代的C3-10环烷基；在一些实施方案中，每个RL2b各自独立的选自被1-2个C1-4烷基亚基、卤代C1-4烷基亚基所取代的C4-6环烷基；
RL2c选自-C1-4烷基-(5-10元杂芳基)，所述的杂芳基任选进一步被1-3个选自卤素、CN、OH、NO2、NH2、卤代C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基的取代基取代；在一些实施方案中，RL2c选自-C1-2烷基-(5-6元单环杂芳基)、-C1-2烷基-(8-10元双环杂芳基)，所述的杂芳基任选进一步被1-3个选自F、Cl、CN、OH、NO2、NH2、卤代C1-2烷基的取代基取代；在一些实施方案中，RL2c选自-C1-2烷基-(5-6元单环杂芳基)、-C1-2烷基-(8-10元双环杂芳基)，所述的杂芳基任选进一步被1-3个选自F、Cl、CN、OH、NO2、NH2、-CH2F、-CHF2、-CF3的取代基取代；
p选自0、1、2、3、4；在一些实施方案中，p选自0、1或2；在一些实施方案中，p选自0或1；
无特别说明时，杂环、杂环基、杂环烷基、杂芳基含有1、2、3、4个选自N、O、S的杂原子。
具体而言，本发明第一技术方案，所述的式(I)化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，
环A选自4-8元单环碳环基、6-12元双环碳环基、6-12元单环杂环基、6-12元双环杂环基或无，所述的碳环基、杂环基任选被1-4个RA取代；
环C选自5元杂芳基并5-7元碳环、5元杂芳基并5-7元杂环、C3-6单环碳环、5-6元单环杂环环烷基、C5-10双环环烷基、5-10元双环杂环环烷基，所述的杂芳基、碳环、杂环、环烷基、杂环烷基任选被1-4个RC取代；其中表示环C与吡啶环的连接位点，“*”表示环C与L2连接位点；
Rc1与RB一起形成6-7元杂环或者6-7元碳环；
Rc3与RB一起形成6-7元杂环；
L1选自键、-C1-4烷基-、-C＝O、-O-C(RL1aRL1b)p-、-S-(CRL1aRL1b)p-、-C(＝O)NRL1-、C2-6烯基或C2-6炔基，所述烷基、烯基、炔基任选进一步的被1-4个RL1a取代；
在一些实施方案中，当环A选自不存在时，L1选自被一个COOH取代的-OC1-6烷基；在一些实施方案中，环A选自不存在，L1选自-OCH2C(CH3)2CH2COOH、-OCH2CH2C(CH3)2COOH；
L2选自(CRL2a1RL2a2)p-OC(＝O)N(RL2b)2、-C(＝O)N(RL2b)2、-NRL2b-C(＝O)ORL2c、-(CRL2a1RL2a2)pN(RL2b)2、-(CH2)pRL2d、-(CRL2a1RL2a2)pN(RL2b)S(O)2N(RL2b)2、(CRL2a1RL2a2)pN(RL2b)C(＝O)N(RL2b)2或-(CRL2a1RL2a2)pN(RL2b)C(＝O)ORL2b；
RA各自独立的选自H、卤素、CN、OH、-(CH2)p-COORa1、-(CH2)p-C(＝O)NRa1Ra2、-(CH2)p-C(＝O)NHC(＝O)Ra1、-(CH2)p-C(＝O)NHS(O)2Ra1、-(CH2)p-C(＝O)NHS(O)Ra1、-(CH2)p-S(O)2OH、-(CH2)p-S(O)2NHCORa1、-(CH2)p-P(O)(OH)2、C1-4烷基、C2-6烯基、C2-6炔基、-OC1-4烷基或-(CH2)p-(5-10元杂环基)，所述的烷基、烯基、炔基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、-O-卤代C1-4烷基的基团取代；
RB独立的选自H；
RC各自独立的选自卤素、CN、OH、NO2、NH2、＝O、C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基，所述的烷氧基、烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；
Ra1、Ra2各自独立的选自H、卤素、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、＝O、OH、NH2、CN、乙酰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
Rc2选自-(CRL2a1RL2a2)p-C3-7元环烷基、-(CRL2a1RL2a2)p-(4-7元杂环烷基)、卤素、CN、OH、NO2、NH2、卤代C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基；
每个RL1a、RL1b各自独立的选自H、卤素、CN、OH、NO2、NH2、＝O、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基或-(CH2)p-COORa1，所述的烷基、烯基、炔基、环烷基任选进一步被1-4 个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
RL1独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、＝O、OH、NH2、CN、乙酰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
每个RL2a1、RL2a2各自独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基，所述的烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
作为选择，RL2a1与RB一起形成6-7元杂环或6-7元碳环；
每个RL2b各自独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；
每个RL2d各自独立的选自C1-4烷基、卤素、OH、NH2、CN、C2-6烯基、C2-6炔基、-C(＝O)H、-C(＝O)OH、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、N3、C1-4烷氧基、卤代C1-4烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；
RL2c选自-C1-4烷基-(5-10元杂芳基)，所述的杂芳基任选进一步被1-3个选自卤素、CN、OH、NO2、NH2、卤代C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基的取代基取代；
p选自0、1、2、3、4；
无特别说明时，杂环、杂环基、杂环烷基、杂芳基含有1-4个选自N、O、S、S(O)、S(O)2的杂原子。
进一步，所述的式(I)化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，
环A选自4-8元单环碳环基、6-12元双环碳环基、6-12元单环杂环基、6-12元双环杂环基，所述的碳环基、杂环基任选被1-4个RA取代；
环C选自5元杂芳基并5-7元碳环、5元杂芳基并5-7元杂环，所述的杂芳基、碳环、杂环任选被1-4个RC取代；其中表示环C与吡啶环的连接位点，“*”表示环C与L2连接位点；
L1选自键、-C1-4烷基-、-C＝O、-O-C(RL1aRL1b)p-、-S-(CRL1aRL1b)p-、-C(＝O)NRL1-、C2-6烯基或C2-6炔基,所述烷基、烯基、炔基任选进一步的被1-4个RL1a取代；
Rc1与RB一起形成6-7元杂环或者6-7元碳环；
Rc3与RB一起形成6-7元杂环；
L2选自(CRL2a1RL2a2)p-OC(＝O)N(RL2b)2、-C(＝O)N(RL2b)2、-NRL2b-C(＝O)ORL2c、-(CRL2a1RL2a2)pN(RL2b)2、-(CH2)pRL2d、-(CRL2a1RL2a2)pN(RL2b)S(O)2N(RL2b)2、(CRL2a1RL2a2)pN(RL2b)C(＝O)N(RL2b)2；
RA各自独立的选自H、卤素、CN、OH、-(CH2)p-COORa1、-(CH2)p-C(＝O)NRa1Ra2、-(CH2)p-C(＝O)NHC(＝O)Ra1、-(CH2)p-C(＝O)NHS(O)2Ra1、-(CH2)p-C(＝O)NHS(O)Ra1、-(CH2)p-S(O)2OH、-(CH2)p-S(O)2NHCORa1、-(CH2)p-P(O)(OH)2、C1-4烷基、C2-6烯基、C2-6炔基、 -OC1-4烷基或-(CH2)p-(5-10元杂环基)，所述的烷基、烯基、炔基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、-O-卤代C1-4烷基的基团取代；
RB独立的选自H；
RC各自独立的选自卤素、CN、OH、NO2、NH2、C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基，所述的烷氧基、烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；
Ra1、Ra2各自独立的选自H、卤素、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、＝O、OH、NH2、CN、乙酰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
Rc2选自C3-7元环烷基、4-7元杂环烷基、卤素、CN、OH、NO2、NH2、卤代C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基；
Rc1与RB一起形成6-7元杂环或者6-7元碳环；
Rc3与RB一起形成6-7元杂环；
每个RL1a、RL1b各自独立的选自H、卤素、CN、OH、NO2、NH2、＝O、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基，所述的烷基、烯基、炔基、环烷基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
RL1独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、＝O、OH、NH2、CN、乙酰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
