WO2023098426A1 - 7-(naphthalene-l-yl)pyrido[4,3-d]pyrimidine derivatives, preparation method therefor, and use thereof - Google Patents

7-(naphthalene-l-yl)pyrido[4,3-d]pyrimidine derivatives, preparation method therefor, and use thereof Download PDF

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WO2023098426A1
WO2023098426A1 PCT/CN2022/130789 CN2022130789W WO2023098426A1 WO 2023098426 A1 WO2023098426 A1 WO 2023098426A1 CN 2022130789 W CN2022130789 W CN 2022130789W WO 2023098426 A1 WO2023098426 A1 WO 2023098426A1
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alkyl
deuterium
hydrogen
group
cyano
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PCT/CN2022/130789
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French (fr)
Chinese (zh)
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寻国良
马志雄
喻红平
陈椎
徐耀昌
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上海和誉生物医药科技有限公司
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Priority to CN202280057185.2A priority Critical patent/CN117940436A/en
Publication of WO2023098426A1 publication Critical patent/WO2023098426A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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 invention belongs to the field of medicine synthesis, and specifically relates to 7-(naphthalene-1-yl)pyrido[4,3-d]pyrimidine derivatives and their preparation and application.
  • the RAS gene family includes HRAS, KRAS and NRAS, which are frequently mutated in cancer as oncogenes. Mutated RAS proteins are present in 20-30% of human tumors. Activated RAS proteins lead to malignant phenotypes in cancer cells, including dysregulation of cell growth and programmed cell death, increased invasiveness and neovascularization. Due to its high affinity for GTP/GDP and the lack of a clear binding pocket, the development of drugs targeting RAS proteins has been slow.
  • RAS proteins function as molecular switches, alternating between a GDP-bound inactive state and a GTP-bound active state.
  • RAS protein After exogenous growth factor stimulation, RAS protein is transformed from an inactive GDP-binding form to an active GTP-binding form, which can bind and activate downstream signaling pathways, through the promotion of guanine nucleotide exchange factors (GEFs).
  • GEFs guanine nucleotide exchange factors
  • GAP GTPase activating/accelerating protein
  • K-RAS is the most frequently mutated subtype in the RAS family in human cancers, including pancreatic cancer (71%), small bowel cancer (35%), colon cancer (35%), biliary tract cancer (26%), endometrial cancer (17%) and lung cancer (19%).
  • pancreatic cancer 71%
  • small bowel cancer 35%
  • colon cancer 35%
  • biliary tract cancer 26%
  • endometrial cancer 17%)
  • lung cancer (19%).
  • G12D/G12V/G12C/G13D are the most common mutation types of K-RAS in pancreatic cancer, lung cancer and colorectal cancer.
  • KRAS-G12D-mediated cancers The development of inhibitors of KRAS is challenging because the protein lacks a distinct pocket. Recent studies have identified a previously undiscovered pocket in the KRAS-GDP bound state. Based on these new findings, covalent binding inhibitors targeting codon 12 mutant cysteine have become a hot spot in the research and development of KRAS inhibitors and some progress has been made. However, in addition to the G12C mutation, other activating mutations targeting KRAS remain to be resolved, especially the KRAS G12D mutation. Therefore, it is necessary to develop safe and effective KRAS G12D inhibitors for the treatment of KRAS-G12D-mediated cancers.
  • the object of the present invention is to provide a 7-(naphthalene-1-yl)pyrido[4,3-d]pyrimidine derivative and its preparation and application.
  • the series of compounds of the present invention have a strong inhibitory effect on KRas G12D, and can be widely used in the preparation of drugs for the treatment and/or prevention of KRas G12D-related cancers or tumors, so that it is expected to develop a new generation of KRas G12D inhibitors.
  • the first aspect of the present invention provides a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and -C 0-4 alkyl-NR 16 R 17 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1 -10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl The substituent of the group is substituted;
  • R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-10 alkoxy, halogen substituted C 1-10 alkoxy and deuterium substituted C 1-10 alkoxy;
  • R 7 is selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)SR 14 , -C 0-8 alkane -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -P(O)(R 15 ) 2 , -C 0-8alkyl- NR 16 R 17 , -C 0-8 alkyl-C(S)NR 16 R 17 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 ,
  • Each R 10 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycle base, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)R 15 or -C 0-8 alkyl-C(O)NR 16 R 17 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, Nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3 -10 cycloalkyl, 3-10 membered heterocyclyl, C 6
  • Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3 -10-membered heterocyclic group, C 6-10 aryl or 5-10-membered heteroaryl group, or, R 11 and R 12 form a 3-10-membered heterocyclic group together with the sulfur atom directly connected to it, the above-mentioned groups are optional Further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1- 10 alkyl, deuterium substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkane -S(O) r
  • n 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • Each r is independently 0, 1 or 2.
  • R is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3 -6 cycloalkyl, 3-6 membered heterocyclic group and -C 0-4 alkyl-NR 16 R 17 , the above groups are independently optionally further selected from deuterium, halogen, cyano, nitro Base, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- Substituents of 6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl and 5-8 membered heteroaryl;
  • R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy and deuterium substituted C 1-4 alkoxy;
  • R 7 is selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 alkyl-C(O)OR 14 , -C 0-4 alkyl-C(O)SR 14 , -C 0-4 alkane -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -P(O)(R 15 ) 2 , -C 0-4alkyl- NR 16 R 17 , -C 0-4 alkyl-C(S)NR 16 R 17 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 ,
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
  • each R 10 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 13 , -C 0-4alkyl -C(O)OR 14 , -C 0-4alkyl -C(O)R 15 or -C 0-4alkyl -C (O)NR 16 R 17 , the above groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4
  • Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclic group, C 6-8 aryl group or 5-8 membered heteroaryl group, or, R 11 and R 12 form a 3-6 membered heterocyclic group together with the sulfur atom directly connected to it, the above-mentioned groups are optional Further by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1- 4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkane -S(O) r R 13
  • the compound of formula (I) is the compound of formula (II):
  • R 1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group and -NR 16 R 17 , the above groups are independently any selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C Substituents of 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl;
  • R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy and deuterium substituted C 1-4 alkoxy;
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
  • R is selected from hydrogen, deuterium, fluorine, cyano, methyl, ethyl, isopropyl Difluoromethyl, trifluoromethyl, dideuteriomethyl, trideuteromethyl, cyclopropylmethyl, cyclopropyl, oxetanyl, oxolyl, azetidinyl, nitrogen Heterocyclopentyl, amino and dimethylamino;
  • R 2a , R 2b , R 2c and R 2d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
  • R 13 and R 14 are as defined in the compound of formula (I).
  • the compound of formula (I) is the compound of formula (III):
  • R 2a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
  • R 3 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
  • R 4 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
  • R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy and deuterium substituted C 1-4 alkoxy;
  • R 6a , R 6b , R 6c and R 6d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
  • R 9a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
  • the compound of formula (I) is the compound of formula (IV1):
  • R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from the group consisting of hydrogen, deuterium, trideuteriomethoxy, dideriomethoxy and trideuteroethoxy;
  • R is selected from the group consisting of hydrogen, deuterium, trideuteriomethoxy, dideriomethoxy and trideuteroethoxy;
  • R is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuteriomethyl, monodeuteromethyl, trideuteriomethoxy, dideuuteriomethoxy and trideuteroethoxy;
  • R6b is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuteriomethyl, monodeuteromethyl, trideuteriomethoxy, diduteriomethoxy and trideuteroethoxy;
  • R is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuteriomethyl, monodeuteromethyl, trideuteriomethoxyl, diduteriomethoxy and trideuteroethoxy;
  • R is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuteriomethyl, monodeuteromethyl, trideuteriomethoxy, dideuuteriomethoxy and trideuteroethoxy;
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, Monodeuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl and Azetidinyl, or, R 8a and R 8b together with the carbon atom to which they are directly attached Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
  • R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom.
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Sulfur base.
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
  • the compound of formula (I) is the compound of formula (V1):
  • R 5a is hydrogen or deuterium;
  • R 5b is hydrogen or deuterium;
  • R 6a is hydrogen or deuterium;
  • R 6b is hydrogen or deuterium;
  • R 6c is hydrogen or deuterium;
  • R 6d is hydrogen or deuterium;
  • R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom, preferably, 1, 2, 4 or 6 deuterium atoms.
  • the compound of formula (I) is the compound of formula (IV2):
  • R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, dideriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R 7a and R 7b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkane Base, C 2-4 alkynyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C(O)OR 14 and -C(O)NR 16 R 17 , or, R 7a and R 7b form a C 3-6 cycloalkyl group or a 3-6 membered heterocyclic group together with the directly connected carbon atoms, and the above-mentioned groups are independently optionally further selected from one or more deuterium , halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6 cyclo
  • R 7c is selected from hydrogen, deuterium, halogen, cyano, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dide
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
  • R 14 , R 15 , R 16 and R 17 are as defined in the compound of formula (I).
  • the compound of formula (I) is the compound of formula (V2):
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy , Dideriomethoxy, Trifluoroethoxy and Trideuteroethoxy;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R 7a and R 7b are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, ethynyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl and Alternatively, R 7a and R 7b form a cyclopropyl group together with their directly connected carbon atoms, and the above-mentioned groups are independently and optionally further selected from one or more groups selected from deuterium, fluorine, chlorine, cyano, hydroxyl, and methoxy , methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, dimethylamino, methoxy substituted methyl and phenyl substituents;
  • R 7c is hydrogen, deuterium or fluorine
  • R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideuteriomethoxy;
  • R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
  • R 7a and R 7b are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl and
  • the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy Substituents of methyl and phenyl substituted by radicals;
  • R 7c is hydrogen, deuterium or fluorine.
  • the compound of the formula (I) is the compound of the following formula (IV3):
  • R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, dideriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more of deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, did
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
  • the compound of formula (I) is the compound of formula (V3):
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethyl, Deuteromethyl, dideuteriomethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy , Trifluoromethoxy, Difluoromethoxy, Trideuteromethoxy, Dideuteromethoxy, Trifluoroethoxy, Trideuteroethoxy, Cyclopropoxy, Cyclobutoxy, Methylthio and ethylthio;
  • R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R 7d is methyl or ethyl, and the above-mentioned methyl or ethyl is optionally further replaced by one or more selected from deuterium, fluorine, chlorine, cyano, hydroxyl, monofluoromethyl, difluoromethyl, trifluoromethyl , a deuteromethyl, dide deuteromethyl, trideuteromethyl, cyclopropyl, methoxy, phenyl, replaced by substituents.
  • the compound of formula (I) is the compound of formula (IV4):
  • R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dide
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl
  • R 16 and R 17 are as defined in the compound of formula (I).
  • the compound of formula (I) is the compound of formula (V4):
  • R 5a is selected from hydrogen, deuterium, methoxyl group, trifluoromethoxyl group, difluoromethoxyl group, trideuterium methoxy group and didereter methoxy group;
  • R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
  • the compound of formula (I) is the compound of formula (IV5):
  • R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio
  • R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom
  • R 7g is C 1-4 alkyl
  • R 7h is C 1-4 alkyl
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dide
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl.
