WO2023072188A1 - Kras g12d inhibitors and use thereof in medicine - Google Patents

Kras g12d inhibitors and use thereof in medicine Download PDF

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Publication number
WO2023072188A1
WO2023072188A1 PCT/CN2022/127912 CN2022127912W WO2023072188A1 WO 2023072188 A1 WO2023072188 A1 WO 2023072188A1 CN 2022127912 W CN2022127912 W CN 2022127912W WO 2023072188 A1 WO2023072188 A1 WO 2023072188A1
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alkylene
alkyl
halogen
cycloalkyl
cyano
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PCT/CN2022/127912
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French (fr)
Chinese (zh)
Inventor
吴颢
陈小平
路渊
徐人奇
何将旗
李波燕
赵志昌
匡翠文
夏洪峰
王冬
张洪波
湛波
张运来
王国建
杨翔
沈少聪
黄传龙
周全
王家炳
兰宏
丁列明
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贝达药业股份有限公司
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Publication of WO2023072188A1 publication Critical patent/WO2023072188A1/en

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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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • 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 invention relates to a novel compound which has KRAS inhibitory activity, especially KRAS G12D inhibitory activity.
  • the invention also relates to processes for the preparation of these compounds and pharmaceutical compositions containing them.
  • RAS is the gene with the highest mutation rate in human tumors. About 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, 43% of multiple myeloma, And 32% of lung adenocarcinomas have RAS gene mutations.
  • the most common mutation of RAS is point mutation, which often occurs at codons 12, 13, and 61, and the mutation at codon 12 is the most common, such as G12C, G12D or G12V.
  • KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered the late clinical stage; while MIRATI is leading the development of G12D inhibitors (WO2021041671A1).
  • MRTX1133 is a selective and reversible KRAS-G12D inhibitor, which can inhibit KRAS G12D mutant cells in activated and inactive states, but not KRAS wild-type tumor cells.
  • the specificity of MRTX1133 for KRAS G12D is more than 1000 times that of wild-type KRAS .
  • MRTX1133 has a half-life of more than 24 hours, has no potential hERG activity, and is relatively safe. At present, MRTX1133 is still in the preclinical research stage, and there is great uncertainty about whether it can be made into a drug. Therefore, it is necessary to conduct more in-depth research on KRAS-G12D inhibitors.
  • MRTX1133 has multiple chiral centers, its disassembly The synthesis cost is higher, and the production process is more complicated.
  • the present invention provides a compound represented by the general formula (I), or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, the structure of the formula (I) is:
  • A is selected from CR 6 or N;
  • B is selected from CR 7 or N;
  • R 7 is selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 Alkoxy is optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C alkoxy ;
  • R 1 is selected from Wherein R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano
  • R 13 is preferably H; wherein R 14 is selected from hydroxyl, halogen, cyano, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, The C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl are optionally substituted by one or more R b ;
  • X 1 is selected from CR 8 or N;
  • X 2 is selected from CR 9 or N;
  • R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
  • X3 is selected from CH or N;
  • X is selected from CH or N;
  • X is selected from O or S
  • L is selected from a bond, -OC 0-8 alkylene , -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene, the -OC 0-8 alkylene Alkyl, -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene is optionally substituted by one or more R 10 ;
  • R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to them form a C 3-6 cycloalkyl group;
  • R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
  • R 4 is selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, and the C 1-6 alkyl or C 1-6 alkoxy is optionally replaced by one or Replaced by multiple substituents selected from halogen, cyano, oxo, hydroxyl, amino or C 1-6 alkoxy;
  • R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituents of radicals, oxo groups, hydroxyl groups or C 1-6 alkoxyl groups;
  • Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • Each R b is independently selected from hydroxyl, C 1-3 alkyl, 3-8 membered heterocyclyl, -N(R a ) 2 , -CH 2 N(R a ) 2 ;
  • R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
  • n are each independently selected from 0, 1, 2, 3 or 4.
  • the compound represented by formula (I) has the following general formula (II) structure:
  • X 1 is selected from CR 8 or N;
  • X 2 is selected from CR 9 or N;
  • R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
  • X3 is selected from CH or N;
  • X is selected from CH or N;
  • X is selected from O or S
  • L is selected from a bond, -OC 0-8 alkylene , -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene, the -OC 0-8 alkylene Alkyl, -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene is optionally substituted by one or more R 10 ;
  • R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to them form a C 3-6 cycloalkyl group;
  • R 1 is selected from Wherein R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano
  • R 13 is preferably H; wherein R 14 is selected from hydroxyl, halogen, cyano, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, The C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl are optionally substituted by one or more R b ;
  • R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
  • R 4 or R 7 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C 1-6 alkoxy;
  • R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituents of radicals, oxo groups, hydroxyl groups or C 1-6 alkoxyl groups;
  • Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • Each R b is independently selected from hydroxyl, C 1-3 alkyl, 3-8 membered heterocyclyl, -N(R a ) 2 , -CH 2 N(R a ) 2 ;
  • R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
  • n are each independently selected from 0, 1, 2 or 3.
  • the compound represented by formula (I) has the following structure of general formula (III):
  • X 1 is selected from CR 8 or N;
  • X 2 is selected from CR 9 or N;
  • R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
  • X3 is selected from CH or N;
  • X is selected from CH or N;
  • X is selected from O or S
  • L is selected from a bond, -OC 0-4 alkylene , -SC 0-4 alkylene, -NH-C 0-4 alkylene or C 2-4 alkynylene, the -OC 0-4 alkylene Alkyl, -SC 0-4 alkylene, -NH-C 0-4 alkylene or C 2-4 alkynylene is optionally substituted by one or more R 10 ;
  • R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to it form a 3-6 membered cycloalkyl group;
  • R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano; preferably R1 is H;
  • R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
  • R 4 or R 7 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C 1-6 alkoxy;
  • R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituent group, oxo group, hydroxyl group or C 2-6 alkoxyl group;
  • Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
  • n is selected from 0, 1, 2 or 3.
  • the compound represented by formula (I) has the following structure of formula (IV):
  • X 1 is selected from CR 8 or N;
  • R 8 is selected from H, amino, substituted amino, cyano, C 1-6 alkyl, substituted C 1-6 alkyl, halogen, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl;
  • B is selected from CR 7 or N;
  • R 7 is selected from H, halogen, cyano or C 1-6 alkyl;
  • X 2 is selected from CR 9 or N;
  • R 9 is selected from H, halogen, hydroxyl, C 1-6 alkoxy, cyano or C 1-6 alkyl;
  • A is selected from CR 6 or N;
  • R 6 is selected from H, halogen, cyano or C 1-6 alkyl;
  • L is selected from bond, O, S, NR 10 , -OC 1-4 alkylene or C 2-4 alkynylene, said -OC 1-4 alkylene or C 2-4 alkynylene optionally Substituted by one or more R 10 ;
  • R 10 is selected from H, halogen, cyano, hydroxyl or C 1-6 alkyl, or two R 10 on the same carbon atom together with the atoms connected to form 3-6 Cycloalkyl;
  • R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano; preferably R 13 is H;
  • R 2 is selected from -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2.
  • R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 alkoxy or cyclopropyl;
  • R 4 or R 5 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 2-6 alkoxy, the C 1-6 alkyl or C 2-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxyl or C2-6alkoxy ;
  • n is selected from 0, 1, 2, 3 or 4.
  • the X 2 is selected from CR 9 or N;
  • R 9 is selected from H, halogen, cyano or C 1-6 alkyl;
  • R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R ;
  • the X 1 is selected from CR 8 or N;
  • R a each independently selected from H or C 1-6 alkyl.
  • the X 2 is selected from CR 9 or N; R 9 is cyano.
  • the L is selected from a bond, preferred
  • the R is selected from preferably
  • the R 3 is selected from H, halogen or -OR 12 , and the R 12 is selected from C 1-6 Alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl.
  • the R 4 is selected from H, halogen or C 1-6 alkyl.
  • the R 5 is selected from H or C 1-6 alkyl; preferably H.
  • the R 7 is selected from H, halogen or C 1-6 alkyl; preferably H.
  • the m is selected from 1 or 2; preferably 1.
  • n is selected from 1 or 2; preferably 1.
  • the compound represented by formula (I) has the following formula (IA) or (IB) structure:
  • each substituent is as defined in formula (I).
  • the compound represented by formula (I) has the following formula (IC) or (ID) structure:
  • the compound represented by formula (I) has the following formula (IC-3) structure:
  • R 13 is selected from H
  • R 3 is selected from H, C 1-6 alkyl or halogen
  • R is selected from H, cyano, hydroxyl or halogen
  • R is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl,
  • R c or R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
  • n is selected from 0, 1, 2, 3 or 4.
  • the alkene structure in the present invention compares with The chiral fluorine atom structure not only reduces the chiral center, but also has a simple synthesis process and greatly reduces production costs, which is conducive to large-scale industrial production, and some of the compounds such as etc., the activity of KRAS G12D is generally higher than that of chiral fluorine compounds.
  • the compound in general formula (I), (II), (III) or (IV), is selected from:
  • the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound represented by formula (I), or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, optionally Further include pharmaceutically acceptable auxiliary materials.
  • the present invention provides the compound represented by formula (I), or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, or the application of its pharmaceutical composition in the preparation of medicine.
  • the application in the preparation of medicaments is the application in the preparation of medicaments for treating and/or preventing cancer.
  • the application in the preparation of the medicament is the application in the preparation of a medicament for treating and/or preventing diseases mediated by KRAS G12D.
  • the KRAS G12D-mediated disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • the present invention also provides a method for treating and/or preventing diseases, comprising administering a therapeutically effective amount of at least one compound represented by structural formula (I), or its stereoisomers, tautomers, Deuterated substances or pharmaceutically acceptable salts, or pharmaceutical compositions containing them.
  • the present invention also provides a method for treating and/or preventing diseases mediated by KRAS G12D, comprising administering a therapeutically effective amount of at least one compound represented by structural formula (I), or its stereoisomer, Tautomers, deuterated substances or pharmaceutically acceptable salts, or pharmaceutical compositions containing them.
  • the present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any one represented by structural formula (I), or its stereoisomers, tautomers, deuteriums, or medicinal salt, or a pharmaceutical composition containing it.
  • the KRAS G12D-mediated disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatocholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • halogen refers to fluorine, chlorine, bromine or iodine, unless otherwise specified.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and the like.
  • “1-6” in “C 1-6 alkyl” refers to a group comprising 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain.
  • alkylene refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which the two CH bonds are replaced by the point of attachment of the alkylene to the rest of the compound. Similarly, “C 1-6 " in C 1-6 alkylene refers to an alkylene group containing 1, 2, 3, 4, 5 or 6 carbon atoms, including but not limited to methylene, 1, 2-ethylene, 1,3-propylene or 1,2-isopropylidene.
  • alkoxy refers to the oxygen ether form of the aforementioned linear or branched alkyl, ie -O-alkyl.
  • aryl in the present invention, unless otherwise stated, refers to an unsubstituted or substituted aromatic group including 6-14 membered monocyclic or condensed rings.
  • the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group.
  • Preferred are phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl, where the ring bonded to the parent structure is an aryl ring, non-limiting examples include, but are not limited to, benzocyclopentyl.
  • heterocyclyl in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable ring system consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is Saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents comprising 3 to 14 carbon atoms, wherein the nitrogen or sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatoms may be optionally quaternized .
  • the heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure.
  • heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro Oxadiazolyl.
  • the heterocyclyl may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring bonded to the parent structure is the heterocyclyl.
  • heteroaryl in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- to 14-membered benzo
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene Thiadiazolyl, benzotriazolyladenine, quinolinyl or isoquinolinyl.
  • the heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring where the ring attached to the parent structure is a heteroaryl ring.
  • cycloalkyl refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .
  • the cycloalkyl group may be fused to an aryl, heterocyclyl, or heteroaryl ring where the ring bonded to the parent structure is a cycloalkyl group.
  • substituted means that one or more hydrogen atoms in the group are respectively replaced by the same or different substituents.
  • substituents include, but are not limited to, H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR b , -C 0-6 alkylene- OC(O)N(R b ) 2 , -C 0-6 alkylene-N(R b ) 2 , -C 0-6 alkylene-NR b C(O)R b , -C 0-6 Alkylene-NR b C(O)N(R b ) 2 , -C 0-6 Alkylene-NR b S(O)R b , -C 0-6 Alkylene-NR b S(O) 2 R b , -C 0-6 alkylene-S(O) 2 R b , -C 0-6 alkylene-S(O)
  • Each R b is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl.
  • the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy Butyl, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl Amino, methylthio, sulfonyl and acetyl groups.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • salts derived from inorganic bases include aluminum, ammonium, calcium, copper (superior and subvalent), ferric, ferrous, lithium, magnesium, manganese (superior and subvalent), potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Nontoxic organic bases from which pharmaceutically acceptable salts can be derived include primary, secondary and tertiary amines, also cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines.
  • non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine acid, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine wait.
  • ion exchange resins and arginine betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylamino
  • the compound provided by the present invention is a base
  • its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoro
  • prodrugs of the compounds of the present invention are included in the protection scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted in vivo into the desired compound.
  • any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite or Residues.
  • the compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and optical isomers.
  • the present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
  • the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and their mixtures.
  • substitution of compounds of formula (I) with heavier isotopes may afford certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or their pharmaceutically acceptable salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • compositions comprising "a” pharmaceutically acceptable excipient may be interpreted to mean that the pharmaceutical composition includes “one or more” pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, Subcutaneous, intravenous administration.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie arresting its development; or (b) relieving the symptoms of the disease, ie causing regression of the disease or symptoms.
  • the term "effective amount” means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described in .
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
  • Step I Compound A-1 is reacted with Obtain compound A-2 through substitution reaction;
  • Step II compound A-2 is under the effect of Pd catalyst such as Pd(dtbpf)Cl 2 , and compound The corresponding groups were introduced through Suzuki coupling reaction;
  • Pd catalyst such as Pd(dtbpf)Cl 2
  • Step III The target compound A can be obtained by removing the TG protecting group of compound A-3 under acidic conditions such as the action of TFA.
  • DABCO triethylenediamine
  • DBU 1,8-diazabicycloundec-7-ene
  • CPME cyclopentyl methyl ether
  • m-CPBA m-chloroperoxybenzoic acid
  • DIEA N,N-Diisopropylethylamine
  • Dioxane dioxane
  • POCl 3 phosphorus oxychloride
  • THF Tetrahydrofuran
  • TFA trifluoroacetic acid
  • Pre-TLC preparation of thin-layer plates
  • TosMIC p-Methylsulfonylmethylisonitrile
  • DMSO dimethyl sulfoxide
  • Pd(dtbpf)Cl 2 dichloro[1,1'-bis(er-tert-butylphosphine)ferrocenepalladium(II);
  • Pd(DPEPhos)Cl 2 bis(diphenylphosphine phenyl ether) dichloropalladium(II);
  • CataCXium A Pd G3 [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate;
  • Pre-HPLC high performance liquid phase preparation method.
  • Bis(imidazol-1-yl)methanone (2.70 g) was added to compound 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (4.0 g) in THF (20 mL) at room temperature, N-ethyl-N-isopropylpropan-2-amine (1.4 g) was added thereto, and the mixture was moved to 50° C. for 2 hours.
  • the compound 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid was almost completely converted into an intermediate product, and then the mixture was added dropwise into iced ammonia water (35 mL), and stirred for 5 min to complete the reaction.
  • compound M6-4 (187g) and difluoromethyl (2-pyridyl) sulfone (184g) were dissolved in anhydrous DMF (1.4L), and potassium tert-butoxide (107g) was added dropwise at -50°C DMF (460mL) solution, after the dropwise addition, control the temperature and react at -40°C for 2 hours. After the reaction, add saturated ammonium chloride solution dropwise at -50°C until the solution becomes weakly acidic, then naturally warm to room temperature and react for 18 hours. , filtered to obtain the filtrate, added EA (1.4 L) to dilute, then filtered to obtain the filtrate, and concentrated.
  • compound M7-1 (0.3g) was dissolved in tetrahydrofuran, lithium aluminum hydride (123mg) was added under ice bath, and then a solution of borane in tetrahydrofuran (3.2mL) was added, and the reaction was quenched with water immediately after 1 minute. Quench the reaction until bubbles no longer emerge, add 15% sodium hydroxide (0.3mL), then add water (0.9mL), after stirring and quenching completely, add sodium sulfate to dry, filter to obtain the filtrate, concentrate to obtain the product M12 (80mg, 33% yield).
  • Embodiment 1 Compound 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-8-fluoro-2-(( 2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3 -Synthesis of carbonitrile
  • Example 148 Compound 7-(2-amino-3-cyano-7-fluorobenzothiophen-4-yl)-4-((1R,5S)-3,8-diazacyclo[3.2.1 Synthesis of ]octane-3-yl)-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinoline-3-carbonitrile
  • Example 149 Compound 3-((7-(2-amino-3-cyano-7-fluorobenzothiophen-4-yl)-4-((1R,5S)-3,8-diazacyclo Synthesis of [3.2.1] octane-3-yl)-6-chloro-3-cyano-8-fluoroquinolin-2-yl)amino)-N,N-dimethylpropylamine
  • Example 162 Compound 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-8-fluoro-2-(( 2-Oxytrihydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile synthesis
  • Example 163 Compound 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-2-((2-(di Fluoromethylene)tetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene -Synthesis of 3-carbonitrile
  • Example 180 Compound 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-8-fluoro-2-(( 2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-2-aminobenzo[b]thiophene-3-carbonitrile synthesis
  • Example 181 2-Amino-4-(6-chloro-4-((1-(dimethylamino)cyclobutyl)methyl)amino)-8-fluoro-2-((2R, 7aS) of the compound Synthesis of -2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example 187 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-8-fluoro-2-( Synthesis of (2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-aminobenzo[b]thiophene-3-carbonitrile
  • Example 188 Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-2-((2-( Difluoromethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-2-aminobenzo[b]thiophene-3-carbonitrile Synthesis
  • the KRas-G12D mutant tumor cell AGS ( CRL-1739 TM ) were spread in a low-adsorption 96-well plate at a cell density of 1 ⁇ 10 3 /well, and placed in a cell culture incubator for overnight culture.
  • the compounds to be tested were added to the 96-well plate at the final concentrations of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, and 0 nM (the final concentration of DMSO was 0.5%), and incubated at 37 °C After 96 hours, add 50 ⁇ L of Cell-titer GLO working solution to each well, shake and mix well, and incubate at room temperature for 10 minutes. Read the Luminescence luminescence value on a multi-functional microplate reader, and convert the luminescence value data into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation:
  • Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
  • Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
  • KRas-G12D mutant tumor cells AGS CRL-1739 TM
  • Panc 04.03 CRL-2555 TM
  • CRL-2555 TM Two kinds of KRas-G12D mutant tumor cells AGS ( CRL-1739 TM ) or Panc 04.03 ( CRL-2555 TM ) were plated in a 96-well plate at a cell density of 5 ⁇ 10 4 /well, and placed in a cell culture incubator for overnight culture.
  • the compounds to be tested were added to the 96-well plate according to the final concentration of 10000nM, 3333nM, 1111nM, 370.4nM, 123.4nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM, 0.51nM, 0.1% DMSO, and incubated After 3 hours, use the lysis buffer (50 ⁇ L) in the MSD (Meso Scale Discovery) electrochemiluminescence immunoassay kit to extract the protein lysate of each treated cell sample in the 96-well plate, use the BCA method to quantify the protein lysate, and use The analysis buffer dilutes the protein sample concentration to 0.1 ⁇ g/ ⁇ L.
  • MSD Meso Scale Discovery
  • p-ERK% value ((2 ⁇ phosphorylation signal value)/(phosphorylation signal value+total signal value)) ⁇ 100
  • Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
  • Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
  • the second group G2 is compound 163 single drug.
  • the third group G3 is compound 188 single drug.
  • the fourth group G4 is compound 1 single drug.
  • PO oral gavage
  • Bid administration twice a day
  • the tumor size and the body weight of the mice were measured twice a week, and each administration was referred to the body weight of the animal on the day.
  • tumor growth inhibition rate (Tumor growth inhibition) of each administration group is shown in Table 6.

Abstract

Provided are compounds represented by formula (I) having KRAS G12D modulating activity, a preparation method for said compounds, pharmaceutical compositions comprising said compounds, and a use thereof in the preparation of a medicament for treating or preventing diseases mediated by KRAS G12D.

Description

KRAS G12D抑制剂及其在医药上的应用KRAS G12D inhibitor and its application in medicine 技术领域technical field
本发明涉及一种新型化合物，其具有KRAS抑制活性，特别是KRAS G12D抑制活性。本发明还涉及这些化合物的制备方法以及包含其的药物组合物。The present invention relates to a novel compound which has KRAS inhibitory activity, especially KRAS G12D inhibitory activity. The invention also relates to processes for the preparation of these compounds and pharmaceutical compositions containing them.
背景技术Background technique
临床数据显示，RAS是人类肿瘤中发生突变率最高的基因，所有肿瘤中，约20-30％有RAS突变，大约98％的胰腺癌，52％的结肠癌，43％的多发性骨髓瘤，及32％的肺腺癌中存在RAS基因突变。RAS最常见的突变方式是点突变，经常发生在12、13、61密码子，其中又以第12位密码子突变最常见，例如G12C、G12D或G12V。Clinical data show that RAS is the gene with the highest mutation rate in human tumors. About 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, 43% of multiple myeloma, And 32% of lung adenocarcinomas have RAS gene mutations. The most common mutation of RAS is point mutation, which often occurs at codons 12, 13, and 61, and the mutation at codon 12 is the most common, such as G12C, G12D or G12V.
目前针对KRAS突变的药物研发是当前新药研究热点之一。KRAS G12C抑制剂AMG510(WO2018217651A1)和MRTX849(WO2019099524A1)已进入后期临床阶段；而MIRATI在G12D抑制剂(WO2021041671A1)研发上进展领先。At present, the development of drugs targeting KRAS mutations is one of the current research hotspots for new drugs. KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered the late clinical stage; while MIRATI is leading the development of G12D inhibitors (WO2021041671A1).
MRTX1133是选择性和可逆KRAS-G12D抑制剂，可抑制激活和失活状态的KRAS G12D突变体细胞，但不抑制KRAS野生型肿瘤细胞，MRTX1133对KRAS G12D的特异性是野生型KRAS的1000倍以上。MRTX1133的半衰期超过24小时，没有潜在hERG活性，相对比较安全。目前MRTX1133仍处于临床前研究阶段，是否可以成药还具有极大的不确定性，因此有必要对KRAS-G12D抑制剂进行更多的深入研究，同时MRTX1133因其具有多个手性中心，其拆分合成成本较高，生产工艺较复杂。MRTX1133 is a selective and reversible KRAS-G12D inhibitor, which can inhibit KRAS G12D mutant cells in activated and inactive states, but not KRAS wild-type tumor cells. The specificity of MRTX1133 for KRAS G12D is more than 1000 times that of wild-type KRAS . MRTX1133 has a half-life of more than 24 hours, has no potential hERG activity, and is relatively safe. At present, MRTX1133 is still in the preclinical research stage, and there is great uncertainty about whether it can be made into a drug. Therefore, it is necessary to conduct more in-depth research on KRAS-G12D inhibitors. At the same time, because MRTX1133 has multiple chiral centers, its disassembly The synthesis cost is higher, and the production process is more complicated.