每个RL2a1、RL2a2各自独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基，所述的烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
作为选择，RL2a1与RB一起形成6-7元杂环或6-7元碳环；
每个RL2b各自独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；
每个RL2d各自独立的选自C1-4烷基、卤素、OH、NH2、CN、C2-6烯基、C2-6炔基、-C(＝O)H、-C(＝O)OH、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、N3、C1-4烷氧基、卤代C1-4烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；
RL2c选自-C1-4烷基-(5-10元杂芳基)，所述的杂芳基任选进一步被1-3个选自卤素、CN、OH、NO2、NH2、卤代C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基的取代基取代；
p选自0、1、2、3、4；
无特别说明时，杂环、杂环基、杂环烷基、杂芳基含有1-4个选自N、O、S的杂原子。
本发明第二技术方案，所述的式(I)化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，其中，
环A选自4-7元单环碳环基、6-10元双环碳环基、6-10元单环杂环基、6-10元双环杂环基，所述杂环基含有1-3个选自N、O、S的杂原子；在一些实施方案中，环A选自4-7元单环碳环 基；在一些实施方案中，环A选自所述环A被1个COOH取代；和/或
RA各自独立的选自卤素、CN、OH、COOH、-CH2COOH、C1-2烷基、C2-4烯基、C2-4炔基或-OC1-2烷基，所述的烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN、-O-卤代C1-2烷基的基团取代；在一些实施方案中，RA各自独立的选自COOH、-CH2COOH。
本发明第三技术方案，所述的式(I)、(I-1)化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，
环C选自5元杂芳基并5-7元环烷基、5元杂芳基并芳基、5元杂芳基并5-7元杂环烷基、5元杂芳基并5-7元杂芳基、C3-6单环环烷基、5-6元单环杂环环烷基、C5-10双环环烷基、5-10元双环杂环环烷基，所述杂芳基、杂环含有1-3个选自N、O、S的杂原子；所述的杂芳基、环烷基、苯基、杂环烷基、杂芳基任选被1-4个RC取代；其中表示环C与吡啶环的连接位点，“*”表示环C与L2连接位点；在一些实施方案中，环C选自5元杂芳基并5-6元环烷基、5元杂芳基并5-6元杂环烷基、C3-6单环环烷基、5-6元单环杂环环烷基、C5-10双环环烷基、5-10元双环杂环环烷基，所述杂芳基、杂环含有1-3个选自N、O、S的杂原子；所述的杂芳基、环烷基、苯基、杂环烷基、杂芳基任选被1-3个RC取代；在一些实施方案中，环C选自
和/或
RC各自独立的选自H、卤素、CN、OH、＝O、NH2、C1-2烷基、-OC1-2烷基、C2-4烯基、C2-4炔基、C3-6环烷基，所述的烷基、烯基、炔基、环烷基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；在一些实施方案中，RC各自独立的选自H、卤素、CN、OH、＝O、NH2、C1-2烷基，所述的烷基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；在一些实施方案中，RC各自独立的选自H、F、Cl、＝O、CH3、CH2CH3；和/或
Rc2选自C3-4元环烷基、4-5元杂环烷基、-CH2-C3-4元环烷基、-CH2-(4-5元杂环烷基)、氟代C1-2烷基；在一些实施方案中，Rc2选自环丙基、环丁基、氧杂环丁基、氧杂环戊基、氮杂环丁基、氮杂环戊基、-CH2-环丙基、-CH2-环丁基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH2F、-CHFCHF2、-CHFCF3、-CF2CH2F、-CF2CHF2、-CF2CF3；
Rc1、Rc4、Rc5各自独立地选自H、F、Cl、甲基、乙基、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH2F、-CHFCHF2、-CHFCF3、-CF2CH2F、-CF2CHF2、-CF2CF3；
Rc3选自H、甲基、乙基；
作为选择，Rc1与RB一起形成6-7元杂环或者6-7元碳环；
作为选择，Rc3与RB一起形成6-7元杂环。
进一步，所述的式(I)、(I-1)化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，
环C选自5元杂芳基并5-7元环烷基、5元杂芳基并芳基、5元杂芳基并5-7元杂环烷基、5元杂芳基并5-7元杂芳基，所述杂芳基、杂环含有1-3个选自N、O、S的杂原子；所述的杂芳基、环烷基、苯基、杂环烷基、杂芳基任选被1-4个RC取代；其中表示环C与吡啶环的连接位点，“*”表示环C与L2连接位点；在一些实施方案中，环C选自5元杂芳基并5-6元环烷基、5元杂芳基并5-6元杂环烷基，所述杂芳基、杂环含有1-3个选自N、O、S的杂原子；所述的杂芳基、环烷基、苯基、杂环烷基、杂芳基任选被1-3个RC取代；在一些实施方案中，环C选自
和/或
RC各自独立的选自H、卤素、CN、OH、NH2、C1-2烷基、-OC1-2烷基、C2-4烯基、C2-4炔基、C3-6环烷基，所述的烷基、烯基、炔基、环烷基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；在一些实施方案中，RC各自独立的选自H、卤素、CN、OH、NH2、C1-2烷基，所述的烷基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；在一些实施方案中，RC各自独立的选自H、F、Cl、CH3、CH2CH3；和/或
Rc2选自C3-4元环烷基、4-5元杂环烷基、氟代C1-2烷基；在一些实施方案中，Rc2选自环丙基、环丁基、氧杂环丁基、氧杂环戊基、氮杂环丁基、氮杂环戊基、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH2F、-CHFCHF2、-CHFCF3、-CF2CH2F、-CF2CHF2、-CF2CF3；
Rc1与RB一起形成6-7元杂环或者6-7元碳环；
Rc3与RB一起形成6-7元杂环。
进一步地，所述的式(I)化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，其中，
环C选自其中表示环C与吡啶环的连接位点，“*”表示环C与L2连接位点；
L1选自-O-；和/或
L2选自-(CRL2a1RL2a2)p-OC(＝O)NHRL2b、-(CRL2a1RL2a2)p-OC(＝O)N(C1-4烷基)RL2b、-C(＝O)NHRL2b、-C(＝O)N(C1-4烷基)RL2b、-NHC(＝O)ORL2c、-N(C1-4烷基)C(＝O)ORL2c、-(CRL2a1RL2a2)pNHC(＝O)ORL2b、-(CRL2a1RL2a2)pN(C1-4烷基)C(＝O)ORL2b；
每个RL2a1、RL2a2各自独立的选自H、C1-2烷基，所述的烷基任选进一步被1-4个选自F、Cl、OH、NH2、CN的基团取代；
作为选择，RL2a1与RB一起形成6-7元杂环或6-7元碳环；
每个RL2b各自独立的选自被1-2个C1-4烷基亚基、卤代C1-4烷基亚基所取代的C3-10环烷基；
RL2c选自-C1-2烷基-(5-6元单环杂芳基)、-C1-2烷基-(8-10元双环杂芳基)，所述的杂芳基任选进一步被1-3个选自F、Cl、CN、OH、NO2、NH2、卤代C1-2烷基的取代基取代；优选地，RL2c选自-C1-2烷基-(5-6元单环杂芳基)、-C1-2烷基-(8-10元双环杂芳基)，所述的杂芳基任选进一步被1-3个选自F、Cl、CN、OH、NO2、NH2、-CH2F、-CHF2、-CF3的取代基取代；
p选自0、1或2。
本发明第四技术方案，所述的式(I)化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，其中，
L1选自键、-O-、-O-CH2-、-C＝O、-CH2-或-O-CH2-C(CH3)2-CH2-；在一些实施方案中，L1选自-O-；和/或
L2选自(CRL2a1RL2a2)p-OC(＝O)N(RL2b)2、-C(＝O)N(RL2b)2、-NRL2b-C(＝O)ORL2c或-(CRL2a1RL2a2)pN(RL2b)C(＝O)ORL2b；
每个RL2a1、RL2a2各自独立的选自H、C1-2烷基，所述的烷基任选进一步被1-4个选自F、Cl、OH、NH2、CN的基团取代；在一些实施方案中，每个RL2a1、RL2a2各自独立的选自H、甲基、乙基；
作为选择，RL2a1与RB一起形成6-7元杂环或6-7元碳环；
每个RL2b各自独立的选自H、C1-4烷基、C3-10环烷基，所述的烷基、环烷基任选进一步被1-2个选自F、Cl、OH、NH2、CN、C1-4烷基、C1-4烷基亚基、卤代C1-4烷基亚基、C1-2烷氧基、氟代C1-2烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；优选地，每个RL2b各自独立的选自H、C1-4烷基、C4-6环烷基，所述的环烷基任选进一步被1-2个选自F、Cl、OH、NH2、CN、C1-4烷基、C1-4烷基亚基、卤代C1-4烷基亚基；或者在一些实施方案中，每个RL2b各自独立的选自H、C1-4烷基，所述的烷基任选进一步被1-2个选自F、Cl、OH、NH2、CN、C1-2烷氧基、氟代C1-2烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；在一些实施方案中，每个RL2b各自独立的选自H、C1-4烷基；
RL2c选自-C1-2烷基-(5-6元单环杂芳基)、-C1-2烷基-(8-10元双环杂芳基)，所述的杂芳基任选进一步被1-3个选自F、Cl、CN、OH、NO2、NH2、卤代C1-2烷基的取代基取代；在一些实施方案中，RL2c选自-C1-2烷基-(5-6元单环杂芳基)、-C1-2烷基-(8-10元双环杂芳基)，所述的杂芳基任选进一步被1-3个选自F、Cl、CN、OH、NO2、NH2、-CH2F、-CHF2、-CF3的取代基取代；