  • the compound of formula (I) is the compound of formula (V5):
  • R 5a is selected from hydrogen, deuterium, methoxyl group, trifluoromethoxyl group, difluoromethoxyl group, trideuterium methoxy group and didereter methoxy group;
  • R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
  • R 7g is hydrogen, methyl or ethyl
  • R 7h is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl or isobutyl
  • R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom.
  • the compound of formula (I) is the compound of formula (IV6):
  • R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dide
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
  • the compound of formula (I) is the compound of formula (V6):
  • R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethyl, Deuteromethyl, Dideuteriomethyl, One-Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy , Trifluoromethoxy, Difluoromethoxy, Trideuteromethoxy, Dideriomethoxy, Trifluoroethoxy, Trideuteroethoxy, Cyclopropoxy, Cyclobutoxy, Methylthio and ethylthio;
  • R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideudemethoxy;
  • R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
  • the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt includes but not limited to the following compounds:
  • the second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 6c , R 6d , R 7 , R 8a , R 8b , R 9 , m and n are as in the formula ( I) Compound definition.
  • the third aspect of the present invention provides a pharmaceutical composition, which comprises the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicines for treating and/or preventing cancers or tumors related to KRas G12D.
  • the present invention also relates to the use of the aforementioned formula (I) compound, its stereoisomer or pharmaceutically acceptable salt thereof in the preparation of prevention and/or treatment of KRas G12D-related sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), Myxoma, rhabdomyoma, fibroid, lipoma, teratoma; bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole carcinoma) carcinoma, bronchial adenoma, lymphoid tumor, chondromatoid hamartoma, mesothelioma; esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (lymphoma, leiomy
  • the present invention also relates to said compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention also relates to the use of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof for treating and/or preventing cancer or tumor related to KRas G12D.
  • the present invention also relates to the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, which is used for the treatment and/or prevention of KRas G12D related sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, adipose sarcoma), myxoma, rhabdomyoma, fibroid, lipoma, teratoma; bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole carcinoma) carcinoma, bronchial gland tumor, lymphoma, chondromatoid hamartoma, mesothelioma; esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (lymphoma, leiomyosarcom
  • the present invention also relates to a method for treating and/or preventing cancer or tumor related to KRas G12D, which comprises administering a therapeutically effective amount of the compound of formula (I), its stereoisomer or its pharmaceutically effective amount to the patient in need. Salt is acceptable.
  • the present invention also relates to a method for treating and/or preventing sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma associated with KRas G12D; bronchial carcinoma ( Squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar carcinoma) carcinoma, bronchial adenoma, lymphoma, chondromatoid hamartoma, mesothelioma; esophageal carcinoma (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulino
  • KRas G12D inhibitor with the structure of formula (I) for the first time.
  • the series of compounds of the present invention can be widely used in the preparation, treatment and/or prevention of cancers or tumors related to KRas G12D Drugs are expected to be developed into a new generation of KRas G12D inhibitors. On this basis, the present invention has been accomplished.
  • Alkyl refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched-chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethyl
  • C 1-21 alkyl refers to straight chain alkyl and branched chain alkyl including 1 to 21 carbon atoms
  • C 1-10 alkyl refers to straight chain alkyl and branched chain including 1 to 10 carbon atoms Containing branched chain alkyl
  • C 1-4 alkyl refers to straight chain alkyl and branched chain containing 1 to 4 carbon atoms
  • C 0-8 alkyl refers to containing 0 to 8 carbon atoms
  • C 0-4 alkyl refers to a straight chain alkyl group and a branched alkyl group containing 0 to 4 carbon atoms.
  • Cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ -electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 A cycloalkyl group of up to 6 carbon atoms, for example, "C 3-12 cycloalkyl” refers to a cycloalkyl group containing 3 to 12 carbon atoms, and “C 3-10 cycloalkyl” refers to a cycloalkyl group containing 3 to 10 carbon atoms atom, “C 3-8 cycloalkyl” refers to a cycloalkyl group comprising 3 to 8 carbon atom
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl et al.
  • Multicyclic cycloalkyls include spiro, fused and bridged cycloalkyls.
  • “Spirocycloalkyl” refers to polycyclic groups in which single rings share one carbon atom (called a spiro atom), these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has A fully conjugated ⁇ -electron system. According to the number of spiro atoms shared between rings, spirocycloalkyl groups are divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, spirocycloalkyl includes but not limited to:
  • fused cycloalkyl means an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated ⁇ -electron system. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
  • Bridged cycloalkyl means an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated ⁇ -electron system. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Bridged cycloalkyl groups include but are not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , Benzocycloheptyl, etc.
  • Heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon can contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ -electron system, and one or more (preferably 1, 2, 3 or 4) ring atoms in the heterocyclyl group are selected from N, O, N O or a heteroatom of S(O) r (where r is an integer 0, 1, 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • a heterocyclic group comprising 3 to 12 or 3 to 8 or 3 to 6 ring atoms is preferred, for example, "3-6 membered heterocyclic group” refers to a heterocyclic group comprising 3 to 6 ring atoms, “3- 8-membered heterocyclic group” refers to a heterocyclic group containing 3 to 8 ring atoms, “4-8 membered heterocyclic group” refers to a heterocyclic group containing 4 to 8 ring atoms, and “4-10 membered heterocyclic group” Refers to a heterocyclic group containing 4 to 10 ring atoms, “5-8 membered heterocyclic group” refers to a heterocyclic group containing 5 to 8 ring atoms, “3-12 membered heterocyclic group” refers to a heterocyclic group containing 3 to 12 ring atom heterocyclyl.
  • Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O , N ⁇ O or S(O) r (where r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system.
  • spiroheterocyclyls are classified as single spiroheterocyclyls, double spiroheterocyclyls or polyspiroheterocyclyls.
  • Spiroheterocyclyls include, but are not limited to:
  • “Fused heterocyclyl” means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may be Contains one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ -electron system, where one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N ⁇ O or S(O) r (where r is an integer of 0, 1, 2) is a heteroatom, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups.
  • the fused heterocyclyl groups include but are not limited to:
  • Bridged heterocyclyl means a polycyclic heterocyclic group in which any two rings share two atoms not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings Has a fully conjugated ⁇ -electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N O or S(O) r (where r is an integer 0, 1 , 2), and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include but are not limited to:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring attached to the parent structure is a heterocyclyl, including but not limited to:
  • Aryl or "aromatic ring” means an all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of For ring) groups of carbon atoms, preferably a full-carbon aryl group containing 6-10 or 6-8 carbons, for example, “C 6-10 aryl” refers to a full-carbon aryl group containing 6-10 carbons, Including but not limited to phenyl and naphthyl, "C 6-8 aryl” refers to a full carbon aryl group containing 6-8 carbons.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, including but not limited to:
  • Heteroaryl means a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms, including N, O, N.O and S(O)r (where r is an integer (0, 1, 2) heteroatom, preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered heteroaryl” means containing A heteroaromatic system with 5-8 ring atoms, "5-10 membered heteroaryl” refers to a heteroaromatic system with 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl , N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight chain or branched alkenyl group containing 2-10 or 2-4 carbons
  • C 2-10 alkenyl refers to a straight-chain or branched alkenyl group containing 2-10 carbons
  • C 2-4 alkenyl refers to a straight-chain or branched alkenyl group containing 2-4 carbons.
  • branched alkenyl Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.
  • Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons,
  • C 2-10 alkynyl refers to a straight-chain or branched alkynyl group containing 2-10 carbons
  • C 2-4 alkynyl refers to a straight-chain or branched alkynyl group containing 2-4 carbons.
  • Alkynyl Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.
  • Alkoxy refers to -O-alkyl, wherein the definition of alkyl is as above, for example, “C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, “C 1-4 Alkoxy” refers to an alkyloxy group containing 1-4 carbons, and “C 1-2 alkoxy” refers to an alkyloxy group containing 1-2 carbons, including but not limited to methoxy, ethoxy , Propoxy, Butoxy, etc.
  • the substituents preferably one or more (preferably 1, 2, 3 or 4) of the following groups, are independently selected from deuterium , halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 al
  • Cycloalkoxy or “cycloalkyloxy” refers to -O-cycloalkyl, wherein the definition of cycloalkyl is as above, for example, “C 3-12 cycloalkoxy” refers to 3-12 Carbon cycloalkyloxy, “C 3-6 cycloalkoxy” refers to cycloalkyloxy containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy , Cyclohexyl and so on.
  • Heterocyclyloxy or “heterocyclyloxy” refers to -O-heterocyclyl, where the definition of heterocyclyl is as above, including but not limited to azetidinyloxy, oxetanyloxy radical, azacyclopentyloxy, nitrogen, oxepyloxy, etc.
  • C 1-10 alkanoyl refers to the monovalent atomic group left after C 1-10 alkanoic acid removes the hydroxyl group, and is usually expressed as "C 0-9 alkyl-C(O)-", for example, “C 1 Alkyl-C(O)-” refers to acetyl; “C 2 alkyl-C(O)-” refers to propionyl; “C 3 alkyl-C(O)-” refers to butyryl or isobutyryl Acyl.
  • Halogen substituted C 1-10 alkyl refers to 1-10 carbon alkyl groups whose hydrogen on the alkyl is optionally substituted by fluorine, chlorine, bromine, iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • Halogen substituted C 1-10 alkoxy refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally replaced by fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
  • Deuterium-substituted C 1-10 alkyl refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl is optionally replaced by a deuterium atom. Including but not limited to mono-deuteromethyl, dide-deuteromethyl, tri-deuteromethyl, etc.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes the occasion where the event or circumstance occurs or does not occur, that is, includes two situations of substitution or non-substitution .
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more "hydrogen atoms" in a group are independently substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, consistent with the valence bond theory in chemistry, and a person skilled in the art can determine (by experiment or theory) that it is possible or impossible without undue effort of the replacement. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond such as an alkene.
  • Stepoisomer its English name is stereoisomer, refers to the isomer produced by the different arrangement of atoms in the molecule in space, it can be divided into two kinds of cis-trans isomers and enantiomers, It can also be divided into two categories: enantiomers and diastereomers.
  • Stereoisomers due to the rotation of a single bond are called conformational stereo-isomers, sometimes also called rotamers.
  • Stereoisomers caused by bond length, bond angle, double bonds in the molecule, rings, etc. are called configuration isomers (configuration stereo-isomers), and configuration isomers are divided into two categories.
  • geometric isomers also known as cis-trans isomers (cis-trans isomers), which are divided into Z, E two configurations.
  • cis-2-butene and trans-2-butene are a pair of geometric isomers, and the stereoisomers with different optical rotation properties caused by the absence of anti-axis symmetry in the molecule are called optical isomers ( optical isomer), divided into R and S configurations.
  • optical isomer optical isomer
  • the "stereoisomer" mentioned in the present invention can be understood as including one or more of the above-mentioned enantiomers, configuration isomers and conformational isomers unless otherwise specified.
  • “Pharmaceutically acceptable salt” in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which salts can be prepared by methods known in the art.
  • Prodrug or “prodrug” in the present invention refers to a pharmaceutically acceptable compound that can be converted or solvolyzed into a specific compound or such compound under physiological conditions before exhibiting its physiological effect. Salt compounds.
  • Prodrugs are generally, although not necessarily, pharmacologically inactive until converted to a specific compound (also known as a parent drug or parent drug).