发明内容Contents of the invention
本发明提供了一种通式(I)所示的化合物，或其立体异构体、互变异构体、氘代物或药用盐，所述式(I)结构为：The present invention provides a compound represented by the general formula (I), or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, the structure of the formula (I) is:
Figure PCTCN2022127912-appb-000001
Figure PCTCN2022127912-appb-000001
其中，in,
A为选自CR 6或N；R 6选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或3-6元杂环基任选地被一个或多个R a取代； A is selected from CR 6 or N; R 6 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N( R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , - S(R a ) 5 , -C(=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl are optionally substituted by one or more R a ;
B为选自CR 7或N；R 7选自H、氰基、羟基、卤素、C 1-6烷基或C 1-6烷氧基，所述C 1- 6烷基或C 1-6烷氧基任选地被一个或多个选自卤素、氰基、氧代基、羟基、氨基或C 1-6烷氧基的取代基所取代； B is selected from CR 7 or N; R 7 is selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 Alkoxy is optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C alkoxy ;
R 1选自
Figure PCTCN2022127912-appb-000002
其中R 13选自H、羟基、氰基、卤素或C 1-3烷基，所述C 1-3烷基任选地被一个或多个选自卤素、羟基或氰基的取代基所取代；R 13优选为H；其中R 14选自羟基、卤素、氰基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基，所述C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地被一个或多个R b取代； R 1 is selected from
Figure PCTCN2022127912-appb-000002
Wherein R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano R 13 is preferably H; wherein R 14 is selected from hydroxyl, halogen, cyano, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, The C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl are optionally substituted by one or more R b ;
X 1选自CR 8或N；R 8选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基或C 3-6环烷基任选地被一个或多个R a取代； X 1 is selected from CR 8 or N; R 8 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, - OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , - C(=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl or C 3-6 cycloalkyl is optionally substituted by one or more R ;
X 2选自CR 9或N；R 9选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6卤代烷氧基； X 2 is selected from CR 9 or N; R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
X 3选自CH或N； X3 is selected from CH or N;
X 4选自CH或N； X is selected from CH or N;
X 5选自O或S； X is selected from O or S;
L选自键、-O-C 0-8亚烷基、-S-C 0-8亚烷基、-NH-C 0-8亚烷基或C 2-8亚炔基，所述-O-C 0- 8亚烷基、-S-C 0-8亚烷基、-NH-C 0-8亚烷基或C 2-8亚炔基任选地被一个或多个R 10取代；R 10选自H、卤素、氰基、羟基或C 1-6烷基，或者同一个碳原子上的两个R 10连同其连接的原子共同形成C 3-6环烷基； L is selected from a bond, -OC 0-8 alkylene , -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene, the -OC 0-8 alkylene Alkyl, -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene is optionally substituted by one or more R 10 ; R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to them form a C 3-6 cycloalkyl group;
R 2选自H、卤素、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a、-C(＝O)N(R a) 2、
Figure PCTCN2022127912-appb-000003
C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14 元杂芳基，所述C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地进一步被一个或多个R 11取代；R 11选自H、卤素、氰基、C 1-6烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基、-C 0-6亚烷基-(5-14元杂芳基)、＝O、＝S、
Figure PCTCN2022127912-appb-000004
＝NCH 3，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基、-C 0- 6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代； R 2 is selected from H, halogen, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N (R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 ,
Figure PCTCN2022127912-appb-000003
C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the C 1-6 alkyl, C 3- 14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl are optionally further substituted by one or more R 11 ; R 11 is selected from H, halogen, cyano , C 1-6 alkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N (R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0- 6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0- 6 alkylene-C(=O)R a , -C 0-6 alkylene-C(=O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene -C 3-14 cycloalkyl, -C 0-6 alkylene - (3-14 membered heterocyclyl) , -C 0-6 alkylene-C 6-14 aryl, -C 0-6 alkylene-(5-14 membered heteroaryl), =O, =S,
Figure PCTCN2022127912-appb-000004
= NCH 3 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene, -C 0-6 alkylene-C 3-14 cycloalkane Base, -C 0-6 alkylene-(3-14 membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 Member heteroaryl) optionally can also be substituted by 1 or more R a ;
R 3选自H、卤素、C 1-6烷基或-OR 12，所述R 12选自C 1-6烷基或C 3-8环烷基，R 12任选地被一个或多个选自羟基、卤素、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或环丙基的取代基所取代； R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
R 4选自H、氰基、羟基、卤素、C 1-6烷基或C 1-6烷氧基，所述C 1-6烷基或C 1-6烷氧基任选地被一个或多个选自卤素、氰基、氧代基、羟基、氨基或C 1-6烷氧基的取代基所取代； R 4 is selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, and the C 1-6 alkyl or C 1-6 alkoxy is optionally replaced by one or Replaced by multiple substituents selected from halogen, cyano, oxo, hydroxyl, amino or C 1-6 alkoxy;
R 5选自H、C 1-6烷基或C 3-14环烷基，所述C 1-6烷基或C 3-14环烷基任选地被一个或多个选自卤素、氰基、氧代基、羟基或C 1-6烷氧基的取代基所取代； R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituents of radicals, oxo groups, hydroxyl groups or C 1-6 alkoxyl groups;
每个R a各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6杂烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基； Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
每个R b各自独立地选自羟基、C 1-3烷基、3-8元杂环基、-N(R a) 2、-CH 2N(R a) 2； Each R b is independently selected from hydroxyl, C 1-3 alkyl, 3-8 membered heterocyclyl, -N(R a ) 2 , -CH 2 N(R a ) 2 ;
R c和R d各自独立选自H、卤素、C 0-3亚烷基C 3-6环烷基、C 0-3亚烷基C 6-8芳基、C 1-6烷基或C 1-6卤代烷基；或者，R c和R d与其连接的碳原子一起形成3-8元的杂环基或C 3-8的环烷基； R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
m、n各自独立地选自0、1、2、3或4。m and n are each independently selected from 0, 1, 2, 3 or 4.
本发明的一些实施方式，式(I)所示的化合物具有如下通式(II)结构：In some embodiments of the present invention, the compound represented by formula (I) has the following general formula (II) structure:
Figure PCTCN2022127912-appb-000005
Figure PCTCN2022127912-appb-000005
其中，in,
X 1选自CR 8或N；R 8选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基或C 3-6环烷基任选地被一个或多个R a取代； X 1 is selected from CR 8 or N; R 8 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, - OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , - C(=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl or C 3-6 cycloalkyl is optionally substituted by one or more R ;
X 2选自CR 9或N；R 9选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6卤代烷氧基； X 2 is selected from CR 9 or N; R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
X 3选自CH或N； X3 is selected from CH or N;
X 4选自CH或N； X is selected from CH or N;
X 5选自O或S； X is selected from O or S;
L选自键、-O-C 0-8亚烷基、-S-C 0-8亚烷基、-NH-C 0-8亚烷基或C 2-8亚炔基，所述-O-C 0- 8亚烷基、-S-C 0-8亚烷基、-NH-C 0-8亚烷基或C 2-8亚炔基任选地被一个或多个R 10取代；R 10选自H、卤素、氰基、羟基或C 1-6烷基，或者同一个碳原子上的两个R 10连同其连接的原子共同形成C 3-6环烷基； L is selected from a bond, -OC 0-8 alkylene , -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene, the -OC 0-8 alkylene Alkyl, -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene is optionally substituted by one or more R 10 ; R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to them form a C 3-6 cycloalkyl group;
R 1选自
Figure PCTCN2022127912-appb-000006
其中R 13选自H、羟基、氰基、卤素或C 1-3烷基，所述C 1-3烷基任选地被一个或多个选自卤素、羟基或氰基的取代基所取代；R 13优选为H；其中R 14选自羟基、卤素、氰基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基，所述C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地被一个或多个R b取代； R 1 is selected from
Figure PCTCN2022127912-appb-000006
Wherein R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano R 13 is preferably H; wherein R 14 is selected from hydroxyl, halogen, cyano, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, The C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl are optionally substituted by one or more R b ;
R 2选自H、卤素、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a、-C(＝O)N(R a) 2、
Figure PCTCN2022127912-appb-000007
C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基，所述C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地 进一步被一个或多个R 11取代；R 11选自H、卤素、氰基、C 1-6烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基、-C 0-6亚烷基-(5-14元杂芳基)、＝O、＝S、
Figure PCTCN2022127912-appb-000008
＝NCH 3，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基、-C 0- 6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代； R 2 is selected from H, halogen, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N (R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 ,
Figure PCTCN2022127912-appb-000007
C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the C 1-6 alkyl, C 3- 14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl are optionally further substituted by one or more R 11 ; R 11 is selected from H, halogen, cyano , C 1-6 alkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N (R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0- 6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0- 6 alkylene-C(=O)R a , -C 0-6 alkylene-C(=O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene -C 3-14 cycloalkyl, -C 0-6 alkylene - (3-14 membered heterocyclyl) , -C 0-6 alkylene-C 6-14 aryl, -C 0-6 alkylene-(5-14 membered heteroaryl), =O, =S,
Figure PCTCN2022127912-appb-000008
= NCH 3 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene, -C 0-6 alkylene-C 3-14 cycloalkane Base, -C 0-6 alkylene-(3-14 membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 Member heteroaryl) optionally can also be substituted by 1 or more R a ;
R 3选自H、卤素、C 1-6烷基或-OR 12，所述R 12选自C 1-6烷基或C 3-8环烷基，R 12任选地被一个或多个选自羟基、卤素、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或环丙基的取代基所取代； R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
R 4或R 7各自独立地选自H、氰基、羟基、卤素、C 1-6烷基或C 1-6烷氧基，所述C 1-6烷基或C 1-6烷氧基任选地被一个或多个选自卤素、氰基、氧代基、羟基、氨基或C 1-6烷氧基的取代基所取代； R 4 or R 7 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C 1-6 alkoxy;
R 5选自H、C 1-6烷基或C 3-14环烷基，所述C 1-6烷基或C 3-14环烷基任选地被一个或多个选自卤素、氰基、氧代基、羟基或C 1-6烷氧基的取代基所取代； R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituents of radicals, oxo groups, hydroxyl groups or C 1-6 alkoxyl groups;
R 6选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或3-6元杂环基任选地被一个或多个R a取代； R 6 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S (O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C (=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Base, C 3-6 cycloalkyl or 3-6 membered heterocyclyl are optionally substituted by one or more R a ;
每个R a各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6杂烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基； Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
每个R b各自独立地选自羟基、C 1-3烷基、3-8元杂环基、-N(R a) 2、-CH 2N(R a) 2； Each R b is independently selected from hydroxyl, C 1-3 alkyl, 3-8 membered heterocyclyl, -N(R a ) 2 , -CH 2 N(R a ) 2 ;
R c和R d各自独立选自H、卤素、C 0-3亚烷基C 3-6环烷基、C 0-3亚烷基C 6-8芳基、C 1-6烷基或C 1-6卤代烷基；或者，R c和R d与其连接的碳原子一起形成3-8元的杂环基或C 3-8的环烷基； R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
m、n各自独立地选自0、1、2或3。m and n are each independently selected from 0, 1, 2 or 3.
本发明的一些实施方式，式(I)所示的化合物具有如下通式(III)结构：In some embodiments of the present invention, the compound represented by formula (I) has the following structure of general formula (III):
Figure PCTCN2022127912-appb-000009
Figure PCTCN2022127912-appb-000009
其中，in,
X 1选自CR 8或N；R 8选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基或C 3-6环烷基任选地被一个或多个R a取代； X 1 is selected from CR 8 or N; R 8 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, - OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , - C(=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl or C 3-6 cycloalkyl is optionally substituted by one or more R ;
X 2选自CR 9或N；R 9选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6卤代烷氧基； X 2 is selected from CR 9 or N; R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
X 3选自CH或N； X3 is selected from CH or N;
X 4选自CH或N； X is selected from CH or N;
X 5选自O或S； X is selected from O or S;
L选自键、-O-C 0-4亚烷基、-S-C 0-4亚烷基、-NH-C 0-4亚烷基或C 2-4亚炔基，所述-O-C 0- 4亚烷基、-S-C 0-4亚烷基、-NH-C 0-4亚烷基或C 2-4亚炔基任选地被一个或多个R 10取代；R 10选自H、卤素、氰基、羟基或C 1-6烷基，或者同一个碳原子上的两个R 10连同其连接的原子共同形成3-6元环烷基； L is selected from a bond, -OC 0-4 alkylene , -SC 0-4 alkylene, -NH-C 0-4 alkylene or C 2-4 alkynylene, the -OC 0-4 alkylene Alkyl, -SC 0-4 alkylene, -NH-C 0-4 alkylene or C 2-4 alkynylene is optionally substituted by one or more R 10 ; R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to it form a 3-6 membered cycloalkyl group;
R 13选自H、羟基、氰基、卤素或C 1-3烷基，所述C 1-3烷基任选地被一个多个选自卤素、羟基或氰基的取代基所取代；优选R 1为H； R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano; preferably R1 is H;
R 2选自H、卤素、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a、-C(＝O)N(R a) 2、
Figure PCTCN2022127912-appb-000010
C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6- 14芳基或5-14元杂芳基，所述C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地进一步被一个或多个R 11取代；R 11选自H、卤素、氰基、C 1-6烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2- 6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基、-C 0-6亚烷基-(5-14元杂芳基)、＝S、
Figure PCTCN2022127912-appb-000011
＝NCH 3，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代； R 2 is selected from H, halogen, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N (R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 ,
Figure PCTCN2022127912-appb-000010
C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the C 1-6 alkyl, C 3- 14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl are optionally further substituted by one or more R 11 ; R 11 is selected from H, halogen, cyano , C 1-6 alkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N (R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0- 6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0- 6 alkylene-C(=O)R a , -C 0-6 alkylene-C(=O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl , C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl) , -C 0-6 alkylene -C 6-14 aryl, -C 0-6 alkylene -(5-14 membered heteroaryl), =S,
Figure PCTCN2022127912-appb-000011
= NCH 3 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene, -C 3-14 cycloalkyl, -C 0-6 alkylene Alkyl-(3-14 membered heterocyclic group),-C 0-6 alkylene-C 6-14 aryl or-C 0-6 alkylene-(5-14 membered heteroaryl) optionally It can also be replaced by 1 or more R a ;
R 3选自H、卤素、C 1-6烷基或-OR 12，所述R 12选自C 1-6烷基或C 3-8环烷基，R 12任选地被一个或多个选自羟基、卤素、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或环丙基的取代基所取代； R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
R 4或R 7各自独立地选自H、氰基、羟基、卤素、C 1-6烷基或C 1-6烷氧基，所述C 1-6烷基或C 1-6烷氧基任选地被一个或多个选自卤素、氰基、氧代基、羟基、氨基或C 1-6烷氧基的取代基所取代； R 4 or R 7 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C 1-6 alkoxy;
R 5选自H、C 1-6烷基或C 3-14环烷基，所述C 1-6烷基或C 3-14环烷基任选地被一个或多个选自卤素、氰基、氧代基、羟基或C 2-6烷氧基的取代基所取代； R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituent group, oxo group, hydroxyl group or C 2-6 alkoxyl group;
R 6选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或3-6元杂环基任选地被一个或多个R a取代； R 6 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S (O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C (=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Base, C 3-6 cycloalkyl or 3-6 membered heterocyclyl are optionally substituted by one or more R a ;
每个R a各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6杂烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基； Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
R c和R d各自独立选自H、卤素、C 0-3亚烷基C 3-6环烷基、C 0-3亚烷基C 6-8芳基、C 1-6烷基或C 1-6卤代烷基；或者，R c和R d与其连接的碳原子一起形成3-8元的杂环基或C 3-8的环烷基； R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
m选自0、1、2或3。m is selected from 0, 1, 2 or 3.
本发明的一些实施方式，通式(III)结构中，所述R 2选自H、卤素、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a、-C(＝O)N(R a) 2、C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基，所述C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地进一步被一个或多个R 11取代；R 11选自H、卤素、氰基、C 1-6烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代。 In some embodiments of the present invention, in the structure of general formula (III), the R 2 is selected from H, halogen, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , - NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O) R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N (R a ) 2 , C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl are optionally further substituted by one or more R 11 ; R 11 is selected from H, halogen, cyano, C 1-6 alkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0- 6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S( =O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5. -C 0-6 alkylene-C(=O)R a , -C 0-6 alkylene-C(=O)OR a , -C 0-6 alkylene-C(=O) N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3- 14-membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl), the C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene -C 3-14 cycloalkyl, -C 0-6 alkylene - (3-14 membered heterocyclyl) , -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl) can optionally be substituted by one or more R a .
本发明的一些实施方式，式(I)所示的化合物具有如下式(IV)结构：In some embodiments of the present invention, the compound represented by formula (I) has the following structure of formula (IV):
Figure PCTCN2022127912-appb-000012
Figure PCTCN2022127912-appb-000012
其中，in,
X 1选自CR 8或N；R 8选自H、氨基、取代的氨基、氰基、C 1-6烷基、取代的C 1-6烷基、卤素、C 2-6烯基、取代的C 2-6烯基、C 3-6环烷基或取代的C 3-6环烷基； X 1 is selected from CR 8 or N; R 8 is selected from H, amino, substituted amino, cyano, C 1-6 alkyl, substituted C 1-6 alkyl, halogen, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl;
B选自CR 7或N；R 7选自H、卤素、氰基或C 1-6烷基； B is selected from CR 7 or N; R 7 is selected from H, halogen, cyano or C 1-6 alkyl;
X 2选自CR 9或N；R 9选自H、卤素、羟基、C 1-6烷氧基、氰基或C 1-6烷基； X 2 is selected from CR 9 or N; R 9 is selected from H, halogen, hydroxyl, C 1-6 alkoxy, cyano or C 1-6 alkyl;
A选自CR 6或N；R 6选自H、卤素、氰基或C 1-6烷基； A is selected from CR 6 or N; R 6 is selected from H, halogen, cyano or C 1-6 alkyl;
L选自键、O、S、NR 10、-O-C 1-4亚烷基或C 2-4亚炔基，所述-O-C 1-4亚烷基或C 2-4亚炔基任选地被一个或多个R 10取代；R 10选自H、卤素、氰基、羟基或C 1-6烷基，或者同一个碳原子上的两个R 10连同其连接的原子共同形成3-6元环烷基； L is selected from bond, O, S, NR 10 , -OC 1-4 alkylene or C 2-4 alkynylene, said -OC 1-4 alkylene or C 2-4 alkynylene optionally Substituted by one or more R 10 ; R 10 is selected from H, halogen, cyano, hydroxyl or C 1-6 alkyl, or two R 10 on the same carbon atom together with the atoms connected to form 3-6 Cycloalkyl;
R 13选自H、羟基、氰基、卤素或C 1-3烷基，所述C 1-3烷基任选地被一个多个选自卤素、羟基或氰基的取代基所取代；优选R 13为H； R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano; preferably R 13 is H;
R 2选自-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a、-C(＝O)N(R a) 2、环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选地进一步被一个或多个R 11取代； R 2 is selected from -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2. -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , cycloalkyl, heterocyclyl, aryl or heteroaryl, The cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R 11 ;
R 11选自H、氰基、卤素、C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代；每个R a各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6杂烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基； R 11 is selected from H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O) N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene- NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0 -6alkylene -S(R a ) 5 , -C 0-6alkylene -C(=O)R a , -C 0-6alkylene -C(=O)OR a , -C 0 -6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkyl, - C 0-6 alkylene-(3-14 membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl base), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene -C 3-14 cycloalkyl, -C 0-6 alkylene Base-(3-14 membered heterocyclic group),-C 0-6 alkylene-C 6-14 aryl or-C 0-6 alkylene-(5-14 membered heteroaryl) optionally also Can be substituted by 1 or more R a ; each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1 -6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 heteroalkyl , C 3-8 ring Alkyl, 3-8 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl;
R 3选自H、卤素、C 1-6烷基或-OR 12，所述R 12选自C 1-6烷基或C 3-8环烷基，R 12任选地被一个或多个选自羟基、卤素、C 1-3烷基、C 1-3烷氧基或环丙基的取代基所取代； R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 alkoxy or cyclopropyl;
R 4或R 5各自独立地选自H、氰基、羟基、卤素、C 1-6烷基或C 2-6烷氧基，所述C 1-6烷基或C 2-6烷氧基任选地被一个或多个选自卤素、氰基、氧代基、羟基或C 2-6烷氧基的取代基所取代； R 4 or R 5 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 2-6 alkoxy, the C 1-6 alkyl or C 2-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxyl or C2-6alkoxy ;
m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
本发明的一些实施方式，式(IV)结构中，所述X 2选自CR 9或N；R 9选自H、卤素、氰基或C 1-6烷基； In some embodiments of the present invention, in the structure of formula (IV), the X 2 is selected from CR 9 or N; R 9 is selected from H, halogen, cyano or C 1-6 alkyl;
R 2选自环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选地进一步被一个或多个R 11取代； R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R ;
R 11选自H、氰基、卤素、C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代；每个R a各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6杂烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基。 R 11 is selected from H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O) N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene- NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0 -6alkylene -S(R a ) 5 , -C 0-6alkylene -C(=O)R a , -C 0-6alkylene -C(=O)OR a , -C 0 -6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkyl, - C 0-6 alkylene-(3-14 membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl base), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene -C 3-14 cycloalkyl, -C 0-6 alkylene Base-(3-14 membered heterocyclic group),-C 0-6 alkylene-C 6-14 aryl or-C 0-6 alkylene-(5-14 membered heteroaryl) optionally also Can be substituted by 1 or more R a ; each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1 -6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 heteroalkyl , C 3-8 ring Alkyl, 3-8 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl.
本发明的一些实施方式，通式(I)、(II)、(III)或(IV)中，所述X 1选自CR 8或N；R 8选自H、卤素、CN、-SR a、-C(＝O)R a、-C(＝O)OR a、-C(＝O)N(R a) 2、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或C 3-6环烷基；R a各自独立地选自H或C 1-6烷基。 Some embodiments of the present invention, in the general formula (I), (II), (III) or (IV), the X 1 is selected from CR 8 or N; R 8 is selected from H, halogen, CN, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 Alkoxy or C 3-6 cycloalkyl; R a each independently selected from H or C 1-6 alkyl.
本发明的一些实施方式，通式(I)、(II)、(III)或(IV)中，所述X 2选自CR 9或N；R 9为氰基。 In some embodiments of the present invention, in the general formula (I), (II), (III) or (IV), the X 2 is selected from CR 9 or N; R 9 is cyano.
本发明的一些实施方式，通式(I)、(II)、(III)或(IV)中，所述L选自键、
Figure PCTCN2022127912-appb-000013
Figure PCTCN2022127912-appb-000014
优选
Figure PCTCN2022127912-appb-000015
In some embodiments of the present invention, in the general formula (I), (II), (III) or (IV), the L is selected from a bond,
Figure PCTCN2022127912-appb-000013
Figure PCTCN2022127912-appb-000014
preferred
Figure PCTCN2022127912-appb-000015
本发明的一些实施方式，通式(I)或(II)中，所述R 1选自
Figure PCTCN2022127912-appb-000016
Figure PCTCN2022127912-appb-000017
优选为
Figure PCTCN2022127912-appb-000018
Some embodiments of the present invention, in the general formula (I) or (II), the R is selected from
Figure PCTCN2022127912-appb-000016
Figure PCTCN2022127912-appb-000017
preferably
Figure PCTCN2022127912-appb-000018
本发明的一些实施方式，通式(I)、(II)、(III)或(IV)中，所述R 2选自H、-N(R a) 2、-C(＝O)OR a、-C(＝O)N(R a) 2、C 3-8环烷基、 In some embodiments of the present invention, in the general formula (I), (II), (III) or (IV), the R 2 is selected from H, -N(R a ) 2 , -C(=O)OR a , -C(=O)N(R a ) 2 , C 3-8 cycloalkyl,
Figure PCTCN2022127912-appb-000019
Figure PCTCN2022127912-appb-000020
所述
Figure PCTCN2022127912-appb-000019
Figure PCTCN2022127912-appb-000020
said
Figure PCTCN2022127912-appb-000021
Figure PCTCN2022127912-appb-000021
任选地被一个或多个选自H、卤素、羟基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷基氧、3-8元杂环基、
Figure PCTCN2022127912-appb-000022
-N(R a) 2、-C 0-3亚烷基-SR a、＝O、＝S、＝CH 2、＝CHF、＝CF 2、＝NCH 3的取代基所取代；每个R a各自独立地选自H、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基。 Optionally replaced by one or more selected from H, halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyloxy, 3-8 membered heterocyclyl,
Figure PCTCN2022127912-appb-000022
Substituents of -N(R a ) 2 , -C 0-3 alkylene-SR a , =O, =S, =CH 2 , =CHF, =CF 2 , =NCH 3 ; each R a Each independently selected from H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkane Oxygen, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl.
本发明的一些实施方式，通式(I)、(II)、(III)或(IV)中，所述R 3选自H、卤素或-OR 12，所述R 12选自C 1-6烷基、C 1-6卤代烷基或C 3-8环烷基。 In some embodiments of the present invention, in the general formula (I), (II), (III) or (IV), the R 3 is selected from H, halogen or -OR 12 , and the R 12 is selected from C 1-6 Alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl.
本发明的一些实施方式，通式(I)、(II)、(III)或(IV)中，所述R 4选自H、卤素或C 1-6烷基。 In some embodiments of the present invention, in the general formula (I), (II), (III) or (IV), the R 4 is selected from H, halogen or C 1-6 alkyl.
本发明的一些实施方式，通式(I)、(II)、(III)或(IV)中，所述R 5选自H或C 1-6烷基；优选为H。 In some embodiments of the present invention, in the general formula (I), (II), (III) or (IV), the R 5 is selected from H or C 1-6 alkyl; preferably H.
本发明的一些实施方式，通式(I)、(II)、(III)或(IV)中，所述R 6选自CN、-SR a、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或C 3-6环烷基；R a各自独立地选自H或C 1-6烷基；优选R 6为CN。 Some embodiments of the present invention, in the general formula (I), (II), (III) or (IV), the R 6 is selected from CN, -SR a , -C(=O)R a , -C( =O)OR a or -C(=O)N(R a ) 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 3-6 cycloalkyl; R a is each independently selected from H or C 1-6 alkyl; preferably R 6 is CN.
本发明的一些实施方式，通式(I)、(II)、(III)或(IV)中，所述R 7选自H、卤素或C 1-6烷基；优选为H。 In some embodiments of the present invention, in the general formula (I), (II), (III) or (IV), the R 7 is selected from H, halogen or C 1-6 alkyl; preferably H.
本发明的一些实施方式，通式(I)、(II)、(III)或(IV)中，所述m选自1或2；优选为1。In some embodiments of the present invention, in the general formula (I), (II), (III) or (IV), the m is selected from 1 or 2; preferably 1.
本发明的一些实施方式，通式(I)、(II)、(III)或(IV)中，所述n选自1或2；优选为1。In some embodiments of the present invention, in the general formula (I), (II), (III) or (IV), the n is selected from 1 or 2; preferably 1.
在本发明的一些实施方式中，式(I)所示的化合物具有如下的式(IA)或(IB)结构：In some embodiments of the present invention, the compound represented by formula (I) has the following formula (IA) or (IB) structure:
Figure PCTCN2022127912-appb-000023
Figure PCTCN2022127912-appb-000023
优选为preferably
Figure PCTCN2022127912-appb-000024
Figure PCTCN2022127912-appb-000024
其中，各取代基如同式(I)中所定义。Wherein, each substituent is as defined in formula (I).
在本发明的一些实施方式中，式(I)所示的化合物具有如下式(IC)或(ID)结构：In some embodiments of the present invention, the compound represented by formula (I) has the following formula (IC) or (ID) structure:
Figure PCTCN2022127912-appb-000025
Figure PCTCN2022127912-appb-000025
优选为preferably
Figure PCTCN2022127912-appb-000026
Figure PCTCN2022127912-appb-000026
更优选为more preferably
Figure PCTCN2022127912-appb-000027
Figure PCTCN2022127912-appb-000027
其中，各取代基的定义同式(IV)中所定义。Wherein, the definition of each substituent is the same as defined in formula (IV).