p选自0、1或2。
进一步地，所述的式(I)化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，其中，
L2选自-(CRL2a1RL2a2)p-OC(＝O)NHRL2b、-(CRL2a1RL2a2)p-OC(＝O)N(CH3)RL2b、-(CRL2a1RL2a2)pNHC(＝O)ORL2b、-(CRL2a1RL2a2)pN(CH3)C(＝O)ORL2b；
每个RL2a1、RL2a2各自独立的选自H、C1-2烷基；
每个RL2b各自独立的选自被1-2个C1-4烷基亚基、卤代C1-4烷基亚基所取代的C4-6环烷基；
p选自0或1。
本发明第五技术方案，所述通式(I)进一步如通式(I-1)所示：
其中L2、RB如前述任一技术方案所述。
进一步地，本发明所述式(I)、(I-1)的化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，其化合物选自但不限于如下表一中的结构：
表一：



其次，本发明还提供了一种药物组合物，其中含有前述任意一项方案所述的化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，以及药学上可接受的载体和/或辅料。
进一步地，本发明的药物组合物或药物制剂，其中含有1-1500mg的前述任意一项方案所述的化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，以及药学上可接受的载体和/或辅料。
进一步地，本发明还提供了前述任意一项方案所述的化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐在在制备治疗/预防LPAR1介导的疾病的药物中的用途。进一步地，所述LPAR1介导的疾病选自特发性肺纤维化、进展性肺纤维化、系统性硬化症、良性前列腺增生、多发性硬化症、神经损伤、神经痛，优选特发性肺纤维化、进展性肺纤维化。
本发明还提供了一种用于治疗哺乳动物或人的疾病的方法，所述方法包括给予受试者治疗有效量的前述任意一项方案所示的化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐或者本发明所述的组合物，所述疾病选自特发性肺纤维化、进展性肺纤维化、系统性硬化症、良性前列腺增生、多发性硬化症、神经损伤、神经痛，优选所述治疗有效量为1-1500mg。一些实施方案中，本发明中所述哺乳动物不包括人。
本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统的任何其它希望改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的化合物的量。治疗有效量的实例包括但不限于1-1500mg、1-1400mg、1-1300mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、1-500mg、1-400mg、1-300mg、1-250mg、1-200mg、1-150mg、1-125mg、1-100mg、1-80mg、1-60mg、1-50mg、1-40mg、1-25mg、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、10-200mg、10-150mg、10-125mg、10-100mg、10-90mg、10-80mg、10-70mg、10-60mg、10-50mg、10-40mg、10-30mg、10-20mg；20-1500mg、20-1000mg、20-900mg、20-800mg、20-700mg、20-600mg、20-500mg、20-400mg、20-350mg、20-300mg、20-250mg、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、50-100mg；100-1500mg、100-1000mg、100-900mg、100-800mg、100-700mg、100-600mg、100-500mg、100-400mg、100-300mg、100-250mg、100-200mg。
本发明涉及一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含治疗有效量的本发明所述的化合物或者其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐以及载体和/或辅料。该药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。在一些实施方案中，该药物组合物包括但不限于1-1500mg、5-1000mg、10-800mg、20-600mg、25-500mg、40-200mg、50-100mg、1mg、1.25mg、2.5mg、5mg、10mg、12.5mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg、600mg、625mg、650mg、675mg、700mg、725mg、750mg、775mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg的本发明化合物或者其立体异构体、氘代物、溶剂化物、 共晶或药学上可接受的盐。
一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，以及药学上可接受的载体和/或辅料，治疗有效量优选1-1500mg，所述的疾病优选特发性肺纤维化、进展性肺纤维化。
一种用于治疗哺乳动物或人的疾病的方法所述方法包括，将药物本发明化合物，其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，以及药学上可接受的载体和/或辅料，以1-1500mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于10-1500mg/天、20-1500mg/天、25-1500mg/天、50-1500mg/天、75-1500mg/天、100-1500mg/天、200-1500mg/天、10-1000mg/天、20-1000mg/天、25-1000mg/天、50-1000mg/天、75-1000mg/天、100-1000mg/天、200-1000mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于1mg/天、5mg/天、10mg/天、20mg/天、25mg/天、50mg/天、75mg/天、100mg/天、125mg/天、150mg/天、200mg/天、400mg/天、600mg/天、800mg/天、1000mg/天、1200mg/天、1400mg/天、1500mg/天。
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本发明化合物或者其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，本发明化合物或者其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐量与上述药物组合物中其量相同。
本发明中本发明化合物或者其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐的量在每种情况下以游离碱的形式换算。
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。
合成路线
本领域技术人员可以结合该文献以及已知的有机合成技术制备本发明的化合物，其起始原料为市售化学品和(或)化学文献中所述的化合物。“市售化学品”是从正规商业来源获得的，供应商包括：泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。
通过美国化学会化学文摘社制备的已知化学物质的索引，可以选择性地识别特定和类似
的反应物，这些索引可在大多数公共图书馆和大学图书馆以及在线获得。已知但在目录中不可商购的化学品可选地由定制化学合成工厂制备，其中许多标准化学供应工厂(例如，上面列出的那些)提供定制合成服务。
术语
在本发明未特殊说明的情况下，本发明的术语具有以下含义：
“卤素”在本文中是指F、Cl、Br、I、或者它们的同位素。
“卤代”或“卤素取代”是指氢原子被一个以上选自F、Cl、Br、I、或者它们的同位素取代，卤素取代基数量的上限等于被取代基团可被取代的氢数之和，在未作特殊限定下，卤素取代基数量为1至该上限之间的任意整数，当卤素取代基数量大于1时，可以是相同或不同的卤素进行取代。
“氘代”或“氘代物”是指烷基、环烷基、亚烷基、芳基、杂芳基、巯基、杂环烷基、烯基、炔基等基团上的氢原子被至少一个同位素氘取代的情形，氘代的数量上限等于被取代基团可被取代的氢数之和，在未作特殊限定下，氘代数量为1至该上限之间的任意整数，优选1-20个氘原子取 代，更优选为1-10个氘原子取代，更优选为1-6个氘原子取代，进一步优选为1-3个氘原子取代。
“烷基”是指一价的直链或支链饱和脂肪族烃基，无特殊说明时，为1至20个碳原子的烷基，优选为1至8个碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基，进一步优选1-2个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体。
“亚烷基”是指二价的直链和支链饱和烷基，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等。
“烷基亚基”指失去两个氢原子形成的二价游离价键烷基结构，其中烷基如上所定义。非限制性实例包括：甲亚基乙亚基1-甲基乙亚基
“卤代烷基亚基”指被一个或多个卤素取代的烷基亚基，其中烷基亚基如上所定义。非限制性实例包括：氟甲亚基二氟甲亚基
“环烷基”是指一价非芳族、部分不饱和或完全饱和的、取代或未取代的碳环烃基，无特殊说明时，通常有3至12个碳原子，优选有3-10个碳原子，更优选有3-6个碳原子，进一步优选有3-4个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基、或环庚基等。环烷基可为单环环烷基、多环环烷基(如双环环烷基、三环环烷基)。
“亚环烷基”是指“环烷基”的二价基团，非限制性实施例包括亚环丙基、亚环丁基等。