  • the purpose of the prodrug is to improve chemical stability, improve patient acceptance and compliance, improve bioavailability, prolong the duration of action, improve organ selectivity, increase water solubility and/or reduce side effects, etc.
  • the preparation technology of prodrug can use the method known in the prior art, such as Burger's Medicinal Chemistry and Drug Chemistry, 1,172-178,949-982 (1995) etc.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the determination of NMR is to use Bruker AVANCE-400/500 nuclear magnetic apparatus, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard For tetramethylsilane (TMS).
  • Agilent 6120 mass spectrometer was used for liquid chromatography-mass chromatography LC-MS determination.
  • the determination of HPLC used Agilent 1200DAD high pressure liquid chromatography (Sunfire C18 150 ⁇ 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150 ⁇ 4.6mm column).
  • Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates.
  • the specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.
  • the first step the synthesis of (bromoethynyl) triisopropylsilane
  • Ethynyltriisopropylsilane (15g, 82.2mmol) was dissolved in acetone (100mL), and silver nitrate (1g, 6.45mmol) and N-bromosuccinimide (15g, 86.3mmol) were added respectively. React at room temperature for 1 hour under the protection of reaction liquid nitrogen. Concentrate under reduced pressure to remove the solvent, add 300 mL of petroleum ether to the residue, make a slurry, filter, and concentrate the filtrate under reduced pressure to remove the solvent to obtain (bromoethynyl)triisopropylsilane (21 g, yield: 97.7%).
  • the second step Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol
  • the third step the synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol
  • Step 4 Synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yltrifluoromethanesulfonic acid
  • reaction solution was poured into 200 mL of water. Extract with 100 mL of dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain 7-fluoro-3-(methoxymethoxy)-8- ((Triisopropylsilyl)ethynyl)naphthalen-1-yltrifluoromethanesulfonic acid (3.05 g, yield: 57.4%).
  • the fifth step ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of yl)naphthalen-1-yl)ethynyl)triisopropylsilane
  • reaction solution was diluted with 200mL ethyl acetate, washed with saturated aqueous sodium chloride (100mL*2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain ((2-fluoro-6 -(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl) Triisopropylsilane (2.6 g, yield: 53.2%).
  • the first step the synthesis of tert-butyl (2-chloro-3-fluoropyridin-4-yl) carbamate
  • tert-butyl (2-chloro-3-fluoropyridin-4-yl) carbamate (30g, 122mmol) in tetrahydrofuran (300mL)
  • n-butyllithium 121mL
  • tert-butyl isocyanate (14.3 mL, 243 mmol) was added dropwise to the reaction solution at -20°C, the reaction solution was slowly raised to room temperature for 1 small test, and then heated to 70°C for overnight reaction.
  • reaction solution was slowly poured into saturated aqueous sodium bicarbonate solution (300 mL), extracted with ethyl acetate (500 mL*2), the organic phase was dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated by flash silica gel column to obtain 3-(tert-butyl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (248g, yield : 72.6%).
  • the fifth step tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) Synthesis of pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Intermediates C2-C3 can be prepared by referring to all or part of the synthesis method of intermediate C1 and selecting corresponding raw materials:
  • the first step tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8-carboxylate synthesis
  • the second step 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)acetylene Base) Synthesis of Naphthalene-2-ol
  • the third step 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro Synthesis of -1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Intermediate D2 can be prepared by selecting corresponding raw materials with reference to all or part of the synthetic method of intermediate D1:
  • Step 1 Synthesis of tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]octyl-8-carboxylate
  • reaction solution was poured into 100 mL of water, extracted with dichloromethane (200 mL), the organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain tert-butyl 3-trityl-3 , 8-diazabicyclo[3.2.1]octane-8-carboxylate (6 g, yield: 93.4%).
  • the second step Synthesis of tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]oct-8-carboxylate-1,5- d2
  • tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]oct-8-carboxylate (1 g, 2.20 mmol) and TMEDA (1.66 mL, 10.9 mmol) in THF (20 mL
  • tert-butyllithium (8.46 mL, 10.9 mmol) was added dropwise to the above solution under nitrogen protection. After the dropwise addition was completed, the mixture was stirred at 0° C. for 0.5 hours. Then deuterium water (0.8mL, 44.0mmol) was added to the reaction solution, and after the dropwise addition was completed, it was stirred at 0°C for 0.5 hours.
  • reaction solution was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (60 mL), the organic phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent to obtain tert-butyl 3-trityl-3 ,8-diazabicyclo[3.2.1]oct-8-carboxylate-1,5-d 2 (650 mg, yield: 65.0%).
  • Step 3 Synthesis of tert-butyl 3,8-diazabicyclo[3.2.1]oct-8-carboxylate-1,5-d 2
  • Intermediates E2-E5 can be prepared by referring to the whole or part of the synthesis method of intermediate E1 and selecting corresponding raw materials:
  • Example 1 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 )-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- Preparation of 2-ol
  • the second step tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) Synthesis of pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-carboxylate-1,5-d 2
  • the third step tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8-carboxylate-1,5-d 2 synthesis
  • the fourth step 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 )-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triiso Synthesis of Propylsilyl)ethynyl)naphthalene-2-ol
  • the fifth step 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 )-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- Synthesis of 2-alcohols
  • Embodiment 2 ⁇ 6 can select corresponding raw material to prepare with reference to all or part of the synthetic method of embodiment 1:
  • Example 7 Methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 - Preparation of carboxylate
  • the first step 3-(7-(8-ethynyl-7-fluoro-3-((methoxycarbonyl))oxy)naphthalene-1-yl)-8-fluoro-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Synthesis of Heterobicyclo[3.2.1]octane-8-carboxylic Acid
  • Embodiments 8-25, 54, 55 can be prepared by referring to all or part of the synthetic method of embodiment 7 to select corresponding raw materials:
  • Example 26 4-(4-(8-Benzyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 - Preparation of alcohol
  • the first step 4-(4-(8-benzyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl Synthesis of (yl)ethynyl)naphthalen-2-ol
  • Embodiments 27-44, 52, 53 can be prepared by referring to all or part of the synthetic method of embodiment 26 and selecting corresponding raw materials:
  • Example 45 1-(isobutoxy)ethyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo [3.2.1] Preparation of octane-8-carboxylate-1,5- d2
  • Embodiments 46-48, 56-58, and 62 can be prepared by referring to all or part of the synthetic method of embodiment 45 and selecting corresponding raw materials:
  • Example 49 4-((3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane Preparation of -8-yl-1,5-d 2 )methyl)-5-methyl-1,3-dioxazol-2-one
  • Embodiments 59-61 can be prepared by referring to all or part of the synthetic method of embodiment 49 and selecting corresponding raw materials:
  • Example 50 ((isopropoxycarbonyl)oxy)methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Preparation of heterobicyclo[3.2.1]oct-8-carboxylate-1,5-d 2
  • the first step the synthesis of iodomethyl isopropyl carbonate
  • the second step ((isopropoxycarbonyl)oxy)methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Synthesis of Heterobicyclo[3.2.1]oct-8-carboxylate-1,5-d 2
  • Example 51 ((tert-Butoxycarbonyl)oxy)methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-di
  • Example 51 Compound ((tert-butoxycarbonyl)oxy)methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylate-1,5-d 2 can be prepared by selecting corresponding raw materials according to the synthesis method in Example 50.
  • ESI-MS 777 [M+1] + .
  • the compound was dissolved in 100% DMSO with an initial concentration of 5 mM, and was serially diluted 3 times in DMSO, and a total of 8 concentration points were diluted. Add 1 ⁇ L of compound or DMSO at each concentration point to 99 ⁇ L of assay buffer to make a 10X stock solution.
  • Ratios at each compound concentration were calculated based on the signal from the DMSO control contained in each assay plate and the Alphalisa signal from the individual compound wells.
  • concentration of compound required for 50% inhibition ( IC50 ) was determined using the four parameter logarithmic dose response equation from the concentration of test compound and the value of the ratio.
  • Endpoint values ( IC50 ) of reference compounds were assessed in each experiment as a quality control measure. The experiment was considered acceptable if the endpoint value was within three times the expected value.
  • Serial 10-point dilutions were made 1:5 from the 10 mM stock solution. Transfer 10X compound-containing media to corresponding wells of the 96-well. The final peak compound concentration was 10 [mu]M and the final DMSO concentration was 0.1%.
  • the 96-well plate was placed in a 37°C incubator, AGS cells were incubated for 3 days, and GP2D cells were incubated for 4 days.
  • the percent inhibition (%) at each compound concentration was calculated from the signal in the HPE and ZPE control wells contained in each assay plate and the fluorescence signal in the individual compound wells.
  • ZPE control wells containing enzyme and substrate had an inhibition rate of 0%
  • HPE control wells containing only substrate had an inhibition rate of 100%.
  • the concentration of compound required for 50% inhibition was determined using the four parameter logarithmic dose response equation from the concentration of test compound and the value of percent inhibition.
  • Endpoint values ( IC50 ) of reference compounds were assessed in each experiment as a quality control measure. The experiment was considered acceptable if the endpoint value was within three times the expected value.
  • the series of compounds of the present invention have strong inhibitory effect on KRAS cell activity.
  • the cytostatic activity of some of the compounds or prodrug compounds of the examples is even comparable to that of the positive compounds, or improved to a certain extent.
  • the compounds used in this test are from the compounds of the specific examples of the present invention.
  • ICR mice Male N 3 Original source: Shanghai Xipuer-Bikay Experimental Animal Co., Ltd.
  • the compounds were weighed and added to the solvent of 0.5% CMC+1% Tween 80, shake well, and ultrasonic to obtain a light yellow suspension. 3 mice were given orally after fasting overnight. The dosage is 10mg/kg.
  • the way of administration was single oral administration (PO) in ICR mice respectively.
  • blood was drawn from the orbit, anticoagulated with heparin sodium, placed on ice after collection, and centrifuged within 1 hour to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C).
  • the blood collection time points are 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours.
  • the samples were stored in a -20°C refrigerator.
  • the series of compounds of the present invention are absorbed into mice after a single oral administration (10 mg/kg), and have very good PK data.
  • the AUC of some of the compounds in the examples is increased by more than ten times, even dozens of times.
  • the test proves that the series of compounds of the present invention have very good development prospects and are expected to solve the problem that the positive compounds have poor pK and are not suitable for oral administration.

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Abstract

Disclosed are 7-(naphthalene-l-yl)pyrido[4,3-d]pyrimidine derivatives, a preparation method therefor, and the use thereof. In particular relating to KRas G12D inhibitors having the structure of formula (I), a preparation method therefor, a pharmaceutical composition containing same, a use of same as a KRas G12D inhibitor, and a use of same in the treatment and/or prevention of cancer or tumours related to KRas G12D. Each substituent of formula (I) has the same definition as in the description.

Description

一种7-(萘-1-基)吡啶并[4,3-d]嘧啶衍生物及其制备和应用A 7-(naphthalene-1-yl)pyrido[4,3-d]pyrimidine derivative and its preparation and application 技术领域technical field
本发明属于药物合成领域，具体涉及7-(萘-1-基)吡啶并[4,3-d]嘧啶衍生物及其制备和应用。The invention belongs to the field of medicine synthesis, and specifically relates to 7-(naphthalene-1-yl)pyrido[4,3-d]pyrimidine derivatives and their preparation and application.