在本发明的一些实施方式中，式(I)所示的化合物具有如下的式(IC-3)结构：In some embodiments of the present invention, the compound represented by formula (I) has the following formula (IC-3) structure:
Figure PCTCN2022127912-appb-000028
Figure PCTCN2022127912-appb-000028
其中，in,
R 13选自H； R 13 is selected from H;
R 3选自H、C 1-6烷基或卤素； R 3 is selected from H, C 1-6 alkyl or halogen;
R 4选自H、氰基、羟基或卤素； R is selected from H, cyano, hydroxyl or halogen;
R 8选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、 R is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl,
R c或R d各自独立选自H、卤素、C 0-3亚烷基C 3-6环烷基、C 0-3亚烷基C 6-8芳基、C 1-6烷基或C 1-6卤代烷基；或者，R c和R d与其连接的碳原子一起形成3-8元的杂环基或C 3-8的环烷基； R c or R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
在本发明的一些实施方式中，式(IC-3)所述结构中，所述
Figure PCTCN2022127912-appb-000029
选自
Figure PCTCN2022127912-appb-000030
Figure PCTCN2022127912-appb-000031
In some embodiments of the present invention, in the structure described in formula (IC-3), the
Figure PCTCN2022127912-appb-000029
selected from
Figure PCTCN2022127912-appb-000030
Figure PCTCN2022127912-appb-000031
在本发明的一些实施方式中，式(IC-3)所述结构中，所述
Figure PCTCN2022127912-appb-000032
选自
Figure PCTCN2022127912-appb-000033
Figure PCTCN2022127912-appb-000034
In some embodiments of the present invention, in the structure described in formula (IC-3), the
Figure PCTCN2022127912-appb-000032
selected from
Figure PCTCN2022127912-appb-000033
Figure PCTCN2022127912-appb-000034
本发明中的烯烃结构，对比于
Figure PCTCN2022127912-appb-000035
手性氟原子结构，不仅减少了手性中心，其合成工艺简单，生产成本大幅降低，有利于工业化大生产，而且其中一些化合物如
Figure PCTCN2022127912-appb-000036
等，其KRAS G12D活性普遍高于手性氟化合物。 The alkene structure in the present invention, compares with
Figure PCTCN2022127912-appb-000035
The chiral fluorine atom structure not only reduces the chiral center, but also has a simple synthesis process and greatly reduces production costs, which is conducive to large-scale industrial production, and some of the compounds such as
Figure PCTCN2022127912-appb-000036
etc., the activity of KRAS G12D is generally higher than that of chiral fluorine compounds.
在本发明的一些实施方式中，通式(I)、(II)、(III)或(IV)中，所述化合物选自：In some embodiments of the present invention, in general formula (I), (II), (III) or (IV), the compound is selected from:
Figure PCTCN2022127912-appb-000037
Figure PCTCN2022127912-appb-000037
Figure PCTCN2022127912-appb-000038
Figure PCTCN2022127912-appb-000038
Figure PCTCN2022127912-appb-000039
Figure PCTCN2022127912-appb-000039
Figure PCTCN2022127912-appb-000040
Figure PCTCN2022127912-appb-000040
本发明还提供了一种药物组合物，其中，所述药物组合物包括式(I)所示化合物、或其立体异构体、互变异构体、氘代物或药用盐，任选地进一步包括药学上可接受的辅料。The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound represented by formula (I), or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, optionally Further include pharmaceutically acceptable auxiliary materials.
本发明提供了式(I)所示化合物、或其立体异构体、互变异构体、氘代物或药用盐，或其药物组合物在制备药物中的应用。The present invention provides the compound represented by formula (I), or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, or the application of its pharmaceutical composition in the preparation of medicine.
作为优选，所述制备药物中的应用为在制备治疗和/或预防癌症的药物中的应用。Preferably, the application in the preparation of medicaments is the application in the preparation of medicaments for treating and/or preventing cancer.
作为优选，所述制备药物中的应用为在制备用于治疗和/或预防由KRAS G12D介导的疾病的药物中的应用。Preferably, the application in the preparation of the medicament is the application in the preparation of a medicament for treating and/or preventing diseases mediated by KRAS G12D.
作为优选，所述KRAS G12D介导的疾病是癌症。Preferably, the KRAS G12D-mediated disease is cancer.
作为优选，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
本发明还提供了一种治疗和/或预防疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物，或其立体异构体、互变异构体、氘代物或药用盐，或含其的药物组合物。The present invention also provides a method for treating and/or preventing diseases, comprising administering a therapeutically effective amount of at least one compound represented by structural formula (I), or its stereoisomers, tautomers, Deuterated substances or pharmaceutically acceptable salts, or pharmaceutical compositions containing them.
本发明还提供了一种治疗和/或预防由KRAS G12D介导的疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物，或其立体异构体、互变异构体、氘代物或药用盐，或含其的药物组合物。The present invention also provides a method for treating and/or preventing diseases mediated by KRAS G12D, comprising administering a therapeutically effective amount of at least one compound represented by structural formula (I), or its stereoisomer, Tautomers, deuterated substances or pharmaceutically acceptable salts, or pharmaceutical compositions containing them.
本发明还提供了一种治疗癌症的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示，或其立体异构体、互变异构体、氘代物或药用盐，或含其的药物组合物。The present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any one represented by structural formula (I), or its stereoisomers, tautomers, deuteriums, or medicinal salt, or a pharmaceutical composition containing it.
作为优选，在上述方法中，所述KRAS G12D介导的疾病是癌症。Preferably, in the above method, the KRAS G12D-mediated disease is cancer.
作为优选，在上述方法中，所述的癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增 生异常综合征、恶性胶质瘤、***癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatocholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
除非另有说明，所述结构通式中使用的一般化学术语具有通常的含义。Unless otherwise stated, general chemical terms used in the structural formulae have their usual meanings.
例如，除非另有说明，本发明所用的术语“卤素”是指氟、氯、溴或碘。For example, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine, unless otherwise specified.
在本发明中，除非另有说明，“烷基”包括直链或支链的一价饱和烃基。例如，烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的，“C 1-6烷基”中的“1-6”是指包含有1、2、3、4、5或6个碳原子的直链或支链形式排列的基团。 In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and the like. Similarly, "1-6" in "C 1-6 alkyl" refers to a group comprising 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain.
术语“亚烷基”是指二价烷基连接基团。亚烷基在形式上是指两个C-H键替换为亚烷基与化合物其余部分的连接点的烷烃。类似的，C 1-6亚烷基中的“C 1-6”是指含有1、2、3、4、5或6个碳原子的亚烷基，包括但不限于亚甲基、1,2-亚乙基、1,3-亚丙基或1,2-亚异丙基。 The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which the two CH bonds are replaced by the point of attachment of the alkylene to the rest of the compound. Similarly, "C 1-6 " in C 1-6 alkylene refers to an alkylene group containing 1, 2, 3, 4, 5 or 6 carbon atoms, including but not limited to methylene, 1, 2-ethylene, 1,3-propylene or 1,2-isopropylidene.
术语“烷氧基”是指前述的直链或支链烷基的氧醚形式，即-O-烷基。The term "alkoxy" refers to the oxygen ether form of the aforementioned linear or branched alkyl, ie -O-alkyl.
术语“芳基”，在本发明中，除非另有说明，是指未取代或取代的包括6-14元单环或稠环芳香基团。优选芳基为6到10元的单环或双环的芳香环基团。优选为苯基、萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基上，其中与母体结构连接在一起的环为芳基环，非限制性实例包括但不限于苯并环戊基。The term "aryl" in the present invention, unless otherwise stated, refers to an unsubstituted or substituted aromatic group including 6-14 membered monocyclic or condensed rings. Preferably, the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group. Preferred are phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl, where the ring bonded to the parent structure is an aryl ring, non-limiting examples include, but are not limited to, benzocyclopentyl.
术语“杂环基”，在本发明中，除非另有说明，是指由碳原子和1-3个选自N、O或S的杂原子组成的未取代或取代的稳定环***，其为饱和或部分不饱和单环或多环环状烃取代基，其包括3至14个碳原子，其中氮或硫杂原子可以选择性地被氧化，并且氮杂原子可以选择性地被季铵化。该杂环基可以被连接到任何的杂原子或碳原子上以形成稳定的结构。这些杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜基和四氢恶二唑基。所述杂环基可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。The term "heterocyclyl", in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable ring system consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is Saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents comprising 3 to 14 carbon atoms, wherein the nitrogen or sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatoms may be optionally quaternized . The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro Oxadiazolyl. The heterocyclyl may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring bonded to the parent structure is the heterocyclyl.
术语“杂芳基”，在本发明中，除非另有说明，是指未取代或取代的稳定的5元或6元单环芳族环***或未取代或取代的9元-14元苯并稠合杂芳族环***或多环杂芳族环***，其由碳原子和1-4个选自N、O或S的杂原子组成，并且其中所述氮或硫杂原子可以选择性地被氧化，所述氮杂原子可以选择性地被季铵化。杂芳基可以连接在任何杂原子或 碳原子上以形成稳定的结构。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、***基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并***基腺嘌呤、喹啉基或异喹啉基。所述杂芳基可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。The term "heteroaryl", in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- to 14-membered benzo A fused heteroaromatic ring system or a polycyclic heteroaromatic ring system consisting of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms can optionally be Being oxidized, the nitrogen heteroatoms can optionally be quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene Thiadiazolyl, benzotriazolyladenine, quinolinyl or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring where the ring attached to the parent structure is a heteroaryl ring.
术语“环烷基”是指具有3-14个碳原子的环状饱和或部分不饱和单环或多环环状烃取代基，例如，环丙基、环丁基、环戊基或环己基。所述环烷基可以稠合于芳基、杂环基或杂芳基环上，其中与母体结构连接在一起的环为环烷基。The term "cycloalkyl" refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl . The cycloalkyl group may be fused to an aryl, heterocyclyl, or heteroaryl ring where the ring bonded to the parent structure is a cycloalkyl group.
术语“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于H、氰基、卤素、C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-OR b、-C 0-6亚烷基-OC(O)N(R b) 2、-C 0-6亚烷基-N(R b) 2、-C 0-6亚烷基-NR bC(O)R b、-C 0-6亚烷基-NR bC(O)N(R b) 2、-C 0-6亚烷基-NR bS(O)R b、-C 0-6亚烷基-NR bS(O) 2R b、-C 0-6亚烷基-S(＝O)R b、-C 0-6亚烷基-S(＝O) 2R b、-C 0-6亚烷基-SR b、-C 0-6亚烷基-S(R b) 5、-C 0-6亚烷基-C(＝O)R b、-C 0-6亚烷基-C(＝O)OR b、-C 0-6亚烷基-C(＝O)N(R b) 2、
Figure PCTCN2022127912-appb-000041
C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R b所取代。每个R b各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6杂烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基。在一些实施例中，取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH 3、-SC 2H 5、甲醛基、-C(OCH 3)、氰基、硝基、-CF 3、-OCF 3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。 The term "substituted" means that one or more hydrogen atoms in the group are respectively replaced by the same or different substituents. Typical substituents include, but are not limited to, H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR b , -C 0-6 alkylene- OC(O)N(R b ) 2 , -C 0-6 alkylene-N(R b ) 2 , -C 0-6 alkylene-NR b C(O)R b , -C 0-6 Alkylene-NR b C(O)N(R b ) 2 , -C 0-6 Alkylene-NR b S(O)R b , -C 0-6 Alkylene-NR b S(O) 2 R b , -C 0-6 alkylene-S(=O)R b , -C 0-6 alkylene-S(=O) 2 R b , -C 0-6 alkylene-SR b , -C 0-6 alkylene-S(R b ) 5 , -C 0-6 alkylene-C(=O)R b , -C 0-6 alkylene-C(=O)OR b , -C 0-6 alkylene -C(=O)N(R b ) 2 ,
Figure PCTCN2022127912-appb-000041
C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl), -C 0-6 alkylene Alkyl-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl) can optionally be substituted by one or more R b . Each R b is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy Butyl, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl Amino, methylthio, sulfonyl and acetyl groups.
当一个连接基团的数量为0时，比如-(CH 2) 0-表示该连接基团为键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
当本发明提供的化合物是酸时，可以从药学上可接受的无毒的碱，包括无机碱和有机碱，方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之类的盐。特别优选铵、钙、镁、钾和 钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺，也包括环胺及含有取代基的胺，如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱，包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、异丙胺、赖氨酸，甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、氯普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (superior and subvalent), ferric, ferrous, lithium, magnesium, manganese (superior and subvalent), potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Nontoxic organic bases from which pharmaceutically acceptable salts can be derived include primary, secondary and tertiary amines, also cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine acid, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine wait.
当本发明提供的化合物是碱时，可以从药学上可接受的无毒的酸，包括无机酸和有机酸，方便制得其相应的盐。这样的酸包括，如，醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、草酸、丙酸、乙醇酸、氢碘酸、高氯酸、环己氨磺酸、水杨酸、2-萘磺酸、糖精酸、三氟乙酸、酒石酸和对甲苯磺酸等。较优地，柠檬酸、氢溴酸、甲酸、盐酸、马来酸、磷酸、硫酸和酒石酸。更优地，甲酸和盐酸。When the compound provided by the present invention is a base, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.
本发明化合物的药物前体包含在本发明的保护范围内。通常，所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。例如，本申请化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物，其在向受体施用后能够直接或间接地提供本申请的化合物或其具有药学活性的代谢物或残基。The prodrugs of the compounds of the present invention are included in the protection scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted in vivo into the desired compound. For example, any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application, which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite or Residues.
本发明所述化合物可能含有一个或多个不对称中心，并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药用盐。The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and optical isomers. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
当式(I)所示化合物存在互变异构体时，除非特别声明，本发明包括任何可能的互变异构体和其药用盐，及它们的混合物。When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and their mixtures.
当式(I)所示化合物用较重的同位素(例如氘)替代可能提供某些治疗优势，这是由于更大的代谢稳定性，例如增加体内半衰期或减少剂量要求。Substitution of compounds of formula (I) with heavier isotopes (eg deuterium) may afford certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.
术语“药物组合物”是指一种或多种本申请的化合物或其药用盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their pharmaceutically acceptable salts and pharmaceutically acceptable auxiliary materials. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
在本发明中，“一”、“一个”、“该”、“至少一个”和“一个或多个”可互换使用。因此，例如，包含“一种”药学上可接受的辅料组成的混合物可以被解释为表示该药物组合物包括“一种或多种”药学上可接受的辅料。In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient may be interpreted to mean that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
本发明的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical composition of the present invention can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
给予本发明化合物或其药用盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, Subcutaneous, intravenous administration.
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。The term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie arresting its development; or (b) relieving the symptoms of the disease, ie causing regression of the disease or symptoms.
术语“有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "effective amount" means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described in . The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
合成方案：Synthesis scheme:
Figure PCTCN2022127912-appb-000042
Figure PCTCN2022127912-appb-000042
步骤I：化合物A-1在碱性条件下如Cs 2CO 3等作用下，与
Figure PCTCN2022127912-appb-000043
经过取代反应得到化合物A-2； Step I : Compound A-1 is reacted with
Figure PCTCN2022127912-appb-000043
Obtain compound A-2 through substitution reaction;
步骤II：化合物A-2在Pd催化剂如Pd(dtbpf)Cl 2作用下，与化合物
Figure PCTCN2022127912-appb-000044
经过Suzuki偶联反应引入相应基团； Step II: compound A-2 is under the effect of Pd catalyst such as Pd(dtbpf)Cl 2 , and compound
Figure PCTCN2022127912-appb-000044
The corresponding groups were introduced through Suzuki coupling reaction;
步骤III：化合物A-3在酸性条件下如TFA的作用下，脱去TG保护基团的可得到目标化合物A。Step III: The target compound A can be obtained by removing the TG protecting group of compound A-3 under acidic conditions such as the action of TFA.
具体实施方式Detailed ways
为使上述内容更清楚、明确，本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。In order to make the above content more clear and definite, the present invention will use the following examples to further illustrate the technical solution of the present invention. The following examples are only used to illustrate specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific implementation of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art.
除非另有说明，本发明所有温度均指摄氏度。Unless otherwise stated, all temperatures herein refer to degrees Celsius.
实施例中使用了下列缩略语：The following abbreviations are used in the examples:
DABCO：三乙烯二胺；DABCO: triethylenediamine;
DBU：1,8-二氮杂二环十一碳-7-烯；、DBU: 1,8-diazabicycloundec-7-ene;,
BOP：1H-苯并***-1-基氧代三(二甲氨基)磷鎓六氟磷酸盐；BOP: 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate;
CPME：环戊基甲醚；CPME: cyclopentyl methyl ether;
m-CPBA：间氯过氧苯甲酸；m-CPBA: m-chloroperoxybenzoic acid;
DIEA：N，N-二异丙基乙胺；DIEA: N,N-Diisopropylethylamine;
DCM:二氯甲烷；DCM: dichloromethane;
Dioxane：二氧六环；Dioxane: dioxane;
ESI-MS：电喷雾电离质谱；ESI-MS: electrospray ionization mass spectrometry;
POCl 3：三氯氧磷； POCl 3 : phosphorus oxychloride;
THF：四氢呋喃；THF: Tetrahydrofuran;
TFA：三氟乙酸；TFA: trifluoroacetic acid;
Pre-TLC：制备薄层板；Pre-TLC: preparation of thin-layer plates;
DME：乙二醇二甲醚；DME: Ethylene glycol dimethyl ether;
t-BuOK：叔丁醇钾；t-BuOK: potassium tert-butoxide;
TosMIC：对甲基磺酰甲基异腈；TosMIC: p-Methylsulfonylmethylisonitrile;
DMF：N,N-二甲基甲酰胺；DMF: N,N-dimethylformamide;
DMSO：二甲亚砜；DMSO: dimethyl sulfoxide;
DMAP：4-二甲氨基吡啶；DMAP: 4-dimethylaminopyridine;
(BOC) 2O：二碳酸二叔丁酯； (BOC) 2 O: di-tert-butyl dicarbonate;
B 2Pin 2：联硼酸频那醇酯； B 2 Pin 2 : pinacol diborate;
Cs 2CO 3：碳酸铯； Cs 2 CO 3 : cesium carbonate;
Pd(dtbpf)Cl 2：二氯[1,1'-双(耳叔丁基膦)二茂铁钯(II)； Pd(dtbpf)Cl 2 : dichloro[1,1'-bis(er-tert-butylphosphine)ferrocenepalladium(II);
[PdCl 2(dppf)]CH 2Cl 2：[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物； [PdCl 2 (dppf)]CH 2 Cl 2 : [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex;
Pd(DPEPhos)Cl 2：双(二苯基膦苯基醚)二氯化钯(II)； Pd(DPEPhos)Cl 2 : bis(diphenylphosphine phenyl ether) dichloropalladium(II);
CataCXium A Pd G3:甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)；CataCXium A Pd G3: [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate;
Pre-TLC：薄层色谱分离法；Pre-TLC: thin layer chromatography;
Pre-HPLC：高效液相制备法。Pre-HPLC: high performance liquid phase preparation method.
中间体M1的合成：Synthesis of Intermediate M1:
Figure PCTCN2022127912-appb-000045
Figure PCTCN2022127912-appb-000045
步骤1：化合物M1-1的合成Step 1: Synthesis of compound M1-1
在室温下，将二(咪唑-1-基)甲酮(2.70g)加入到化合物2-氨基-4-溴-5-氯-3-氟苯甲酸(4.0g)的THF(20mL)中，再将N-乙基-N-异丙基丙-2-胺(1.4g)加入其中，混合物移至50℃反应，反应2小时。化合物2-氨基-4-溴-5-氯-3-氟苯甲酸基本完全转化为中间产物，接着将混合物逐滴加入到冰的氨水(35mL)中，搅拌5min即反应完全。将混合物倾注入冰水中，用乙酸乙酯萃取混合物，有机层用盐水洗涤，经Na 2SO 4干燥且真空浓缩，剩余物通过快速硅胶柱色谱(石油醚/乙酸乙酯＝70:30)纯化，得到褐色固体状的所要目标产物化合物M1-1(1.6g)。 Bis(imidazol-1-yl)methanone (2.70 g) was added to compound 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (4.0 g) in THF (20 mL) at room temperature, N-ethyl-N-isopropylpropan-2-amine (1.4 g) was added thereto, and the mixture was moved to 50° C. for 2 hours. The compound 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid was almost completely converted into an intermediate product, and then the mixture was added dropwise into iced ammonia water (35 mL), and stirred for 5 min to complete the reaction. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the residue was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate=70:30) , the desired target compound M1-1 (1.6 g) was obtained as a brown solid.
步骤2：化合物M1-2的合成Step 2: Synthesis of compound M1-2
将化合物M1-1与脲的混合物在200℃搅拌反应3小时。将混合物冷却至室温，用乙酸乙酯洗涤固体，将固体干燥即得所要粗品固体产物M1-2(209mg,78％产率)。The mixture of compound M1-1 and urea was stirred and reacted at 200° C. for 3 hours. The mixture was cooled to room temperature, the solid was washed with ethyl acetate, and the solid was dried to obtain the desired crude solid product M1-2 (209 mg, 78% yield).
步骤3：化合物M1-3的合成Step 3: Synthesis of compound M1-3
在室温下，将DIPEA加入到M1-2的POCl 3的溶液中，110℃回流16小时。将混合物冷却至室温，真空浓缩除去POCl 3，将残余物通过硅胶管柱色谱法(石油醚/乙酸乙酯＝100:1至50:1)纯化，得到呈棕色固体状所要产物M1-3。 At room temperature, DIPEA was added to the POCl 3 solution of M1-2, and refluxed at 110°C for 16 hours. The mixture was cooled to room temperature, concentrated in vacuo to remove POCl 3 , and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1 to 50:1) to obtain the desired product M1-3 as a brown solid.
步骤4：化合物M1的合成Step 4: Synthesis of Compound M1
在室温下，向M1-3(3.0g)溶于1,4-二氧六环(20ml)中，向溶液中添加叔丁基(1R，5S)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸盐(1.6g)及DIPEA(2.8g)，所得混合物在室温搅拌10分钟。使混合物真空浓缩，残余物通过硅胶管柱色谱法(石油醚/乙酸乙酯＝75:25至65:35)纯化，得到呈黄色固体状的所要产物M1(2.5g，57％产率)。ESI-MS m/z:505[M+H] +。 M1-3 (3.0 g) was dissolved in 1,4-dioxane (20 ml) at room temperature, and tert-butyl (1R,5S)-3,8-diazacyclo[3.2 .1] Octane-8-carboxylate (1.6 g) and DIPEA (2.8 g), and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=75:25 to 65:35) to afford the desired product M1 (2.5 g, 57% yield) as a yellow solid. ESI-MS m/z: 505 [M+H] + .
中间体M2的合成步骤：Synthetic steps of intermediate M2:
Figure PCTCN2022127912-appb-000046
Figure PCTCN2022127912-appb-000046
步骤1：化合物M2-1的合成Step 1: Synthesis of compound M2-1
在室温下，将t-BuOK(27.93g)溶于DME(100.00mL)中，在-78℃下，将TosMIC(24.29g)的DME(100.00mL)溶液加入其中，再将6-溴-2,3-二氟苯甲醛(25.00g)的DME (100.00mL)溶液加入其中，保温搅拌1h。将反应混合物直接浓缩，加水，用DCM萃取，有机相浓缩，浓缩物经柱层析(EA:PE＝0-10％)纯化分离得到白色固体状目标产物M2-1(11.0g，产率41.91％)。ESI-MS m/z:232[M+H] +。 Dissolve t-BuOK (27.93g) in DME (100.00mL) at room temperature, add TosMIC (24.29g) in DME (100.00mL) at -78°C, and add 6-bromo-2 , 3-Difluorobenzaldehyde (25.00g) in DME (100.00mL) solution was added therein, and stirred for 1h. The reaction mixture was directly concentrated, added water, extracted with DCM, the organic phase was concentrated, and the concentrate was purified and separated by column chromatography (EA:PE=0-10%) to obtain the target product M2-1 (11.0 g, yield 41.91 %). ESI-MS m/z: 232 [M+H] + .
步骤2：化合物M2-2的合成Step 2: Synthesis of compound M2-2
在室温下，将化合物M2-1(10.00g)溶于DMF(100.00mL)中，在冰浴下，将t-BuOK(5.32g)加入其中，搅拌反应10min，溶液变深红色。再将异硫氰酰甲酸乙酯(6.22g)加入其中，室温搅拌1h，移至100℃搅拌反应30min。反应完成后用冰浴降温至0℃，慢慢加入水，过滤，滤饼用水、PE洗涤，烘干，即得到目标产物M2-2(11.0g，产率74.37％)。ESI-MS m/z:343[M+H] +。 Compound M2-1 (10.00 g) was dissolved in DMF (100.00 mL) at room temperature, t-BuOK (5.32 g) was added thereto under ice-cooling, stirred for 10 min, the solution turned deep red. Ethyl isothiocyanate (6.22 g) was added thereto, stirred at room temperature for 1 h, then moved to 100° C. and stirred for 30 min. After the reaction was completed, the temperature was cooled to 0°C with an ice bath, water was slowly added, filtered, the filter cake was washed with water and PE, and dried to obtain the target product M2-2 (11.0 g, yield 74.37%). ESI-MS m/z: 343 [M+H] + .
步骤3：化合物M2-3的合成Step 3: Synthesis of compound M2-3
在室温下，将化合物M2-2(11.00g)溶于DMSO(80.00mL)，加入NaOH(12.82g)的H 2O(60.00mL)的水溶液中，100℃搅拌过夜。向反应液中加水稀释，用EA萃取。合并有机相，干燥后浓缩即可得到目标化合物M2-3(11.0g)。ESI-MS m/z:271[M+H] +。 Compound M2-2 (11.00 g) was dissolved in DMSO (80.00 mL) at room temperature, added to an aqueous solution of NaOH (12.82 g) in H 2 O (60.00 mL), and stirred at 100° C. overnight. The reaction solution was diluted with water and extracted with EA. The organic phases were combined, dried and concentrated to obtain the target compound M2-3 (11.0 g). ESI-MS m/z: 271 [M+H] + .
步骤4：化合物M2-4的合成Step 4: Synthesis of compound M2-4
在室温下，将化合物M2-3(15.00g)，DMAP(0.54g)，(BOC) 2O(13.28g)溶于THF(200.00mL)和DMF(30.00mL)中，向其中滴加DIEA(13.72mL)，室温搅拌3h。向反应中加入水，用乙酸乙酯萃取，有机相干燥，浓缩。浓缩物用EA:PE＝1:5打浆，过滤，得到黄色固体状目标化合物M2-4(7.3g，35.54％)。ESI-MS m/z:371[M+H] +。 Compound M2-3 (15.00 g), DMAP (0.54 g), (BOC) 2 O (13.28 g) was dissolved in THF (200.00 mL) and DMF (30.00 mL) at room temperature, and DIEA ( 13.72mL), stirred at room temperature for 3h. Water was added to the reaction, extracted with ethyl acetate, the organic phase was dried and concentrated. The concentrate was slurried with EA:PE=1:5 and filtered to obtain the target compound M2-4 (7.3 g, 35.54%) as a yellow solid. ESI-MS m/z: 371 [M+H] + .
