WO2020244539A1 - Dérivé de pyridone, son procédé de préparation et son application pharmaceutique - Google Patents

Dérivé de pyridone, son procédé de préparation et son application pharmaceutique Download PDF

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Publication number
WO2020244539A1
WO2020244539A1 PCT/CN2020/094126 CN2020094126W WO2020244539A1 WO 2020244539 A1 WO2020244539 A1 WO 2020244539A1 CN 2020094126 W CN2020094126 W CN 2020094126W WO 2020244539 A1 WO2020244539 A1 WO 2020244539A1
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group
cycloalkyl
alkyl
general formula
heteroaryl
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PCT/CN2020/094126
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English (en)
Chinese (zh)
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张晓敏
张睿
王珏
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202080038158.1A priority Critical patent/CN113874354B/zh
Publication of WO2020244539A1 publication Critical patent/WO2020244539A1/fr

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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
    • A61K31/395—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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a pyridone derivative, a preparation method thereof, and application in medicine.
  • the present disclosure relates to a pyridone derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as an ATX inhibitor to treat cancer or fibrotic diseases or disorders.
  • ATX Autotaxin
  • ENPP2 is a secreted enzyme, which is mainly expressed in cancer cells, bronchial epithelial cells of the lung and alveolar macrophages.
  • ATX was first isolated from melanoma cells in 1992 (Stracke, ML, et al. J. Biol. Chem. 1992, 267, 2524-2529), and belongs to one of the seven members of the ENPP family, among which ENPP1 and ENPP3 are the closest ATX (Albers, HMHG, et al. Chem. Rev. 2012, 112, 2593-2603).
  • ATX is the only ENPP enzyme with lysophospholipase D (lysoPLD) activity, and mainly converts LPC into lipid lysophosphatidic acid (LPA) with biological activity.
  • LPA is a kind of lipid, mainly LPA 16:0, LPA 18:1, LPA 18:2, LPA 20:4 in plasma (Bandoh, K., et al. FEBS Lett. 2000, 478, 159-165).
  • LPA works through six receptor proteins (LPA1-6) on the cell surface, that is, protein-coupled receptors (GPCRs) (Lin, M.E., et al. Prostaglandins Other Lipid Mediators 2010, 91, 130-138).
  • the LPA receptor family can be further divided into two categories: (1) EDG receptor family, including LPA1-3; (2) non-EDG receptor family LPA4-6. The similarity between the two is less than 40% (Zhao, Y., et al. Cell Signaling 2009, 21, 367-377).
  • Each LPA receptor mediates a series of cell signaling cascades through specific G body proteins.
  • the main signaling pathways include protein kinase (MAPK) activation, inhibition of adenylate cyclase pathway, arachidonic acid release, activation of PI3K-AKT pathway, regulation of cell apoptosis and survival; activation of Rho, Rock, Rac and Ras signaling pathways (Mills, GB, et al. Nat. Rev.
  • ATX-LPA signaling pathway involves many physiological and pathological processes, leading to important links with many serious diseases, including cancer, fibrotic diseases, pain, immune diseases, inflammatory nervous system and cardiovascular diseases (Nicolas, D., et al.US8993590B2).
  • ATX is related to the invasion and metastasis of tumor cells, such as in ovarian cancer (Vidot, S., et al. Cell Signal, 2010, 22, 926-935), breast cancer (Panupinthu, N., et al. British Journal of Cancer 2010, 102, 941-946), prostate cancer (Nouh, MA, et al. Cancer Sci.
  • hepatocellular carcinoma Wu, J., et al. Mol Cancer, 2010, 9, 71
  • lung cancer Xu, X., et al. Cancer, 2010, 116, 1739-1750
  • tumor tissues can be observed overexpression of ATX.
  • the LPA produced by it promotes tumor formation by increasing cell motility and aggressiveness. Therefore, ATX inhibitors can prevent the production of LPA and have the potential to treat many diseases.
  • IPF Idiopathic Pulmonary Fibrosis
  • ATX-LPA signaling pathway is a progressive, chronic, and fibrotic disease of the lung.
  • the pathogenesis of IPF is generally believed to be through repeated stimulation of alveolar cells, leading to the activation of alveolar epithelial cells, thereby secreting some pro-fibrotic growth factors (TGF ⁇ , PDGF, FGF%) and pro-fibrotic cytokines, these factors will recruiting fibroblasts to the surface of alveoli to deposit and activate, further leading to the deposition of collagen and the precipitation of extracellular matrix.
  • TGF ⁇ , PDGF, FGF pro-fibrotic growth factors
  • pro-fibrotic cytokines pro-fibrotic cytokines
  • mice with bronchial epithelial cells and macrophages knocked out of ATX are less sensitive to lung fibrosis models (Oikonomo, N., et al. Am. J. Repir. Cell Mol. Biol. 2012,47,566-574).
  • LPA1 lung fibroblasts
  • LPA2 epithelial cells
  • Xu ,M.,et al.Am.J.pathol.2009,174,1264-1279 The role of LPA in remodeling and fibrosis is related to COPD, IPF and asthma.