背景技术Background technique
RAS基因家族包含HRAS，KRAS和NRAS，它们作为癌基因在癌症中经常发生突变。20-30％的人类肿瘤中有突变的RAS蛋白。活化的RAS蛋白导致癌细胞的恶性表型，包括细胞生长和程序性细胞死亡的失调，侵袭性和新血管生成的增加。由于其对GTP/GDP的高亲和力和缺乏清晰的结合口袋，靶向RAS蛋白药物的开发进展较慢。The RAS gene family includes HRAS, KRAS and NRAS, which are frequently mutated in cancer as oncogenes. Mutated RAS proteins are present in 20-30% of human tumors. Activated RAS proteins lead to malignant phenotypes in cancer cells, including dysregulation of cell growth and programmed cell death, increased invasiveness and neovascularization. Due to its high affinity for GTP/GDP and the lack of a clear binding pocket, the development of drugs targeting RAS proteins has been slow.
在正常情况下，RAS蛋白起分子开关的作用，在GDP结合的无活性状态和GTP结合的激活状态之间交替。在外源性生长因子刺激后，经鸟嘌呤核苷酸交换因子(GEFs)的促进，RAS蛋白从无活性的GDP结合形式转变为激活态的GTP结合形式，能够结合并激活下游信号通路。随后，凭借其固有的GTPase活性和GTPase激活/加速蛋白(GAP)的帮助，RAS恢复为无活性的GDP结合形式。Under normal conditions, RAS proteins function as molecular switches, alternating between a GDP-bound inactive state and a GTP-bound active state. After exogenous growth factor stimulation, RAS protein is transformed from an inactive GDP-binding form to an active GTP-binding form, which can bind and activate downstream signaling pathways, through the promotion of guanine nucleotide exchange factors (GEFs). Subsequently, with the help of its intrinsic GTPase activity and the GTPase activating/accelerating protein (GAP), RAS reverts to the inactive GDP-bound form.
12、13或61位密码子的错义突变导致RAS的异常激活。这些突变延长了RAS蛋白停留在GTP结合状态的时间，从而导致下游信号通路的持续性激活。K-RAS是人类癌症中RAS家族中最常见的突变亚型，包括胰腺癌(71％)，小肠癌(35％)，结肠癌(35％)，胆道癌(26％)，子宫内膜癌(17％)和肺癌(19％)。就突变位点而言，G12D/G12V/G12C/G13D是胰腺癌、肺癌和大肠癌中K-RAS的最常见的突变类型。Missense mutations in codons 12, 13, or 61 lead to aberrant activation of RAS. These mutations prolong the time that RAS proteins remain in the GTP-bound state, resulting in persistent activation of downstream signaling pathways. K-RAS is the most frequently mutated subtype in the RAS family in human cancers, including pancreatic cancer (71%), small bowel cancer (35%), colon cancer (35%), biliary tract cancer (26%), endometrial cancer (17%) and lung cancer (19%). In terms of mutation sites, G12D/G12V/G12C/G13D are the most common mutation types of K-RAS in pancreatic cancer, lung cancer and colorectal cancer.
由于该蛋白缺乏明显的口袋，因此对KRAS的抑制剂研发充满挑战性。最近的研究发现在KRAS与GDP结合状态中存在一个之前未被发现的口袋。基于这些新发现，靶向密码子12位突变半胱氨酸的共价结合抑制剂成为KRAS抑制剂的研发热点并取得了一定进展。但是，除G12C突变外，靶向KRAS其他的激活突变仍然亟待解决，特别是KRAS G12D突变。因此，有必要开发出安全且有效的KRAS G12D抑制剂用以治疗KRAS-G12D介导的癌症。The development of inhibitors of KRAS is challenging because the protein lacks a distinct pocket. Recent studies have identified a previously undiscovered pocket in the KRAS-GDP bound state. Based on these new findings, covalent binding inhibitors targeting codon 12 mutant cysteine have become a hot spot in the research and development of KRAS inhibitors and some progress has been made. However, in addition to the G12C mutation, other activating mutations targeting KRAS remain to be resolved, especially the KRAS G12D mutation. Therefore, it is necessary to develop safe and effective KRAS G12D inhibitors for the treatment of KRAS-G12D-mediated cancers.
发明内容Contents of the invention
本发明的目的在于提供一种7-(萘-1-基)吡啶并[4,3-d]嘧啶衍生物及其制备和应用。本发明系列化合物对KRas G12D具有很强的抑制作用，可广泛应用于制备治疗 和/或预防与KRas G12D相关癌症或肿瘤的药物，从而有望开发出新一代KRas G12D抑制剂。The object of the present invention is to provide a 7-(naphthalene-1-yl)pyrido[4,3-d]pyrimidine derivative and its preparation and application. The series of compounds of the present invention have a strong inhibitory effect on KRas G12D, and can be widely used in the preparation of drugs for the treatment and/or prevention of KRas G12D-related cancers or tumors, so that it is expected to develop a new generation of KRas G12D inhibitors.
本发明第一方面提供式(I)化合物、其立体异构体或其药学上可接受盐：The first aspect of the present invention provides a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022130789-appb-000001
Figure PCTCN2022130789-appb-000001
其中，R 1选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基和-C 0-4烷基-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代； Wherein, R 1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and -C 0-4 alkyl-NR 16 R 17 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1 -10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl The substituent of the group is substituted;
每个R 2各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15； Each R is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0 -8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0 -8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O) 2 R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkane -OR 14 , -C 0-8alkyl -C(O)OR 14 , -C 0-8alkyl -C(O)SR 14 , -C 0-8alkyl -SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 ) 2 , -C 0-8 alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 ;
R 3选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15； R3 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl- SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl- N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8Alkyl -OC(O)R 15 , -C 0-8Alkyl -P(O)(R 15 ) 2 , -C 0-8Alkyl -NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0- 8 alkyl-C (O) NR 16 R 17 and -C 0-8 alkyl-N (R 16 )-C (O) R 15 ;
R 4选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、 -C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15； R is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl- SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl- N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8Alkyl -OC(O)R 15 , -C 0-8Alkyl -P(O)(R 15 ) 2 , -C 0-8Alkyl -NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0- 8 alkyl-C (O) NR 16 R 17 and -C 0-8 alkyl-N (R 16 )-C (O) R 15 ;
R 5a和R 5b各自独立地选自氢、氘、卤素、C 1-10烷氧基、卤取代C 1-10烷氧基和氘取代C 1-10烷氧基； R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-10 alkoxy, halogen substituted C 1-10 alkoxy and deuterium substituted C 1-10 alkoxy;
R 6a、R 6b、R 6c和R 6d各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15，或者，R 6a、R 6b、R 6c和R 6d其中两个与其直接相连的部分原子一起形成一个C 3-10环烷基和3-10元杂环基，另两个如前所定义，所述C 3-10环烷基和3-10元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代； R 6a , R 6b , R 6c and R 6d are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered Heteroaryl, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)SR 14 , -C 0-8 alkyl- SC(O)R 15 , -C 0-8alkyl -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -P(O)( R 15 ) 2 , -C 0-8alkyl -NR 16 R 17 , -C 0-8alkyl -C(=NR 16 )R 15 , -C 0-8alkyl -N(R 16 )-C (=NR 17 )R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 , or, R 6a , R 6b , R 6c and R 6d , two of which are directly connected to some atoms form a C 3-10 cycloalkyl group and a 3-10 membered heterocyclic group, and the other two are as defined above, and the C 3- The 10 -cycloalkyl group and the 3-10-membered heterocyclic group are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1- 10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aromatic radical, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0 -8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O) 2 R 13 , -C 0 -8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O )SR 14 , -C 0-8 alkyl-SC(O)R 15 , -C 0-8 alkyl-C(O)R 15 , -C 0-8 alkyl-OC(O)R 15 , - C 0-8 Alkyl-P(O)(R 15 ) 2 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0 -8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 ) -C(O)R 15 is replaced by a substituent;
R 7选自氢、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(S)NR 16R 17、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代，上述基团独立地任选再进一步被一个或多个选 自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代，条件是，当R 7为氢、-C(O)O-叔丁基、-C(O)O-芳基、-C(O)-C 1-6烷基或-C(O)O-C 1-4烷基-O-C(O)-C 1-21烷基时，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子，或者，R 4为-C 0-8烷基-S-R 13； R 7 is selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)SR 14 , -C 0-8 alkane -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -P(O)(R 15 ) 2 , -C 0-8alkyl- NR 16 R 17 , -C 0-8 alkyl-C(S)NR 16 R 17 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 , the above groups are independently optionally further selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, - C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 ,- C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O) 2 R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0- 8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 alkyl-C(O)R 15 , -C 0-8 alkyl-OC(O)R 15 , -C 0-8 alkyl-P(O)(R 15 ) 2 , -C 0-8 alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 ,-C 0-8 alkyl-N(R 16 )-C(=NR 17 ) Substituents of R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 are substituted, the above groups are independently Optionally, one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O , =S, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)SR 14 , -C 0-8 alkyl- SC(O)R 15 , -C 0-8alkyl -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -P(O)( R 15 ) 2 , -C 0-8alkyl -NR 16 R 17 , -C 0-8alkyl -C(=NR 16 )R 15 , -C 0-8alkyl -N(R 16 )-C (=NR 17 )R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 are substituted by substituents , with the proviso that when R 7 is hydrogen, -C(O)O-tert-butyl, -C(O)O-aryl, -C(O)-C 1-6 alkyl or -C(O)OC When 1-4 alkyl-OC(O)-C 1-21 alkyl, R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom, or, R 4 is -C 0-8 alkyl-SR 13 ;
R 8a和R 8b各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-10环烷基和3-10元杂环基，所述C 3-10环烷基和3-10元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O) 2 R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 alkyl-C(O)R 15 , -C 0-8 alkyl-OC(O)R 15 , -C 0-8 alkyl-P(O)(R 15 ) 2 ,- C 0-8 alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 ,-C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15. -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 , or, R 8a and R 8b are directly connected to it The carbon atoms together form a C 3-10 cycloalkyl group and a 3-10 membered heterocyclic group, and the C 3-10 cycloalkyl group and the 3-10 membered heterocyclic group are independently optionally further selected by one or more From deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl -SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl -N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0- 8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 ) 2 , -C 0-8 Alkane -NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0 Substituents of -8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 ;
每个R 9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15，或者，相邻的两个R 9与其直接相连的部分一起形成一个环烷基和杂环基，上述基 团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代； Each R 9 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S( O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkane -OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)SR 14 , -C 0-8 alkyl-SC(O)R 15 , -C 0-8 alkyl-C(O)R 15 , -C 0 -8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 ) 2 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl -C(=NR 16 )R 15 , -C 0-8alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0-8alkyl -C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 , or, two adjacent R 9 and the part directly connected together form a cycloalkyl group and a heterocyclic group, and the above groups are independently Optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC (O)R 15 , -C 0-8alkyl -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -P(O)(R 15 ) 2 , -C 0-8alkyl -NR 16 R 17 , -C 0-8alkyl -C(=NR 16 )R 15 , -C 0-8alkyl -N(R 16 )-C( =NR 17 )R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 are substituted by substituents;
每个R 10各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)R 15或-C 0-8烷基-C(O)NR 16R 17，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17或-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代； Each R 10 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycle base, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)R 15 or -C 0-8 alkyl-C(O)NR 16 R 17 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, Nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3 -10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 ,-C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 or -C 0-8 alkyl-N(R 16 )-C(O)R 15 are substituted by substituents;
每个R 11和R 12各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，或者，R 11和R 12与其直接相连的硫原子一起形成3-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17或-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代； Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3 -10-membered heterocyclic group, C 6-10 aryl or 5-10-membered heteroaryl group, or, R 11 and R 12 form a 3-10-membered heterocyclic group together with the sulfur atom directly connected to it, the above-mentioned groups are optional Further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1- 10 alkyl, deuterium substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkane -S(O) r R 13 , -C 0-8alkyl -OR 14 , -C 0-8alkyl -C(O)OR 14 , -C 0-8alkyl -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -NR 16 R 17 , -C 0-8alkyl -C(=NR 16 )R 15 , -C 0- 8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 or -C 0-8 Alkyl-N(R 16 )- C(O)R 15 is replaced by a substituent;
每个R 13独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 16R 17的取代基所取代； Each R 13 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl group, 5-10 membered heteroaryl group and -NR 16 R 17 , the above groups are independently optionally further selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 1- 10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 heterocyclic, 3-12 heterocyclic, C 6-10 aryl, C 6-10 Substituted by aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 ;
每个R 14独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12 元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 16R 17的取代基所取代； Each R 14 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the above-mentioned groups are optionally further independently selected from one or more of deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclyl group, C 6-10 aryl group, C 6-10 aryloxy group, 5 Substituents of -10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 16 R 17 ;
每个R 15独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 16R 17的取代基所取代； Each R 15 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 ring Alkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heteroaryl group group, 5-10 membered heteroaryloxy group and -NR 16 R 17 , the above groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl , C 1-10 alkoxy group, C 3-12 cycloalkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 aryl group, Substituents of C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 ;
每个R 16和R 17各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基和C 1-10烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Each R 16 and R 17 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, C 6-10 aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl and C 1-10 alkanoyl, the above groups are independently optionally further selected from one or more deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3- 12 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryl group Heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl substituents;
或者，R 16和R 17与其直接相连的氮原子一起形成一个4-10元杂环基或5-10元杂芳基，所述4-10元杂环基或5-10元杂芳基任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Alternatively, R 16 and R 17 form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group together with the nitrogen atom directly connected to it, and any of the 4-10 membered heterocyclic group or 5-10 membered heteroaryl group is further selected by one or more selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, Deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group , C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 alkylamino, two C 1-10 alkane Substituents of amino group and C 1-10 alkanoyl;
m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
n为0、1、2、3、4、5或6；且n is 0, 1, 2, 3, 4, 5 or 6; and
每个r独立地为0、1或2。Each r is independently 0, 1 or 2.