步骤5：化合物M2的合成Step 5: Synthesis of compound M2
在室温下，将化合物M2-4(1.00g)，B 2Pin 2(2.05g)，[PdCl 2(dppf)]CH 2Cl 2(0.44g)，AcOK(1.32g)溶于1,4-二氧六环(20.00mL)，80℃搅拌3h。向反应液中加入水、乙酸乙酯萃取，有机相干燥，浓缩。浓缩物经柱色谱(EA:PE＝3-5％)分离纯化得到白色固体状目标产物M2(750mg)。ESI-MS m/z:419[M+H] +。 Compound M2-4 (1.00 g), B 2 Pin 2 (2.05 g), [PdCl 2 (dppf)]CH 2 Cl 2 (0.44 g), AcOK (1.32 g) were dissolved in 1,4- Dioxane (20.00 mL), stirred at 80°C for 3h. Water and ethyl acetate were added to the reaction solution for extraction, and the organic phase was dried and concentrated. The concentrate was separated and purified by column chromatography (EA:PE=3-5%) to obtain the target product M2 (750 mg) as a white solid. ESI-MS m/z: 419 [M+H] + .
中间体M3的合成：Synthesis of intermediate M3:
Figure PCTCN2022127912-appb-000047
Figure PCTCN2022127912-appb-000047
步骤1：化合物M3-1的合成Step 1: Synthesis of compound M3-1
在室温下，将化合物2-氨基-4-溴-5-氯-3-氟苯甲酸(4.00g)溶于四氢呋喃(100.00mL)中，0℃下将双(三氯甲基)碳酸酯(4.42g)加入其中，移至50℃反应2-3h。将反应液直接浓缩，浓缩物经硅胶柱分离纯化得到目标化合物M3-1(4.35g，产率99.2％)。ESI-MS m/z:294[M+H] +。 The compound 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (4.00g) was dissolved in tetrahydrofuran (100.00mL) at room temperature, and bis(trichloromethyl)carbonate ( 4.42g) was added therein, and moved to 50°C for 2-3h. The reaction solution was directly concentrated, and the concentrate was separated and purified by silica gel column to obtain the target compound M3-1 (4.35 g, yield 99.2%). ESI-MS m/z: 294 [M+H] + .
步骤2：化合物M3-2的合成Step 2: Synthesis of compound M3-2
在室温下，将上述化合物M3-1(4.35g)、2-氰基乙酸乙酯(2.51g)和TEA(8.22mL)溶于DMF(40.00mL)中，移至120℃反应3-6h。用隔膜泵将DMF浓缩，浓缩物经硅胶柱分离纯化得到目标化合物M3-2(4.36g，产率92.8％)。ESI-MS m/z:317[M+H] +。 The above compound M3-1 (4.35g), ethyl 2-cyanoacetate (2.51g) and TEA (8.22mL) were dissolved in DMF (40.00mL) at room temperature, and moved to 120°C for 3-6h. The DMF was concentrated with a diaphragm pump, and the concentrate was separated and purified through a silica gel column to obtain the target compound M3-2 (4.36 g, yield 92.8%). ESI-MS m/z: 317 [M+H] + .
步骤3：化合物M3-3的合成Step 3: Synthesis of compound M3-3
在室温下，将化合物M3-2(4.36g)溶于POCl 3(30.00mL)中，将DIPEA(3.55g)滴入，移至105℃反应2-3h。将反应液慢慢加入到冰水中，过滤，滤饼用DCM溶解，拌样，经硅胶柱分离纯化得目标产物M3-3(2.12g。产率43.5％)。ESI-MS m/z:353[M+H] +。 At room temperature, compound M3-2 (4.36g) was dissolved in POCl 3 (30.00mL), DIPEA (3.55g) was added dropwise, and the mixture was moved to 105°C for 2-3h. The reaction solution was slowly added to ice water, filtered, the filter cake was dissolved in DCM, the sample was mixed, separated and purified by silica gel column to obtain the target product M3-3 (2.12 g. Yield 43.5%). ESI-MS m/z: 353 [M+H] + .
步骤4：化合物M3的合成Step 4: Synthesis of compound M3
在室温下，将化合物M3-3(2.04g)、3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(1.35g)和DIPEA(2.24g)溶于THF(100.00mL)中，室温反应2-3h。将反应液直接浓缩，浓缩物经硅胶柱分离纯化得到目标化合物M3(2.3g，产率75.1％)。ESI-MS m/z:529[M+H] +。 Compound M3-3 (2.04 g), tert-butyl 3,8-diazacyclo[3.2.1]octane-8-carboxylate (1.35 g) and DIPEA (2.24 g) were dissolved in THF at room temperature (100.00mL), react at room temperature for 2-3h. The reaction solution was directly concentrated, and the concentrate was separated and purified by a silica gel column to obtain the target compound M3 (2.3 g, yield 75.1%). ESI-MS m/z: 529 [M+H] + .
中间体M4的合成：Synthesis of intermediate M4:
Figure PCTCN2022127912-appb-000048
Figure PCTCN2022127912-appb-000048
步骤1：化合物M4-1的合成Step 1: Synthesis of compound M4-1
在0℃下，将2,6-二溴苯甲醛(25.0g)溶于乙醇(300mL)，分批次加入硼氢化钠(3.58g)，加完后恢复至室温，搅拌30min。反应结束后，加水(500mL)稀释，用DCM(200mL)萃取两次，合并有机相，用饱和食盐水(100mL)洗一遍，无水硫酸钠干燥，旋干，得到化合物M4-1(25.0g，产率99％)。ESI-MS m/z＝267[M+H] +。 At 0°C, 2,6-dibromobenzaldehyde (25.0 g) was dissolved in ethanol (300 mL), and sodium borohydride (3.58 g) was added in batches. After the addition was complete, return to room temperature and stir for 30 min. After the reaction, dilute with water (500mL), extract twice with DCM (200mL), combine the organic phases, wash with saturated brine (100mL), dry over anhydrous sodium sulfate, and spin dry to obtain compound M4-1 (25.0g , yield 99%). ESI-MS m/z = 267 [M+H] + .
步骤2：化合物M4-2的合成Step 2: Synthesis of compound M4-2
在室温下将化合物M4-1(25g)、三苯基膦(32.1g)溶于DCM(300mL)，降温至0℃，分批次加入NBS(18.4g)，加完后保温并搅拌30min。反应完成后，将反应液浓缩。浓缩物经柱色谱纯化(EA:PE＝0-50％)得到产物M4-2(20g，产率64％)。Compound M4-1 (25 g) and triphenylphosphine (32.1 g) were dissolved in DCM (300 mL) at room temperature, cooled to 0° C., NBS (18.4 g) was added in batches, and then kept warm and stirred for 30 min. After the reaction was completed, the reaction solution was concentrated. The concentrate was purified by column chromatography (EA:PE=0-50%) to obtain product M4-2 (20 g, yield 64%).
步骤3：化合物M4-3的合成Step 3: Synthesis of compound M4-3
在室温下，将化合物M4-2(20g)、***(11.9g)溶于乙醇(100mL)和水(30mL)的混合溶液中，加热回流3-5h。反应完成后，将反应液浓缩，加EA(100mL)稀释，用水(30mL)洗一遍，饱和碳酸氢钠溶液(30mL)洗一遍，饱和食盐水(30mL)洗一遍。有机相用无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(EA:PE＝10％)得到产物M4-3(13g，产率77％)。Dissolve compound M4-2 (20 g) and potassium cyanide (11.9 g) in a mixed solution of ethanol (100 mL) and water (30 mL) at room temperature, and heat to reflux for 3-5 h. After the reaction was completed, the reaction solution was concentrated, diluted with EA (100 mL), washed with water (30 mL), saturated sodium bicarbonate solution (30 mL), and saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (EA:PE=10%) to obtain product M4-3 (13 g, yield 77%).
步骤4：化合物M4-4的合成Step 4: Synthesis of compound M4-4
在冰浴下，向DMF(130mL)中加入NaH(3.0g，60％纯度)，加入化合物M4-3(20.0g)，加完后搅拌10min。再向反应液中滴加异硫氰酰甲酸乙酯(10.5g)，加完后搅拌10min，再恢复至室温，搅拌20min。向反应液中加入CuI(1.39g)和L-脯氨酸(1.68g)，加完后升温至65℃搅拌2-5h。反应完成后，向反应液中加入0.2M的EDTA水溶液(500mL)和EA(100mL)，搅拌过夜。过滤，滤饼用水(200mL)洗两遍，烘干，得到化合物M4-4(23g，产率97％)。ESI-MS m/z＝323[M-H] -。 Under ice-cooling, NaH (3.0 g, 60% purity) was added to DMF (130 mL), compound M4-3 (20.0 g) was added, and stirred for 10 min after the addition was complete. Add ethyl isothiocyanate (10.5 g) dropwise to the reaction liquid, stir for 10 min after the addition, return to room temperature, and stir for 20 min. CuI (1.39g) and L-proline (1.68g) were added to the reaction solution, and after the addition was completed, the temperature was raised to 65°C and stirred for 2-5h. After the reaction was completed, 0.2M EDTA aqueous solution (500 mL) and EA (100 mL) were added to the reaction liquid, and stirred overnight. After filtering, the filter cake was washed twice with water (200 mL) and dried to obtain compound M4-4 (23 g, yield 97%). ESI-MS m/z = 323 [MH] - .
步骤5：化合物M4-5的合成Step 5: Synthesis of compound M4-5
在室温下，将化合物M4-4(23g)溶于DMSO(100mL)，加入氢氧化钠(6M，90mL)，升温至110℃搅拌6h。反应完成后，将反应液降至室温，缓缓倒入水(300mL)中。过滤，滤饼烘干，得到化合物M4-5(15.0g，产率84％)。ESI-MS m/z＝251[M-H] -。 Compound M4-4 (23 g) was dissolved in DMSO (100 mL) at room temperature, sodium hydroxide (6M, 90 mL) was added, and the temperature was raised to 110° C. and stirred for 6 h. After the reaction was completed, the reaction solution was lowered to room temperature, and slowly poured into water (300 mL). After filtering, the filter cake was dried to obtain compound M4-5 (15.0 g, yield 84%). ESI-MS m/z = 251 [MH] - .
步骤6：化合物M4-6的合成Step 6: Synthesis of compound M4-6
在冰浴下将M4-5(15.0g)、DIEA(14.7mL)、DMAP(0.58g)、二碳酸二叔丁醇酯(14.2g)加入到THF(200mL)和DMF(30mL)中，室温搅拌1h。反应结束后，将反应液用500mL EA稀释，用300mL水洗一遍，300mL饱和食盐水洗一遍，无水硫酸钠干燥，旋干。柱色谱纯化(EA:PE＝0-20％)得到产物M4-6(16.0g，产率76.4％)。ESI-MS m/z＝351[M-H] -。 M4-5 (15.0g), DIEA (14.7mL), DMAP (0.58g), di-tert-butanol dicarbonate (14.2g) were added to THF (200mL) and DMF (30mL) under ice bath, room temperature Stir for 1h. After the reaction, the reaction liquid was diluted with 500mL EA, washed once with 300mL water, washed once with 300mL saturated saline, dried over anhydrous sodium sulfate, and spin-dried. Purification by column chromatography (EA:PE=0-20%) gave the product M4-6 (16.0 g, yield 76.4%). ESI-MS m/z = 351 [MH] - .
步骤7：化合物M4的合成Step 7: Synthesis of compound M4
在室温下，将化合物M4-6(16.0g)溶于THF(250mL)，分批次加入NaH(3.6g，60％纯度)，加完后室温搅拌30min。降温至-78℃，滴加正丁基锂(36mL，2.5M)，加 完后保温30min。滴加甲氧基频哪醇硼酸酯(35.8g)，加完后缓慢恢复至室温。将反应液滴加到800mL饱和氯化铵溶液中，分液，水相加EA(200mL)萃取，合并有机相。有机相用100mL饱和食盐水洗一遍，用无水硫酸钠干燥，旋干。柱色谱纯化(EA:PE＝1-20％)得到中间体M4(11g，产率60％)。ESI-MS m/z＝399.2[M-H] -。 Compound M4-6 (16.0 g) was dissolved in THF (250 mL) at room temperature, NaH (3.6 g, 60% purity) was added in batches, and stirred at room temperature for 30 min after the addition was complete. Cool down to -78°C, add n-butyllithium (36mL, 2.5M) dropwise, and keep warm for 30min after the addition is complete. Methoxy pinacol borate (35.8 g) was added dropwise, and the mixture was slowly returned to room temperature after the addition. The reaction solution was added dropwise to 800 mL of saturated ammonium chloride solution, separated, the aqueous phase was extracted with EA (200 mL), and the organic phases were combined. The organic phase was washed once with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and spin-dried. Purification by column chromatography (EA:PE=1-20%) gave intermediate M4 (11 g, yield 60%). ESI-MS m/z = 399.2 [MH] - .
中间体M5的合成：Synthesis of intermediate M5:
Figure PCTCN2022127912-appb-000049
Figure PCTCN2022127912-appb-000049
步骤1：化合物M5-1的合成Step 1: Synthesis of compound M5-1
在室温下，将中间体M1-1(19.00g)加入四氢呋喃(200.00mL)中，室温下分批加入氢化钠(7.10g)。N 2保护下，升至40℃搅拌0.5小时。在分批加入二(1H-咪唑-1-基)甲硫磷(18.99g)。在升至70℃搅拌0.5小时。LCMS监测反应完成。加入饱和NH 4Cl(20mL)淬灭反应，再用1N HCl调节至PH＝5-6，再用EA(80mL)萃取2次，有机层经饱和食盐水洗涤再用无水硫酸钠干燥，浓缩，得黄色粉末17.4g粗品M5-1，粗品直接用于下一步。 Intermediate M1-1 (19.00 g) was added into tetrahydrofuran (200.00 mL) at room temperature, and sodium hydride (7.10 g) was added in portions at room temperature. Under the protection of N 2 , it was raised to 40°C and stirred for 0.5 hours. Bis(1H-imidazol-1-yl)methion (18.99 g) was added in portions. Stir at 70°C for 0.5 hours. LCMS monitored the completion of the reaction. The reaction was quenched by adding saturated NH 4 Cl (20 mL), adjusted to pH=5-6 with 1N HCl, extracted twice with EA (80 mL), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated , 17.4 g of crude product M5-1 was obtained as a yellow powder, which was directly used in the next step.
步骤2：化合物M5-2的合成Step 2: Synthesis of compound M5-2
在室温下，将M5-1(16.40g)加入甲醇(300.00mL)，再加入甲醇钠(4.29g)，最后滴加入碘甲烷(4.95mL)，室温搅拌0.5小时。加入H 2O(20mL)稀释，再用2N HCl调至PH＝5-6，减压浓缩，粗品加入H 2O(20mL)搅拌5分钟，过滤，滤饼用水冲洗再用PE/EA＝3/1(20mL)冲洗3次，干燥后得黄色粉末状产物M5-2(14.6g)。ESI-MS m/z:323[M+H] +。 At room temperature, M5-1 (16.40g) was added to methanol (300.00mL), then sodium methoxide (4.29g), and finally methyl iodide (4.95mL) was added dropwise, and stirred at room temperature for 0.5 hours. Add H 2 O (20 mL) to dilute, then use 2N HCl to adjust to PH=5-6, concentrate under reduced pressure, add H 2 O (20 mL) to the crude product and stir for 5 minutes, filter, rinse the filter cake with water and use PE/EA=3 /1 (20mL) was washed 3 times, and the product M5-2 (14.6g) was obtained as a yellow powder after drying. ESI-MS m/z: 323 [M+H] + .
步骤3：化合物M5-3的合成Step 3: Synthesis of compound M5-3
在室温下，将M5-2(14.19g)，叔丁基(1R，5S)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸酯(12.10g)加入乙腈(220.00mL)，再加入DBU(32.76mL)和BOP(58.19g)。室温搅 拌2小时。加入EA(100mL)和H 2O(100mL)萃取2次，有机层用饱和食盐水洗涤再用无水硫酸钠干燥。经柱层析纯化(PE/EA,10％EA)得黄色粉末状化合物M5-3(16g)。ESI-MS m/z:517[M+H] +。 At room temperature, M5-2 (14.19 g), tert-butyl (1R, 5S)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (12.10 g) was added to acetonitrile ( 220.00 mL), DBU (32.76 mL) and BOP (58.19 g) were added. Stir at room temperature for 2 hours. EA (100 mL) and H 2 O (100 mL) were added to extract twice, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography (PE/EA, 10% EA) gave compound M5-3 (16 g) as a yellow powder. ESI-MS m/z: 517 [M+H] + .
步骤4：化合物M5-4的合成Step 4: Synthesis of compound M5-4
在室温下，将M5-3(11.00g)，中间体M2(15.46g)加入CPME(165.00mL)中，再加入Pd(DPEPhos)Cl 2(3.04g)，K 3PO 4(13.53g)和KF(4.94g)。N 2置换三次，N 2保护下，升至83℃搅拌过夜。加入EA(80mL)和H 2O(100mL)萃取2次，有机层用饱和食盐水洗涤再用无水硫酸钠干燥，浓缩，浓缩物经柱层析纯化(PE/EA,25％EA)得黄色粉末状化合物M5-4(5.1g)，ESI-MS m/z:729[M+H] +。 At room temperature, M5-3 (11.00g), intermediate M2 (15.46g) were added to CPME (165.00mL), then Pd(DPEPhos)Cl 2 (3.04g), K 3 PO 4 (13.53g) and KF (4.94g). N 2 was replaced three times, under the protection of N 2 , raised to 83°C and stirred overnight. Add EA (80mL) and H 2 O (100mL) to extract twice, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by column chromatography (PE/EA, 25% EA) to obtain Yellow powder compound M5-4 (5.1 g), ESI-MS m/z: 729[M+H] + .
步骤5：化合物M5的合成Step 5: Synthesis of compound M5
在室温下，将化合物M5-4(4.60g)加入DCM(100.00mL)中，再加入m-CPBA(4.35g)。室温搅拌0.5小时。LCMS监测反应完成。加入饱和NaHCO 3调至PH＝8,再用亚硫酸钠溶液淬灭过量的m-CPBA，减压浓缩除去DCM。再用EA(70ML)萃取2次，有机层用饱和NaHCO 3洗涤最后用食盐水洗涤，无水硫酸钠干燥，浓缩。浓缩物经经柱层析纯化(PE/EA,50％EA)得黄色粉末状目标中间体M5(4.54g)。ESI-MS m/z:761[M+H] +。 Compound M5-4 (4.60 g) was added to DCM (100.00 mL) followed by m-CPBA (4.35 g) at room temperature. Stir at room temperature for 0.5 hours. LCMS monitored the completion of the reaction. Add saturated NaHCO 3 to adjust the pH to 8, then quench the excess m-CPBA with sodium sulfite solution, and concentrate under reduced pressure to remove DCM. It was extracted twice with EA (70ML), and the organic layer was washed with saturated NaHCO 3 and finally with brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE/EA, 50% EA) to obtain the target intermediate M5 (4.54 g) as a yellow powder. ESI-MS m/z: 761 [M+H] + .
中间体M6的合成：Synthesis of intermediate M6:
Figure PCTCN2022127912-appb-000050
Figure PCTCN2022127912-appb-000050
步骤1：化合物M6-1的合成Step 1: Synthesis of Compound M6-1
室温下，将化合物M6-0(208g)溶解在无水MeOH(2L)中,在0℃滴加氯化亚砜(286mL)，控制温度在5℃反应1小时，反应结束后，浓缩反应液，加入无水DCM(1L)稀释，0℃下，将稀释液体滴加到饱和碳酸氢钠溶液中，分液，有机层用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(EA:DCM＝0-50％)得到产物M6-1(240g，95％产率)。ESI-MS m/z＝258.1[M+H] +。 Dissolve compound M6-0 (208g) in anhydrous MeOH (2L) at room temperature, add thionyl chloride (286mL) dropwise at 0°C, control the temperature at 5°C for 1 hour, and concentrate the reaction solution after the reaction , added anhydrous DCM (1 L) to dilute, at 0°C, the diluted liquid was added dropwise to saturated sodium bicarbonate solution, separated, the organic layer was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (EA:DCM=0-50%) to obtain the product M6-1 (240 g, 95% yield). ESI-MS m/z = 258.1 [M+H] + .
步骤2：化合物M6-2的合成Step 2: Synthesis of Compound M6-2
在室温下，将化合物M6-1(235g)溶于无水THF(2.4L)，在0℃分批次加入四氢铝锂(69.4g)，加完后60℃搅拌30min。反应结束后，冷却反应液，冰浴下滴加水(69.4mL),再滴加15％的氢氧化钠水溶液(69.4mL)，最后滴加水(208.2mL)，加入无水硫酸钠干燥，过滤得到滤液浓缩即得到产物M6-2(165g，90％产率)直接用于下一步。ESI-MS m/z＝202.1[M+H] +。 Compound M6-1 (235 g) was dissolved in anhydrous THF (2.4 L) at room temperature, lithium aluminum hydride (69.4 g) was added in batches at 0° C., and stirred at 60° C. for 30 min after the addition was complete. After the reaction, cool the reaction solution, add water (69.4mL) dropwise under an ice bath, then add 15% aqueous sodium hydroxide solution (69.4mL) dropwise, and finally add water (208.2mL) dropwise, add anhydrous sodium sulfate to dry, and filter to obtain The filtrate was concentrated to give the product M6-2 (165 g, 90% yield) which was directly used in the next step. ESI-MS m/z = 202.1 [M+H] + .
步骤3：化合物M6-3的合成Step 3: Synthesis of compound M6-3
室温下，将化合物M6-2(160g)溶于三氟乙酸(500mL)，加入水(67mL)，60℃下反应过夜，浓缩反应液体得到粗品M6-3(320g，259％)直接用于下一步。ESI-MS m/z＝156.1[M+H] +。 At room temperature, compound M6-2 (160g) was dissolved in trifluoroacetic acid (500mL), water (67mL) was added, reacted overnight at 60°C, and the reaction liquid was concentrated to obtain crude product M6-3 (320g, 259%) which was directly used in the following step. ESI-MS m/z = 156.1 [M+H] + .
步骤4：化合物M6-4的合成Step 4: Synthesis of compound M6-4
在室温下，将化合物M6-3(308g)溶于DMF(350mL)中，0℃加入咪唑(540g)后滴加TBDPSCl(170mL)，加完后室温搅拌1小时。反应结束后，加入水和EA稀释，用EA萃取水相3遍。合并有机相，有机相用饱和食盐水洗三遍，用无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(EA:PE＝0-15％)得到产物M6-4(192g，25％产率)。ESI-MS m/z＝394.1[M+H] +。 Compound M6-3 (308g) was dissolved in DMF (350mL) at room temperature, imidazole (540g) was added at 0°C and TBDPSCl (170mL) was added dropwise, and then stirred at room temperature for 1 hour. After the reaction was completed, water and EA were added for dilution, and the aqueous phase was extracted 3 times with EA. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (EA:PE=0-15%) to obtain the product M6-4 (192 g, 25% yield). ESI-MS m/z = 394.1 [M+H] + .
步骤5：化合物M6的合成Step 5: Synthesis of compound M6
室温下，将化合物M6-4(187g)和二氟甲基(2-吡啶基)砜(184g)溶解在无水DMF(1.4L)中,在-50℃滴加叔丁醇钾(107g)的DMF(460mL)溶液，滴加完毕后控制温度在-40℃反应2小时，反应结束后，在-50℃下滴加饱和氯化铵溶液直至溶液成弱酸性，自然升温至室温反应18小时，过滤得到滤液，加入EA(1.4L)稀释，再过滤得到滤液，浓缩。浓缩物经柱色谱纯化(MeOH:DCM＝0-10％)得到产物M6(60g，67％产率)。 1H NMR(500MHz,DMSO-d6)δ3.95-3.92(m,1H),3.70-3.67(m,1H),3.32-3.27(m,2H),2.94-2.89(m,1H),2.69-2.66(m,1H),2.50-3.45(m,1H),1.99-1.92(m,2H),1.88-1.75(m,2H)。ESI-MS m/z＝190.1[M+H] +。 At room temperature, compound M6-4 (187g) and difluoromethyl (2-pyridyl) sulfone (184g) were dissolved in anhydrous DMF (1.4L), and potassium tert-butoxide (107g) was added dropwise at -50°C DMF (460mL) solution, after the dropwise addition, control the temperature and react at -40°C for 2 hours. After the reaction, add saturated ammonium chloride solution dropwise at -50°C until the solution becomes weakly acidic, then naturally warm to room temperature and react for 18 hours. , filtered to obtain the filtrate, added EA (1.4 L) to dilute, then filtered to obtain the filtrate, and concentrated. The concentrate was purified by column chromatography (MeOH:DCM=0-10%) to obtain product M6 (60 g, 67% yield). 1 H NMR (500MHz, DMSO-d6) δ3.95-3.92(m,1H),3.70-3.67(m,1H),3.32-3.27(m,2H),2.94-2.89(m,1H),2.69- 2.66 (m, 1H), 2.50-3.45 (m, 1H), 1.99-1.92 (m, 2H), 1.88-1.75 (m, 2H). ESI-MS m/z = 190.1 [M+H] + .