  • IPF The main symptoms of IPF are dyspnea, dry cough, fever in the acute phase, and flu-like symptoms.
  • the disease is very poor after recovery.
  • the median survival period is 2-4 years, and the 5-year survival rate is 20-30%, which is lower than many malignant tumors.
  • Pirfenidone pirfenidone
  • Nintedanib is a tyrosine kinase inhibitor.
  • PDGFR pirfenidone
  • FGFR FGFR
  • VEGFR receptors tyrosine kinase inhibitors
  • GLGP-1690 Phase III
  • ATX inhibitors regulate the signal pathways related to cell proliferation, survival, apoptosis and migration by inhibiting the formation of LPA, and can potentially be used in the treatment of a variety of cancers, and due to the signal of LPA
  • the pathway is closely related to the fibrosis of multiple organs and is an important target for the study of new fibrotic diseases.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof,
  • Ring A is aryl or heteroaryl
  • Ring B is heteroaryl
  • Ring C is cycloalkyl or heterocyclyl
  • G 1 , G 2 and G 3 are the same or different, and each independently is CR 8 or N;
  • L 1 does not exist, or is selected from NR 9 , O and S;
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxy, aldehyde, cycloalkyl , Heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxy, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl;
  • R 3 is selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally selected from halogen, alkyl, alkoxy, cyano, amino, nitro, and hydroxy , Hydroxyalkyl, carboxyl, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;
  • R 4 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, cyano, amino, -NR 10 R 11 , -C( O) NR 10 R 11 , -C(O)OR 12 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 5 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxy, aldehyde, hydroxyl, hydroxyalkyl, oxo , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen , Alkyl, alkoxy, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;
  • R 6 is -ML 2 -R a ;
  • M does not exist or is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl , Substituted by one or more substituents in heterocyclyl, aryl and heteroaryl;
  • L 2 does not exist, or is selected from -C(O)-, -C(O)O-, -C(O)NR b -, -C(O)NR b R f -, -NR b C(O) -, -NR b C(O)O-, -O-, -OC(O)-, -C(O)-C(O)-, -C(O)-C(O)NR b -,- NR b , -S(O) 2 -, -S(O) 2 NR b -and -NR b S(O) 2 -;
  • R a is selected from a hydrogen atom, an alkyl group, a hydroxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently Optionally selected from halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is substituted by one or more substituents;
  • R b and R f are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group and a cycloalkyl group; or R b , R f and the connected N atom form a heterocyclic group;
  • R 7 are each the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl;
  • R 8 is selected from hydrogen atom, alkyl group, hydroxyl group, hydroxyalkyl group and halogenated alkyl group;
  • R 9 is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group and cycloalkyl group;
  • R 10 and R 11 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group; or R 10 and R 11 together with the attached N atom form a hetero Cyclic group, the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy and hydroxyalkyl replace;
  • R 12 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group and a cycloalkyl group; n is 0, 1, 2, 3 or 4;
  • s 0, 1, 2 or 3;
  • t 0, 1, 2, 3, or 4.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, the structure of the compound represented by the general formula (I) is as follows:
  • Ring A is aryl or heteroaryl
  • Ring B is heteroaryl
  • Ring C is cycloalkyl or heterocyclyl
  • G 1 , G 2 and G 3 are the same or different, and each independently is CR 8 or N;
  • L 1 does not exist, or is selected from NR 9 , O and S;
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxy, aldehyde, cycloalkyl , Heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxy, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl;
  • R 3 is selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally selected from halogen, alkyl, alkoxy, cyano, amino, nitro, and hydroxy , Hydroxyalkyl, carboxyl, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;
  • R 4 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, Substituted by one or more substituents in cycloalkyl, heterocyclic, aryl and heteroaryl;
  • R 5 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxy, aldehyde, hydroxyl, hydroxyalkyl, oxo , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen , Alkyl, alkoxy, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;
  • R 6 is -ML 2 -R a ;
  • M does not exist or is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl , Substituted by one or more substituents in heterocyclyl, aryl and heteroaryl;
  • L 2 does not exist, or is selected from -C(O)-, -C(O)O-, -C(O)NR b -, -C(O)NR b R f -, -NR b C(O) -, -NR b C(O)O-, -O-, -OC(O)-, -C(O)-C(O)-, -C(O)-C(O)NR b -,- NR b , -S(O) 2 -, -S(O) 2 NR b -and -NR b S(O) 2 -;
  • R a is selected from a hydrogen atom, an alkyl group, a hydroxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently Optionally selected from halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is substituted by one or more substituents;
  • R b and R f are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group and a cycloalkyl group; or R b , R f and the connected N atom form a heterocyclic group;
  • R 7 are each the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl;
  • R 8 is selected from hydrogen atom, alkyl group, hydroxyl group, hydroxyalkyl group and halogenated alkyl group;
  • R 9 is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group and cycloalkyl group;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2 or 3;
  • t 0, 1, 2, 3, or 4.
  • a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is hydrochloride or quaternary ammonium salt.