“杂环”或“杂环基”是指取代或未取代、饱和或不饱和的芳香环或者非芳香环，未特殊限定时，包含1至3个选自N、O或S的杂原子，包括单环杂环、双环桥杂环、双环并杂环和双环螺杂环等，未特殊限定时，为3至12元杂环，更优选为4-12元杂环，更优选为4-10元杂环，进一步优选为4-7元杂环。其定义包括杂环烷基和杂芳基。杂环基环中的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、吡唑基、哒嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、噁唑基、二氢噁唑基、四氢噁唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基、 等。
“亚杂环基”是“杂环基”对应的二价基团，非限制性实施例包括亚咪唑基、亚哌啶基、亚氮杂环丙基等。
“碳环”或“碳环基”是指取代或未取代、饱和或不饱和的、芳香或非芳香的碳环基团，包括单 环碳环、双环桥环、双环并环和双环螺环等，未特殊说明时，有3至12个碳原子，优选有3-10个碳原子，进一步优选有3-6个碳原子。其定义包括环烷基和芳基。非限制性实施例中，单环碳环包括环丙基、环丁基、环戊基、环己基、环庚基或苯基、等，双环桥环包括 等，双环并环包括等，双环螺环包括 等。
“芳基”是指具有芳香性的碳环。非限制性实施例包括苯基、萘基等。
“炔基”是指直链或支链的、含有一个以上碳碳三键的一价不饱和烃基，除非特殊说明，炔基含有2-6个碳原子，优选含有2-4个碳原子，非限制性地的实施例为乙炔基、丙炔基、炔丙基等。
“烯基”是指直链或支链的、含有一个以上碳碳双键的一价不饱和烃基，除非特殊说明，炔基含有2-6个碳原子，优选含有2-4个碳原子，非限制性地的实施例为乙烯基、丙烯基、烯丙基、2-丁烯基、1-丁烯基等。
“烷氧基”或“烷基氧基”是指-O-烷基，未特殊限定时，为-O-C1-8烷基，优选为-O-C1-6烷基，更优选为-O-C1-4烷基，进一步优选为-O-C1-2烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基等。
“卤代烷氧基”是指-O-卤代烷基，未特殊限定时，为-O-卤代C1-8烷基，优选为-O-卤代C1-6烷基，更优选为-O-卤代C1-4烷基，进一步优选为-O-卤代C1-2烷基。非限制性实施例包括一氟甲氧基、二氟甲氧基、三氟甲氧基、二氟乙基氧基等。
“C1-4烷基酰基”是指C1-4烷基-C(O)-。非限制性实施例包括甲酰基、乙酰基、丙酰基。
“C1-4烷基磺酰基”是指C1-4烷基-S(O)2-。非限制性实施例包括甲磺酰基、乙磺酰基、丙磺酰基。
“杂芳环”或“杂芳基”是指具有芳香性的杂环。非限制性实施例包括吡唑基、嘧啶基、噻唑基、吡啶基、呋喃基等。
“杂环烷基”是指非芳族、部分不饱和或完全饱和的杂环，其一般具有4至12个环成员，优选有4至10个环成员，更优选有4至7个环成员，进一步优选为5个或6个环成员。除碳原子以外杂环烷基还包含1-3个选自选自N、S、O、Si、P的杂原子作为环成员。非限制性实施例包括氮杂环丁基、吗啉基、哌嗪基、哌啶基、四氢吡喃基、氧杂环丁基等。杂环烷基可为单环杂环环烷基、多环杂环环烷基(如双环杂环环烷基、三环杂环环烷基)。多环杂环环烷基的环体系中至少一个环含有杂原子。
“烷基氨基”或“烷氨基”是指被单个或两个烷基取代的氨基，也写作-N-(烷基)2或-NH-烷基，后者也写作单烷基氨基。非限制实施例包括二甲氨基、单甲基氨基、二乙氨基、单乙氨基等。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述 的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”表示一种或多种本文所述化合物或其立体异构体、溶剂化物、药学上可接受的盐或共晶，与其他组成成分的混合物，其中其他组分包含生理学/药学上可接受的载体和/赋形剂。
“载体”指的是：不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性，并能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系，非限制性的实例包括微囊与微球、纳米粒、脂质体等。
“赋形剂”指的是：其本身并非治疗剂，用作稀释剂、辅料、粘合剂和/或媒介物，用于添加至药物组合物中以改善其处置或储存性质或允许或促进化合物或药物组合物形成用于给药的单位剂型。如本领域技术人员所已知的，药用赋形剂可提供各种功能且可描述为润湿剂、缓冲剂、助悬剂、润滑剂、乳化剂、崩解剂、吸收剂、防腐剂、表面活性剂、着色剂、矫味剂及甜味剂。药用赋形剂的实例包括但不限于：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉及马铃薯淀粉；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素、乙酸纤维素、羟丙基甲基纤维素、羟丙基纤维素、微晶纤维素及交联羧甲基纤维素(例如交联羧甲基纤维素钠)；(4)黄蓍胶粉；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂及栓剂蜡；(9)油，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨醇、甘露醇及聚乙二醇；(12)酯，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格溶液(Ringer’s solution)；(19)乙醇；(20)pH缓冲溶液；(21)聚酯、聚碳酸酯和/或聚酐；及(22)其他用于药物制剂中的无毒相容物质。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
“溶剂化物”指本发明化合物或其盐与分子间非共价力结合的化学计量或非化学计量的溶剂形成的物质。当溶剂为水时，则为水合物。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。
具体实施方式
以下将通过实施例对本发明的内容进行详细描述。实施例中未注明具体条件的，按照常规条件的实验方法进行。所举实施例是为了更好地对本发明的内容进行说明，但并不能理解为本发明的内容仅限于所举实例。本领域常规技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。
测试方法
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘 代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例1
第一步：室温下，将1A(7.0g,37.2mmol)溶解于干燥的甲苯(300mL)中，向其中加入(1S，3R)-3-羟基环己烷-1-甲酸异丙酯(20.8g,111.6mmol)，三正丁基膦(37.6g,186.0mmol)，搅拌均匀，再加入偶氮二甲酰二哌啶(28.1g,111.6mmol)，氮气气氛下，80℃反应16小时。冷却至室温，向反应液中加入乙酸乙酯(300mL)，有机相用水(100mL×3)洗涤，饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，残余物经硅胶柱层析分离纯化得到目标化合物1B(3.0g,22％)。
LC-MS(ESI):m/z＝356.2[M+H]+。
第二步：将1B(3.0g，8.5mmol)，(3-甲酰基噻吩-2-基)硼酸(2.7g，17.0mmol)和氟化钾(3.0g，51.0mmol)加入到四氢呋喃(60mL)中，然后加入双(三叔丁基膦)钯(436mg，0.85mmol)，氮气气氛下，在室温下反应过夜。向反应液中加入乙酸乙酯(100mL)，有机相用水(100mL×3)洗涤，饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，残余物经硅胶柱层析分离纯化得到目标化合物1C(2.9g,87％)。
LC-MS(ESI):m/z＝388.2[M+H]+。
第三步：将1C(2.9g，7.49mmol)和硼氢化钠(570mg，15.0mmol)溶于无水乙醇(30mL)中，室温下反应1小时。反应完成后减压浓缩，硅胶柱层析分离纯化得到目标化合物1D(2.9g,99％)。
LC-MS(ESI):m/z＝390.1[M+H]+。
第四步：将1D(2.9g，7.45mmol)溶于N,N-二甲基甲酰胺(30mL)，加入N-氯代丁二酰亚胺(1.1g，8.19mmol)，45℃反应16小时。反应完成后，向反应液中加入乙酸乙酯(100mL)，有机相用水(100mL×3)洗涤，饱和食盐水(100mL×1)洗涤，无水硫酸钠干燥，过滤，浓缩滤液到目标化合物1E(3.0g,95％)。
LC-MS(ESI):m/z＝424.2[M+H]+。
第五步：室温下，向1E(3.0g，7.07mmol)和4-硝基氯甲酸苯酯(4.3g，21.21mmol)的二氯甲烷(60mL)中加入吡啶(2.8g，35.35mmol)，室温反应2小时。反应完成后减压浓缩，硅胶柱层析到目标化合物1F(2.2g,53％)。
LC-MS(ESI):m/z＝589.1[M+H]+。
第六步：室温下，向1F(1.0g，1.7mmol)和3-亚甲基环丁烷-1-胺三氟乙酸盐(0.31g，1.7mmol)的四氢呋喃(20mL)中加N,N-二异丙基乙胺(0.66g，5.1mmol)，室温反应2小时。反应完成后减压浓缩，硅胶柱层析到目标化合物1G(0.7g,77％)。
LC-MS(ESI):m/z＝533.1[M+H]+。
第七步：室温下，向1G(0.3g，0.56mmol)和碘甲烷(0.24g，1.7mmol)的N,N-二甲基甲酰胺(5mL)中加氢化钠(68mg，1.7mmol，60％)，室温反应2小时。向反应液中加入乙酸乙酯(20mL)，有机相用水(20mL×3)洗涤，饱和食盐水(10mL×1)洗涤，无水硫酸钠干燥，过滤，浓缩滤液后硅胶柱层析到目标化合物1H(0.25g,82％)。
LC-MS(ESI):m/z＝547.1[M+H]+。
第八步：将化合物1H(250mg，0.46mmol)用四氢呋喃:甲醇:水＝1:1:1(6ml)溶解，然后加入无水氢氧化锂(55mg，2.3mmol)，在50℃反应1小时。TLC监测反应完成后，用稀盐酸调节pH＝5～6，乙酸乙酯萃取(20mL×3)洗涤，饱和食盐水(10mL×1)洗涤，无水硫酸钠干燥，过滤，浓缩滤液后HPLC制备分离纯化得到化合物1(100mg,产率：43％)。
LC-MS(ESI):m/z＝505.2[M+H]+.