中间体M7的合成：Synthesis of intermediate M7:
Figure PCTCN2022127912-appb-000051
Figure PCTCN2022127912-appb-000051
在室温下，在反应瓶中将2-亚甲基-5-氧代-1,3,6,7-四氢吡咯利嗪-8-羧酸乙酯(10.00g)溶于THF(150.00mL)，缓慢加入LAH(2.5M/THF)(3.63g)，控制温度在60℃以下，加完搅拌0.2h。降温至0℃，加3.6ml水淬灭反应，再加15％的氢氧化钠水溶液3.6ml，最后加10.8ml水，搅拌10min后加入无水硫酸镁干燥，搅拌10min后过滤，滤饼用EA洗三次，母液浓缩即可得到目标中间体M7(6.5g，89.34％产率)。Dissolve ethyl 2-methylene-5-oxo-1,3,6,7-tetrahydropyrrolizine-8-carboxylate (10.00 g) in THF (150.00 mL ), slowly added LAH (2.5M/THF) (3.63g), controlled the temperature below 60°C, and stirred for 0.2h after the addition. Cool down to 0°C, add 3.6ml of water to quench the reaction, add 3.6ml of 15% sodium hydroxide aqueous solution, and finally add 10.8ml of water, stir for 10 minutes, add anhydrous magnesium sulfate to dry, stir for 10 minutes, filter, filter cake with EA After washing three times, the mother liquor was concentrated to obtain the target intermediate M7 (6.5 g, 89.34% yield).
中间体M8的合成：Synthesis of intermediate M8:
Figure PCTCN2022127912-appb-000052
Figure PCTCN2022127912-appb-000052
步骤1：化合物M8-1的合成Step 1: Synthesis of compound M8-1
在室温下，将化合物M7-0(500mg)、苯乙烯(373mg)和Grubbs 2代催化剂(405.72mg)溶于无水DCM(20mL)中，50℃反应过夜。反应完毕后，将反应液减压浓缩，浓缩物经柱色谱分离纯化得目标化合物M8-1(400mg)。Compound M7-0 (500 mg), styrene (373 mg) and Grubbs 2nd generation catalyst (405.72 mg) were dissolved in anhydrous DCM (20 mL) at room temperature, and reacted overnight at 50°C. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography to obtain the target compound M8-1 (400 mg).
步骤2：化合物M8的合成Step 2: Synthesis of Compound M8
在室温下，将化合物M8-1(400mg)溶于无水THF(10mL)中，0℃下，将LAH(160mg)加入，再升温至70℃反应30min。反应完毕后，降至0℃，先慢慢加入170uL水，再将170uL 15％氢氧化钠水溶液加入，最后加入510uL水，室温反应15min，加入无水硫酸钠干燥，硅藻土过滤，滤液浓缩，即可得到目标化合物M8(277mg)。Compound M8-1 (400 mg) was dissolved in anhydrous THF (10 mL) at room temperature, LAH (160 mg) was added at 0°C, and the temperature was raised to 70°C for 30 min. After the reaction is completed, lower it to 0°C, first slowly add 170uL of water, then add 170uL of 15% sodium hydroxide aqueous solution, and finally add 510uL of water, react at room temperature for 15min, add anhydrous sodium sulfate to dry, filter with diatomaceous earth, and concentrate the filtrate , the target compound M8 (277mg) could be obtained.
中间体M9的合成：Synthesis of intermediate M9:
Figure PCTCN2022127912-appb-000053
Figure PCTCN2022127912-appb-000053
步骤1：化合物M9-1的合成Step 1: Synthesis of compound M9-1
在室温下，将化合物M7-0(800mg)、对氯苯乙烯(795mg)和Grubbs 2代催化剂(325mg)溶于无水DCM(20mL)中，50℃反应过夜。反应完毕后，将反应液减压浓缩，浓缩物经柱色谱分离纯化得目标化合物M9-1(729mg)。ESI-MS m/z＝320.1[M+H] +。 Compound M7-0 (800 mg), p-chlorostyrene (795 mg) and Grubbs 2nd generation catalyst (325 mg) were dissolved in anhydrous DCM (20 mL) at room temperature, and reacted overnight at 50°C. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography to obtain the target compound M9-1 (729 mg). ESI-MS m/z = 320.1 [M+H] + .
步骤2：化合物M9的合成Step 2: Synthesis of Compound M9
在室温下，将化合物M9-1(729mg)溶于无水THF(10mL)中，0℃下将LAH(260mg)加入，再升温至70℃反应30min。反应完毕后，降至0℃，先慢慢加入280uL水，再将280uL15％氢氧化钠水溶液加入，最后加入840uL水，室温反应15min，加入无水硫酸钠干燥，硅藻土过滤，滤液浓缩，即可得到目标化合物M9(563mg)。ESI-MS m/z＝264.1[M+H] +。 Compound M9-1 (729 mg) was dissolved in anhydrous THF (10 mL) at room temperature, LAH (260 mg) was added at 0°C, and then heated to 70°C for 30 min. After the reaction is completed, lower the temperature to 0°C, first slowly add 280uL of water, then add 280uL of 15% sodium hydroxide aqueous solution, and finally add 840uL of water, react at room temperature for 15min, add anhydrous sodium sulfate to dry, filter with diatomaceous earth, and concentrate the filtrate. The target compound M9 (563 mg) could be obtained. ESI-MS m/z = 264.1 [M+H] + .
中间体M10的合成：Synthesis of intermediate M10:
Figure PCTCN2022127912-appb-000054
Figure PCTCN2022127912-appb-000054
步骤1：化合物M10-1的合成Step 1: Synthesis of compound M10-1
在室温下，将化合物M7-0(400mg)、亚甲基环戊烷(236mg)和Grubbs 2代催化剂(325mg)溶于无水DCM(20mL)中，50℃反应过夜。反应完毕后，将反应液减压浓缩至少量，直接湿法上样进行柱色谱纯化得目标化合物M10-1(410mg)。Compound M7-0 (400 mg), methylenecyclopentane (236 mg) and Grubbs 2nd generation catalyst (325 mg) were dissolved in anhydrous DCM (20 mL) at room temperature, and reacted overnight at 50°C. After the reaction was completed, the reaction solution was concentrated under reduced pressure to a certain amount, and directly wet-loaded for column chromatography purification to obtain the target compound M10-1 (410 mg).
步骤2：化合物M10的合成Step 2: Synthesis of Compound M10
将化合物M10-1(410mg)溶于无水THF(10mL)中，0℃下将LAH(204mg)加入，再升温至70℃反应30min。反应完毕后，降至0℃，先慢慢加入210uL水，再将210uL15％氢氧化钠水溶液加入，再加入630uL水，室温反应15min，加入无水硫酸钠干燥，硅藻土过滤，滤液浓缩，即可得到目标化合物M10(370mg)。Compound M10-1 (410 mg) was dissolved in anhydrous THF (10 mL), LAH (204 mg) was added at 0°C, and the temperature was raised to 70°C for 30 min. After the reaction was completed, lower the temperature to 0°C, first slowly add 210uL of water, then add 210uL of 15% sodium hydroxide aqueous solution, then add 630uL of water, react at room temperature for 15min, add anhydrous sodium sulfate to dry, filter with diatomaceous earth, and concentrate the filtrate. The target compound M10 (370 mg) could be obtained.
中间体M11的合成：Synthesis of Intermediate M11:
Figure PCTCN2022127912-appb-000055
Figure PCTCN2022127912-appb-000055
步骤1：化合物M11-1的合成Step 1: Synthesis of compound M11-1
在室温下，将M7-0(1.00g),2,3-二甲基-2-烯(2.01g)加入DCM(20.00mL)中，再加入Grubbs 2代催化剂(0.41g)。N 2置换三次，N 2保护下，反应升至50℃搅拌20小时。反应冷却，减压浓缩，浓缩物经柱层析纯化得到目标化合物M11-1。 M7-0 (1.00 g), 2,3-dimethyl-2-ene (2.01 g) were added to DCM (20.00 mL) followed by Grubbs 2nd generation catalyst (0.41 g) at room temperature. N 2 was replaced three times, and under the protection of N 2 , the reaction was raised to 50°C and stirred for 20 hours. The reaction was cooled, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound M11-1.
步骤2：化合物M11的合成Step 2: Synthesis of Compound M11
在室温下，将M11-1(0.20g)加入THF(4.00mL)，冰浴下，分批加入LAH(0.10g)。反应升至70℃搅拌1小时。反应冷却，在冰浴下滴加入H 2O(100uL)，接着滴加入15％NaOH(100uL)溶液，最后滴加入H 2O(300uL)，室温搅拌10分钟，再加入无水硫酸钠干燥并搅拌5分钟。过滤，滤饼用EA冲洗，滤液减压浓缩得到目标化合物M11(0.18g)。 M11-1 (0.20 g) was added to THF (4.00 mL) at room temperature, and LAH (0.10 g) was added in portions under ice-cooling. The reaction was warmed to 70°C and stirred for 1 hour. The reaction was cooled, and H 2 O (100uL) was added dropwise in an ice bath, followed by 15% NaOH (100uL) solution, and finally H 2 O (300uL) was added dropwise, stirred at room temperature for 10 minutes, then added anhydrous sodium sulfate to dry and Stir for 5 minutes. After filtration, the filter cake was washed with EA, and the filtrate was concentrated under reduced pressure to obtain the target compound M11 (0.18 g).
中间体M12的合成：Synthesis of intermediate M12:
Figure PCTCN2022127912-appb-000056
Figure PCTCN2022127912-appb-000056
步骤1：化合物M12-1的合成Step 1: Synthesis of compound M12-1
在室温下，将化合物M7-0(0.5g)，Togni's reagent II(1.51g)和四丁基碘化铵(0.44g)溶解于1,4-二氧六环(10mL)中抽换氮气，80度反应10小时，将反应液直接浓缩，浓缩物经层析柱(DCM/EA＝2/1)分离纯化得到产物M12-1(0.45g,68％收率)。At room temperature, compound M7-0 (0.5g), Togni's reagent II (1.51g) and tetrabutylammonium iodide (0.44g) were dissolved in 1,4-dioxane (10mL) to pump nitrogen, After reacting at 80°C for 10 hours, the reaction solution was directly concentrated, and the concentrate was separated and purified by chromatography (DCM/EA=2/1) to obtain the product M12-1 (0.45g, 68% yield).
步骤2：化合物M12的合成Step 2: Synthesis of Compound M12
在室温下，将化合物M7-1(0.3g)溶解于四氢呋喃中，在冰浴下加入四氢铝锂(123mg)，然后加入硼烷的四氢呋喃溶液(3.2mL)，反应1分钟后立刻用水淬灭反应至不再冒出气泡，加入15％氢氧化钠(0.3mL)，再加入水(0.9mL)，搅拌淬灭完全后，加入硫酸钠干燥，过滤得滤液，浓缩得到产物M12(80mg,33％收率)。At room temperature, compound M7-1 (0.3g) was dissolved in tetrahydrofuran, lithium aluminum hydride (123mg) was added under ice bath, and then a solution of borane in tetrahydrofuran (3.2mL) was added, and the reaction was quenched with water immediately after 1 minute. Quench the reaction until bubbles no longer emerge, add 15% sodium hydroxide (0.3mL), then add water (0.9mL), after stirring and quenching completely, add sodium sulfate to dry, filter to obtain the filtrate, concentrate to obtain the product M12 (80mg, 33% yield).
中间体M13的合成：Synthesis of intermediate M13:
Figure PCTCN2022127912-appb-000057
Figure PCTCN2022127912-appb-000057
在室温下，将化合物M12-1(0.3g)溶解于四氢呋喃中，在冰浴下加入四氢铝锂(123mg)，然后加入硼烷的四氢呋喃溶液(3.2mL)，撤去冰浴反应5分钟，LC-MS监测反应完全，用水淬灭反应至不再冒出气泡，加入15％氢氧化钠(0.3mL)，再加入水(0.9mL)，搅拌淬灭完全后，加入硫酸钠干燥，过滤得滤液，旋干得到产物M13(164mg， 73％收率)。At room temperature, compound M12-1 (0.3 g) was dissolved in tetrahydrofuran, and lithium aluminum hydride (123 mg) was added under an ice bath, and then a solution of borane in tetrahydrofuran (3.2 mL) was added, and the ice bath was removed to react for 5 minutes. LC-MS monitored that the reaction was complete, quenched the reaction with water until no more bubbles emerged, added 15% sodium hydroxide (0.3mL), then added water (0.9mL), after stirring and quenching completely, added sodium sulfate to dry, and filtered to obtain The filtrate was spin-dried to obtain the product M13 (164 mg, 73% yield).
实施例1：化合物4-(4-((1R，5S)-3,8-二氮杂环[3.2.1]辛基-3-基)-6-氯-8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯啉-7a(5H-基)甲氧基)喹唑啉-7-基)-2-氨基-7-氟苯并[b]噻吩-3-碳腈的合成Embodiment 1: Compound 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-8-fluoro-2-(( 2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3 -Synthesis of carbonitrile
Figure PCTCN2022127912-appb-000058
Figure PCTCN2022127912-appb-000058
步骤1：化合物1-1的合成Step 1: Synthesis of compound 1-1
在室温下，依次加入3-(7-溴-2,6-二氯-8-氟-喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(100.00mg)，[(2R，8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-8-基]甲醇(34.61mg)，Cs 2CO 3(193.15mg)，DABCO(2.22mg)到DMF(1.00mL)和THF/四氢呋喃(1.00mL)的混合溶液中。氮气保护下，室温搅拌反应过夜。反应液加水稀释，EA萃取，有机层用饱和食盐水洗涤三次，干燥浓缩，经柱层析纯化得到淡黄色固体状化合物1-1(62.00mg，产率49.89％)。ESI-MS m/z:628[M+H] +。 At room temperature, sequentially add 3-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8 - tert-butyl carboxylate (100.00 mg), [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methanol (34.61 mg), Cs 2 CO 3 (193.15 mg), DABCO (2.22 mg) into a mixed solution of DMF (1.00 mL) and THF/tetrahydrofuran (1.00 mL). Under the protection of nitrogen, the reaction was stirred overnight at room temperature. The reaction solution was diluted with water, extracted with EA, the organic layer was washed three times with saturated brine, dried and concentrated, and purified by column chromatography to obtain compound 1-1 (62.00 mg, yield 49.89%) as a pale yellow solid. ESI-MS m/z: 628 [M+H] + .
步骤2：化合物1-2的合成Step 2: Synthesis of Compound 1-2
在室温下，将化合物1-1(20.00mg)，叔丁基N-[3-氰基-7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)苯并噻吩-2-基]氨基甲酸酯(26.60mg)，Pd(dtbpf)Cl 2(4.13mg)，K 3PO 4(16.88mg)依次加入到1,4-二氧六环(1.00mL)和水(0.10mL)的混合溶液中。氮气保护下，置于90℃油浴反应。加水稀释，DCM萃取，有机相干燥浓缩，浓缩物经Pre-TLC分离纯化得到淡黄色固体状目标化合物1-2(24.00mg，产率90.3％)。ESI-MS m/z:840[M+H] +。 At room temperature, compound 1-1 (20.00 mg), tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- Dioxybenzaldehyde-2-yl)benzothiophen-2-yl]carbamate (26.60 mg), Pd(dtbpf)Cl 2 (4.13 mg), K 3 PO 4 (16.88 mg) were sequentially added to 1, In a mixed solution of 4-dioxane (1.00mL) and water (0.10mL). Under the protection of nitrogen, put it in a 90°C oil bath for reaction. It was diluted with water, extracted with DCM, and the organic phase was dried and concentrated. The concentrate was separated and purified by Pre-TLC to obtain the target compound 1-2 (24.00 mg, yield 90.3%) as a pale yellow solid. ESI-MS m/z: 840 [M+H] + .
步骤3：化合物1的合成Step 3: Synthesis of Compound 1
在室温下，将化合物1-2(48.00mg)加入到三氟乙酸(1.00mL)和二氯甲烷(1.00mL)的混合溶剂中，室温搅拌30min。将反应液浓缩，DCM稀释，冰水浴环境下用饱和碳酸氢钠调节pH至弱碱性，分液萃取，有机相干燥浓缩。浓缩物经Pre-TLC分离纯化得到白色固体状目标化合物1(22.00mg，产率60.19％)。ESI-MS m/z:640[M+H] +。 1H NMR(500MHz,MeOD)δ7.84(d,J＝8.2Hz,1H),7.24-7.15(m,1H),7.02(dd,J＝16.9,8.0Hz,1H),5.41-5.19(m,1H),4.57-4.39(m,1H),4.32-4.15(m,1H),3.69-3.53(m,1H),3.20(dd,J＝20.2,10.5Hz,1H),2.99(d,J＝22.1Hz,1H),2.37-2.10(m,1H),2.06-1.74(m,1H),1.45- 1.21(m,1H)。 Compound 1-2 (48.00 mg) was added into a mixed solvent of trifluoroacetic acid (1.00 mL) and dichloromethane (1.00 mL) at room temperature, and stirred at room temperature for 30 min. The reaction solution was concentrated, diluted with DCM, and the pH was adjusted to weak alkaline with saturated sodium bicarbonate in an ice-water bath environment, separated and extracted, and the organic phase was dried and concentrated. The concentrate was separated and purified by Pre-TLC to obtain the target compound 1 (22.00 mg, yield 60.19%) as a white solid. ESI-MS m/z: 640 [M+H] + . 1 H NMR (500MHz, MeOD) δ7.84(d, J=8.2Hz, 1H), 7.24-7.15(m, 1H), 7.02(dd, J=16.9, 8.0Hz, 1H), 5.41-5.19(m ,1H),4.57-4.39(m,1H),4.32-4.15(m,1H),3.69-3.53(m,1H),3.20(dd,J=20.2,10.5Hz,1H),2.99(d,J =22.1Hz, 1H), 2.37-2.10(m, 1H), 2.06-1.74(m, 1H), 1.45-1.21(m, 1H).
实施例148：化合物7-(2-氨基-3-氰基-7-氟苯并噻吩-4-基)-4-((1R，5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-6-氯-2-(3-(二甲氨基)氮杂环丁烷-1-基)-8-氟喹啉-3-碳腈的合成Example 148: Compound 7-(2-amino-3-cyano-7-fluorobenzothiophen-4-yl)-4-((1R,5S)-3,8-diazacyclo[3.2.1 Synthesis of ]octane-3-yl)-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinoline-3-carbonitrile
Figure PCTCN2022127912-appb-000059
Figure PCTCN2022127912-appb-000059
步骤1：化合物148-1的合成Step 1: Synthesis of compound 148-1
在室温下，将中间体M3(100.00mg)，N、N-二甲基氮杂环丁胺(38.65mg)和DIPEA(121.87mg)溶于DMF(2.00mL)中，氮气保护下，30℃反应1.5h。反应液用EA和水萃取3遍，合并有机相，干燥，浓缩，浓缩物经硅胶柱分离纯化得油状化合物目标化合物148-1(91mg，产率97.71％)。ESI-MS m/z:493[M+H] +。 Dissolve intermediate M3 (100.00mg), N,N-dimethylazetidinamine (38.65mg) and DIPEA (121.87mg) in DMF (2.00mL) at room temperature, under nitrogen protection, 30°C Reaction 1.5h. The reaction solution was extracted 3 times with EA and water, the organic phases were combined, dried and concentrated, and the concentrate was separated and purified by silica gel column to obtain the target compound 148-1 (91 mg, yield 97.71%) as an oily compound. ESI-MS m/z: 493 [M+H] + .
后续合成步骤参考实施例1的合成。ESI-MS m/z:605[M+H] +。 1H NMR(500MHz,DMSO-d 6)δ10.39(s,1H),9.14(d,J＝46.6Hz,2H),8.14(s,2H),8.04(s,1H),7.28-7.12(m,2H),4.60(dt,J＝15.8,9.5Hz,2H),4.54-4.38(m,2H),4.25(s,2H),4.00(d,J＝12.2Hz,1H),3.93(d,J＝12.3Hz,1H),2.83(s,6H),2.28(dt,J＝18.1,8.7Hz,2H),2.09(q,J＝6.2,5.7Hz,2H),2.03-1.94(m,1H),1.27-1.19(m,2H)。 For subsequent synthesis steps, refer to the synthesis of Example 1. ESI-MS m/z: 605 [M+H] + . 1 H NMR (500MHz, DMSO-d 6 ) δ10.39(s, 1H), 9.14(d, J=46.6Hz, 2H), 8.14(s, 2H), 8.04(s, 1H), 7.28-7.12( m,2H),4.60(dt,J=15.8,9.5Hz,2H),4.54-4.38(m,2H),4.25(s,2H),4.00(d,J=12.2Hz,1H),3.93(d ,J=12.3Hz,1H),2.83(s,6H),2.28(dt,J=18.1,8.7Hz,2H),2.09(q,J=6.2,5.7Hz,2H),2.03-1.94(m, 1H), 1.27-1.19 (m, 2H).
实施例149：化合物3-((7-(2-氨基-3-氰基-7-氟苯并噻吩-4-基)-4-((1R，5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-6-氯-3-氰基-8-氟喹啉-2-基)氨基)-N，N-二甲基丙胺的合成Example 149: Compound 3-((7-(2-amino-3-cyano-7-fluorobenzothiophen-4-yl)-4-((1R,5S)-3,8-diazacyclo Synthesis of [3.2.1] octane-3-yl)-6-chloro-3-cyano-8-fluoroquinolin-2-yl)amino)-N,N-dimethylpropylamine
Figure PCTCN2022127912-appb-000060
Figure PCTCN2022127912-appb-000060
具体合成步骤参考实施例148。ESI-MS m/z:621[M+H] +。 1H NMR(500MHz,DMSO-d 6)δ9.36–8.81(m,2H),8.10(s,2H),7.95(s,1H),7.40(t,J＝5.5Hz,1H),7.15(s,2H),4.22(s,2H),3.92(t,J＝13.8Hz,2H),3.68(q,J＝6.8Hz,2H),2.99(s,3H),2.81(s,3H),2.67(t,J＝7.0Hz,2H),2.33–2.25(m,2H),2.08(s,2H),1.99(dd,J＝10.6,7.0Hz,1H),0.85(t,J＝6.5Hz,1H)。 For specific synthesis steps, refer to Example 148. ESI-MS m/z: 621 [M+H] + . 1 H NMR (500MHz, DMSO-d 6 ) δ9.36–8.81 (m, 2H), 8.10 (s, 2H), 7.95 (s, 1H), 7.40 (t, J=5.5Hz, 1H), 7.15 ( s,2H),4.22(s,2H),3.92(t,J=13.8Hz,2H),3.68(q,J=6.8Hz,2H),2.99(s,3H),2.81(s,3H), 2.67(t, J=7.0Hz, 2H), 2.33–2.25(m, 2H), 2.08(s, 2H), 1.99(dd, J=10.6, 7.0Hz, 1H), 0.85(t, J=6.5Hz ,1H).
实施例162：化合物4-(4-((1R，5S)-3,8-二氮杂环[3.2.1]辛基-3-基)-6-氯-8-氟-2-((2- 氧三氢-1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-氨基-7-氟苯并[b]噻吩-3-碳腈的合成Example 162: Compound 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-8-fluoro-2-(( 2-Oxytrihydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile synthesis
Figure PCTCN2022127912-appb-000061
Figure PCTCN2022127912-appb-000061
步骤1：化合物162-1的合成Step 1: Synthesis of compound 162-1
在室温下，将四氢铝锂(87.06mg)加入四氢呋喃(4.00mL)中，N 2保护下，冰浴下滴加入2-亚甲基-5-氧三氢-1H-吡咯利嗪-7a(5H)-羧酸乙酯的四氢呋喃(0.30mL)溶液。升至70℃搅拌3小时。将反应冷却，在冰浴下滴加入H 2O(87uL)，接着滴加入15％NaOH(87uL)溶液，最后滴加入H 2O(261uL)。室温搅拌10分钟，再加入无水硫酸钠干燥并搅拌5分钟。过滤，滤饼用EA冲洗，滤液减压浓缩得到粗品162-1，直接用于下一步。 At room temperature, lithium aluminum tetrahydrogen (87.06mg) was added to tetrahydrofuran (4.00mL), under the protection of N2 , 2-methylene-5-oxotrihydro-1H-pyrrolizine-7a was added dropwise under ice-cooling A solution of (5H)-ethyl carboxylate in tetrahydrofuran (0.30 mL). Warm up to 70°C and stir for 3 hours. The reaction was cooled, and H2O (87 uL) was added dropwise under ice bath, followed by 15% NaOH (87 uL) solution, and finally H2O (261 uL) was added dropwise. Stir at room temperature for 10 minutes, then add anhydrous sodium sulfate to dry and stir for 5 minutes. After filtration, the filter cake was washed with EA, and the filtrate was concentrated under reduced pressure to obtain the crude product 162-1, which was directly used in the next step.
步骤2：化合物162-2的合成Step 2: Synthesis of compound 162-2
在室温下，将162-1(120.00mg)和中间体M5(36.22mg)加入四氢呋喃(2.50mL)中，再加入叔丁醇钠(30.29mg)。室温搅拌10分钟。LCMS监测反应完成。过滤，滤饼用DCM冲洗，经柱层析纯化(DCM/MeOH,5％MeOH)得到目标化合物162-2(101mg，产率76.81％)。ESI-MS m/z:834[M+H] +。 162-1 (120.00 mg) and intermediate M5 (36.22 mg) were added to tetrahydrofuran (2.50 mL) at room temperature, followed by sodium tert-butoxide (30.29 mg). Stir at room temperature for 10 minutes. LCMS monitored the completion of the reaction. After filtration, the filter cake was washed with DCM, and purified by column chromatography (DCM/MeOH, 5% MeOH) to obtain the target compound 162-2 (101 mg, yield 76.81%). ESI-MS m/z: 834 [M+H] + .