  • a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or its mixture form, or its pharmaceutically acceptable salt which is a compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • r 0, 1, 2 or 3;
  • Ring A, ring B, ring C, L 1 , R 1 to R 8 , n, s, and t are as defined in the general formula (I).
  • a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is an aryl group; preferably a phenyl group.
  • a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 5-membered or 6-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 atoms selected from N atoms, O atoms or S A heteroatom of an atom; preferably selected from thiazolyl.
  • a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or its mixture form, or its pharmaceutically acceptable salt which is a compound represented by the general formula (III) or its tautomer, meso, racemate, or enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • W is CR 2 or N
  • r 0, 1, 2 or 3;
  • Ring C, L 1 , R 1 to R 8 , n and t are as defined in the general formula (I).
  • a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (IIIG) or a tautomer, a mesosome, a racemate, or an enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • Rings C, R 1 to R 7 , n and t are as defined in the compound of general formula (I).
  • a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof wherein ring C is a 3 to 12 membered cycloalkyl group or a 4 to 11 membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 Selected from N atom, O atom, S atom, S(O) 2 and The heteroatom; preferably a 3 to 12 membered cycloalkyl group or a 4 to 11 membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N atoms, O atoms or S atoms.
  • a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (IV) or a tautomer, meso, racemate, or enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • Ring C is a 4- to 11-membered heterocyclic group, in addition to containing one N atom, it also optionally contains 1 to 2 heteroatoms selected from N atoms, O atoms or S atoms; preferably selected from 4 to 7-membered heteroatoms Cyclic heterocyclic group, 7 to 11 membered spiro heterocyclic group, 6 to 11 membered fused ring heterocyclic group and 7 to 11 membered bridged ring heterocyclic group, in addition to containing one N atom, optionally containing 1 ⁇ 2 heteroatoms selected from N atom, O atom or S atom;
  • R 1 to R 7 , n and t are as defined in the general formula (I).
  • a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof wherein R 4 , R 7 and R 8 are the same or different, and are each independently a hydrogen atom or an alkyl group; R 4 is preferably an alkyl group, and R 7 is preferably A hydrogen atom, R 8 is preferably a hydrogen atom.
  • Typical compounds of the present disclosure include but are not limited to:
  • the present disclosure additionally provides a compound represented by general formula (IA), or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or a pharmaceutically acceptable salt thereof, which is an intermediate for preparing the compound of general formula (I),
  • Ring A is aryl or heteroaryl
  • Ring B is heteroaryl
  • Ring C is cycloalkyl or heterocyclyl
  • G 1 , G 2 and G 3 are the same or different, and each independently is CR 8 or N;
  • L 1 does not exist, or is selected from NR 9 , O and S;
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, carboxy, aldehyde, cycloalkyl , Heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxy, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl;
  • R 3 is selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally selected from halogen, alkyl, alkoxy, cyano, amino, nitro, and hydroxy , Hydroxyalkyl, carboxyl, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;
  • R 4 is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, Substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 5 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxy, aldehyde, hydroxyl, hydroxyalkyl, oxo , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen , Alkyl, alkoxy, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;
  • R 7 are each the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl;
  • R 8 is selected from hydrogen atom, alkyl group, hydroxyl group, hydroxyalkyl group and halogenated alkyl group;
  • R 9 is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group and cycloalkyl group;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2 or 3;
  • t 0, 1, 2, 3, or 4.
  • the present disclosure additionally provides a compound represented by general formula (IA), which is a compound represented by general formula (IIA), or a tautomer, meso, racemate, enantiomer Conformers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, which are intermediates for the preparation of compounds of general formula (II),
  • ring A, ring B, ring C, L 1 , R 1 to R 5 , R 7 , R 8 , r, n, s and t are as defined in the general formula (II).
  • the present disclosure additionally provides a compound represented by general formula (IA), which is a compound represented by general formula (IIIA), or a tautomer, meso, racemate, enantiomer Conformers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, which are intermediates for preparing compounds of general formula (III),
  • ring C, L 1 , Y, W, R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , r, n and t are as defined in the general formula (III).
  • the present disclosure additionally provides a compound represented by general formula (IA), which is a compound represented by general formula (IIIA), or a tautomer, meso, racemate, enantiomer Conformers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, which are intermediates for preparing compounds of general formula (IVA),
  • Ring C is a 4- to 11-membered heterocyclic group, in addition to containing one N atom, it also optionally contains 1 to 2 heteroatoms selected from N atoms, O atoms or S atoms; preferably selected from 4 to 7-membered heteroatoms Cyclic heterocyclic group, 7 to 11 membered spiro heterocyclic group, 6 to 11 membered fused ring heterocyclic group and 7 to 11 membered bridged ring heterocyclic group, in addition to containing one N atom, optionally containing 1 ⁇ 2 heteroatoms selected from N atom, O atom or S atom;
  • R 1 to R 5 , R 7 , n and t are as defined in the general formula (IV).
  • Typical intermediate compounds of general formula (IA) in the present disclosure include but are not limited to:
  • the present disclosure additionally provides a compound represented by the general formula (IB), or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or a pharmaceutically acceptable salt thereof, which is an intermediate for preparing the compound of general formula (I),
  • Y is an I atom
  • Ring C is a heterocyclic group
  • L 1 , G 1 , G 2 , G 3 , R 4 to R 7 and t are as defined in the compound of general formula (I).