作为优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，R 1选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基和-C 0-4烷基-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基的取代基所取代； As a preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3 -6 cycloalkyl, 3-6 membered heterocyclic group and -C 0-4 alkyl-NR 16 R 17 , the above groups are independently optionally further selected from deuterium, halogen, cyano, nitro Base, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- Substituents of 6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl and 5-8 membered heteroaryl;
每个R 2各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、 -C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15； Each R is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0 -4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0 -4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O) 2 R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkane -OR 14 , -C 0-4alkyl -C(O)OR 14 , -C 0-4alkyl -C(O)SR 14 , -C 0-4alkyl -SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -P(O)(R 15 ) 2 , -C 0-4alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 ;
R 3选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15； R is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl- SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl- N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4Alkyl -OC(O)R 15 , -C 0-4Alkyl -P(O)(R 15 ) 2 , -C 0-4Alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0- 4 alkyl-C (O) NR 16 R 17 and -C 0-4 alkyl-N (R 16 )-C (O) R 15 ;
R 4选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15； R is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl- SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl- N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4Alkyl -OC(O)R 15 , -C 0-4Alkyl -P(O)(R 15 ) 2 , -C 0-4Alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0- 4 alkyl-C (O) NR 16 R 17 and -C 0-4 alkyl-N (R 16 )-C (O) R 15 ;
R 5a和R 5b各自独立地选自氢、氘、卤素、C 1-4烷氧基、卤取代C 1-4烷氧基和氘取代C 1-4烷氧基； R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy and deuterium substituted C 1-4 alkoxy;
R 6a、R 6b、R 6c和R 6d各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15，或者，R 6a、R 6b、R 6c和R 6d其中两个与其直接相连的部分原子一起形成一个C 3-6环烷基和3-6元杂环基，另两个如前所定义，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、 -C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代； R 6a , R 6b , R 6c and R 6d are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered Heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl-N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 alkyl-C(O)OR 14 , -C 0-4 alkyl-C(O)SR 14 , -C 0-4 alkyl- SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -P(O)( R 15 ) 2 , -C 0-4alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C (=NR 17 )R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 , or, R 6a , R 6b , R 6c and R 6d , two of which are directly connected to some atoms together form a C 3-6 cycloalkyl group and a 3-6 membered heterocyclic group, and the other two are as defined above, and the C 3- The 6- cycloalkyl group and the 3-6-membered heterocyclic group are independently optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1- 4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aromatic radical, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0 -4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O) 2 R 13 , -C 0 -4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O )SR 14 , -C 0-4alkyl -SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 ,- C 0-4alkyl -P(O)(R 15 ) 2 , -C 0-4alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0 -4alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0-4alkyl -C(O)NR 16 R 17 and -C 0-4alkyl -N(R 16 ) -C(O)R 15 is replaced by a substituent;
R 7选自氢、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(S)NR 16R 17、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代，上述基团独立地任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代，条件是，当R 7为氢、-C(O)O-叔丁基、-C(O)O-芳基、-C(O)-C 1-6烷基或-C(O)O-C 1-4烷基-O-C(O)-C 1-21烷基时，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子，或者，R 4为-S-R 13； R 7 is selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 alkyl-C(O)OR 14 , -C 0-4 alkyl-C(O)SR 14 , -C 0-4 alkane -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -P(O)(R 15 ) 2 , -C 0-4alkyl- NR 16 R 17 , -C 0-4 alkyl-C(S)NR 16 R 17 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 , the above groups are independently optionally further selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, - C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 ,- C 0-4 alkyl-N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0- 4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 alkyl-C(O)R 15 , -C 0-4 alkyl-OC(O)R 15 , -C 0-4 alkyl-P(O)(R 15 ) 2 , -C 0-4 alkyl-NR 16 R 17 , -C 0-4 alkyl-C(=NR 16 )R 15 , -C 0-4 alkyl-N(R 16 )-C(=NR 17 ) Substituents of R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 are substituted, the above groups are independently Optionally, one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O , =S, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl-N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 alkyl-C(O)OR 14 , -C 0-4 alkyl-C(O)SR 14 , -C 0-4 alkyl- SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -P(O)( R 15 ) 2 , -C 0-4alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C (=NR 17 )R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 are substituted by substituents , with the proviso that when R 7 is hydrogen, -C(O)O-tert-butyl, -C(O)O-aryl, -C(O)-C 1-6 alkyl or -C(O)OC When 1-4 alkyl-OC(O)-C 1-21 alkyl, R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom, or, R 4 is -SR 13 ;
R 8a和R 8b各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基 -N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O) 2 R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 alkyl-C(O)R 15 , -C 0-4 alkyl-OC(O)R 15 , -C 0-4 alkyl-P(O)(R 15 ) 2 ,- C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15. -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 , or, R 8a and R 8b are directly connected to it The carbon atoms together form a C 3-6 cycloalkyl group and a 3-6 membered heterocyclic group, and the C 3-6 cycloalkyl group and the 3-6 membered heterocyclic group are independently optionally further selected by one or more From deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl -N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0- 4Alkyl -C(O)R 15 , -C 0-4Alkyl -OC(O)R 15 , -C 0-4Alkyl -P(O)(R 15 ) 2 , -C 0-4Alkane -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0 Substituents of -4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 ;
每个R 9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15，或者，相邻的两个R 9与其直接相连的部分一起形成一个环烷基和杂环基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代； Each R is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0 -4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0 -4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O) 2 R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkane -OR 14 , -C 0-4alkyl -C(O)OR 14 , -C 0-4alkyl -C(O)SR 14 , -C 0-4alkyl -SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -P(O)(R 15 ) 2 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 , or, two adjacent R 9 directly The connected parts together form a cycloalkyl group and a heterocyclic group, and the above-mentioned groups are independently and optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, Halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl-N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 alkyl-C(O)OR 14 , -C 0-4 alkane -C(O)SR 14 , -C 0-4alkyl -SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O )R 15 , -C 0-4alkyl -P(O)(R 15 ) 2 , -C 0-4alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl- Substituents of N(R 16 )-C(O)R 15 ;
其中，R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17和r如式(I)化合物所定义。 Wherein, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
作为优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，每个R 10各自独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)R 15或-C 0-4烷基-C(O)NR 16R 17，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17或-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代； As a preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 10 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 13 , -C 0-4alkyl -C(O)OR 14 , -C 0-4alkyl -C(O)R 15 or -C 0-4alkyl -C (O)NR 16 R 17 , the above groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5 -8 membered heteroaryl, -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 alkyl-C(O)OR 14 , - C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl- C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0-4alkyl -C(O)NR 16 R 17 or - Substituents of C 0-4 alkyl-N(R 16 )-C(O)R 15 ;
每个R 11和R 12各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基或5-8元杂芳基，或者，R 11和R 12与其直接相连的硫原子一起形成3-6元杂环基，上述基团任选进一步被一个或多个选 自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17或-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代； Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclic group, C 6-8 aryl group or 5-8 membered heteroaryl group, or, R 11 and R 12 form a 3-6 membered heterocyclic group together with the sulfur atom directly connected to it, the above-mentioned groups are optional Further by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1- 4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkane -S(O) r R 13 , -C 0-4alkyl -OR 14 , -C 0-4alkyl -C(O)OR 14 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0- 4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 or -C 0-4 Alkyl-N(R 16 )- C(O)R 15 is replaced by a substituent;
每个R 13独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17的取代基所取代； Each R 13 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl group, 5-8 membered heteroaryl group and -NR 16 R 17 , the above-mentioned groups are independently optionally further selected from deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 1- 4 alkoxyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 heterocyclyl, 3-6 heterocyclyl, C 6-8 aryl, C 6-8 Substituents of aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 ;
每个R 14独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17的取代基所取代； Each R is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, the above-mentioned groups are optionally further independently selected from one or more of deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5 -8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 16 R 17 substituents;
每个R 15独立地选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17的取代基所取代； Each R is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring Alkyl group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group group, 5-8 membered heteroaryloxy group and -NR 16 R 17 , the above groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl , C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 heterocyclic, 3-6 heterocyclic, C 6-8 aryl, Substituents of C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 ;
每个R 16和R 17各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基和C 1-4烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代； Each R 16 and R 17 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, C 6-8 aryl group, 5-8 membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, amino group Sulfonyl, dimethylaminosulfonyl and C 1-4 alkanoyl, the above groups are independently optionally further selected from one or more of deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3- 6- cycloalkoxy, 3-6-membered heterocyclic group, 3-6-membered heterocyclic epoxy group, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered Heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl substituents;
或者，R 16和R 17与其直接相连的氮原子一起形成一个4-8元杂环基或5-8元杂芳基，所述4-8元杂环基或5-8元杂芳基任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代。 Alternatively, R 16 and R 17 form a 4-8 membered heterocyclic group or a 5-8 membered heteroaryl group together with the nitrogen atom directly connected to it, and the 4-8 membered heterocyclic group or 5-8 membered heteroaryl group is any is further selected by one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, Deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 heterocyclic, 3-6 heterocyclic , C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkane Substituted by substituents of amino group and C 1-4 alkanoyl group.