1H 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).
实施例2：
第一步：将化合物2A(500mg，2.73mmol)加入反应瓶，N,N-二甲基甲酰胺(10ml)溶解，在0℃下加入氢化钠(160mg，4.10mmol，纯度60％)，维持此温度反应30min，然后加入碘甲烷(775mg，5.46mmol)，升到室温反应3小时。TLC监测反应完成后，加水(50ml)稀释，然后用乙酸乙酯(50ml)萃取两次，合并有机相并用无水硫酸钠干燥，过滤，滤液浓缩后所得残余物正相柱纯化得到化合物2B(475mg，产率：88.29％)。
1H 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).
第二步：将化合物2B(470mg，2.38mmol)加入反应瓶，用二氯甲烷(10ml)溶解，然后加入三氟乙酸(0.5ml)，室温反应1h。TLC监测反应完成后，减压浓缩，得粗品化合物2C(250mg，TFA盐)，直接用于下一步。
LC-MS(ESI):m/z＝98.1[M+H]+.
第三步:将化合物2D(0.30g，0.77mmol，按照专利WO2019126085A1的方法合成)加入到二氯甲烷(15mL)中，再依次加入吡啶(0.24g，3.08mmol)、4-硝基氯甲酸苯酯(0.23g，1.16mmol)，加完室温下反应3小时，TLC监测反应完成后，减压浓缩，所得残余物溶入四氢呋喃(15mL)中，再依次加入再依次加入三乙胺(0.39g，3.85mmol)、化合物2C(250mg，TFA盐)，加完室温下反应3小时，TLC监测反应完成后，减压浓缩，所得残余物正相柱纯化得到化合2E(0.32g，产率：81％)。
LC-MS(ESI):m/z＝511.2[M+H]+.
第四步:将化合物2E(0.32g，0.63mmol)溶于甲醇(5mL)，四氢呋喃(5mL)和水(5mL)中，然后加入氢氧化锂(112mg，2.71mmol)，常温反应15小时。反应完成后，直接加入1M稀盐酸调pH到弱酸性，然后加少量水，乙酸乙酯(20mL)萃取3次，合并有机相浓缩后送HPLC制备纯化得到化合物2(0.15g，51％)。
LC-MS(ESI):m/z＝469.2[M+H]+.
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).
实施例3：
第一步：将叔丁醇钾(9.53g，85.13mmol)加入三口瓶，用DMF(100ml)溶解，氮气置换三次，冷却到-45℃，缓慢滴加3A(10g，56.75mmol)的DMF(25ml)溶液和2-(二氟甲烷磺酰基)吡啶(9.86g，51.08mmol)的DMF(25ml)溶液，滴加完成后在此温度下反应一小时。然后加入氯化铵饱和溶液(30mL)和盐酸水溶液(1N,50mL)，缓慢升到室温反应16小时。TLC监测反应完成后,然后加水(100ml)稀释，用甲基叔丁基醚萃取两次(100ml×2)，合并有机相并干燥，30℃下减压浓缩，所得残余物经硅胶柱层析纯化(PE:EA＝10:1)，得到化合物3B(4g，33.5％)。
1H 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).
第二步：将化合物3B(4g，19.05mmol)加入反应瓶，用二氯甲烷(100ml)溶解，氮气置换三次，冷却到-78℃，然后滴加三溴化硼(9.52g，38.10mmol)，维持此温度反应半小时。TLC监测反应完成后，加入饱和碳酸氢钠溶液(200ml)调至pH大于7，二氯甲烷萃取两次(50ml×2)，合并有机相干燥过滤后，得到化合物3C的粗品溶液直接用于下一步。
第三步：将化合物3C加入反应瓶，用四氢呋喃(20ml)溶解，然后加入吡啶(4.52g,57.2mmol)和对硝基苯基氯甲酸酯(7.67g,38.1mmol)，室温反应1小时。TLC监测反应完成后，减压浓缩，所得残余物经硅胶柱层析纯化(PE:EA＝5:1)，得到化合物3D(2.5g，两步产率：46.0％)。
1H 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).
第四步:将化合物3E(330mg，0.86mmol，按照专利WO2019126085A1的方法合成)溶解四氢呋喃(20mL)中，加入化合物3D(368mg,1.29mmol)和N,N-二异丙基乙胺(333mg,2.58mmol)，室温下反应1h，原料完全消失后，浓缩，粗品经硅胶柱层析(二氯甲烷：甲醇＝10：1)分离后得到目标化合物3F(210mg，46.2％)
LC-MS(ESI):m/z＝533.1[M+H]+
第五步:将化合物3F(210mg，0.39mmol)溶于四氢呋喃(10mL)，甲醇(2mL)和水(2mL)中，然后加入氢氧化锂(81mg，1.97mmol)，常温反应15小时。反应完成后，直接加入1M稀盐酸调pH到5-6，浓缩后送HPLC制备纯化得到化合物3(30mg，15.1％)。
LC-MS(ESI):m/z＝491.3[M+H]+.
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).
实施例4：
第一步：将化合物4A(15.00g，102.64mmol)溶于入甲醇(150mL)中，降温至0～5℃，缓慢滴加浓硫酸(2mL)，加完回至室温搅拌17小时，反应完毕后加压浓缩，然后分批加入饱和碳酸氢钠水溶液(150mL)并用石油醚(100mL)萃取杂质两次。将水相冷却至0℃，用6N盐酸水溶液调pH＝3～4，并用乙酸乙酯(100mL)萃取产物两次。将合并的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物4B(9.20g，产率：56％)。
第二步：将化合物4B(5.00g，31.22mmol)溶于干燥四氢呋喃(50mL)中，氮气置换三次，降 温至0～5℃，缓慢滴加硼烷四氢呋喃溶液(62.44mL，62.44mmol，1.0mol/L的四氢呋喃溶液)，滴加完缓慢回至室温下反应3小时，TLC监测反应完成后降温至0℃，缓慢滴加甲醇(100mL)淬灭反应，淬灭完全后减压浓缩，所得残余物正相柱纯化得到化合物4C(2.60g，产率：57％)。
第三步:将化合物4C(2g,13.68mmol)加入到二氯甲烷(20mL)溶液中，再加入三乙胺(4.15g，41.04mmol)，加完降温至0～5℃分批次加入甲磺酸酐(4.77g，27.36mmol)，室温下反应16小时，TLC监测反应完成后，减压浓缩，所得残余物正相柱纯化得到化合物4D(3g，产率：97％)。
LC-MS(ESI):m/z＝225.1[M+H]+.
第四步：将化合物4D(3g,13.38mmol)和6-溴-3-羟基-2-甲基吡啶(2.5g，13.38mmol)溶于N,N-二甲基甲酰胺(10mL)中，再依次加入碳酸铯(13.08g，40.13mmol)和碘化钠(200.5mg,1.34mmol)，加完升温至100℃反应16小时，反应完毕后冷却至室温，加入水(50mL)并用乙酸乙酯(50mL)萃取产物两次。将合并的有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩后所得残余物正相柱纯化得到化合物4E(400mg，产率：9.5％)。
LC-MS(ESI):m/z＝316.1&318.1[M+H]+.