  • the present disclosure additionally provides a compound represented by the general formula (IIB), or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or a pharmaceutically acceptable salt thereof, which is an intermediate for preparing the compound of general formula (II),
  • Y is an I atom
  • Ring C is a heterocyclic group
  • L 1 , R 4 to R 8 , r and t are as defined in the compound of general formula (II).
  • the present disclosure additionally provides a compound represented by the general formula (IIIGB), or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or a pharmaceutically acceptable salt thereof, which is an intermediate for preparing the compound of general formula (IIIG),
  • Y is an I atom
  • Ring C is a heterocyclic group
  • R 4 to R 7 and t are as defined in the compound of general formula (I).
  • Typical intermediate compounds of general formula (IB) of the present disclosure include but are not limited to:
  • the present disclosure additionally provides a method for preparing a compound according to general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen, hydroxyl or -B(OH) 2 ;
  • R 6 is -ML 2 -R a ;
  • R a is selected from alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Is selected from one of halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;
  • Ring A, ring B, ring C, M, L 1 , L 2 , G 1 to G 3 , R 1 to R 5 , R 7 , n, s, and t are as defined in the general formula (I).
  • the present disclosure additionally provides a method for preparing a compound according to general formula (II) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen, hydroxyl or -B(OH) 2 ;
  • R 6 is -ML 2 -R a ;
  • R a is selected from alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Is selected from one of halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Multiple substituents are substituted; ring A, ring B, ring C, M, L 1 , L 2 , R 1 ⁇ R 5 , R 7 , R 8 , r, n, s and t are as in the general formula (II) Defined.
  • the present disclosure additionally provides a method for preparing a compound according to general formula (III) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen, hydroxyl or -B(OH) 2 ;
  • R 6 is -ML 2 -R a ;
  • R a is selected from alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Is selected from one of halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;
  • Rings C, M, L 1 , L 2 , Y, W, R 1 , R 3 to R 5 , R 7 , R 8 , r, n, and t are as defined in the general formula (III).
  • the present disclosure additionally provides a method for preparing a compound according to general formula (IIIG) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen, hydroxyl or -B(OH) 2 ;
  • R 6 is -ML 2 -R a ;
  • R a is selected from alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Is selected from one of halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl or Replaced by multiple substituents;
  • Rings C, M, L 1 , L 2 , R 1 to R 5 , R 7 , n, and t are as defined in the general formula (IIIG).
  • the present disclosure additionally provides a method for preparing a compound according to general formula (IV) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen, hydroxyl or -B(OH) 2 ;
  • Ring C is a 4- to 11-membered heterocyclic group, in addition to containing one N atom, it also optionally contains 1 to 2 heteroatoms selected from N atoms, O atoms or S atoms; preferably selected from 4 to 7-membered heteroatoms Cyclic heterocyclic group, 7 to 11 membered spiro heterocyclic group, 6 to 11 membered fused ring heterocyclic group and 7 to 11 membered bridged ring heterocyclic group, in addition to containing one N atom, optionally containing 1 ⁇ 2 heteroatoms selected from N atom, O atom or S atom;
  • R 6 is -ML 2 -R a ;
  • R a is selected from alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Is selected from one of halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;
  • R 1 to R 5 , M, L 2 , R 7 , n and t are as defined in the general formula (IV).
  • the present disclosure additionally provides a method for preparing a compound according to general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • Y is an I atom
  • Ring C is a heterocyclic group
  • Ring A, ring B, L 1 , G 1 , G 2 , G 3 , R 1 to R 7 , n, s, and t are as defined in the general formula (I).
  • the present disclosure additionally provides a method for preparing a compound according to general formula (II) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • Y is an I atom
  • Ring C is a heterocyclic group
  • Ring A, ring B, L 1 , R 1 to R 8 , r, n, s, and t are as defined in the general formula (II).
  • the present disclosure additionally provides a method for preparing a compound according to general formula (III) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • Y is an I atom
  • Ring C is a heterocyclic group
  • L 1 , W, R 1 , R 3 to R 8 , r, n, and t are as defined in the general formula (III).
  • the present disclosure additionally provides a method for preparing a compound according to general formula (IIIG) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • Y is an I atom
  • Ring C is a heterocyclic group
  • R 1 to R 7 , n and t are as defined in the general formula (IIIG).
  • the present disclosure additionally provides a method for preparing a compound according to general formula (IV) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • Y is an I atom
  • Ring C is a 4- to 11-membered heterocyclic group, in addition to containing one N atom, it also optionally contains 1 to 2 heteroatoms selected from N atoms, O atoms or S atoms; preferably selected from 4 to 7-membered heteroatoms Cyclic heterocyclic group, 7 to 11 membered spiro heterocyclic group, 6 to 11 membered fused ring heterocyclic group and 7 to 11 membered bridged ring heterocyclic group, in addition to containing one N atom, optionally containing 1 ⁇ 2 heteroatoms selected from N atom, O atom or S atom;
  • R 1 to R 7 , n and t are as defined in the general formula (IV).