作为优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅱ)化合物：As a preferred scheme, in the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, the compound of formula (I) is the compound of formula (II):
Figure PCTCN2022130789-appb-000002
Figure PCTCN2022130789-appb-000002
其中，R 1选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基的取代基所取代； Wherein, R 1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group and -NR 16 R 17 , the above groups are independently any selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C Substituents of 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl;
R 2a、R 2b、R 2c和R 2d各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15； R 2a , R 2b , R 2c and R 2d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O )(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and - N(R 16 )-C(O)R 15 ;
R 3选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15； R is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 ;
R 4选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15； R 4 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 ;
R 5a和R 5b各自独立地选自氢、氘、卤素、C 1-4烷氧基、卤取代C 1-4烷氧基和氘取代C 1-4烷氧基； R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy and deuterium substituted C 1-4 alkoxy;
R 6a、R 6b、R 6c和R 6d各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、 -O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15； R 6a , R 6b , R 6c and R 6d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O )(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and - N(R 16 )-C(O)R 15 ;
R 7选自氢、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(S)NR 16R 17、-C(O)NR 16R 17和-N(R 16)-C(O)R 15，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代，上述基团独立地任选再进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、C 0-2烷基-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代，条件是，当R 7为氢、-C(O)O-叔丁基、-C(O)O-芳基、-C(O)-C 1-6烷基或-C(O)O-C 1-4烷基-O-C(O)-C 1-21烷基时，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子，或者，R 4为-S-C 1-4烷基； R 7 is selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , - C(S)NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , the above groups are independently optionally further selected from one or more of deuterium, Halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl , 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C (O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C( =NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 are substituted by substituents, the above groups are independently optionally further replaced by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , C 0-2 alkyl-OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 is substituted with the proviso that when R 7 is hydrogen, -C(O)O-tert-butyl, -C(O)O-aryl, -C(O)- When C 1-6 alkyl or -C(O)OC 1-4 alkyl-OC(O)-C 1-21 alkyl, among R 5a , R 5b , R 6a , R 6b , R 6c and R 6d Contains at least one deuterium atom, or, R 4 is -SC 1-4 alkyl;
R 8a和R 8b各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenes Base, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O) (=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )- C(O)R 15 , or, R 8a and R 8b form a C 3-6 cycloalkyl group and a 3-6 membered heterocyclic group together with the carbon atoms directly connected to them, and the C 3-6 cycloalkyl group and 3 -6-membered heterocyclic group is optionally further independently selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , - S(O) rR 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O) Substituents of NR 16 R 17 and -N(R 16 )-C(O)R 15 ;
R 9a、R 9b、R 9c、R 9d和R 9e各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、 -C(O)NR 16R 17和-N(R 16)-C(O)R 15，或者，R 9d和R 9e与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，另三个如前所定义，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代； R 9a , R 9b , R 9c , R 9d and R 9e are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O ) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , - P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 9d and R 9e form a C 3-6 cycloalkyl group and a 3-6 membered heterocyclic group together with the carbon atoms directly connected to them, and the other three As defined above, the C 3-6 cycloalkyl and 3-6 membered heterocyclyl are independently optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, halogen Substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , - N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O) R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 ) Substituents of -C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 ;
其中，R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17和r如式(I)化合物所定义。 Wherein, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
作为进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，R 1选自氢、氘、氟、氰基、甲基、乙基、异丙基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、环丙甲基、环丙基、氧杂环丁基、氧杂环戊基、氮杂环丁基、氮杂环戊基、氨基和二甲氨基； As a further preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R is selected from hydrogen, deuterium, fluorine, cyano, methyl, ethyl, isopropyl Difluoromethyl, trifluoromethyl, dideuteriomethyl, trideuteromethyl, cyclopropylmethyl, cyclopropyl, oxetanyl, oxolyl, azetidinyl, nitrogen Heterocyclopentyl, amino and dimethylamino;
R 2a、R 2b、R 2c和R 2d各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-S-R 13和-O-R 14； R 2a , R 2b , R 2c and R 2d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
其中，R 13和R 14如式(I)化合物所定义。 Wherein, R 13 and R 14 are as defined in the compound of formula (I).
作为优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅲ)化合物：As a preferred scheme, in the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, the compound of formula (I) is the compound of formula (III):
Figure PCTCN2022130789-appb-000003
Figure PCTCN2022130789-appb-000003
其中，R 2a选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-S-R 13和-O-R 14； Wherein, R 2a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
R 3选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-S-R 13和-O-R 14； R 3 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
R 4选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-S-R 13和-O-R 14； R 4 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
R 5a和R 5b各自独立地选自氢、氘、卤素、C 1-4烷氧基、卤取代C 1-4烷氧基和氘取代C 1-4烷氧基； R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy and deuterium substituted C 1-4 alkoxy;
R 6a、R 6b、R 6c和R 6d各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代 C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-S-R 13和-O-R 14； R 6a , R 6b , R 6c and R 6d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
R 7选自氢、C 1-4烷基、C 3-6环烷基、3-6元杂环基、-S(O) rR 13、-C(O)OR 14、-P(O)(R 15) 2、-C(O)R 15、-C(S)NR 16R 17和-C(O)NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代，上述基团独立地任选再进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、C 0-2烷基-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代，条件是，当R 7为氢、-C(O)O-叔丁基、-C(O)O-芳基、-C(O)-C 1-6烷基或-C(O)O-C 1-4烷基-O-C(O)-C 1-21烷基时，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子，或者，R 4为-S-C 1-4烷基； R 7 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -S(O) r R 13 , -C(O)OR 14 , -P(O )(R 15 ) 2 , -C(O)R 15 , -C(S)NR 16 R 17 and -C(O)NR 16 R 17 , the above groups are independently optionally further selected from one or more Deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )- C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 are substituted by substituents, the above groups are independently optionally further replaced by one or Multiple selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne base, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(= NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , C 0-2 alkyl -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)( R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N( R 16 )-C(O)R 15 is substituted with the proviso that when R 7 is hydrogen, -C(O)O-tert-butyl, -C(O)O-aryl, -C(O )-C 1-6 alkyl or -C(O)OC 1-4 alkyl-OC(O)-C 1-21 alkyl, R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contains at least one deuterium atom, or, R 4 is -SC 1-4 alkyl;
R 8a和R 8b各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基和3-6元杂环基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、＝O、＝S、C 3-6环烷基和3-6元杂环基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenes group, C 2-4 alkynyl group, C 3-6 cycloalkyl group and 3-6 membered heterocyclyl group, or, R 8a and R 8b together form a C 3-6 cycloalkyl group and their directly connected carbon atoms 3-6 membered heterocyclic group, the C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, halogen, cyano, C 1-4 alkyl , halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, =O, =S, C 3-6 cycloalkyl and 3 -substituted by a substituent of a 6-membered heterocyclic group;
R 9a选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基和3-6元杂环基； R 9a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
其中，R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17和r如式(I)化合物所定义。 Wherein, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
作为进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅳ1)化合物：As a further preferred solution, in the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, the compound of formula (I) is the compound of formula (IV1):
Figure PCTCN2022130789-appb-000004
Figure PCTCN2022130789-appb-000004
其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、 异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 5a选自氢、氘、三氘甲氧基、二氘甲氧基和三氘乙氧基； R is selected from the group consisting of hydrogen, deuterium, trideuteriomethoxy, dideriomethoxy and trideuteroethoxy;
R 5b选自氢、氘、三氘甲氧基、二氘甲氧基和三氘乙氧基； R is selected from the group consisting of hydrogen, deuterium, trideuteriomethoxy, dideriomethoxy and trideuteroethoxy;
R 6a选自氢、氘、三氘甲基、二氘甲基、一氘甲基、三氘甲氧基、二氘甲氧基和三氘乙氧基； R is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuteriomethyl, monodeuteromethyl, trideuteriomethoxy, dideuuteriomethoxy and trideuteroethoxy;
R 6b选自氢、氘、三氘甲基、二氘甲基、一氘甲基、三氘甲氧基、二氘甲氧基和三氘乙氧基； R6b is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuteriomethyl, monodeuteromethyl, trideuteriomethoxy, diduteriomethoxy and trideuteroethoxy;
R 6c选自氢、氘、三氘甲基、二氘甲基、一氘甲基、三氘甲氧基、二氘甲氧基和三氘乙氧基； R is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuteriomethyl, monodeuteromethyl, trideuteriomethoxyl, diduteriomethoxy and trideuteroethoxy;
R 6d选自氢、氘、三氘甲基、二氘甲基、一氘甲基、三氘甲氧基、二氘甲氧基和三氘乙氧基； R is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuteriomethyl, monodeuteromethyl, trideuteriomethoxy, dideuuteriomethoxy and trideuteroethoxy;
R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, Monodeuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl and Azetidinyl, or, R 8a and R 8b together with the carbon atom to which they are directly attached Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
条件是，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子。 Provided that R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom.
R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 6a选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6b选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6c选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6d选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基。 R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Sulfur base.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，R 7选自C 1-4烷基，所述C 1-4烷基独立地进一步被一个或多个选自氘、卤素、氰基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、
Figure PCTCN2022130789-appb-000005
＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代； As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 7 is selected from C 1-4 alkyl, and the C 1-4 alkyl is independently Further by one or more selected from deuterium, halogen, cyano, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl,
Figure PCTCN2022130789-appb-000005
=O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC( O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C Substituents of (O)NR 16 R 17 and -N(R 16 )-C(O)R 15 ;
其中，R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17和r如式(I)化合物所定义。 Wherein, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅴ1)化合物：As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is the compound of formula (V1):
Figure PCTCN2022130789-appb-000006
Figure PCTCN2022130789-appb-000006
其中，R 5a为氢或氘；R 5b为氢或氘；R 6a为氢或氘；R 6b为氢或氘；R 6c为氢或氘；R 6d为氢或氘； Wherein, R 5a is hydrogen or deuterium; R 5b is hydrogen or deuterium; R 6a is hydrogen or deuterium; R 6b is hydrogen or deuterium; R 6c is hydrogen or deuterium; R 6d is hydrogen or deuterium;
条件是，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子，优选的，包含1、2、4或6个氘原子。 The condition is that R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom, preferably, 1, 2, 4 or 6 deuterium atoms.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅳ2)化合物：As a further preferred solution, in the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, the compound of formula (I) is the compound of formula (IV2):
Figure PCTCN2022130789-appb-000007
Figure PCTCN2022130789-appb-000007
其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, dideriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 6a选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6b选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6c选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6d选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 7a和R 7b各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、C 2-4链炔基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C(O)OR 14和-C(O)NR 16R 17，或者，R 7a和R 7b与其直接相连的碳原子一起形成一个C 3-6环烷基或3-6元杂环基，上述基团独立地任选再进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-O-R 14、-NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代； R 7a and R 7b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkane Base, C 2-4 alkynyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C(O)OR 14 and -C(O)NR 16 R 17 , or, R 7a and R 7b form a C 3-6 cycloalkyl group or a 3-6 membered heterocyclic group together with the directly connected carbon atoms, and the above-mentioned groups are independently optionally further selected from one or more deuterium , halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -OR 14 , -NR 16 R 17 and -N(R 16 ) -C(O)R 15 is replaced by a substituent;
R 7c选自氢、氘、卤素、氰基、卤取代C 1-4烷基和氘取代C 1-4烷基； R 7c is selected from hydrogen, deuterium, halogen, cyano, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
其中，R 14、R 15、R 16和R 17如式(I)化合物所定义。 Wherein, R 14 , R 15 , R 16 and R 17 are as defined in the compound of formula (I).