步骤3：化合物162的合成Step 3: Synthesis of compound 162
在室温下，将162-2(55.00mg)加入二氯甲烷(3.00mL)，再加入TFA(0.80mL)。室温搅拌1.5小时。LCMS监测反应完成。减压浓缩，粗品经饱和NaHCO 3调至PH＝8，在用DCM/MeOH(10/1)萃取2次，有机层用饱和食盐水洗涤再用无水硫酸钠干燥，浓缩，浓缩物经Pre-HPLC制备得化合物162(16.4mg，产率38.80％，纯度98.9％)。 1H NMR(500MHz，氘代甲醇)δ7.95(d,J＝1.6Hz,1H),7.22(dd,J＝8.3,5.0Hz,1H),7.06(dd,J＝9.4,8.3Hz,1H),5.28(d,J＝13.4Hz,2H),4.78–4.63(m,6H),4.41–4.31(m,1H),4.23(s,2H),3.91(dd,J＝26.3,13.9Hz,3H),3.77(dq,J＝11.9,5.9Hz,1H),3.10–3.01(m,1H),2.80(d,J＝16.5Hz,1H),2.38(dp,J＝18.3,5.9Hz,1H),2.28–2.13(m,4H),1.31(d,J＝20.6Hz,2H)。ESI-MS m/z:634[M+H] +。 162-2 (55.00 mg) was added to dichloromethane (3.00 mL) followed by TFA (0.80 mL) at room temperature. Stir at room temperature for 1.5 hours. LCMS monitored the completion of the reaction. Concentrated under reduced pressure, the crude product was adjusted to PH=8 with saturated NaHCO 3 , extracted twice with DCM/MeOH (10/1), the organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, concentrated, and the concentrate was treated with Pre - Compound 162 (16.4 mg, yield 38.80%, purity 98.9%) was prepared by HPLC. 1 H NMR (500MHz, deuterated methanol) δ7.95 (d, J = 1.6Hz, 1H), 7.22 (dd, J = 8.3, 5.0Hz, 1H), 7.06 (dd, J = 9.4, 8.3Hz, 1H ),5.28(d,J＝13.4Hz,2H),4.78–4.63(m,6H),4.41–4.31(m,1H),4.23(s,2H),3.91(dd,J＝26.3,13.9Hz, 3H), 3.77(dq, J=11.9, 5.9Hz, 1H), 3.10–3.01(m, 1H), 2.80(d, J=16.5Hz, 1H), 2.38(dp, J=18.3, 5.9Hz, 1H ), 2.28–2.13 (m, 4H), 1.31 (d, J=20.6Hz, 2H). ESI-MS m/z: 634 [M+H] + .
实施例163：化合物4-(4-((1R，5S)-3,8-二氮杂环[3.2.1]辛基-3-基)-6-氯-2-((2- (二氟亚甲基)四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-8-氟喹唑啉-7-基)-2-氨基-7-氟苯并[b]噻吩-3-碳腈的合成Example 163: Compound 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-2-((2-(di Fluoromethylene)tetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene -Synthesis of 3-carbonitrile
Figure PCTCN2022127912-appb-000062
Figure PCTCN2022127912-appb-000062
步骤1：化合物163-1的合成Step 1: Synthesis of compound 163-1
在室温下，将化合物2,5-二氧三氢-1H-吡咯利嗪-7a(5H)-羧酸乙酯(500mg)溶于甲醇(10mL)中，0℃下将二氯亚砜(0.69mL)慢慢加入，然后升温至室温反应1h。反应完毕后，将反应液减压浓缩，残余物加饱和碳酸氢钠水溶液(50mL)和DCM(50mL)萃取，有机相无水硫酸钠干燥，浓缩得化合物163-1的粗品，不经纯化直接用于下一步反应。At room temperature, the compound 2,5-dioxotrihydro-1H-pyrrolizine-7a(5H)-carboxylate ethyl ester (500mg) was dissolved in methanol (10mL), and at 0°C, thionyl chloride ( 0.69mL) was slowly added, and then warmed to room temperature for 1h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was extracted with saturated aqueous sodium bicarbonate solution (50 mL) and DCM (50 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain the crude product of compound 163-1, which was directly obtained without purification. for the next reaction.
步骤2：化合物163-2的合成Step 2: Synthesis of compound 163-2
在室温下，将上一步化合物163-1的粗产物溶于20mL无水THF中，0℃下将LAH(222mg)慢慢加入，70℃反应1h。然后降温至0℃，加入222mL水，再加入222mL15％强氧化钠水溶液，再将666mL水加入，室温反应30min，加适量无水硫酸钠，室温反应15min，过滤，滤液旋干，得化合物163-2(370mg)。At room temperature, the crude product of compound 163-1 from the previous step was dissolved in 20 mL of anhydrous THF, LAH (222 mg) was slowly added at 0°C, and reacted at 70°C for 1 h. Then cool down to 0°C, add 222mL of water, then add 222mL of 15% strong sodium oxide aqueous solution, then add 666mL of water, react at room temperature for 30min, add an appropriate amount of anhydrous sodium sulfate, react at room temperature for 15min, filter, and spin the filtrate to obtain compound 163- 2 (370 mg).
步骤3：化合物163-3的合成Step 3: Synthesis of compound 163-3
在室温下，将中间体M5(900mg)和化合物163-2(357mg)溶于无水THF(20mL)中，然后将t-BuONa(228mg)慢慢加入，室温反应10min反应完全。加入水(50mL)淬灭，并加入EA(50mL)萃取，有机相无水硫酸钠干燥，过滤，浓缩，柱色谱纯化得目标化合物163-3(963mg)。ESI-MS m/z:882[M+H] +。 Intermediate M5 (900 mg) and compound 163-2 (357 mg) were dissolved in anhydrous THF (20 mL) at room temperature, then t-BuONa (228 mg) was added slowly, and the reaction was complete at room temperature for 10 min. Water (50 mL) was added to quench, and EA (50 mL) was added to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 163-3 (963 mg). ESI-MS m/z: 882 [M+H] + .
步骤4：化合物163-4的合成Step 4: Synthesis of compound 163-4
在室温下，将化合物163-3(800mg)溶于THF(2mL)和4M HCl·1,4-二氧六环(8mL)中，50℃反应10min，有固体析出，过滤，得目标化合物163-4的盐酸盐(845mg)。 ESI-MS m/z:636[M+H] +。 Compound 163-3 (800mg) was dissolved in THF (2mL) and 4M HCl·1,4-dioxane (8mL) at room temperature, reacted at 50°C for 10min, a solid precipitated, filtered to obtain the target compound 163 -4 hydrochloride (845mg). ESI-MS m/z: 636 [M+H] + .
步骤5：化合物163-5的合成Step 5: Synthesis of compound 163-5
在室温下，将化合物163-4(800mg)，(Boc) 2O(1.37g)，DIPEA(1.6g)和DMAP(31mg)溶于THF(12mL)和DMF(3mL)中，室温反应10min。将反应液慢慢倒入饱和碳酸氢钠中(20mL)，搅拌30min，然后加入EA(50mL)和水(30mL)萃取，有机相无水硫酸钠干燥，过滤，浓缩，柱色谱纯化得目标化合物163-5(568mg)。 1H NMR(500MHz,Chloroform-d)δ8.02(d,J＝1.5Hz,1H),7.79-7.67(m,1H),7.30(td,J＝5.5,4.9,2.4Hz,1H),7.15(t,J＝8.7Hz,1H),4.46-4.21(m,6H),3.66(d,J＝18.9Hz,2H),3.35(dtd,J＝10.1,5.1,2.9Hz,1H),3.26-3.13(m,1H),2.80(d,J＝18.8Hz,1H),2.74(dt,J＝9.8,7.9Hz,1H),2.46-2.36(m,1H),2.33-2.21(m,1H),2.03-1.97(m,2H),1.97-1.92(m,2H),1.92-1.73(m,4H),1.56(s,9H),1.53(s,9H)。ESI-MS m/z:836[M+H] +。 Compound 163-4 (800 mg), (Boc) 2 O (1.37 g), DIPEA (1.6 g) and DMAP (31 mg) were dissolved in THF (12 mL) and DMF (3 mL) at room temperature for 10 min at room temperature. The reaction solution was slowly poured into saturated sodium bicarbonate (20mL), stirred for 30min, then added EA (50mL) and water (30mL) for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 163-5 (568 mg). 1 H NMR (500MHz, Chloroform-d) δ8.02 (d, J = 1.5Hz, 1H), 7.79-7.67 (m, 1H), 7.30 (td, J = 5.5, 4.9, 2.4Hz, 1H), 7.15 (t, J=8.7Hz, 1H), 4.46-4.21(m, 6H), 3.66(d, J=18.9Hz, 2H), 3.35(dtd, J=10.1, 5.1, 2.9Hz, 1H), 3.26- 3.13(m,1H),2.80(d,J=18.8Hz,1H),2.74(dt,J=9.8,7.9Hz,1H),2.46-2.36(m,1H),2.33-2.21(m,1H) ,2.03-1.97(m,2H),1.97-1.92(m,2H),1.92-1.73(m,4H),1.56(s,9H),1.53(s,9H). ESI-MS m/z: 836 [M+H] + .
步骤6：化合物163-6的合成Step 6: Synthesis of Compound 163-6
在室温下，将化合物163-5(50mg)和二氟甲基(2-吡啶基)砜(116mg)溶解在无水DMF(3mL)中，在-50℃滴加叔丁醇钾(67mg)的DMF(1mL)溶液，控制温度在-40℃反应2小时，反应结束后，在-50℃下滴加饱和氯化铵溶液(5mL)，自然升温至室温反应8小时，加入EA(10mL)稀释，用水(20mL)洗一遍，饱和食盐水(20mL)洗一遍，无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(MeOH:DCM＝0-10％)得到产物163-6(25mg，产率48％)。ESI-MS m/z＝870[M+H] +。 Compound 163-5 (50mg) and difluoromethyl(2-pyridyl)sulfone (116mg) were dissolved in anhydrous DMF (3mL) at room temperature, and potassium tert-butoxide (67mg) was added dropwise at -50°C DMF (1mL) solution, the temperature was controlled at -40°C for 2 hours, after the reaction, saturated ammonium chloride solution (5mL) was added dropwise at -50°C, the temperature was naturally raised to room temperature for 8 hours, and EA (10mL) was added Dilute, wash once with water (20mL) and saturated brine (20mL), dry over anhydrous sodium sulfate, and concentrate. The concentrate was purified by column chromatography (MeOH:DCM=0-10%) to obtain product 163-6 (25 mg, yield 48%). ESI-MS m/z = 870 [M+H] + .
步骤7：化合物163的合成Step 7: Synthesis of compound 163
在室温下，将化合物163-6(22mg)溶于DCM(1mL)，加入TFA(1mL)，加完后室温搅拌30min。反应结束后，将反应液滴加到10mL饱和碳酸氢钠溶液中，用4mL DCM萃取水相3遍。合并有机相，有机相用5mL饱和食盐水洗一遍，用无水硫酸钠干燥，浓缩。浓缩物经Pre-HPCL纯化得到产物163(20.1mg，产率87％)。 1HNMR(500MHz,)δ10.81(s,1H),9.32(s,1H),9.05(s,1H),8.14(s,2H),7.98(s,1H),7.26-7.15(m,2H),4.70-4.57(m,3H),4.40(d,J＝13.9Hz,1H),4.28-4.24(m,1H),4.23-4.06(m,4H),3.92(d,J＝14.0Hz,1H),3.73-3.70(m,1H),3.31(s,1H),2.97(d,J＝16.1Hz,1H),2.83(d,J＝15.5Hz,1H),2.23-2.01(m,4H),1.93-1.48(m,4H)。ESI-MS m/z＝670[M+H] +。 Compound 163-6 (22 mg) was dissolved in DCM (1 mL) at room temperature, TFA (1 mL) was added, and stirred at room temperature for 30 min after the addition was complete. After the reaction, the reaction solution was added dropwise into 10 mL of saturated sodium bicarbonate solution, and the aqueous phase was extracted 3 times with 4 mL of DCM. The organic phases were combined, washed once with 5 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by Pre-HPCL to give product 163 (20.1 mg, 87% yield). 1 H NMR (500MHz,) δ10.81 (s, 1H), 9.32 (s, 1H), 9.05 (s, 1H), 8.14 (s, 2H), 7.98 (s, 1H), 7.26-7.15 (m, 2H ),4.70-4.57(m,3H),4.40(d,J=13.9Hz,1H),4.28-4.24(m,1H),4.23-4.06(m,4H),3.92(d,J=14.0Hz, 1H),3.73-3.70(m,1H),3.31(s,1H),2.97(d,J=16.1Hz,1H),2.83(d,J=15.5Hz,1H),2.23-2.01(m,4H ), 1.93-1.48 (m, 4H). ESI-MS m/z = 670 [M+H] + .
实施例180：化合物4-(4-((1R，5S)-3,8-二氮杂环[3.2.1]辛基-3-基)-6-氯-8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯啉-7a(5H-基)甲氧基)喹唑啉-7-基)-2-氨基苯并[b] 噻吩-3-碳腈的合成Example 180: Compound 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-8-fluoro-2-(( 2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-2-aminobenzo[b]thiophene-3-carbonitrile synthesis
Figure PCTCN2022127912-appb-000063
Figure PCTCN2022127912-appb-000063
步骤1：化合物180-1的合成Step 1: Synthesis of compound 180-1
在室温下，在氮气氛围下，将中间体M4(10.5g)、中间体1-1(10.0g)、Pd(DPEPhos)Cl 2(2.3g)和磷酸钾(10.1g)溶于甲苯(150mL)，升温至100℃搅拌9h。反应完成后，将反应液用EA(300mL)稀释，用水(100mL)洗一遍，饱和食盐水(100mL)洗一遍，有机相用无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(EA:PE＝1-20％)得到产物180-1(8.5g，产率65％)。ESI-MS m/z＝822[M+H] +。 Intermediate M4 (10.5 g), Intermediate 1-1 (10.0 g), Pd(DPEPhos)Cl 2 (2.3 g) and potassium phosphate (10.1 g) were dissolved in toluene (150 mL) at room temperature under nitrogen atmosphere ), heated to 100°C and stirred for 9h. After the reaction was completed, the reaction solution was diluted with EA (300 mL), washed once with water (100 mL) and saturated brine (100 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (EA:PE=1-20%) to obtain product 180-1 (8.5 g, yield 65%). ESI-MS m/z = 822 [M+H] + .
步骤2：化合物180的合成Step 2: Synthesis of compound 180
在室温下，将化合物180-1(8.5g)溶于DCM(80mL)中，室温下滴加TFA(80mL)，加完后室温搅拌30min。反应结束后，将反应液浓缩。加入NH 3的甲醇溶液(7M，20mL)中和，再浓缩。浓缩物经柱色谱纯化((7M NH 3in MeOH):DCM＝1-10％)得到目标化合物180(5.4g，产率86％)。ESI-MS m/z＝622[M+H] +。 Compound 180-1 (8.5 g) was dissolved in DCM (80 mL) at room temperature, TFA (80 mL) was added dropwise at room temperature, and stirred at room temperature for 30 min after the addition was complete. After the reaction was completed, the reaction solution was concentrated. Neutralize by adding NH 3 in methanol (7M, 20 mL), and concentrate. The concentrate was purified by column chromatography ((7M NH 3 in MeOH):DCM=1-10%) to obtain the target compound 180 (5.4 g, yield 86%). ESI-MS m/z = 622 [M+H] + .
实施例181：化合物的2-氨基-4-(6-氯-4-((1-(二甲氨基)环丁基)甲基)氨基)-8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-腈合成Example 181: 2-Amino-4-(6-chloro-4-((1-(dimethylamino)cyclobutyl)methyl)amino)-8-fluoro-2-((2R, 7aS) of the compound Synthesis of -2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
Figure PCTCN2022127912-appb-000064
Figure PCTCN2022127912-appb-000064
步骤1：化合物181-1的合成Step 1: Synthesis of compound 181-1
在室温下，把化合物环丁酮(7.0g)，二甲胺盐酸盐(8.14g)加入反应瓶中，降温至 0℃，取***(6.50g)溶解在H 2O(60mL)中，然后缓慢滴加到反应液中，加完室温反应12h。加入***萃取两次(60mL x 2)，再用饱和氯化钠水溶液60mL×2洗涤、分液。加入无水硫酸钠干燥。过滤，浓缩，得到无色液体状目标化合物181-1(9.7g，产率78.2％)ESI-MS m/z:125[M+H] +。 Add the compound cyclobutanone (7.0g) and dimethylamine hydrochloride (8.14g) into the reaction flask at room temperature, cool down to 0°C, and dissolve potassium cyanide (6.50g) in H 2 O (60mL) , and then slowly added dropwise to the reaction solution, and the reaction was completed at room temperature for 12 hours. Diethyl ether was added to extract twice (60mL x 2), and then washed with saturated aqueous sodium chloride solution 60mL x 2 and separated. Add anhydrous sodium sulfate to dry. After filtration and concentration, the target compound 181-1 was obtained as a colorless liquid (9.7 g, yield 78.2%) ESI-MS m/z: 125[M+H] + .
步骤2：化合物181-2的合成Step 2: Synthesis of compound 181-2
在室温下，将化合物181-1(250mg)溶于THF(4mL)中，降温至0℃，缓慢加四氢铝锂(153mg)，加完恢复室温反应1h。将反应液降温至0℃，先加0.15mL水淬灭，再加0.15mL的15％氢氧化钠水溶液，加0.45mL水，恢复室温搅拌5min后加无水硫酸镁干燥，过滤，滤饼用DCM冲洗三次，浓缩母液，得到无色液体状目标化合物181-2(170mg，产率65.9％)。ESI-MS m/z:129[M+H] +。 Compound 181-1 (250mg) was dissolved in THF (4mL) at room temperature, cooled to 0°C, lithium aluminum hydride (153mg) was added slowly, and the reaction was resumed at room temperature for 1h after addition. Cool the reaction solution to 0°C, first add 0.15mL water to quench, then add 0.15mL 15% sodium hydroxide aqueous solution, add 0.45mL water, return to room temperature and stir for 5 minutes, then add anhydrous magnesium sulfate to dry, filter, and use the filter cake DCM was washed three times, and the mother liquor was concentrated to obtain the target compound 181-2 (170 mg, yield 65.9%) as a colorless liquid. ESI-MS m/z: 129 [M+H] + .
步骤3：化合物181-3的合成Step 3: Synthesis of compound 181-3
在室温下，在反应瓶中加入中间体M1-3(400.00mg)，乙腈(8.00mL)，降温至0℃，加入化合物181-2(155.24mg)和N,N-二异丙基乙胺(0.60mL)，加完0℃下反应0.2h后恢复室温反应0.3h。向反应混合物中加EA和水萃取，干燥，浓缩。用DCM:PE＝1:3打浆，过滤，拿到黄色固体状目标化合物181-3(435.00mg，产率85.11％)。ESI-MS m/z:421[M+H] +。 At room temperature, add intermediate M1-3 (400.00mg), acetonitrile (8.00mL) to the reaction flask, cool down to 0°C, add compound 181-2 (155.24mg) and N,N-diisopropylethylamine (0.60mL), react at 0°C for 0.2h after the addition, return to room temperature and react for 0.3h. The reaction mixture was extracted with EA and water, dried and concentrated. Slurry with DCM:PE=1:3, filter to obtain the target compound 181-3 (435.00 mg, yield 85.11%) as a yellow solid. ESI-MS m/z: 421 [M+H] + .
步骤4：化合物181-4的合成Step 4: Synthesis of Compound 181-4
在室温下，在反应瓶中加入化合物181-3(360.00mg)，二碳酸二叔丁酯(372.25mg)，三乙胺(0.36mL)，4-二甲氨基吡啶(10.42mg)和二氯甲烷(6.00mL)，室温反应8h。向反应混合物中加DCM和水萃取，干燥，浓缩。浓缩物经Pre-TLC分离(DCM:MeOH＝30:1)，得到黄色固体状目标化合物181-4(390.00mg，产率87.57％)。ESI-MS m/z:521[M+H] +。 At room temperature, compound 181-3 (360.00 mg), di-tert-butyl dicarbonate (372.25 mg), triethylamine (0.36 mL), 4-dimethylaminopyridine (10.42 mg) and dichloro Methane (6.00mL) was reacted at room temperature for 8h. The reaction mixture was extracted with DCM and water, dried and concentrated. The concentrate was separated by Pre-TLC (DCM:MeOH=30:1) to obtain the target compound 181-4 (390.00 mg, yield 87.57%) as a yellow solid. ESI-MS m/z: 521 [M+H] + .
步骤5：化合物181-5的合成Step 5: Synthesis of compound 181-5
在室温下，将化合物((2R,7AS)-2-氟六氢-1H-吡咯嗪-7A-基)甲醇(109.74mg)溶于四氢呋喃(5.00mL)，降温至0℃，加入氢化钠(33.09mg)，室温反应0.2h，再降温至0℃，加化合物181-4(360.00mg)，恢复室温反应2h。向反应混合物中加水和EA萃取，干燥，浓缩。浓缩物经Pre-TLC分离(DCM:MeOH:氨水＝25:1:0.25)得到黄色固体状目标化合物181-5(160.00mg，产率35.99％)。ESI-MS m/z:644[M+H] +。 Dissolve the compound ((2R,7AS)-2-fluorohexahydro-1H-pyrrolazin-7A-yl)methanol (109.74mg) in tetrahydrofuran (5.00mL) at room temperature, cool to 0°C, add sodium hydride ( 33.09mg), react at room temperature for 0.2h, then cool down to 0°C, add compound 181-4 (360.00mg), and react at room temperature for 2h. Water and EA were added to the reaction mixture, extracted, dried and concentrated. The concentrate was separated by Pre-TLC (DCM:MeOH:ammonia water=25:1:0.25) to obtain the target compound 181-5 (160.00 mg, yield 35.99%) as a yellow solid. ESI-MS m/z: 644 [M+H] + .
步骤6：化合物181-6的合成Step 6: Synthesis of Compound 181-6
在室温下，在反应瓶中加入化合物181-5(105.00mg)，二氯甲烷(1.00mL)和三氟乙酸(1.00mL)，室温反应0.5h。将反应液浓缩，加DCM溶解，用碳酸氢钠水溶液调pH＝8，DCM萃取，干燥，浓缩。浓缩物经Pre-TLC分离(DCM:MeOH:氨水＝22:1:0.2)得到黄色固体状目标化合物181-6(75.00mg，产率84.55％)。ESI-MS m/z:544[M+H] +。 At room temperature, compound 181-5 (105.00 mg), dichloromethane (1.00 mL) and trifluoroacetic acid (1.00 mL) were added into the reaction flask, and reacted at room temperature for 0.5 h. The reaction solution was concentrated, dissolved in DCM, adjusted to pH=8 with aqueous sodium bicarbonate solution, extracted with DCM, dried and concentrated. The concentrate was separated by Pre-TLC (DCM:MeOH:ammonia water=22:1:0.2) to obtain the target compound 181-6 (75.00 mg, yield 84.55%) as a yellow solid. ESI-MS m/z: 544 [M+H] + .
步骤7：化合物181-7的合成Step 7: Synthesis of Compound 181-7
在室温下，在反应瓶中加入化合物181-6(60.00mg)，中间体M2(89.02mg)，CataCXium A Pd G3(16.02mg)，磷酸钾(70.11mg)和四氢呋喃(2.00mL)，氮气置换后，氮气保护下65℃反应16h。加水和EA萃取，干燥，浓缩。浓缩物经Pre-TLC分离(DCM:MeOH:氨水＝15:1：0.15)得到黄色固体181-7(10.00mg，产率12.01％)。ESI-MS m/z:756[M+H] +。 At room temperature, add compound 181-6 (60.00mg), intermediate M2 (89.02mg), CataCXium A Pd G3 (16.02mg), potassium phosphate (70.11mg) and tetrahydrofuran (2.00mL) in the reaction flask, nitrogen replacement Afterwards, the reaction was carried out at 65° C. for 16 h under the protection of nitrogen. Add water and EA to extract, dry and concentrate. The concentrate was separated by Pre-TLC (DCM:MeOH:ammonia water=15:1:0.15) to obtain yellow solid 181-7 (10.00 mg, yield 12.01%). ESI-MS m/z: 756 [M+H] + .
步骤8：化合物181的合成Step 8: Synthesis of Compound 181
在室温下，在反应瓶中加入化合物181-7(10.00mg)，二氯甲烷(0.50mL)，三氟乙酸(0.50mL),室温反应0.3h。将反应液浓缩，用Pre-HPLC分离得到白色固体状目标化合物181(2.10mg，产率24.25％)。ESI-MS m/z:656[M+H] +。 At room temperature, compound 181-7 (10.00 mg), dichloromethane (0.50 mL), and trifluoroacetic acid (0.50 mL) were added into the reaction flask, and reacted at room temperature for 0.3 h. The reaction solution was concentrated and separated by Pre-HPLC to obtain the target compound 181 (2.10 mg, yield 24.25%) as a white solid. ESI-MS m/z: 656 [M+H] + .
实施例187：化合物4-(4-((1R，5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-6-氯-8-氟-2-((2-亚甲基四氢-1H-吡咯烷-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-氨基苯并[b]噻吩-3-腈的合成Example 187: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-8-fluoro-2-( Synthesis of (2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-aminobenzo[b]thiophene-3-carbonitrile
Figure PCTCN2022127912-appb-000065
Figure PCTCN2022127912-appb-000065
步骤1：化合物187-1的合成Step 1: Synthesis of compound 187-1
将化合物188-2(600.00mg)，中间体M7(185.52mg)分别加入THF(10.00mL)，再加入t-BuONa(155.14mg)。室温搅拌0.5小时反应液减压浓缩，再用DCM(30ml)和H 2O(15ml)萃取2次，有机层用饱和食盐水洗涤再用无水硫酸钠干燥。经柱层析纯化DCM/MeOH，5％MeOH洗脱出化合物187-1(450mg，收率68.29％)。 Compound 188-2 (600.00 mg) and intermediate M7 (185.52 mg) were added to THF (10.00 mL) and t-BuONa (155.14 mg) respectively. The reaction solution was stirred at room temperature for 0.5 hours, concentrated under reduced pressure, extracted twice with DCM (30 ml) and H 2 O (15 ml), and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. DCM/MeOH was purified by column chromatography, and compound 187-1 (450 mg, yield 68.29%) was eluted with 5% MeOH.
步骤2：化合物187的合成Step 2: Synthesis of compound 187
将化合物187-1(450.00mg)加入DCM(10.00mL)中，再加入TFA(5.00mL)，室温搅拌2小时。反应液减压浓缩，粗品经HPLC制备得目标化合物187(180mg，收率 52.47％)ESI-MS m/z:615[M+H] +。 Compound 187-1 (450.00 mg) was added to DCM (10.00 mL), then TFA (5.00 mL) was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain the target compound 187 (180 mg, yield 52.47%) ESI-MS m/z: 615[M+H] + .