  • Another aspect of the present disclosure relates to a pharmaceutical composition, which contains the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, and asymmetric Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure also relates to a method for preparing the above-mentioned pharmaceutical composition, which comprises combining the compounds represented by the general formulas or their tautomers, mesosomes, racemates, enantiomers, and non-pairs The enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof are mixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • Another aspect of the present disclosure relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, and mixture thereof Use of the form, its pharmaceutically acceptable salt, or the pharmaceutical composition protecting it in the preparation of an ATX inhibitor.
  • Another aspect of the present disclosure relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, and mixture thereof Forms, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions protecting them are used in the preparation of prevention and/or treatment of fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, Neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis-related diseases and pain; preferably for use in the preparation of drugs for the prevention and/or treatment of fibrotic diseases and cancer; more preferably for preparation Use in medicine for preventing and/or treating pulmonary fibrosis, liver fibrosis and scleroderma.
  • Another aspect of the present disclosure relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, and mixture thereof
  • the disease is selected from: fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormalities Angiogenesis-related diseases and pain; preferably fibrotic diseases and cancer; more preferably pulmonary fibrosis, liver fibrosis and scleroderma.
  • Another aspect of the present disclosure relates to a method for inhibiting ATX, the method comprising administering to a patient in need thereof a therapeutically effective dose of the compound represented by the general formula (I) of the present disclosure or its tautomer, Meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.
  • Another aspect of the present disclosure relates to a prevention and/or treatment of fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases , Myelodysplastic syndrome, abnormal angiogenesis-related diseases and pain methods, the method comprising administering to a patient in need thereof a therapeutically effective dose of the compound represented by the present disclosure of the present disclosure of general formula (I) or its interconversion Isomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • general formula (I) or its interconversion Isomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • Another aspect of the present disclosure relates to a method for treating a disease characterized by pathological features of increased ATX expression, the method comprising administering to a patient in need thereof a therapeutically effective dose of the compound represented by the general formula (I) of the present disclosure of the present disclosure Or its tautomer, mesosome, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable salt, or pharmaceutical composition containing the same .
  • Diseases with pathological characteristics of increased ATX expression are selected from: fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases , Myelodysplastic syndrome, abnormal angiogenesis-related diseases and pain; preferably fibrotic diseases and cancer; more preferably pulmonary fibrosis, liver fibrosis and scleroderma.
  • Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure, or its tautomer, meso, racemate, enantiomer, and asymmetric Enantiomers or their mixtures, or their pharmaceutically acceptable salts, or pharmaceutical compositions containing them, are used as drugs.
  • Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure, or its tautomer, meso, racemate, enantiomer, and asymmetric Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which act as ATX inhibitors.
  • Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure, or its tautomer, meso, racemate, enantiomer, and asymmetric Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used as the prevention and/or treatment of fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, Drugs for respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis-related diseases and pain; preferably drugs for preventing and/or treating fibrotic diseases and cancer; More preferred is the prevention and/or treatment of pulmonary fibrosis, liver fibrosis and scleroderma.
  • fibrotic diseases cancer
  • proliferative diseases inflammatory diseases
  • autoimmune diseases Drugs for respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis-related diseases and pain
  • Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure, or its tautomer, meso, racemate, enantiomer, and asymmetric Enantiomers or their mixture forms, or their pharmaceutically acceptable salts, or pharmaceutical compositions containing them, which are used as drugs for treating diseases characterized by pathological features of increased ATX expression, wherein the pathology of increased ATX expression
  • the characteristic diseases are selected from: fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, Abnormal angiogenesis-related diseases and pain; preferably fibrotic diseases and cancer; more preferably pulmonary fibrosis, liver fibrosis and scleroderma.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbons Atom of the alkyl group.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • a lower alkyl group containing 1 to 6 carbon atoms non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane
  • One or more substituents among oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo groups are substituted.
  • alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, which has 2 residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 -) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • the alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Substituted by one or more substituents in the group, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl , Hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (which may be specific points, It can also be a range composed of two optional points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), more preferably 3 to 8 carbon atoms, most It preferably contains 3 to 6 (e.g. 3, 4, 5 or 6) carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Cycloalkyl groups, cyclooctyl groups, etc. are preferably cycloalkyl groups; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes the above-mentioned cycloalkyl groups (such as monocyclic, fused ring, spiro ring and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring is connected to the parent structure
  • the ring together is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl.
  • Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio and oxo groups are substituted by one or more substituents.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, sulfur, S( O), S(O) 2 and The heteroatoms of, but do not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • It preferably contains 3 to 12 ring atoms (which can be a specific point or an interval composed of two optional points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms) Atoms, etc.), wherein 1 to 4 are heteroatoms; preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydrofuranyl Hydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen, sulfur, and S (O), S(O) 2 and The other ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 11 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, where one or more ring atoms are selected from nitrogen, oxygen, sulfur, S(O), S(O) 2 and The other ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 11 yuan.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common Conjugated ⁇ -electron system, where one or more ring atoms are selected from nitrogen, oxygen, sulfur, S(O), S(O) 2 and The other ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 11 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclic ring includes the above heterocyclic groups (such as monocyclic, fused ring, spiro ring and bridged heterocyclic group) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the parent structure is connected to The ring together is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio and oxo groups are substituted by one or more substituents.