第五步：将化合物4F(500mg,1.82mmol,按照专利WO2019126085A1的方法合成)和四羟基二硼(326mg,3.63mmol)溶于无水乙醇(10mL)中，加入乙酸钾(357mg,3.63mmol)、乙二醇(338mg,5.45mmol)、XPhos(7mg,0.02mmol)和XPhos Pd G2(14mg,0.02mmol)，经氮气置换后于80℃下搅拌1h，然后冷却至室温，加入磷酸钾(773mg,3.64mmol)搅拌30min，之后添加化合物4E(400mg,1.27mmol)，补加XPhos(7mg,0.02mmol)和XPhos Pd G2(14mg,0.02mmol)，再次通过氮气置换后，升温至80℃搅拌16h，TLC监测反应完全后，滤除固体，减压浓缩，所得残余物正相柱纯化得到化合物4G(450mg,产率：57.4％)。
LC-MS(ESI):m/z＝432.2[M+H]+.
第六步：将化合物4G(100mg,0.23mmol)加入到甲醇(3mL)中，再加入三氟乙酸(1mL)，加完室温下反应16小时，TLC监测反应完成后，减压浓缩，加入二氯甲烷(10mL)溶解，使用饱和碳酸氢钠水溶液(10mL)洗涤两次，将有机相浓缩得到化合物4H(80mg，产率：99.4％)。
LC-MS(ESI):m/z＝348.2[M+H]+.
第七步：将化合物4H(80mg,0.23mmol)加入到二氯甲烷(5mL)中，再依次加入吡啶(91mg,1.15mmol)、4-硝基氯甲酸苯酯(139mg,0.69mmol)，加完室温下反应3小时，TLC监测反应完成后，减压浓缩，所得残余物正相柱纯化得到化合物4I(100mg，产率：84.7％)。
LC-MS(ESI):m/z＝513.2[M+H]+.
第八步：将化合物4I(100mg,0.20mmol)溶于四氢呋喃(2mL)中，然后加入三乙胺(60mg,0.59mmol)和化合物2C(57mg,0.29mmol,TFA盐)，室温反应1h，TLC监测原料消失，加入水(10mL)，使用乙酸乙酯(10mL)萃取三次，将有机相浓缩并使用正向柱纯化得到化合物4J(70mg,76.2％)
LC-MS(ESI):m/z＝471.2[M+H]+.
第九步:将化合物4J(70mg，0.15mmol)溶于甲醇(1.5mL)和水(1.5mL)中，然后加入氢氧化锂(18mg，0.74mmol)，常温反应15小时。反应完成后，直接加入1M稀盐酸调pH到弱酸性，然后加水(10mL)，乙酸乙酯(10mL)萃取三次，合并有机相浓缩后HPLC制备纯化得到化合物4(40mg，58.9％)。
LC-MS(ESI):m/z＝457.3[M+H]+.
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).
实施例5：
第一步：将化合物5A(15.0g，115.26mmol)加入反应瓶，二氯甲烷(200ml)溶解，加入三乙胺(34.99g，345.78mmol)氮气置换三次，冷却到0℃，缓慢加入叔丁基二苯基氯硅烷(38.02g，138.31mmol)，加料完成后在此温度下反应4小时。TLC监测反应完成后,加水(500ml)稀释，用甲基叔丁基醚萃取两次(300ml×2)，合并有机相并干燥，40℃下减压浓缩，所得残余物经硅胶柱层析纯化(PE:EA＝10:1)，得到化合物5B(40g,94.2％)。
LC-MS(ESI):m/z＝369.3[M+H]+.
第二步：将化合物5B(10g，27.13mmol)加入反应瓶，四氢呋喃(50ml)溶解，氮气置换三次，冷却到0℃，加入硼氢化锂(1.18g，54.26mmol)，室温搅拌16小时。TLC监测反应完成后，加入饱和氯化铵溶液(100ml)，乙酸乙酯萃取两次(50ml×2)，合并有机相并干燥，45℃下浓缩，所得残余物经硅胶柱层析纯化(PE:EA＝2:1)，得到化合物5C(4.0g,43.3％)。
LC-MS(ESI):m/z＝341.2[M+H]+.
第三步：将化合物5C(2.0g，5.87mmol)加入反应瓶，用四氢呋喃(20ml)溶解，加入2-硝基苯基丝氰酸酯(4.00g，17.61mmol)和三正丁基磷(3.56g，17.61mmol)，室温反应一小时。减压浓缩，二氯甲烷(20ml)溶解，冷却到0℃，加入间氯过氧苯甲酸(3.04g，17.61mmol)，搅拌1小时，减压浓缩，甲苯(20ml)溶解，加入二异丙胺(1.78g，17.61mmol)，90℃搅拌16小时。TLC监测反应完成后，加入水(50ml)，乙酸乙酯萃取(50ml)，减压浓缩，所得残余物经硅胶柱层析纯化(PE:EA＝10:1)得到化合物5D(1.2g,63.4％)。
1H 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).
第四步:将化合物5D(2.0g，6.20mmol)溶解四氢呋喃(20mL)中，加入四丁基氟化铵(12.4mL,12.4mmol)室温下反应16h，原料完全消失后，浓缩，得到目标化合物5E(2g，粗品),直接用于下一步反应。
第五步:将化合物5E(500mg，5.94mmol)加入反应瓶，用二氯甲烷(15ml)溶解，加入三乙胺(1.80g，17.82mmol)，对硝基苯基氯甲酸酯(1.44g，7.13mmol)在室温下反应16小时。TLC监测反应完成后，加入水(20ml)，二氯甲烷萃取(20ml)，合并有机相，减压浓缩，所得残余物经 硅胶柱层析纯化(PE:EA＝5:1)得到化合物5F(0.2g,13.2％)。
LC-MS(ESI):m/z＝250.1[M+H]+.
第六步:将化合物3E(110mg，0.28mmol)溶解四氢呋喃(5mL)中，加入化合物5F(106mg,0.43mmol)和N,N-二异丙基乙胺(92mg,0.71mmol)，室温下反应1h，原料完全消失后，浓缩，粗品经硅胶柱层析分离后得到目标化合物5G(72mg，50.9％)
LC-MS(ESI):m/z＝497.2[M+H]+
第七步:将化合物5G(72mg，0.14mmol)溶于四氢呋喃(5mL)，甲醇(1mL)和水(1mL)混合溶剂中，然后加入氢氧化锂(30mg，0.72mmol)，常温反应16小时。反应完成后，直接加入1M稀盐酸调pH到5-6，浓缩后送HPLC制备纯化得到化合物5(35mg，53.1％)。
LC-MS(ESI):m/z＝455.2[M+H]+.
1H 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).