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅴ2)化合物：As a further preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is the compound of formula (V2):
Figure PCTCN2022130789-appb-000008
Figure PCTCN2022130789-appb-000008
其中，R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； Wherein, R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy , Dideriomethoxy, Trifluoroethoxy and Trideuteroethoxy;
R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 7a和R 7b各自独立地选自氢、氘、氟、氯、甲基、乙基、乙炔基、一氟甲基、二氟甲基、三氟甲基、环丙基和
Figure PCTCN2022130789-appb-000009
或者，R 7a和R 7b与其直接相连的碳原子一起形成一个环丙基，上述基团独立地任选再进一步被一个或多个选自氘、氟、氯、氰基、羟基、甲氧基、甲基、乙基、一氟甲基、二氟甲基、三氟甲基、二甲氨基、甲氧基取代的甲基和苯基的取代基所取代； R 7a and R 7b are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, ethynyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl and
Figure PCTCN2022130789-appb-000009
Alternatively, R 7a and R 7b form a cyclopropyl group together with their directly connected carbon atoms, and the above-mentioned groups are independently and optionally further selected from one or more groups selected from deuterium, fluorine, chlorine, cyano, hydroxyl, and methoxy , methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, dimethylamino, methoxy substituted methyl and phenyl substituents;
R 7c为氢、氘或氟； R 7c is hydrogen, deuterium or fluorine;
优选地，R 5a选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； Preferably, R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideuteriomethoxy;
R 5b选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
R 7a和R 7b各自独立地选自氢、氘、氟、氯、甲基、乙基、一氟甲基、二氟甲基、三氟甲基和
Figure PCTCN2022130789-appb-000010
上述基团独立地任选再进一步被一个或多个选自氘、氟、氯、氰基、羟基、甲基、乙基、一氟甲基、二氟甲基、三氟甲基、甲氧基取代的甲基和苯基的取代基所取代； R 7a and R 7b are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl and
Figure PCTCN2022130789-appb-000010
The above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy Substituents of methyl and phenyl substituted by radicals;
R 7c为氢、氘或氟。 R 7c is hydrogen, deuterium or fluorine.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接 受盐中，式(I)化合物为如下式(Ⅳ3)化合物：As a further preferred scheme, in the compound of the formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of the formula (I) is the compound of the following formula (Ⅳ3):
Figure PCTCN2022130789-appb-000011
Figure PCTCN2022130789-appb-000011
其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, dideriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 6a选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6b选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧 基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6c选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6d选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, one deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideudemethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 7d为C 1-2烷基，上述C 1-2烷基任选进一步被一个或多个选自氘、卤素、氰基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、
Figure PCTCN2022130789-appb-000012
＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-O-C(O)R 15a、-S-C(O)R 15、-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代； R 7d is a C 1-2 alkyl group, and the above-mentioned C 1-2 alkyl group is optionally further replaced by one or more selected from deuterium, halogen, cyano, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkane Base, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl,
Figure PCTCN2022130789-appb-000012
=O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -OC(O)R 15a , -SC(O)R 15 , -C( O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C Substituents of (O)NR 16 R 17 and -N(R 16 )-C(O)R 15 ;
R 15a选自氢、氘、羟基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17的取代基所取代； R 15a is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy , 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 16 R 17 , the above groups are independently optionally further selected from one or more of deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3 -6 cycloalkyl group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 Substituents of heteroaryl, 5-8-membered heteroaryloxy and -NR 16 R 17 ;
R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more of deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂 环丁基和氮杂环丁基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
其中，R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17和r如式(I)化合物所定义。 Wherein, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅴ3)化合物：As a further preferred solution, in the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, the compound of formula (I) is the compound of formula (V3):
Figure PCTCN2022130789-appb-000013
Figure PCTCN2022130789-appb-000013
其中，R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethyl, Deuteromethyl, dideuteriomethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy , Trifluoromethoxy, Difluoromethoxy, Trideuteromethoxy, Dideuteromethoxy, Trifluoroethoxy, Trideuteroethoxy, Cyclopropoxy, Cyclobutoxy, Methylthio and ethylthio;
R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 7d为甲基或乙基，上述甲基或乙基任选进一步被一个或多个选自氘、氟、氯、氰基、羟基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基、三氘甲基、环丙基、甲氧基、苯基、
Figure PCTCN2022130789-appb-000014
的取代基所取代。 R 7d is methyl or ethyl, and the above-mentioned methyl or ethyl is optionally further replaced by one or more selected from deuterium, fluorine, chlorine, cyano, hydroxyl, monofluoromethyl, difluoromethyl, trifluoromethyl , a deuteromethyl, dide deuteromethyl, trideuteromethyl, cyclopropyl, methoxy, phenyl,
Figure PCTCN2022130789-appb-000014
replaced by substituents.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅳ4)化合物：As a further preferred solution, in the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, the compound of formula (I) is the compound of formula (IV4):
Figure PCTCN2022130789-appb-000015
Figure PCTCN2022130789-appb-000015
其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 6a选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6b选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧 基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6c选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6d选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 7e和R 7f各自独立地选自羟基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基和3-6元杂环氧基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17的取代基所取代； R 7e and R 7f are each independently selected from hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocycle and 3-6 membered heterooxyl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkane Oxygen, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 heterocyclic, 3-6 heterocyclic, C 6-8 aryl, C 6-8 aryloxy Substituents of base, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 ;
R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基 R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl
其中，R 16和R 17如式(I)化合物所定义。 Wherein, R 16 and R 17 are as defined in the compound of formula (I).
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅴ4)化合物：As a further preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is the compound of formula (V4):
Figure PCTCN2022130789-appb-000016
Figure PCTCN2022130789-appb-000016
其中，R 5a选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； Wherein, R 5a is selected from hydrogen, deuterium, methoxyl group, trifluoromethoxyl group, difluoromethoxyl group, trideuterium methoxy group and didereter methoxy group;
R 5b选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
R 7e和R 7f各自独立地选自羟基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、环丙基、环丁基、环丙氧基、环丁氧基、氧杂环丙基和氧杂环丁基，上述基团独立地任选进一步被一个或多个选自氘、氟、氯、羟基、＝O、氰基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、环丙基、环丁基、环丙氧基、环丁氧基、氧杂环丙基、氧杂环丁基、氨基和二甲基氨基的取代基所取代。 R 7e and R 7f are each independently selected from hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopropoxy , cyclobutoxy, oxirane and oxetanyl, the above groups are independently optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, =O, cyano, methyl, Ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopropoxy, cyclobutoxy, oxirane, oxetane Butyl, amino and dimethylamino substituents are substituted.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅳ5)化合物：As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is the compound of formula (IV5):
Figure PCTCN2022130789-appb-000017
Figure PCTCN2022130789-appb-000017
其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧 基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基 R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio
R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 6a选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6b选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6c选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
条件是，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子； The condition is that R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom;
R 7g为C 1-4烷基；R 7h为C 1-4烷基； R 7g is C 1-4 alkyl; R 7h is C 1-4 alkyl;
R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、 二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基。 R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl.
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅴ5)化合物：As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is the compound of formula (V5):
Figure PCTCN2022130789-appb-000018
Figure PCTCN2022130789-appb-000018
其中，R 5a选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； Wherein, R 5a is selected from hydrogen, deuterium, methoxyl group, trifluoromethoxyl group, difluoromethoxyl group, trideuterium methoxy group and didereter methoxy group;
R 5b选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
R 7g为氢、甲基或乙基；R 7h为氢、甲基、乙基、丙基、丁基、异丙基、叔丁基或异丁基； R 7g is hydrogen, methyl or ethyl; R 7h is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl or isobutyl;
条件是，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子。 Provided that R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅳ6)化合物：As a further preferred solution, in the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, the compound of formula (I) is the compound of formula (IV6):
Figure PCTCN2022130789-appb-000019
Figure PCTCN2022130789-appb-000019
其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧 基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
R 6a选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6b选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 6c选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
R 7k选自氢、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、6-8元杂芳基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代； R 7k is selected from hydrogen, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 6-8 membered heteroaryl and -NR 16 R 17 , the above groups are independently any selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S (O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , - OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C (O) R 15 substituents are substituted;
R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原 子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
其中，R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17和r如式(I)化合物所定义。 Wherein, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in the compound of formula (I).
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅴ6)化合物：As a further preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is the compound of formula (V6):
Figure PCTCN2022130789-appb-000020
Figure PCTCN2022130789-appb-000020
其中，R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethyl, Deuteromethyl, Dideuteriomethyl, One-Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy , Trifluoromethoxy, Difluoromethoxy, Trideuteromethoxy, Dideriomethoxy, Trifluoroethoxy, Trideuteroethoxy, Cyclopropoxy, Cyclobutoxy, Methylthio and ethylthio;
R 5a选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideudemethoxy;
R 5b选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
R 7k选自氢、环丙基、环丁基、氧杂环丙基、氧杂环丁基和苯基，上述基团独立地任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、丙基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基、三氘甲基、＝O和＝S的取代基所取代。 R 7k is selected from hydrogen, cyclopropyl, cyclobutyl, oxirane propyl, oxetanyl and phenyl, and the above-mentioned groups are independently optionally further selected from deuterium, fluorine, chlorine, Substituents of cyano, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteromethyl, dideuteriomethyl, trideuteromethyl, =O and =S replaced.
作为最优选的方案，所述式(I)化合物、其立体异构体或其药学上可接受盐包括但不限于如下化合物：As the most preferred solution, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt includes but not limited to the following compounds:
Figure PCTCN2022130789-appb-000021
Figure PCTCN2022130789-appb-000021
Figure PCTCN2022130789-appb-000022
Figure PCTCN2022130789-appb-000022
Figure PCTCN2022130789-appb-000023
Figure PCTCN2022130789-appb-000023
Figure PCTCN2022130789-appb-000024
Figure PCTCN2022130789-appb-000024
Figure PCTCN2022130789-appb-000025
Figure PCTCN2022130789-appb-000025
本发明第二方面提供式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，包括如下步骤：The second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, comprising the following steps:
Figure PCTCN2022130789-appb-000026
Figure PCTCN2022130789-appb-000026
当R 7不为氢时，式(I-a)化合物或其酸式盐反应生成式(I)化合物或其酸式盐； When R is not hydrogen , the compound of formula (Ia) or its acid salt reacts to generate the compound of formula (I) or its acid salt;
其中，R 1、R 2、R 3、R 4、R 5a、R 5b、R 6a、R 6b、R 6c、R 6d、R 7、R 8a、R 8b、R 9、m和n如式(I)化合物所定义。 Wherein, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 6c , R 6d , R 7 , R 8a , R 8b , R 9 , m and n are as in the formula ( I) Compound definition.