  • aryl refers to a 6 to 20-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably 6 members, such as phenyl and naphthyl.
  • the aryl ring includes the above-mentioned aryl group fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • Aryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycle
  • One or more substituents in the alkylthio group are substituted.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 20 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 3 heteroatoms; non-limiting examples are pyrazolyl, imidazolyl, furanyl, Thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio And one or more substituents in the heterocycloalkylthio group.
  • alkylthio refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), where the definition of alkyl is as described above.
  • alkylthio include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio.
  • the alkylthio group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio And one or more substituents in the heterocycloalkylthio group.
  • amino protecting group is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove.
  • Non-limiting examples include tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably tert-butoxycarbonyl.
  • cycloalkyloxy refers to -O-cycloalkyl, where cycloalkyl is as defined above.
  • haloalkyl refers to an alkyl substituted by halogen, where alkyl is as defined above.
  • haloalkoxy refers to an alkoxy substituted by halogen, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • aldehyde group refers to -C(O)H.
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • fibrotic disease refers to a disease characterized by excessive seizures caused by excessive production, deposition and contraction of extracellular matrix, and it is associated with abnormal accumulation of cells and/or fibronectin and/or collagen and/ Or increased fibroblast recruitment is related, and includes, but is not limited to, fibrosis of individual organs or tissues (such as heart, kidney, liver joint, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, muscle bone marrow, and digestive tract) .
  • organs or tissues such as heart, kidney, liver joint, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, muscle bone marrow, and digestive tract
  • idiopathic pulmonary fibrosis IPF
  • cystic fibrosis scleroderma
  • radiation-induced fibrosis COPD
  • bleomycin-induced pulmonary fibrosis bleomycin-induced pulmonary fibrosis
  • chronic asthma sand lung
  • asbestos-induced pulmonary fibrosis fibrosis
  • acute respiratory distress syndrome ARDS
  • other diffuse parenchymal lung diseases of different etiology including iatrogenic drug-induced fibrosis, occupational and/ Or environment-induced fibrosis
  • granulomatous disease sarcoidosis, allergic pneumonia
  • collagen vascular disease alveolar protein deposition
  • Langerhans cell granulomatosis lymphangiomyotysis
  • genetic disease Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibroma, metabolic accumulation disorder, familial interstitial lung disease
  • renal fibrosis liver fibrosis, liver S
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogen atoms in the group, preferably at most 5, more preferably 1 to 3 hydrogen atoms independently of each other by a corresponding number of substituents, wherein each substituent has an independent (I.e. the substituents can be the same or different). It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the organic and inorganic salts of the compounds of the present disclosure, as described in the document: S.M. Berge et al., describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. Such salts are safe and effective when used in mammals, and have due biological activity, preferably hydrochloride, quaternary ammonium salt and amine cation.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivative refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms.
  • in addition to using “deuterium” or “tritium” instead of hydrogen, or using 18 F-fluorine label ( 18 F isotope) instead of fluorine, or using 11 C-, 13 C-, or 14 C-rich Compounds in which a set of carbons ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) replace carbon atoms are within the scope of the present disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) ).
  • the term "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general conditions of the recipient, and also on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine tests.
  • the preparation method of medicinal salt includes the following steps:
  • X is halogen, hydroxyl or -B(OH) 2 ;
  • R 6 is -ML 2 -R a ;
  • R a is selected from alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Is selected from one of halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;
  • Ring A, ring B, ring C, M, L 1 , L 2 , G 1 to G 3 , R 1 to R 5 , R 7 , n, s, and t are as defined in the general formula (I).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and lithium diisopropylamide.
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, hydrogen Lithium oxide and potassium hydroxide; potassium carbonate is preferred.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide , 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or
  • the preparation method of medicinal salt includes the following steps:
  • X is halogen, hydroxyl or -B(OH) 2 ;
  • R 6 is -ML 2 -R a ;
  • R a is selected from alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Is selected from one of halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;
  • Ring A, ring B, ring C, M, L 1 , L 2 , R 1 to R 5 , R 7 , R 8 , r, n, s, and t are as defined in the general formula (II).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and lithium diisopropylamide.
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, hydrogen Lithium oxide and potassium hydroxide; potassium carbonate is preferred.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide , 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • X is halogen, hydroxyl or -B(OH) 2 ;
  • R 6 is -ML 2 -R a ;
  • R a is selected from alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Is selected from one of halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;
  • Rings C, M, L 1 , L 2 , Y, W, R 1 , R 3 to R 5 , R 7 , R 8 , r, n, and t are as defined in the general formula (III).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and lithium diisopropylamide.