实施例6-19
实施例6-19的合成路线参考实施例1-5的合成路线，具体如下表所示。

生物学测试评价
1、细胞钙流实验
实验方法：1)在384孔板中用DMSO将测试化合物稀释至400X储备溶液。
2)将步骤1中的1μl化合物溶液转移至39ul测定缓冲液中，用Bravo自动化液体处理平台在384孔板中制备10X工作溶液。
3)用F12培养基(10％FBS)培养CHO-LPA1细胞。
4)当细胞达到80％融合度时，用0.25％胰蛋白酶-EDTA解离细胞。
5)测量细胞密度，并用F12(10％ FBS)将细胞稀释至4x10e5/ml。
6)用multidrop自动分液器将30μl细胞分装到384孔板(corning 3764#)中，每孔12K细胞。37℃，5％ CO2培养18-20小时。
7)更换为25uL无血清培养基过夜。
8)细胞板每孔加入10ul 3.5X上样染料。在37℃、5％ CO2避光条件下孵育0.5-1小时。
9)孵育后将5μl步骤2中的10X工作溶液转移至细胞板中。
10)25℃避光孵育细胞板15分钟，然后读出钙信号。
11)在384孔测定板(greiner 784075#)中制备至少20μl/孔的5X激动剂(LPA)工作溶液，LPA加在1X HBSS+20mM HEPES+0.1％ BSA中。该测定中使用的激动剂浓度由先前激动剂模式中的剂量反应确定。EC80在测定中用作最终激动剂浓度。
12)在室温下使用指定的设置使用FLIPR读取并保存数据。
13)通过信号值与化合物浓度作图，用GraphPad Prism软件非线性回归方法进行曲线拟合及IC50计算。
实验结果:本发明化合物在体外对LPAR 1酶活性具有显著拮抗作用，实施例化合物对LPAR 1酶活的IC50值小于100μM。IC50值用A、B、C、D等级表示，A表示0<IC50≤10nM，B表示 10nM<IC50≤50nM，C表示50nM<IC50≤100nM，D表示IC50＞100nM。其中，部分实施例的测试结果如表1所示。
表1本发明化合物对LPAR 1的拮抗活性
实验结论：本发明化合物，例如实施例化合物对于LPAR1受体显示出高的拮抗活性。
2、小鼠药代动力学测试
2.1试验动物：雄性C57小鼠，20～25g，6只/化合物。购于成都达硕实验动物有限公司。
2.2试验设计：试验当天，将C57小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。
表2.给药信息
注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：10％ Cremophor-EL+40％PEG400+50％1XPBS(pH＝7.4)
于给药前及给药后异氟烷麻醉经眼眶取血0.06mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。
表3.测试化合物在小鼠血浆中的药代动力学参数
-：不适用。
结论：本发明化合物，例如实施例化合物在小鼠体内具有良好的药代动力学特征。
3、大鼠药代动力学测试
3.1、试验动物：雄性SD大鼠，220g左右，6～8周龄，6只/化合物。购于成都达硕实验动 物有限公司。
3.2、试验设计：试验当天，将SD大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。
表4.给药信息
注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：10％ Cremophor-EL+40％PEG400+50％1XPBS(pH＝7.4)
于给药前及给药后异氟烷麻醉经眼眶取血0.15mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。
表5.测试化合物在大鼠血浆中的药代动力学参数
-：不适用。
结论：本发明化合物，例如实施例化合物3在大鼠中具有良好的药代动力学特征。
4、比格犬药代动力学测试
4.1、试验动物：雄性比格犬，8～11kg左右，6只/化合物，购于北京玛斯生物技术有限公司。
4.2、试验方法：试验当天，将比格犬按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。
表6.给药信息
注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：10％ Cremophor-EL+40％PEG400+50％1XPBS(pH＝7.4)
于给药前及给药后通过颈静脉或四肢静脉取血1mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。
表7.测试化合物在犬血浆中的药代动力学参数

-：不适用。
结论：本发明化合物，例如实施例化合物在比格犬中具有良好的药代动力学特征。
5、猴药代动力学测试
5.1、试验动物：雄性食蟹猴，3～5kg，3～6年龄，4只/化合物。购于苏州西山生物技术有限公司。
5.2、试验方法：试验当天，将猴按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。
于给药前及给药后通过四肢静脉取血1.0mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。
结论：本发明化合物，例如实施例化合物在猴中具有良好的药代动力学特征。
6、hERG钾离子通道作用测试
实验平台：电生理手动膜片钳系统
细胞系：稳定表达hERG钾离子通道的中国仓鼠卵巢(CHO)细胞系
实验方法：稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10，Sutter)经拉制仪拉制而成，灌注电极内液后的尖端电阻为2-5MΩ左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录，采样频率为10kHz，滤波频率为2kHz。在得到全细胞记录后，细胞钳制在-80mV，诱发hERG钾电流(I hERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV，再复极化到-50mV，持续1s后回到-80mV。每10s给予此电压刺激，确定hERG钾电流稳定后(至少1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟，每个浓度至少测试2个细胞(n≥2)。
数据处理：数据分析处理采用pClamp 10，GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：
Inhibition％＝[1-(I/Io)]×100％
其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。
化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。
实验结果：测试化合物对hERG钾通道电流抑制作用的IC50值见下表8：
表8 hERG钾通道电流抑制测试结果
结论：本发明化合物，例如实施例化合物3对于hERG没有抑制。
7、CYP酶抑制测试
本项研究的目的是应用体外测试体系评价受试物对人肝微粒体细胞色素P450(CYP)的5种同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的影响。CYP450同工酶的特异性探针底物分别与人肝微粒体以及不同浓度的受试物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后，通过处理样品并采用液相色谱-串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的代谢产物，测定CYP酶活性的变化，计算IC50值，评价受试物对各CYP酶亚型的抑制潜能。在测试条件下，孵育浓度为0～30μM。
实验结果：测试化合物对CYP酶抑制作用的IC50值见下表9：
表9 CYP酶抑制测试结果
结论：本发明化合物，例如实施例化合物对于CYP酶没有抑制。
8、肝微粒体稳定性测试
本实验采用人、犬、大鼠和小鼠五种属肝微粒体作为体外模型来评价受试物的代谢稳定性。
在37℃条件下，1μM的受试物与微粒体蛋白、辅酶NADPH共同孵育，反应至一定时间(5,10,20,30,60min)加入冰冷含内标的乙腈终止反应，采用LC-MS/MS方法检测样品中受试物浓度，以孵育体系中药物剩余率的ln值和孵育时间求得T1/2，并进一步计算肝微粒体固有清除率CLint(mic)和肝固有清除率CLint(Liver)。
结论：本发明化合物，例如实施例化合物具有良好的肝微粒体稳定性。
9、Caco2渗透性测试
试验使用单层Caco-2细胞，在96孔Transwell板中采用三平行孵育。将含有本发明化合物(2μM)或对照化合物地高辛(10μM)、纳多洛尔(2μM)和美托洛尔(2μM)的转运缓冲溶液(HBSS，10mM HEPES，pH 7.4±0.05)加入顶端侧或基底侧的给药端孔中。对应接收端孔中加入含DMSO的转运缓冲溶液。在37±1℃条件下孵育2小时后，取出细胞板并从顶端和底端各取出适量样品至新的96孔板中。随后加入含内标的乙腈沉淀蛋白。使用LC MS/MS分析样品并测定本发明化合物和对照化合物的浓度。浓度数据用于计算从单层细胞顶端侧向基底侧、以及基底侧向顶端转运的表观渗透系数，从而计算外排率。用荧光黄的渗漏评价孵育2小时后单层细胞的完整性。
结论：本发明化合物，例如实施例化合物具有良好的渗透性。
10、博莱霉素(BLM)诱导的特发性肺纤维化(IPF)小鼠模型
1)筛选和分组：本项目共计使用实验动物9周雄性C57BL/6j小鼠。在实验开始前，根据动物的体重，分为假手术组和模型组。造模后1周，根据动物的体重，将模型组随机分组。
2)动物造模：实验第1天，用舒泰(50mg/kg)和赛拉嗪(10mg/kg)将动物麻醉。模型组小鼠在第1天气管内注射(i.t.)博莱霉素，剂量为0.66mg/kg(1U/kg)，体积为50μL。假手术组组一(n＝10)气管内注射生理盐水，体积为50μL。
3)试验方法：实验第7天开始，对各实验组小鼠分别给予受试化合物，灌胃给药，每日两次；对照组给予尼达尼布，剂量为60mg/kg，给药体积为10mL/kg体重，灌胃给药，每日一次。 假手术组组一和模型组组二给予溶媒，给药体积为10mL/kg体重，灌胃给药，每日两次。
4)检测指标：研究终点时采集肺组织进行病理检测。
结果：博莱霉素(0.66mg/kg,i.t.)注射21天后，显著增加了模型小鼠肺组织的Modified Ashcroft评分，以及肺纤维化面积。与给予溶媒的模型组相比，实施例化合物灌胃给药，每日两次，连续给药14天，在研究终点时均显著降低了模型小鼠肺组织的Modified Ashcroft评分以及肺纤维化面积。

Claims (11)

  1. 一种式(I)所示的化合物、其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，
    环A选自4-8元单环碳环基、6-12元双环碳环基、6-12元单环杂环基、6-12元双环杂环基或无，所述的碳环基、杂环基任选被1-4个RA取代；