1H NMR(500MHz,DMSO-d 6)δ11.12(s,1H),10.02(d,J＝10.1Hz,1H),9.78(s,1H),8.01–7.76(m,4H),7.21(m,2H),5.20(d,J＝12.5Hz,2H),4.62(m,3H),4.39(d,J＝13.6Hz,1H),4.16(m,3H),4.05(d,J＝13.6Hz,1H),3.61(s,2H),3.17(s,1H),2.94(d,J＝16.2Hz,1H),2.75(d,J＝16.2Hz,1H),2.31–1.79(m,9H). 1 H NMR (500MHz, DMSO-d 6 ) δ11.12(s, 1H), 10.02(d, J=10.1Hz, 1H), 9.78(s, 1H), 8.01–7.76(m, 4H), 7.21( m,2H),5.20(d,J=12.5Hz,2H),4.62(m,3H),4.39(d,J=13.6Hz,1H),4.16(m,3H),4.05(d,J=13.6 Hz,1H),3.61(s,2H),3.17(s,1H),2.94(d,J=16.2Hz,1H),2.75(d,J=16.2Hz,1H),2.31–1.79(m,9H ).
实施例188：化合物4-(4-((1R，5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-6-氯-2-((2-(二氟甲基)四氢-1H-吡咯烷-7a(5H)-基)甲氧基)-8-氟喹唑啉-7-基)-2-氨基苯并[b]噻吩-3-腈的合成Example 188: Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-2-((2-( Difluoromethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-2-aminobenzo[b]thiophene-3-carbonitrile Synthesis
Figure PCTCN2022127912-appb-000066
Figure PCTCN2022127912-appb-000066
步骤1：化合物188-1的合成Step 1: Synthesis of compound 188-1
在室温下，将M5-3(10.00g)，中间体M4(15.46g)加入甲苯(150.00mL)中，再加入Pd(DPEPhos)Cl 2(2.76g)和K 3PO 4(12.30g)。N 2置换三次，N 2保护下，升至100℃反应10h。加入EA(80mL)和H 2O(100mL)萃取2次，有机层用饱和食盐水洗涤再用无水硫酸钠干燥，浓缩，浓缩物经柱层析纯化(PE/EA，25％EA)得到化合物188-1(9.0g)，ESI-MS m/z:711[M+H] +。 At room temperature, M5-3 (10.00 g), intermediate M4 (15.46 g) were added to toluene (150.00 mL), and then Pd(DPEPhos)Cl 2 (2.76 g) and K 3 PO 4 (12.30 g) were added. N 2 was replaced three times, and under the protection of N 2 , the temperature was raised to 100°C for 10 h. Add EA (80mL) and H 2 O (100mL) to extract twice, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by column chromatography (PE/EA, 25% EA) to obtain Compound 188-1 (9.0 g), ESI-MS m/z: 711 [M+H] + .
步骤2：化合物188-2的合成Step 2: Synthesis of compound 188-2
在室温下，将化合物188-1(9.0g)加入DCM(100.00mL)再加入m-CPBA(8.73g)。室温搅拌0.5小时。加入饱和NaHCO 3调至PH＝8，再用亚硫酸钠溶液淬灭过量的m-CPBA，减压浓缩除去DCM。再用EA(70mL)萃取2次，有机层用饱和NaHCO 3洗涤最后用食盐水洗涤，无水硫酸钠干燥，浓缩。浓缩物经经柱层析纯化(PE/EA,50％EA)得到目标中间体188-2(7.61g)。ESI-MS m/z:743[M+H] +。 Compound 188-1 (9.0 g) was added to DCM (100.00 mL) followed by m-CPBA (8.73 g) at room temperature. Stir at room temperature for 0.5 hours. Add saturated NaHCO 3 to adjust to PH = 8, then quench excess m-CPBA with sodium sulfite solution, and concentrate under reduced pressure to remove DCM. It was extracted twice with EA (70 mL), and the organic layer was washed with saturated NaHCO 3 and finally with brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE/EA, 50% EA) to obtain the target intermediate 188-2 (7.61 g). ESI-MS m/z: 743 [M+H] + .
步骤3：化合物188-3的合成Step 3: Synthesis of compound 188-3
在室温下，在化合物M6(58mg)中加入THF(2mL)，再加入NaH(36mg)，室温搅 拌5min后加入化合物188-2(150mg)，室温反应15min。冰浴下加饱和氯化铵水溶液淬灭反应，EA萃取，干燥，浓缩，用Pre-TLC分离(DCM:MeOH:氨水＝15:1:0.15)，得到黄色固体化合物188-3(106mg)。ESI-MS m/z:852[M+H] +。 At room temperature, THF (2 mL) was added to compound M6 (58 mg), then NaH (36 mg) was added, stirred at room temperature for 5 min, compound 188-2 (150 mg) was added, and reacted at room temperature for 15 min. The reaction was quenched by adding saturated aqueous ammonium chloride solution in an ice bath, extracted with EA, dried, concentrated, and separated by Pre-TLC (DCM:MeOH:ammonia = 15:1:0.15) to obtain compound 188-3 (106 mg) as a yellow solid. ESI-MS m/z: 852 [M+H] + .
步骤4：化合物188的合成Step 4: Synthesis of Compound 188
在化合物188-3(106mg)中加入DCM(1mL)和TFA(1mL)，室温反应0.3h。将溶剂旋干，用Pre-HPLC分离制备得到目标化合物188(56mg)，ESI-MS m/z:652[M+H] +。 1H NMR(500MHz,DMSO)δ9.61(s,1H),7.96(s,1H),7.89(s,2H),7.82(d,J＝7.9Hz,1H),7.26(t,J＝7.7Hz,1H),7.18(d,J＝7.3Hz,1H),4.76–4.51(m,3H),4.40(d,J＝12.9Hz,1H),4.33–4.09(m,6H),3.84(d,J＝13.6Hz,1H),3.64(d,J＝5.9Hz,1H),3.29(s,1H),2.98(d,J＝16.0Hz,1H),2.84(d,J＝14.8Hz,1H),2.27–2.10(m,3H),1.99(m,4H). Add DCM (1 mL) and TFA (1 mL) to compound 188-3 (106 mg), react at room temperature for 0.3 h. The solvent was spin-dried and separated by Pre-HPLC to obtain the target compound 188 (56 mg), ESI-MS m/z: 652[M+H] + . 1 H NMR (500MHz,DMSO)δ9.61(s,1H),7.96(s,1H),7.89(s,2H),7.82(d,J=7.9Hz,1H),7.26(t,J=7.7 Hz, 1H), 7.18(d, J=7.3Hz, 1H), 4.76–4.51(m, 3H), 4.40(d, J=12.9Hz, 1H), 4.33–4.09(m, 6H), 3.84(d ,J=13.6Hz,1H),3.64(d,J=5.9Hz,1H),3.29(s,1H),2.98(d,J=16.0Hz,1H),2.84(d,J=14.8Hz,1H ),2.27–2.10(m,3H),1.99(m,4H).
下述的实施例采用上述方法合成，或使用相应中间体的类似方法合成。The following examples were synthesized using the above method, or using a similar method using the corresponding intermediates.
Figure PCTCN2022127912-appb-000067
Figure PCTCN2022127912-appb-000067
Figure PCTCN2022127912-appb-000068
Figure PCTCN2022127912-appb-000068
Figure PCTCN2022127912-appb-000069
Figure PCTCN2022127912-appb-000069
Figure PCTCN2022127912-appb-000070
Figure PCTCN2022127912-appb-000070
Figure PCTCN2022127912-appb-000071
Figure PCTCN2022127912-appb-000071
Figure PCTCN2022127912-appb-000072
Figure PCTCN2022127912-appb-000072
Figure PCTCN2022127912-appb-000073
Figure PCTCN2022127912-appb-000073
Figure PCTCN2022127912-appb-000074
Figure PCTCN2022127912-appb-000074
Figure PCTCN2022127912-appb-000075
Figure PCTCN2022127912-appb-000075
药理实验Pharmacological experiment
药理实验1:细胞增殖实验(AGS)Pharmacological Experiment 1: Cell Proliferation Assay (AGS)
将KRas-G12D突变型肿瘤细胞AGS(
Figure PCTCN2022127912-appb-000076
CRL-1739 TM)按1×10 3/孔的细胞密度铺于低吸附96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度20000、6666.67、2222.22、740.74、246.91、82.30、27.43、9.14、3.05、0nM(DMSO终浓度均为0.5％)加入96孔板中，37℃培养96h后向各孔加入50μL Cell-titer GLO工作液，震荡混匀后室温孵育10min，在多功能酶标仪读取Luminescence发光值，将发光值数据计算转换为抑制百分数。并根据以下公式，计算细胞增殖抑制百分数： The KRas-G12D mutant tumor cell AGS (
Figure PCTCN2022127912-appb-000076
CRL-1739 TM ) were spread in a low-adsorption 96-well plate at a cell density of 1×10 3 /well, and placed in a cell culture incubator for overnight culture. After the cells adhered to the wall, the compounds to be tested were added to the 96-well plate at the final concentrations of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, and 0 nM (the final concentration of DMSO was 0.5%), and incubated at 37 °C After 96 hours, add 50 μL of Cell-titer GLO working solution to each well, shake and mix well, and incubate at room temperature for 10 minutes. Read the Luminescence luminescence value on a multi-functional microplate reader, and convert the luminescence value data into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation:
抑制百分数＝(最大值-所测值)/(最大值-Blank)×100Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100
(“最大值”来自0.1％DMSO对照孔，“Blank”来自空白对照孔，“所测值”来自化合物处理孔)。(“Maximum” from 0.1% DMSO control wells, “Blank” from blank control wells, “measured” from compound treated wells).
利用GraphPad Prism软件进行曲线拟合并获取IC 50值。 Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
表1Table 1
化合物名称Compound name AGS IC 50(nM) AGS IC50 (nM) 化合物名称Compound name AGS IC 50(nM) AGS IC50 (nM)
11 2.32.3 112112 586586
77 9393 118118 352352
99 1515 119119 30803080
1010 6868 121121 237237
1111 221221 131131 4545
1212 1111 148148 14561456
1414 346346 149149 21682168
1616 455455 162162 3.43.4
1818 22twenty two 163163 1010
2020 5555 164164 899899
21twenty one 242242 167167 4.34.3
3636 3636 168168 3333
4040 12091209 172172 276276
4444 1818 176176 8.98.9
4747 105105 177177 434434
6565 6868 178178 162162
6666 5.75.7 179179 393393
7676 734734 180180 1.31.3
7878 260260 181181 6464
9595 102102 184184 2727
9696 3434 185185 4.44.4
9797 3636 186186 5.05.0
100100 22twenty two 187187 1.01.0
101101 124124 188188 3.23.2
103103 8585 189189 476476
107107 14541454 190190 954954
110110 1212 191191 571571
111111 446446  the  the
药理实验2:细胞p-ERK检测试验Pharmacological experiment 2: Cell p-ERK detection test
将两种KRas-G12D突变型肿瘤细胞AGS(
Figure PCTCN2022127912-appb-000077
CRL-1739 TM)或Panc 04.03(
Figure PCTCN2022127912-appb-000078
CRL-2555 TM)按5×10 4/孔的细胞密度铺于96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度10000nM、3333nM、1111nM、370.4nM、123.4nM、41.15nM、13.72nM、4.57nM、1.52nM、0.51nM、0.1％DMSO加入96孔板中，培养3h后，利用MSD(Meso Scale Discovery)电化学发光免疫检测试剂盒中的lysis buffer(50μL)提取96孔板中各处理细胞样品的蛋白裂解液，利用BCA方法对蛋白裂解液进行定量，并利用lysis buffer将蛋白样品浓度稀释为0.1μg/μL。向MSD检测96孔板中加入25ul/孔的蛋白稀释液，室温孵育3h后加入25μL detection antibody solution， 继续室温孵育1h，洗板后加入150μL 1×read buffer T。在SECTOR Imager上进行孔板读值，采集原始数据。 Two kinds of KRas-G12D mutant tumor cells AGS (
Figure PCTCN2022127912-appb-000077
CRL-1739 TM ) or Panc 04.03 (
Figure PCTCN2022127912-appb-000078
CRL-2555 TM ) were plated in a 96-well plate at a cell density of 5×10 4 /well, and placed in a cell culture incubator for overnight culture. After the cells adhered to the wall, the compounds to be tested were added to the 96-well plate according to the final concentration of 10000nM, 3333nM, 1111nM, 370.4nM, 123.4nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM, 0.51nM, 0.1% DMSO, and incubated After 3 hours, use the lysis buffer (50 μL) in the MSD (Meso Scale Discovery) electrochemiluminescence immunoassay kit to extract the protein lysate of each treated cell sample in the 96-well plate, use the BCA method to quantify the protein lysate, and use The analysis buffer dilutes the protein sample concentration to 0.1μg/μL. Add 25ul/well protein diluent to the MSD detection 96-well plate, incubate at room temperature for 3h, add 25μL detection antibody solution, continue to incubate at room temperature for 1h, add 150μL 1×read buffer T after washing the plate. Plate readings were performed on a SECTOR Imager to acquire raw data.
根据MSD检测方法中的公式，将读值转化为p-ERK％值：Convert the readings to p-ERK% values according to the formula in the MSD assay method:
p-ERK％值＝((2×磷酸化信号值)/(磷酸化信号值+总信号值))×100p-ERK% value=((2×phosphorylation signal value)/(phosphorylation signal value+total signal value))×100
根据以下公式，计算p-ERK抑制百分数：Calculate the percent inhibition of p-ERK according to the following formula:
抑制百分数＝(最大值-所测值)/(最大值-Blank)×100Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100
(“最大值”来自0.1％DMSO对照孔，“Blank”来自空白对照孔，“所测值”来自化合物处理孔)。(“Maximum” from 0.1% DMSO control wells, “Blank” from blank control wells, “measured” from compound treated wells).
利用GraphPad Prism软件进行曲线拟合并获取IC 50值。 Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
表2Table 2
Figure PCTCN2022127912-appb-000079
Figure PCTCN2022127912-appb-000079
药理实验3：化合物小鼠PK考察Pharmacological experiment 3: PK investigation of compounds in mice
将化合物与溶媒10％DMSO/5％Solutol/85％生理盐水或10％DMSO/10％Solutol/80％生理盐水或10％SBECD的PH5.0柠檬酸盐缓冲液混合(具体溶媒见下表)，涡旋并超声，制备得到0.2mg/ml澄清静脉注射溶液。将化合物与溶媒10％DMSO/5％Solutol/85％水或10％DMSO/10％Solutol/80％水或20％PEG300/10％Solutol/70％含10％SBECD的PH5.0柠檬酸盐缓冲液混合(具体见下表)，涡旋并超声，制备得到1mg/ml澄清口服溶液。选取6至7周龄的Balbc雌性小鼠，静脉和口服分别给予化合物163、化合物188和化合物1，静脉收集5min、15min、30min、1h、2h、4h、7h、24h全血样品，口服收集15min、30min、1h、2h、4h、7h、24h全血样品。以LC-MS/MS方法分析药物浓度，并用Phoenix WinNolin软件(美国Pharsight公司)计算药代参数，结果如表所示。Mix the compound with the vehicle 10% DMSO/5% Solutol/85% normal saline or 10% DMSO/10% Solutol/80% normal saline or pH 5.0 citrate buffer of 10% SBECD (see the table below for the specific vehicle) , vortexed and sonicated to prepare a clear 0.2 mg/ml solution for intravenous injection. Compounds were mixed with vehicle 10% DMSO/5% Solutol/85% water or 10% DMSO/10% Solutol/80% water or 20% PEG300/10% Solutol/70% pH5.0 citrate buffer containing 10% SBECD Mix the solution (see the table below for details), vortex and sonicate to prepare a 1mg/ml clear oral solution. Select Balbc female mice aged 6 to 7 weeks, give compound 163, compound 188 and compound 1 intravenously and orally, respectively, collect whole blood samples intravenously for 5min, 15min, 30min, 1h, 2h, 4h, 7h, 24h, orally collect for 15min , 30min, 1h, 2h, 4h, 7h, 24h whole blood samples. Analyze drug concentration with LC-MS/MS method, and calculate pharmacokinetic parameter with Phoenix WinNolin software (U.S. Pharsight company), and the result is shown in the table.
给药剂量和实验方案如下表3所示。The dosage and experimental scheme are shown in Table 3 below.
表3table 3
Figure PCTCN2022127912-appb-000080
Figure PCTCN2022127912-appb-000080
所测小鼠PK数据如表4：The measured mouse PK data are shown in Table 4:
表4Table 4
Figure PCTCN2022127912-appb-000081
Figure PCTCN2022127912-appb-000081
药理实验4：化合物在Panc04.03CDX模型小鼠中的药效研究Pharmacological experiment 4: Study on the efficacy of compounds in Panc04.03CDX model mice
构建KRAS-G12D突变的人胰腺癌细胞Panc04.03的皮下异种移植肿瘤CD-1小鼠模型，将1*10 7个Panc04.03细胞(加Matrigel，与细胞悬液按照1:1体积混合)接种在每只CD-1裸鼠右后背皮下，每组6只荷瘤小鼠。 To construct a subcutaneous xenograft tumor CD-1 mouse model of human pancreatic cancer cell Panc04.03 with KRAS-G12D mutation, mix 1* 107 Panc04.03 cells (add Matrigel, mix with cell suspension at a volume of 1:1) Inoculate subcutaneously on the right back of each CD-1 nude mouse, 6 tumor-bearing mice in each group.
第一组G1为Vehicle溶媒对照组(PEG300:SOLUTOL:柠檬酸盐缓冲液＝2:1:7)。The first group G1 is the Vehicle vehicle control group (PEG300: SOLUTOL: citrate buffer = 2:1:7).
第二组G2为化合物163单药。The second group G2 is compound 163 single drug.
第三组G3为化合物188单药。The third group G3 is compound 188 single drug.
第四组G4为化合物1单药。The fourth group G4 is compound 1 single drug.
给药剂量和实验方案如下表5所示。The dosage and experimental scheme are shown in Table 5 below.
表5table 5
组别group 动物数number of animals 受试化合物test compound 剂量dose 给药浓度Dosing concentration 给药体积Dosing volume 给药方式和时间How and when to administer
 the 量quantity  the (mg/kg)(mg/kg) (mg/ml)(mg/ml) (ml/kg)(ml/kg)  the
G1G1 66 VehicleVehicle (N/A)(N/A) (N/A)(N/A) 1010 PO,Bid day0-18PO, Bid day0-18
G2G2 66 163163 9090 99 1010 PO,Bid day0-18PO, Bid day0-18
G2G2 66 188188 9090 99 1010 PO,Bid,day0-18PO,Bid,day0-18
G3G3 66 11 9090 99 1010 PO,Bid,day0-18PO,Bid,day0-18
注：PO代表口服灌胃，Bid代表每天两次给药。Note: PO stands for oral gavage, Bid stands for administration twice a day.
实验期间每周2次测量肿瘤大小和小鼠体重，每次给药均参考当天动物体重。During the experiment period, the tumor size and the body weight of the mice were measured twice a week, and each administration was referred to the body weight of the animal on the day.
肿瘤大小测量方法为：利用游标卡尺测量肿瘤的长(a)和宽(b)，肿瘤体积(Tumor volume,TV)的计算公式为：TV＝a*b 2/2 The tumor size measurement method is: use a vernier caliper to measure the length (a) and width (b) of the tumor, and the calculation formula for tumor volume (Tumor volume, TV) is: TV=a*b 2 /2
给药18天后，各给药组的肿瘤生长抑制率(Tumor growth inhibition)如表6。After 18 days of administration, the tumor growth inhibition rate (Tumor growth inhibition) of each administration group is shown in Table 6.
表6Table 6
组别 受试化合物 TGI
G1 Vehicle /
G2 163 27％
G3 188 50％
G4 1 8％
。
group test compound TGI
G1 Vehicle /
G2 163 27%
G3 188 50%
G4 1 8%
.
虽然本发明已通过其实施方式进行了全面的描述，但是值得注意的是，各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。While the invention has been fully described by way of the embodiments thereof, it is to be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should all be included within the scope of the appended claims of the present invention.

Claims (32)

  1. 一种通式(I)所示的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述式(I)结构为：A compound represented by general formula (I), or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts thereof, characterized in that, the structure of the formula (I) is:
    Figure PCTCN2022127912-appb-100001
    Figure PCTCN2022127912-appb-100001
    其中，in,
    A为选自CR 6或N；R 6选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或3-6元杂环基任选地被一个或多个R a取代； A is selected from CR 6 or N; R 6 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N( R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , - S(R a ) 5 , -C(=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl are optionally substituted by one or more R a ;
    B为选自CR 7或N；R 7选自H、氰基、羟基、卤素、C 1-6烷基或C 1-6烷氧基，所述C 1- 6烷基或C 1-6烷氧基任选地被一个或多个选自卤素、氰基、氧代基、羟基、氨基或C 1-6烷氧基的取代基所取代； B is selected from CR 7 or N; R 7 is selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 Alkoxy is optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C alkoxy ;
    R 1选自
    Figure PCTCN2022127912-appb-100002
    其中R 13选自H、羟基、氰基、卤素或C 1-3烷基，所述C 1-3烷基任选地被一个或多个选自卤素、羟基或氰基的取代基所取代；R 13优选为H；其中R 14选自羟基、卤素、氰基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基，所述C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地被一个或多个R b取代；     R 1 is selected from
    Figure PCTCN2022127912-appb-100002
    Wherein R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano R 13 is preferably H; wherein R 14 is selected from hydroxyl, halogen, cyano, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, The C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl are optionally substituted by one or more R b ;
    X 1选自CR 8或N；R 8选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基或C 3-6环烷基任选地被一个或多个R a取代； X 1 is selected from CR 8 or N; R 8 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, - OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , - C(=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl or C 3-6 cycloalkyl is optionally substituted by one or more R ;
    X 2选自CR 9或N；R 9选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6卤代烷氧基； X 2 is selected from CR 9 or N; R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
    X 3选自CH或N； X3 is selected from CH or N;
    X 4选自CH或N； X is selected from CH or N;
    X 5选自O或S； X is selected from O or S;
    L选自键、-O-C 0-8亚烷基、-S-C 0-8亚烷基、-NH-C 0-8亚烷基或C 2-8亚炔基，所述-O-C 0- 8亚烷基、-S-C 0-8亚烷基、-NH-C 0-8亚烷基或C 2-8亚炔基任选地被一个或多个R 10取代；R 10选自H、卤素、氰基、羟基或C 1-6烷基，或者同一个碳原子上的两个R 10连同其连接的原子共同形成C 3-6环烷基； L is selected from a bond, -OC 0-8 alkylene , -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene, the -OC 0-8 alkylene Alkyl, -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene is optionally substituted by one or more R 10 ; R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to them form a C 3-6 cycloalkyl group;
    R 2选自H、卤素、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a、-C(＝O)N(R a) 2、
    Figure PCTCN2022127912-appb-100003
    C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基，所述C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地进一步被一个或多个R 11取代；R 11选自H、卤素、氰基、C 1-6烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基、-C 0-6亚烷基-(5-14元杂芳基)、＝O、＝S、
    Figure PCTCN2022127912-appb-100004
    ＝NCH 3，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基、-C 0- 6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代；     R 2 is selected from H, halogen, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N (R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 ,
    Figure PCTCN2022127912-appb-100003
    C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the C 1-6 alkyl, C 3- 14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl are optionally further substituted by one or more R 11 ; R 11 is selected from H, halogen, cyano , C 1-6 alkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N (R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0- 6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0- 6 alkylene-C(=O)R a , -C 0-6 alkylene-C(=O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene -C 3-14 cycloalkyl, -C 0-6 alkylene - (3-14 membered heterocyclyl) , -C 0-6 alkylene-C 6-14 aryl, -C 0-6 alkylene-(5-14 membered heteroaryl), =O, =S,
    Figure PCTCN2022127912-appb-100004
    = NCH 3 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene, -C 0-6 alkylene-C 3-14 cycloalkane Base, -C 0-6 alkylene-(3-14 membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 Member heteroaryl) optionally can also be substituted by 1 or more R a ;
    R 3选自H、卤素、C 1-6烷基或-OR 12，所述R 12选自C 1-6烷基或C 3-8环烷基，R 12任选地被一个或多个选自羟基、卤素、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或环丙基的取代基所取代； R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
    R 4选自H、氰基、羟基、卤素、C 1-6烷基或C 1-6烷氧基，所述C 1-6烷基或C 1-6烷氧基任选地被一个或多个选自卤素、氰基、氧代基、羟基、氨基或C 1-6烷氧基的取代基所取代； R 4 is selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, and the C 1-6 alkyl or C 1-6 alkoxy is optionally replaced by one or Replaced by multiple substituents selected from halogen, cyano, oxo, hydroxyl, amino or C 1-6 alkoxy;
    R 5选自H、C 1-6烷基或C 3-14环烷基，所述C 1-6烷基或C 3-14环烷基任选地被一个或多个选自卤素、氰基、氧代基、羟基或C 1-6烷氧基的取代基所取代； R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituents of radicals, oxo groups, hydroxyl groups or C 1-6 alkoxyl groups;
    每个R a各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6杂烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基； Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
    每个R b各自独立地选自羟基、C 1-3烷基、3-8元杂环基、-N(R a) 2、-CH 2N(R a) 2； Each R b is independently selected from hydroxyl, C 1-3 alkyl, 3-8 membered heterocyclyl, -N(R a ) 2 , -CH 2 N(R a ) 2 ;
    R c和R d各自独立选自H、卤素、C 0-3亚烷基C 3-6环烷基、C 0-3亚烷基C 6-8芳基、C 1-6烷基或C 1-6卤代烷基；或者，R c和R d与其连接的碳原子一起形成3-8元的杂环基或C 3-8的环烷基； R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
    m、n各自独立地选自0、1、2、3或4。m and n are each independently selected from 0, 1, 2, 3 or 4.