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, hydrogen Lithium oxide and potassium hydroxide; potassium carbonate is preferred.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide , 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the present disclosure additionally provides a method for preparing a compound according to general formula (IIIG) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen, hydroxyl or -B(OH) 2 ;
  • R 6 is -ML 2 -R a ;
  • R a is selected from alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Is selected from one of halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;
  • Rings C, M, L 1 , L 2 , R 1 to R 5 , R 7 , n, and t are as defined in the general formula (IIIG).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and lithium diisopropylamide.
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, hydrogen Lithium oxide and potassium hydroxide; potassium carbonate is preferred.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide , 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the compound represented by the general formula (IV) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or
  • the preparation method of medicinal salt includes the following steps:
  • the compound of general formula (IVB) removes the amino protective group under acidic conditions to obtain the compound of general formula (IVA) or its salt;
  • R w is an amino protecting group; preferably tert-butoxycarbonyl
  • X is halogen, hydroxyl or -B(OH) 2 ;
  • R 6 is -ML 2 -R a ;
  • R a is selected from alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Is selected from one of halogen, alkyl, alkoxy, oxo, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;
  • Ring C is a 4- to 11-membered heterocyclic group, in addition to containing one N atom, it also optionally contains 1 to 2 heteroatoms selected from N atoms, O atoms or S atoms; preferably selected from 4 to 7-membered heteroatoms Cyclic heterocyclic group, 7 to 11 membered spiro heterocyclic group, 6 to 11 membered fused ring heterocyclic group and 7 to 11 membered bridged ring heterocyclic group, in addition to containing one N atom, optionally containing 1 ⁇ 2 heteroatoms selected from N atom, O atom or S atom;
  • M, L 2 , R 1 to R 5 , R 7 , n and t are as defined in the general formula (IV).
  • Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, ammonium chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzene Methanesulfonic acid and TMSOTf.
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and lithium diisopropylamide.
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, hydrogen Lithium oxide and potassium hydroxide; potassium carbonate is preferred.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide , 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the present disclosure additionally provides a method for preparing a compound according to general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IC) or its salt reacts in the presence of a catalyst to obtain the compound of general formula (I);
  • Y is an I atom
  • Ring C is a heterocyclic group
  • Ring A, ring B, L 1 , G 1 , G 2 , G 3 , R 1 to R 7 , n, s, and t are as defined in the general formula (I).
  • the catalyst in the above reaction is selected from: CuI/trans-(1R,2R)-N,N'-dimethyl1,2-cyclohexanediamine, methanesulfonic acid (2-dicyclohexylphosphino-2' ,6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl)palladium(II) and methanesulfonic acid (2-dicyclohexyl) Phosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2- Base) palladium(II); preferably CuI/trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine;
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide , 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the present disclosure additionally provides a method for preparing a compound according to general formula (IIIG) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIIGC) or its salt reacts in the presence of a catalyst to obtain the compound of general formula (IIIG);
  • Y is an I atom
  • Ring C is a heterocyclic group
  • R 1 to R 7 , n and t are as defined in the general formula (IIIG).
  • the catalyst in the above reaction is selected from: CuI/trans-(1R,2R)-N,N'-dimethyl1,2-cyclohexanediamine, methanesulfonic acid (2-dicyclohexylphosphino-2' ,6'-Diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl)palladium(II) and methanesulfonic acid (2-dicyclohexyl Phosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2- Base) palladium(II); preferably CuI/trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine;
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide , 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
  • HPLC preparation uses Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • the silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. ), Darui Chemicals and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the microwave reaction uses the CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC).
  • the developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • the crude compound 14d (4.0g, 8.80mmol) was dissolved in 5mL of toluene, and then copper acetate (1.6g, 8.80mmol), cycloproporonic acid (2.23g, 25.96mmol) and pyridine (3.48g, 37.92mmol) were added to react Stir at 80°C for about 16 hours. After cooling to room temperature, add 5 5mL of water to the reaction solution and extract with ethyl acetate (50mL ⁇ 3).
  • reaction mixture was purified by high performance liquid chromatography (Sharpsil-T C18 Column 21.2*150mm 5um, elution system: water (10mmoL/L ammonium acetate), acetonitrile) to obtain the title product 16 (20mg, yield: 33.7%).
  • azetidine-3-carboxylic acid methyl ester hydrochloride 20a (300mg, 1.98mmol, Shaoyuan Chemical) was dissolved in 10mL of dichloromethane, and N,N-diisopropylethylamine (768mg, 5.94 mmol), chloroacetyl chloride (440 mg, 3.90 mmol) was slowly added dropwise, and reacted for 2 hours.
  • reaction mixture was purified by high performance liquid chromatography (Sharpsil-T C18 Column 21.2*150mm 5um, elution system: water (10mmoL/L ammonium acetate), acetonitrile) to obtain the title product 21 (20mg, yield: 58.53%).
  • reaction mixture was purified by high performance liquid chromatography (Sharpsil-T C18 Column 21.2*150mm 5um, elution system: water (10mmoL/L ammonium acetate), acetonitrile) to obtain the title product 28 (20mg, yield: 17.9%) ).