    环C选自5元杂芳基并5-7元碳环、5元杂芳基并5-7元杂环、C3-6单环碳环、5-6元单环杂环环烷基、C5-10双环环烷基、5-10元双环杂环环烷基，所述的杂芳基、碳环、杂环、环烷基、杂环烷基任选被1-4个RC取代；其中表示环C与吡啶环的连接位点，“*”表示环C与L2连接位点；
    RB选自H；
    Rc1、Rc4、Rc5各自独立地选自H、卤素、C1-4烷基、卤代C1-4烷基；
    Rc3选自H、C1-4烷基；
    作为选择，Rc1与RB一起形成6-7元杂环或者6-7元碳环；
    作为选择，Rc3与RB一起形成6-7元杂环；
    L1选自键、-C1-4烷基-、-C＝O、-O-C(RL1aRL1b)p-、-S-(CRL1aRL1b)p-、-C(＝O)NRL1-、C2-6烯基或C2-6炔基，所述烷基、烯基、炔基任选进一步的被1-4个RL1a取代；
    当环A选自不存在时，L1选自被一个COOH取代的-OC1-6烷基；
    L2选自(CRL2a1RL2a2)p-OC(＝O)N(RL2b)2、-C(＝O)N(RL2b)2、-NRL2b-C(＝O)ORL2c、-(CRL2a1RL2a2)pN(RL2b)2、-(CH2)pRL2d、-(CRL2a1RL2a2)pN(RL2b)S(O)2N(RL2b)2、-(CRL2a1RL2a2)pN(RL2b)C(＝O)N(RL2b)2、-(CRL2a1RL2a2)pN(RL2b)C(＝O)ORL2b；
    RA各自独立的选自H、卤素、CN、OH、-(CH2)p-COORa1、-(CH2)p-C(＝O)NRa1Ra2、-(CH2)p-C(＝O)NHC(＝O)Ra1、-(CH2)p-C(＝O)NHS(O)2Ra1、-(CH2)p-C(＝O)NHS(O)Ra1、-(CH2)p-S(O)2OH、-(CH2)p-S(O)2NHCORa1、-(CH2)p-P(O)(OH)2、C1-4烷基、C2-6烯基、C2-6炔基、-OC1-4烷基或-(CH2)p-(5-10元杂环基)，所述的烷基、烯基、炔基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、-O-卤代C1-4烷基的基团取代；
    RC各自独立的选自卤素、CN、OH、NO2、NH2、＝O、C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基，所述的烷氧基、烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN的基团取代；
    Ra1、Ra2各自独立的选自H、卤素、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、＝O、OH、NH2、CN、乙酰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
    Rc2选自-(CRL2a1RL2a2)p-C3-7元环烷基、-(CRL2a1RL2a2)p-(4-7元杂环烷基)、卤素、CN、OH、NO2、NH2、卤代C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基；
    每个RL1a、RL1b各自独立的选自H、卤素、CN、OH、NO2、NH2、＝O、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、-(CH2)p-COORa1，所述的烷基、烯基、炔基、环烷基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
    RL1独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、＝O、OH、NH2、CN、乙酰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
    每个RL2a1、RL2a2各自独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基，所述的烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷氧基、卤代C1-4烷氧基的基团取代；
    作为选择，RL2a1与RB一起形成6-7元杂环或6-7元碳环；
    每个RL2b各自独立的选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、C1-4烷基、C1-4烷基亚基、卤代C1-4烷基亚基、C1-4烷氧基、卤代C1-4烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；
    每个RL2d各自独立的选自C1-4烷基、卤素、OH、NH2、CN、C2-6烯基、C2-6炔基、-C(＝O)H、-C(＝O)OH、C3-10环烷基、C1-4烷氧基、5-14元杂环基，所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基任选进一步被1-4个选自卤素、OH、NH2、CN、N3、C1-4烷氧基、卤代C1-4烷氧基、C3-5环烷基、4-6元杂环烷基、6-10元芳基、5-10元杂芳基的基团取代；
    RL2c选自-C1-4烷基-(5-10元杂芳基)，所述的杂芳基任选进一步被1-3个选自卤素、CN、OH、NO2、NH2、卤代C1-4烷基、-OC1-4烷基、C2-6烯基或C2-6炔基的取代基取代；
    p选自0、1、2、3、4；
    无特别说明时，杂环、杂环基、杂环烷基、杂芳基含有1-4个选自N、O、S、S(O)、S(O)2的杂原子。
  2. 根据权利要求1所述的式(I)化合物、其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，其中，
    环A选自4-7元单环碳环基、6-10元双环碳环基、6-10元单环杂环基、6-10元双环杂环基或无，所述杂环基含有1-3个选自N、O、S的杂原子；优选地，环A选自4-7元单环碳环基；优选地，环A选自所述环A被1个COOH取代；和/或
    RA各自独立的选自卤素、CN、OH、COOH、-CH2COOH、C1-2烷基、C2-4烯基、C2-4炔基或-OC1-2烷基，所述的烷基、烯基、炔基任选进一步被1-4个选自卤素、OH、NH2、CN、-O-卤代C1-2烷基的基团取代；优选地，RA各自独立的选自COOH、-CH2COOH。
  3. 根据权利要求1所述的式(I)化合物、其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，
    环C选自其中表示环C与吡啶环的连接位点，“*”表示环C与L2连接位点；
    L1选自-O-；和/或
    L2选自-(CRL2a1RL2a2)p-OC(＝O)NHRL2b、-(CRL2a1RL2a2)p-OC(＝O)N(C1-4烷基)RL2b、-C(＝O)NHRL2b、-C(＝O)N(C1-4烷基)RL2b、-NHC(＝O)ORL2c、-N(C1-4烷基)C(＝O)ORL2c、-(CRL2a1RL2a2)pNHC(＝O)ORL2b、-(CRL2a1RL2a2)pN(C1-4烷基)C(＝O)ORL2b；
    每个RL2a1、RL2a2各自独立的选自H、C1-2烷基，所述的烷基任选进一步被1-4个选自F、Cl、OH、NH2、CN的基团取代；
    作为选择，RL2a1与RB一起形成6-7元杂环或6-7元碳环；
    每个RL2b各自独立的选自被1-2个C1-4烷基亚基、卤代C1-4烷基亚基所取代的C3-10环烷基；
    RL2c选自-C1-2烷基-(5-6元单环杂芳基)、-C1-2烷基-(8-10元双环杂芳基)，所述的杂芳基任选进一步被1-3个选自F、Cl、CN、OH、NO2、NH2、卤代C1-2烷基的取代基取代；优选地，RL2c选自-C1-2烷基-(5-6元单环杂芳基)、-C1-2烷基-(8-10元双环杂芳基)，所述的杂芳基任选进一步被1-3个选自F、Cl、CN、OH、NO2、NH2、-CH2F、-CHF2、-CF3的取代基取代；
    p选自0、1或2。
  4. 根据权利要求1所述的式(I)化合物、其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，其中，
    L2选自-(CRL2a1RL2a2)p-OC(＝O)NHRL2b、-(CRL2a1RL2a2)p-OC(＝O)N(CH3)RL2b、-(CRL2a1RL2a2)pNHC(＝O)ORL2b、-(CRL2a1RL2a2)pN(CH3)C(＝O)ORL2b；
    每个RL2a1、RL2a2各自独立的选自H、C1-2烷基；
    每个RL2b各自独立的选自被1-2个C1-4烷基亚基、卤代C1-4烷基亚基所取代的C4-6环烷基；
    p选自0或1。
  5. 根据权利要求1-4中任一项所述的化合物、其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，所述通式(I)进一步如通式(I-1)所示：
  6. 根据权利要求1所述的化合物、其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，所述化合物选自表一中结构之一。
  7. 一种药物组合物或药物制剂，其含有权利要求1-6中任意一项所述的化合物，或其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐，以及药学上可接受的载体和/或赋形剂。
  8. 根据权利要求7所述的药物组合物或药物制剂，包含选1-1500mg的权利要求1-6任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐和载体和/或赋 形剂。
  9. 权利要求1-6中任意一项所述的化合物、其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐、或者权利要求7-8所述的组合物在制备治疗/预防LPAR 1介导的疾病的药物中的用途。
  10. 根据权利要求9所述的用途，所述LPAR 1介导的疾病选自特发性肺纤维化、进展性肺纤维化、系统性硬化症、良性前列腺增生、多发性硬化症、神经损伤、神经痛。
  11. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-6任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、共晶或药学上可接受的盐或者权利要求7-8所述的组合物，治疗有效量优选1-1500mg，所述的疾病选自特发性肺纤维化、进展性肺纤维化、系统性硬化症、良性前列腺增生、多发性硬化症、神经损伤、神经痛。
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