  2. 根据权利要求1所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，式(I)所示的化合物具有如下的通式(II)结构：The compound according to claim 1, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, is characterized in that, the compound shown in formula (I) has the following general formula (II) structure :
    Figure PCTCN2022127912-appb-100005
    Figure PCTCN2022127912-appb-100005
    其中，in,
    X 1选自CR 8或N；R 8选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基或C 3-6环烷基任选地被一个或多个R a取代； X 1 is selected from CR 8 or N; R 8 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, - OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , - C(=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl or C 3-6 cycloalkyl is optionally substituted by one or more R ;
    X 2选自CR 9或N；R 9选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6卤代烷氧基； X 2 is selected from CR 9 or N; R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
    X 3选自CH或N； X3 is selected from CH or N;
    X 4选自CH或N； X is selected from CH or N;
    X 5选自O或S； X is selected from O or S;
    L选自键、-O-C 0-8亚烷基、-S-C 0-8亚烷基、-NH-C 0-8亚烷基或C 2-8亚炔基，所述-O-C 0- 8亚烷基、-S-C 0-8亚烷基、-NH-C 0-8亚烷基或C 2-8亚炔基任选地被一个或多个R 10取代；R 10选自H、卤素、氰基、羟基或C 1-6烷基，或者同一个碳原子上的两个R 10连同其连接的原子共同形成C 3-6环烷基； L is selected from a bond, -OC 0-8 alkylene , -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene, the -OC 0-8 alkylene Alkyl, -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene is optionally substituted by one or more R 10 ; R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to them form a C 3-6 cycloalkyl group;
    R 1选自
    Figure PCTCN2022127912-appb-100006
    其中R 13选自H、羟基、氰基、卤素或C 1-3烷基，所述C 1-3烷基任选地被一个或多个选自卤素、羟基或氰基的取代基所取代；R 13优选为H；其中R 14选自羟基、卤素、氰基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基，所述C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地被一个或多个R b取代；     R 1 is selected from
    Figure PCTCN2022127912-appb-100006
    Wherein R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano R 13 is preferably H; wherein R 14 is selected from hydroxyl, halogen, cyano, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, The C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl are optionally substituted by one or more R b ;
    R 2选自H、卤素、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a、-C(＝O)N(R a) 2、
    Figure PCTCN2022127912-appb-100007
    C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基，所述C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地进一步被一个或多个R 11取代；R 11选自H、卤素、氰基、C 1-6烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基、-C 0-6亚烷基-(5-14元杂芳基)、＝O、＝S、
    Figure PCTCN2022127912-appb-100008
    ＝NCH 3，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基、-C 0- 6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代；     R 2 is selected from H, halogen, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N (R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 ,
    Figure PCTCN2022127912-appb-100007
    C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the C 1-6 alkyl, C 3- 14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl are optionally further substituted by one or more R 11 ; R 11 is selected from H, halogen, cyano , C 1-6 alkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N (R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0- 6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0- 6 alkylene-C(=O)R a , -C 0-6 alkylene-C(=O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene -C 3-14 cycloalkyl, -C 0-6 alkylene - (3-14 membered heterocyclyl) , -C 0-6 alkylene-C 6-14 aryl, -C 0-6 alkylene-(5-14 membered heteroaryl), =O, =S,
    Figure PCTCN2022127912-appb-100008
    = NCH 3 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene, -C 0-6 alkylene-C 3-14 cycloalkane Base, -C 0-6 alkylene-(3-14 membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 Member heteroaryl) optionally can also be substituted by 1 or more R a ;
    R 3选自H、卤素、C 1-6烷基或-OR 12，所述R 12选自C 1-6烷基或C 3-8环烷基，R 12任选地被一个或多个选自羟基、卤素、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或环丙基的取代基所取代； R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
    R 4或R 7各自独立地选自H、氰基、羟基、卤素、C 1-6烷基或C 1-6烷氧基，所述C 1-6烷基或C 1-6烷氧基任选地被一个或多个选自卤素、氰基、氧代基、羟基、氨基或C 1-6烷氧基的取代基所取代； R 4 or R 7 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C 1-6 alkoxy;
    R 5选自H、C 1-6烷基或C 3-14环烷基，所述C 1-6烷基或C 3-14环烷基任选地被一个或多个选自卤素、氰基、氧代基、羟基或C 1-6烷氧基的取代基所取代； R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituents of radicals, oxo groups, hydroxyl groups or C 1-6 alkoxyl groups;
    R 6选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或3-6元杂环基任选地被一个或多个R a取代； R 6 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S (O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C (=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Base, C 3-6 cycloalkyl or 3-6 membered heterocyclyl are optionally substituted by one or more R a ;
    每个R a各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6杂烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基； Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
    每个R b各自独立地选自羟基、C 1-3烷基、3-8元杂环基、-N(R a) 2、-CH 2N(R a) 2； Each R b is independently selected from hydroxyl, C 1-3 alkyl, 3-8 membered heterocyclyl, -N(R a ) 2 , -CH 2 N(R a ) 2 ;
    R c和R d各自独立选自H、卤素、C 0-3亚烷基C 3-6环烷基、C 0-3亚烷基C 6-8芳基、C 1-6烷基或C 1-6卤代烷基；或者，R c和R d与其连接的碳原子一起形成3-8元的杂环基或C 3-8的环烷基； R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
    m、n各自独立地选自0、1、2或3。m and n are each independently selected from 0, 1, 2 or 3.
  3. 据权利要求1所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，式(I)所示的化合物具有如下的通式(III)结构：According to the compound described in claim 1, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, it is characterized in that, the compound shown in formula (I) has following general formula (III) structure :
    Figure PCTCN2022127912-appb-100009
    Figure PCTCN2022127912-appb-100009
    其中，in,
    X 1选自CR 8或N；R 8选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基或C 3-6环烷基任选地被一个或多个R a取代； X 1 is selected from CR 8 or N; R 8 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, - OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , - C(=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl or C 3-6 cycloalkyl is optionally substituted by one or more R ;
    X 2选自CR 9或N；R 9选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6卤代烷氧基； X 2 is selected from CR 9 or N; R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
    X 3选自CH或N； X3 is selected from CH or N;
    X 4选自CH或N； X is selected from CH or N;
    X 5选自O或S； X is selected from O or S;
    L选自键、-O-C 0-4亚烷基、-S-C 0-4亚烷基、-NH-C 0-4亚烷基或C 2-4亚炔基，所述-O-C 0- 4亚烷基、-S-C 0-4亚烷基、-NH-C 0-4亚烷基或C 2-4亚炔基任选地被一个或多个R 10取代；R 10选自H、卤素、氰基、羟基或C 1-6烷基，或者同一个碳原子上的两个R 10连同其连接的原子共同形成3-6元环烷基； L is selected from a bond, -OC 0-4 alkylene , -SC 0-4 alkylene, -NH-C 0-4 alkylene or C 2-4 alkynylene, the -OC 0-4 alkylene Alkyl, -SC 0-4 alkylene, -NH-C 0-4 alkylene or C 2-4 alkynylene is optionally substituted by one or more R 10 ; R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to it form a 3-6 membered cycloalkyl group;
    R 13选自H、羟基、氰基、卤素或C 1-3烷基，所述C 1-3烷基任选地被一个多个选自卤素、羟基或氰基的取代基所取代；优选R 1为H； R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano; preferably R1 is H;
    R 2选自H、卤素、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a、-C(＝O)N(R a) 2、
    Figure PCTCN2022127912-appb-100010
    C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6- 14芳基或5-14元杂芳基，所述C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地进一步被一个或多个R 11取代；R 11选自H、卤素、氰基、C 1-6烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2- 6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基、-C 0-6亚烷基-(5-14元杂芳基)、＝S、
    Figure PCTCN2022127912-appb-100011
    ＝NCH 3，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代；     R 2 is selected from H, halogen, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N (R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 ,
    Figure PCTCN2022127912-appb-100010
    C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the C 1-6 alkyl, C 3- 14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl are optionally further substituted by one or more R 11 ; R 11 is selected from H, halogen, cyano , C 1-6 alkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N (R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0- 6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0- 6 alkylene-C(=O)R a , -C 0-6 alkylene-C(=O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl , C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl) , -C 0-6 alkylene -C 6-14 aryl, -C 0-6 alkylene -(5-14 membered heteroaryl), =S,
    Figure PCTCN2022127912-appb-100011
    = NCH 3 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene, -C 3-14 cycloalkyl, -C 0-6 alkylene Alkyl-(3-14 membered heterocyclic group),-C 0-6 alkylene-C 6-14 aryl or-C 0-6 alkylene-(5-14 membered heteroaryl) optionally It can also be replaced by 1 or more R a ;
    R 3选自H、卤素、C 1-6烷基或-OR 12，所述R 12选自C 1-6烷基或C 3-8环烷基，R 12任选地被一个或多个选自羟基、卤素、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或环丙基的取代基所取代； R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
    R 4或R 7各自独立地选自H、氰基、羟基、卤素、C 1-6烷基或C 1-6烷氧基，所述C 1-6烷基或C 1-6烷氧基任选地被一个或多个选自卤素、氰基、氧代基、羟基、氨基或C 1-6烷氧基的取代基所取代； R 4 or R 7 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C 1-6 alkoxy;
    R 5选自H、C 1-6烷基或C 3-14环烷基，所述C 1-6烷基或C 3-14环烷基任选地被一个或多个选自卤素、氰基、氧代基、羟基或C 2-6烷氧基的取代基所取代； R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituent group, oxo group, hydroxyl group or C 2-6 alkoxyl group;
    R 6选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或3-6元杂环基任选地被一个或多个R a取代； R 6 is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S (O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C (=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Base, C 3-6 cycloalkyl or 3-6 membered heterocyclyl are optionally substituted by one or more R a ;
    每个R a各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6杂烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基； Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
    R c和R d各自独立选自H、卤素、C 0-3亚烷基C 3-6环烷基、C 0-3亚烷基C 6-8芳基、C 1-6烷基或C 1-6卤代烷基；或者，R c和R d与其连接的碳原子一起形成3-8元的杂环基或C 3-8的环烷基； R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
    m选自0、1、2或3。m is selected from 0, 1, 2 or 3.
  4. 根据权利要求3所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于：The compound according to claim 3, or its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts, is characterized in that:
    所述R 2选自H、卤素、-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a、-C(＝O)N(R a) 2、C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基，所述C 1-6烷基、C 3-14环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基任选地进一步被一个或多个R 11取代；R 11选自H、卤素、氰基、C 1-6烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代。 The R 2 is selected from H, halogen, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O )N(R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , C 1-6 alkyl, C 3 -14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered Heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl are optionally further substituted by one or more R 11 ; R 11 is selected from H, halogen, cyano, C 1-6 alkyl, - C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0 -6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S( O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene- S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0-6 alkylene-C(=O )R a , -C 0-6 alkylene-C(=O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl), -C 0-6 alkylene -C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 aromatic or -C 0-6 alkylene-(5-14 membered heteroaryl) can optionally be substituted by 1 or more R a .
  5. 根据权利要求1所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，式(I)所示的化合物具有如下的式(IV)结构：The compound according to claim 1, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, is characterized in that, the compound shown in formula (I) has the following formula (IV) structure:
    Figure PCTCN2022127912-appb-100012
    Figure PCTCN2022127912-appb-100012
    其中，in,
    X 1选自CR 8或N；R 8选自H、氨基、取代的氨基、氰基、C 1-6烷基、取代的C 1-6烷基、卤素、C 2-6烯基、取代的C 2-6烯基、C 3-6环烷基或取代的C 3-6环烷基； X 1 is selected from CR 8 or N; R 8 is selected from H, amino, substituted amino, cyano, C 1-6 alkyl, substituted C 1-6 alkyl, halogen, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl;
    B选自CR 7或N；R 7选自H、卤素、氰基或C 1-6烷基； B is selected from CR 7 or N; R 7 is selected from H, halogen, cyano or C 1-6 alkyl;
    X 2选自CR 9或N；R 9选自H、卤素、羟基、C 1-6烷氧基、氰基或C 1-6烷基； X 2 is selected from CR 9 or N; R 9 is selected from H, halogen, hydroxyl, C 1-6 alkoxy, cyano or C 1-6 alkyl;
    A选自CR 6或N；R 6选自H、卤素、氰基或C 1-6烷基； A is selected from CR 6 or N; R 6 is selected from H, halogen, cyano or C 1-6 alkyl;
    L选自键、O、S、NR 10、-O-C 1-4亚烷基或C 2-4亚炔基，所述-O-C 1-4亚烷基或C 2-4亚炔基任选地被一个或多个R 10取代；R 10选自H、卤素、氰基、羟基或C 1-6烷基，或者同一个碳原子上的两个R 10连同其连接的原子共同形成3-6元环烷基； L is selected from bond, O, S, NR 10 , -OC 1-4 alkylene or C 2-4 alkynylene, said -OC 1-4 alkylene or C 2-4 alkynylene optionally Substituted by one or more R 10 ; R 10 is selected from H, halogen, cyano, hydroxyl or C 1-6 alkyl, or two R 10 on the same carbon atom together with the atoms connected to form 3-6 Cycloalkyl;
    R 13选自H、羟基、氰基、卤素或C 1-3烷基，所述C 1-3烷基任选地被一个多个选自卤素、羟基或氰基的取代基所取代；优选R 13为H； R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano; preferably R 13 is H;
    R 2选自-OR a、-OC(O)N(R a) 2、-N(R a) 2、-NR aC(O)R a、-NR aC(O)N(R a) 2、-NR aS(O)R a、-NR aS(O) 2R a、-S(＝O)R a、-S(＝O) 2R a、-SR a、-S(R a) 5、-C(＝O)R a、-C(＝O)OR a、-C(＝O)N(R a) 2、环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选地进一步被一个或多个R 11取代； R 2 is selected from -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2. -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , cycloalkyl, heterocyclyl, aryl or heteroaryl, The cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R 11 ;
    R 11选自H、氰基、卤素、C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)，所述 C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代；每个R a各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6杂烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基； R 11 is selected from H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O) N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene- NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0 -6alkylene -S(R a ) 5 , -C 0-6alkylene -C(=O)R a , -C 0-6alkylene -C(=O)OR a , -C 0 -6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkyl, - C 0-6 alkylene-(3-14 membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl base), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene -C 3-14 cycloalkyl, -C 0-6 alkylene Base-(3-14 membered heterocyclic group),-C 0-6 alkylene-C 6-14 aryl or-C 0-6 alkylene-(5-14 membered heteroaryl) optionally also Can be substituted by 1 or more R a ; each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1 -6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 heteroalkyl , C 3-8 ring Alkyl, 3-8 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl;
    R 3选自H、卤素、C 1-6烷基或-OR 12，所述R 12选自C 1-6烷基或C 3-8环烷基，R 12任选地被一个或多个选自羟基、卤素、C 1-3烷基、C 1-3烷氧基或环丙基的取代基所取代； R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 alkoxy or cyclopropyl;
    R 4或R 5各自独立地选自H、氰基、羟基、卤素、C 1-6烷基或C 2-6烷氧基，所述C 1-6烷基或C 2-6烷氧基任选地被一个或多个选自卤素、氰基、氧代基、羟基或C 2-6烷氧基的取代基所取代； R 4 or R 5 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 2-6 alkoxy, the C 1-6 alkyl or C 2-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxyl or C2-6alkoxy ;
    m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
  6. 根据权利要求5所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于：The compound according to claim 5, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, is characterized in that:
    所述X 2选自CR 9或N；R 9选自H、卤素、氰基或C 1-6烷基； The X 2 is selected from CR 9 or N; R 9 is selected from H, halogen, cyano or C 1-6 alkyl;
    R 2选自环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选地进一步被一个或多个R 11取代； R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R ;
    R 11选自H、氰基、卤素、C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-OC(O)N(R a) 2、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-NR aC(O)R a、-C 0-6亚烷基-NR aC(O)N(R a) 2、-C 0-6亚烷基-NR aS(O)R a、-C 0-6亚烷基-NR aS(O) 2R a、-C 0-6亚烷基-S(＝O)R a、-C 0-6亚烷基-S(＝O) 2R a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(＝O)R a、-C 0-6亚烷基-C(＝O)OR a、-C 0-6亚烷基-C(＝O)N(R a) 2、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R a所取代；每个R a各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6杂烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基。 R 11 is selected from H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O) N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene- NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0 -6alkylene -S(R a ) 5 , -C 0-6alkylene -C(=O)R a , -C 0-6alkylene -C(=O)OR a , -C 0 -6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkyl, - C 0-6 alkylene-(3-14 membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl base), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene -C 3-14 cycloalkyl, -C 0-6 alkylene Base-(3-14 membered heterocyclic group),-C 0-6 alkylene-C 6-14 aryl or-C 0-6 alkylene-(5-14 membered heteroaryl) optionally also Can be substituted by 1 or more R a ; each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1 -6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 heteroalkyl , C 3-8 ring Alkyl, 3-8 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl.
  7. 根据权利要求1-6任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，X 1选自CR 8或N；R 8选自H、卤素、CN、-SR a、-C(＝O)R a、-C(＝O)OR a、 -C(＝O)N(R a) 2、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或C 3-6环烷基；R a各自独立地选自H或C 1-6烷基。 The compound according to any one of claims 1-6, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, is characterized in that, X 1 is selected from CR 8 or N; R 8 is selected from from H, halogen, CN, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 3-6 cycloalkyl; R a is each independently selected from H or C 1-6 alkyl.
  8. 根据权利要求1-7任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，X 2选自CR 9或N；R 9为氰基。 The compound according to any one of claims 1-7, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, is characterized in that, X 2 is selected from CR 9 or N; R 9 is cyano.
  9. 根据权利要求1-8中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，L选自键、
    Figure PCTCN2022127912-appb-100013
    优选
    Figure PCTCN2022127912-appb-100014
    Figure PCTCN2022127912-appb-100015
    The compound according to any one of claims 1-8, or its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts, wherein L is selected from the group consisting of bonds,
    Figure PCTCN2022127912-appb-100013
    preferred
    Figure PCTCN2022127912-appb-100014
    Figure PCTCN2022127912-appb-100015
  10. 根据权利要求1-2、7-9中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R 1选自
    Figure PCTCN2022127912-appb-100016
    优选为
    Figure PCTCN2022127912-appb-100017
    The compound according to any one of claims 1-2, 7-9, or its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts, wherein R is selected from
    Figure PCTCN2022127912-appb-100016
    preferably
    Figure PCTCN2022127912-appb-100017
  11. 根据权利要求1-10中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R 2选自H、-N(R a) 2、-C(＝O)OR a、-C(＝O)N(R a) 2、C 3-8环烷基、
    Figure PCTCN2022127912-appb-100018
    ；所述
    Figure PCTCN2022127912-appb-100019
    任选地被一个或多个选自H、卤素、羟基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷基氧、3-8元杂环基、
    Figure PCTCN2022127912-appb-100020
    -N(R a) 2、-C 0-3亚烷基-SR a、＝O、＝S、＝CH 2、＝CHF、＝CF 2、＝NCH 3的取代基所取代；每个R a各自独立地选自H、C 1-6烷基、 C 1-6羟基烷基、C 1-6氨基烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基。     The compound according to any one of claims 1-10, or its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts, wherein R is selected from H, -N(R a ) 2 , -C(=O)OR a , -C(=O)N(R a ) 2 , C 3-8 cycloalkyl,
    Figure PCTCN2022127912-appb-100018
    ; said
    Figure PCTCN2022127912-appb-100019
    Optionally replaced by one or more selected from H, halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyloxy, 3-8 membered heterocyclyl,
    Figure PCTCN2022127912-appb-100020
    Substituents of -N(R a ) 2 , -C 0-3 alkylene-SR a , =O, =S, =CH 2 , =CHF, =CF 2 , =NCH 3 ; each R a Each independently selected from H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkane Oxygen, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl.
  12. 根据权利要求1-11中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R 3选自H、卤素或-OR 12，所述R 12选自C 1-6烷基、C 1-6卤代烷基或C 3- 8环烷基。 The compound according to any one of claims 1-11, or its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts, wherein R is selected from H, halogen or -OR 12 , the R 12 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl.
  13. 根据权利要求1-12中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R 4选自H、卤素或C 1-6烷基。 The compound according to any one of claims 1-12, or its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts, wherein R is selected from H, halogen or C 1- 6 alkyl.
  14. 根据权利要求1-13中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R 5选自H或C 1-6烷基；优选为H。 The compound according to any one of claims 1-13, or its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts, wherein R is selected from H or C 1-6 alkane group; preferably H.
  15. 根据权利要求1-14中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R 6选自CN、-SR a、-C(＝O)R a、-C(＝O)OR a或-C(＝O)N(R a) 2、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或C 3-6环烷基；R a各自独立地选自H或C 1-6烷基；优选R 6为CN。 The compound according to any one of claims 1-14, or its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts thereof, wherein R is selected from CN, -SR a , - C(=O)R a , -C(=O)OR a or -C(=O)N(R a ) 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy Group or C 3-6 cycloalkyl; R a each independently selected from H or C 1-6 alkyl; preferably R 6 is CN.
  16. 根据权利要求1-15中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R 7选自H、卤素或C 1-6烷基；优选为H。 The compound according to any one of claims 1-15, or its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts, wherein R 7 is selected from H, halogen or C 1- 6Alkyl ; preferably H.
  17. 根据权利要求1-16中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，m选自1或2；优选为1。The compound according to any one of claims 1-16, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, is characterized in that m is selected from 1 or 2; preferably 1.
  18. 根据权利要求1-17中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，n选自1或2；优选为1。The compound according to any one of claims 1-17, or its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts thereof, characterized in that n is selected from 1 or 2; preferably 1.
  19. 根据权利要求1-18中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，选自下述化合物：The compound according to any one of claims 1-18, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, is characterized in that it is selected from the following compounds:
    Figure PCTCN2022127912-appb-100021
    Figure PCTCN2022127912-appb-100021
    优选为preferably
    Figure PCTCN2022127912-appb-100022
    Figure PCTCN2022127912-appb-100022
    其中，各取代基同权利要求1-18中任一项所定义。Wherein, each substituent is as defined in any one of claims 1-18.
  20. 根据权利要求5或6所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其选自下述化合物：The compound according to claim 5 or 6, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, it is selected from the following compounds:
    Figure PCTCN2022127912-appb-100023
    Figure PCTCN2022127912-appb-100023
    优选为preferably
    Figure PCTCN2022127912-appb-100024
    Figure PCTCN2022127912-appb-100024
    更优选为more preferably
    Figure PCTCN2022127912-appb-100025
    Figure PCTCN2022127912-appb-100025
    其中，各取代基的定义同权利要求5或6中所定义。Wherein, the definition of each substituent is as defined in claim 5 or 6.
  21. 根据权利要求1-20任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，选自下式化合物：The compound according to any one of claims 1-20, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, is characterized in that it is selected from the following compounds:
    Figure PCTCN2022127912-appb-100026
    Figure PCTCN2022127912-appb-100026
    其中，in,
    R 13选自H； R 13 is selected from H;
    R 3选自H、C 1-6烷基或卤素； R 3 is selected from H, C 1-6 alkyl or halogen;
    R 4选自H、氰基、羟基或卤素； R is selected from H, cyano, hydroxyl or halogen;
    R 8选自H、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、 R is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl,
    R c或R d各自独立选自H、卤素、C 0-3亚烷基C 3-6环烷基、C 0-3亚烷基C 6-8芳基、C 1-6烷基或C 1-6卤代烷基；或者，R c和R d与其连接的碳原子一起形成3-8元的杂环基或C 3-8的环烷基； R c or R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
    m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
  22. 根据权利要求21所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，The compound according to claim 21, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, is characterized in that,
    所述
    Figure PCTCN2022127912-appb-100027
    选自
    Figure PCTCN2022127912-appb-100028
    said
    Figure PCTCN2022127912-appb-100027
    selected from
    Figure PCTCN2022127912-appb-100028
  23. 根据权利要求22所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，The compound according to claim 22, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, is characterized in that,
    所述
    Figure PCTCN2022127912-appb-100029
    选自
    Figure PCTCN2022127912-appb-100030
    said
    Figure PCTCN2022127912-appb-100029
    selected from
    Figure PCTCN2022127912-appb-100030
  24. 一种化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述化合物选自：A compound, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, is characterized in that the compound is selected from:
    Figure PCTCN2022127912-appb-100031
    Figure PCTCN2022127912-appb-100031
    Figure PCTCN2022127912-appb-100032
    Figure PCTCN2022127912-appb-100032
    Figure PCTCN2022127912-appb-100033
    Figure PCTCN2022127912-appb-100033
    Figure PCTCN2022127912-appb-100034
    Figure PCTCN2022127912-appb-100034
  25. 一种药物组合物，其特征在于，所述药物组合物含有治疗有效量的权利要求1-24任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，以及至少一种药学上可接受的辅料。A pharmaceutical composition, characterized in that the pharmaceutical composition contains a therapeutically effective amount of the compound of any one of claims 1-24, or its stereoisomers, tautomers, deuteriums or drug Salt and at least one pharmaceutically acceptable auxiliary material are used.
  26. 根据权利要求1-24任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，或权利要求25所述的药物组合物在制备药物中的应用。The compound according to any one of claims 1-24, or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, or the application of the pharmaceutical composition described in claim 25 in the preparation of medicine .
  27. 根据权利要求26所述的应用，其特征在于，所述制备药物为在制备治疗和/或预防癌症的药物。The use according to claim 26, characterized in that the preparation of the medicine is the preparation of a medicine for treating and/or preventing cancer.
  28. 根据权利要求26所述的应用，其特征在于，所述制备药物为在制备用于治疗和/或预防由KRAS G12D介导的疾病的药物中的应用，所述KRAS G12D介导的疾病优选为癌症。The application according to claim 26, characterized in that, the preparation of the medicament is the application in the preparation of a medicament for treating and/or preventing a disease mediated by KRAS G12D, and the disease mediated by KRAS G12D is preferably cancer.
  29. 根据权利要求27或28所述的应用，其特征在于，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。The application according to claim 27 or 28, wherein the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small Cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid Carcinoma, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  30. 一种治疗和/或预防疾病的方法，其特征在于，包括向治疗对象施用治疗有效量的权利要求1-24任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，或权利要求25所述的药物组合物。A method for treating and/or preventing diseases, comprising administering a therapeutically effective amount of the compound of any one of claims 1-24, or its stereoisomers, tautomers, Deuterated substance or pharmaceutically acceptable salt, or the pharmaceutical composition described in claim 25.
  31. 根据权利要求30所述的方法，其特征在于，所述疾病为癌症。The method of claim 30, wherein the disease is cancer.
  32. 根据权利要求31所述的方法，其特征在于，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。The method according to claim 31, wherein the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer , pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatocholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
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