  • reaction mixture was purified by high performance liquid chromatography (Sharpsil-T C18 Column 21.2*150mm 5um, elution system: water (10mmoL/L ammonium acetate), acetonitrile) to obtain title product 29 (25mg, yield: 53.5%) .
  • 3-(6-methylpyridin-3-yl)-3-oxopropionitrile 37a (285 mg, 1.78 mmol, prepared by the method disclosed in Example 22 on page 76 of the specification in the patent application "WO2007098826A3) was dissolved In 5 mL of methanol, tert-butyl hydroperoxide (481 mg, 5.33 mmol) and azobisisobutyronitrile (59 mg, 0.39 mmol) were added, and the mixture was stirred at 70°C for about 16 hours.
  • reaction was quenched by adding sodium thiosulfate solution to the solution, extracted with ethyl acetate (30mL ⁇ 3), combined the organic phases, washed with water (10mL), saturated sodium chloride solution (10mL), dried with anhydrous sodium sulfate, filtered The desiccant was removed, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title product 37b (100 mg, yield: 26.0%).
  • Dissolve compound 32 (30mg, 0.05mmol) in 10mL N,N-dimethylformamide, add N,N-diisopropylethylamine (21mg, 0.16mmol), add hydroxylamine hydrochloride (8mg, 0.12mmol) ) And 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (42 mg, 0.08 mmol), and the reaction was stirred for about 1 hour.
  • reaction mixture was purified by high performance liquid chromatography (Sharpsil-T C18 Column 21.2*150mm 5um, elution system: water (10mmoL/L ammonium acetate), acetonitrile) to obtain the title product 39 (10mg, yield: 32.4%) .
  • reaction solution was quenched by adding water, then extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A From the residue, 41 g (65 mg, yield: 99.5%) of the title product was obtained. MS m/z(ESI): 564.8[M+1].

Abstract

L'invention concerne un dérivé de pyridone, son procédé de préparation et son application pharmaceutique. En particulier, la présente invention concerne un dérivé de pyridone représenté par la formule générale (I), un procédé de préparation dudit dérivé, une composition pharmaceutique contenant le dérivé, l'utilisation du dérivé en tant qu'inhibiteur d'ATX, et l'utilisation de celui-ci dans la préparation de médicaments pour le traitement de cancers ou de maladies ou d'affections fibrotiques. La définition de chaque substituant dans la formule générale (I) est identique à celle donnée dans la description..
PCT/CN2020/094126 2019-06-04 2020-06-03 Dérivé de pyridone, son procédé de préparation et son application pharmaceutique WO2020244539A1 (fr)

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CN112574094A (zh) * 2020-12-14 2021-03-30 成都大学 吲哚酮衍生物及其制药用途
CN114805204A (zh) * 2022-04-01 2022-07-29 云南师范大学 一种制备4-碘异喹啉-1(2h)-酮类化合物的方法
WO2023093832A1 (fr) * 2021-11-25 2023-06-01 上海济煜医药科技有限公司 Dérivé tricyclique et procédé de préparation s'y rapportant et application associée

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CN102695416A (zh) * 2009-10-29 2012-09-26 金纳斯克公司 激酶抑制剂
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WO2014202458A1 (fr) * 2013-06-19 2014-12-24 Galapagos Nv Nouveaux composés et compositions pharmaceutiques les comprenant pour le traitement de troubles inflammatoires
WO2019029620A1 (fr) * 2017-08-09 2019-02-14 广州市恒诺康医药科技有限公司 Inhibiteur d'atx, son procédé de préparation et son utilisation

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Publication number Priority date Publication date Assignee Title
CN101815714A (zh) * 2007-10-05 2010-08-25 默克专利有限公司 治疗癌症的噻唑衍生物
CN102695416A (zh) * 2009-10-29 2012-09-26 金纳斯克公司 激酶抑制剂
WO2014139882A1 (fr) * 2013-03-14 2014-09-18 Galapagos Nv Composés et compositions pharmaceutiques les contenant destinés à traiter les troubles inflammatoires
WO2014202458A1 (fr) * 2013-06-19 2014-12-24 Galapagos Nv Nouveaux composés et compositions pharmaceutiques les comprenant pour le traitement de troubles inflammatoires
WO2019029620A1 (fr) * 2017-08-09 2019-02-14 广州市恒诺康医药科技有限公司 Inhibiteur d'atx, son procédé de préparation et son utilisation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112574094A (zh) * 2020-12-14 2021-03-30 成都大学 吲哚酮衍生物及其制药用途
CN112574094B (zh) * 2020-12-14 2022-07-01 成都大学 吲哚酮衍生物及其制药用途
WO2023093832A1 (fr) * 2021-11-25 2023-06-01 上海济煜医药科技有限公司 Dérivé tricyclique et procédé de préparation s'y rapportant et application associée
CN114805204A (zh) * 2022-04-01 2022-07-29 云南师范大学 一种制备4-碘异喹啉-1(2h)-酮类化合物的方法
CN114805204B (zh) * 2022-04-01 2023-09-15 云南师范大学 一种制备4-碘异喹啉-1(2h)-酮类化合物的方法

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