WO2025051266A1 - Antagoniste de lpar1 dérivé d'un dérivé hétéroaromatique et son utilisation - Google Patents

Antagoniste de lpar1 dérivé d'un dérivé hétéroaromatique et son utilisation 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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Chinese (zh)
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李瑶
陈雷
任磊
林潇
张晨
严庞科
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Tibet Haisco Pharmaceutical Co Ltd
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Tibet Haisco Pharmaceutical Co Ltd
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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

L'invention concerne un antagoniste de LPAR1 et son utilisation. L'invention concerne spécifiquement un composé représenté par la formule (I), ou un stéréoisomère, un composé deutéré, un solvate, un eutectique ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique le comprenant, et une utilisation de celui-ci dans la préparation d'un médicament pour le traitement/la prévention de maladies médiées par LPAR1, chaque groupe dans la formule (I) étant tel que défini dans la description.
PCT/CN2024/117602 2023-09-08 2024-09-06 Antagoniste de lpar1 dérivé d'un dérivé hétéroaromatique et son utilisation Pending WO2025051266A1 (fr)

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