本发明第三方面提供一种药物组合物，其包含式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。The third aspect of the present invention provides a pharmaceutical composition, which comprises the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防与KRas G12D相关的癌症或肿瘤的药物中的用途。The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicines for treating and/or preventing cancers or tumors related to KRas G12D.
本发明还涉及前述式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗与KRas G12D相关的肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤、畸胎瘤；支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、肺泡(细支气管癌)癌、支气管腺瘤、淋巴瘤、软骨瘤样错构瘤、间皮瘤；食管癌(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(淋巴瘤、平滑肌肉瘤)、胰腺癌(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、血管活性肠肽瘤)、小肠癌(腺癌、淋巴瘤、类癌瘤、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠癌(腺癌、管状腺瘤、绒 毛状腺瘤、错构瘤、平滑肌瘤)；肾脏癌(腺癌、肾母细胞瘤(肾胚细胞瘤)、淋巴瘤、白血病)、膀胱和尿道癌(鳞状细胞癌、移行细胞癌、腺癌)、前列腺癌(腺癌、肉瘤)、睾丸癌(精原细胞瘤、畸胎瘤、胚胎性癌、畸胎上皮癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤)；肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤；胆囊癌、壶腹癌、胆管癌；骨原性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨外生骨)、良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤和巨细胞瘤；颅骨癌(骨瘤、血管瘤、肉芽肿、黄色瘤、畸形性骨炎)、脑膜癌(脑膜瘤、脑膜肉瘤、神经胶瘤病)、脑癌(星形细胞瘤、神经管胚细胞瘤、神经胶质瘤、室管膜瘤、胚细胞瘤(松果体瘤)、多形神经胶母细胞瘤、寡树突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤)；子宫癌(子宫内膜癌(浆液性囊腺癌、粘液性囊腺癌、未分类的癌瘤)、粒层泡膜细胞瘤、塞特利氏-雷迪格细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴癌(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道癌(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎性横纹肌肉瘤))、输卵管(癌瘤)；血液癌(骨髓性白血病(急性及慢性)、急性淋巴母细胞白血病、慢性淋巴细胞性白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤)；恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤、牛皮癣及肾上腺瘤或神经母细胞瘤药物中的用途。The present invention also relates to the use of the aforementioned formula (I) compound, its stereoisomer or pharmaceutically acceptable salt thereof in the preparation of prevention and/or treatment of KRas G12D-related sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), Myxoma, rhabdomyoma, fibroid, lipoma, teratoma; bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole carcinoma) carcinoma, bronchial adenoma, lymphoid tumor, chondromatoid hamartoma, mesothelioma; esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, Glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma , neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); kidney cancer (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratoma Fetal epithelial carcinoma, choriocarcinoma, sarcoma, mesenchymal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, liver Cell adenoma, hemangioma; gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma ), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exogenous bone), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; carcinoma of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meningeal cancer (meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma Glioma, ependymoma, blastoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal nerve fibers tumor, meningioma, glioma, sarcoma); uterine cancer (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Setley Lehdig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma); blood cancer (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorder, multiple Myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, Use in medicine for lipoma, hemangioma, dermatofibroma, keloid, psoriasis and adrenal adenoma or neuroblastoma.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用作药物。The present invention also relates to said compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, for use as a medicament.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防与KRas G12D相关的癌症或肿瘤的用途。The present invention also relates to the use of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof for treating and/or preventing cancer or tumor related to KRas G12D.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防与KRas G12D相关的肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤、畸胎瘤；支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、肺泡(细支气管癌)癌、支气管腺瘤、淋巴瘤、软骨瘤样错构瘤、间皮瘤；食管癌(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(淋巴瘤、平滑肌肉瘤)、胰腺癌(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、血管活性肠肽瘤)、小肠癌(腺癌、淋巴瘤、类癌瘤、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠癌(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤)；肾脏癌(腺癌、肾母细胞瘤(肾胚细胞瘤)、淋巴瘤、白血病)、膀胱和尿道癌(鳞状细胞癌、移行细胞癌、腺癌)、前列腺癌(腺癌、肉瘤)、睾丸癌(精原细胞瘤、畸胎瘤、胚胎性癌、畸胎上皮癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤)；肝癌(肝细胞癌)、胆管癌、肝 母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤；胆囊癌、壶腹癌、胆管癌；骨原性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨外生骨)、良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤和巨细胞瘤；颅骨癌(骨瘤、血管瘤、肉芽肿、黄色瘤、畸形性骨炎)、脑膜癌(脑膜瘤、脑膜肉瘤、神经胶瘤病)、脑癌(星形细胞瘤、神经管胚细胞瘤、神经胶质瘤、室管膜瘤、胚细胞瘤(松果体瘤)、多形神经胶母细胞瘤、寡树突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤)；子宫癌(子宫内膜癌(浆液性囊腺癌、粘液性囊腺癌、未分类的癌瘤)、粒层泡膜细胞瘤、塞特利氏-雷迪格细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴癌(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道癌(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎性横纹肌肉瘤))、输卵管(癌瘤)；血液癌(骨髓性白血病(急性及慢性)、急性淋巴母细胞白血病、慢性淋巴细胞性白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤)；恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤、牛皮癣及肾上腺瘤或神经母细胞瘤的用途。The present invention also relates to the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, which is used for the treatment and/or prevention of KRas G12D related sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, adipose sarcoma), myxoma, rhabdomyoma, fibroid, lipoma, teratoma; bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole carcinoma) carcinoma, bronchial gland tumor, lymphoma, chondromatoid hamartoma, mesothelioma; esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, Insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma , lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); kidney cancer (adenocarcinoma, Wilms tumor (kidney blastoma) cancer), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, vascular Sarcoma, hepatocellular adenoma, hemangioma; gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (web sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exogenous bone), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor ; Skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma , glioma, ependymoma, blastoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannomas, retinoblastoma, congenital tumors, Spinal neurofibroma, meningioma, glioma, sarcoma); uterine cancer (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Settley-Rediger cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, Squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma); blood cancer (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders , multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus development Adverse moles, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis, and adrenal tumors or neuroblastomas.
本发明还涉及一种治疗和/或预防与KRas G12D相关的癌症或肿瘤的方法，其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。The present invention also relates to a method for treating and/or preventing cancer or tumor related to KRas G12D, which comprises administering a therapeutically effective amount of the compound of formula (I), its stereoisomer or its pharmaceutically effective amount to the patient in need. Salt is acceptable.
本发明还涉及一种治疗和/或预防与KRas G12D相关的肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤、畸胎瘤；支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、肺泡(细支气管癌)癌、支气管腺瘤、淋巴瘤、软骨瘤样错构瘤、间皮瘤；食管癌(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(淋巴瘤、平滑肌肉瘤)、胰腺癌(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、血管活性肠肽瘤)、小肠癌(腺癌、淋巴瘤、类癌瘤、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠癌(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤)；肾脏癌(腺癌、肾母细胞瘤(肾胚细胞瘤)、淋巴瘤、白血病)、膀胱和尿道癌(鳞状细胞癌、移行细胞癌、腺癌)、前列腺癌(腺癌、肉瘤)、睾丸癌(精原细胞瘤、畸胎瘤、胚胎性癌、畸胎上皮癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤)；肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤；胆囊癌、壶腹癌、胆管癌；骨原性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨外生骨)、良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤和巨细胞瘤；颅骨癌(骨瘤、血管瘤、肉芽肿、黄色瘤、畸形性骨炎)、脑膜癌(脑膜瘤、脑膜肉瘤、神经胶瘤病)、脑癌(星形细胞瘤、神经管胚细胞瘤、神经 胶质瘤、室管膜瘤、胚细胞瘤(松果体瘤)、多形神经胶母细胞瘤、寡树突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤)；子宫癌(子宫内膜癌(浆液性囊腺癌、粘液性囊腺癌、未分类的癌瘤)、粒层泡膜细胞瘤、塞特利氏-雷迪格细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴癌(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道癌(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎性横纹肌肉瘤))、输卵管(癌瘤)；血液癌(骨髓性白血病(急性及慢性)、急性淋巴母细胞白血病、慢性淋巴细胞性白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤)；恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤、牛皮癣及肾上腺瘤或神经母细胞瘤的方法，其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。The present invention also relates to a method for treating and/or preventing sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma associated with KRas G12D; bronchial carcinoma ( Squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar carcinoma) carcinoma, bronchial adenoma, lymphoma, chondromatoid hamartoma, mesothelioma; esophageal carcinoma (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); kidney cancer (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma , adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroma adenoma, adenomatoid tumor, lipoma); liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (bone cartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), Meningeal cancer (meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, blastoma (pineal tumor), multiple Glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, neurofibroma of the spinal cord, meningioma, glioma, sarcoma); uterine cancer (endometrial Carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Settley-Rediger cell tumor, dysgerminoma, malignant teratoma), vulva Carcinoma (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal carcinoma (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma); Blood cancers (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's Lymphoma (malignant lymphoma); malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and adrenal or neurological A method for blastoma comprising administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
具体实施方式Detailed ways
本申请的发明人经过广泛而深入地研究，首次研发出一种具有式(I)结构的KRas G12D抑制剂，本发明系列化合物可广泛应用于制备治疗和/或预防与KRas G12D相关癌症或肿瘤的药物，有望开发成新一代KRas G12D抑制剂。在此基础上，完成了本发明。After extensive and in-depth research, the inventors of the present application have developed a KRas G12D inhibitor with the structure of formula (I) for the first time. The series of compounds of the present invention can be widely used in the preparation, treatment and/or prevention of cancers or tumors related to KRas G12D Drugs are expected to be developed into a new generation of KRas G12D inhibitors. On this basis, the present invention has been accomplished.
详细说明：除非有相反陈述或特别说明，下列用在说明书和权利要求书中的术语具有下述含义。Detailed Description: Unless stated to the contrary or otherwise specified, the following terms used in the specification and claims have the following meanings.
“烷基”指直链或含支链的饱和脂族烃基团，优选包括1至10个或1至6个碳原子或1至4个碳原子的直链烷基和含支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。“C 1-21烷基”指包括1至21个碳原子的直链烷基和含支链烷基，“C 1-10烷基”指包括1至10个碳原子的直链烷基和含支链烷基，“C 1-4烷基”指包括1至4个碳原子的直链烷基和含支链烷基，“C 0-8烷基”指包括0至8个碳原子的直链烷基和含支链烷基，“C 0-4烷基”指包括0至4个碳原子的直链烷基和含支链烷基。 "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched-chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2- Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl Base, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2, 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, etc. "C 1-21 alkyl" refers to straight chain alkyl and branched chain alkyl including 1 to 21 carbon atoms, "C 1-10 alkyl" refers to straight chain alkyl and branched chain including 1 to 10 carbon atoms Containing branched chain alkyl, "C 1-4 alkyl" refers to straight chain alkyl and branched chain containing 1 to 4 carbon atoms, "C 0-8 alkyl" refers to containing 0 to 8 carbon atoms "C 0-4 alkyl" refers to a straight chain alkyl group and a branched alkyl group containing 0 to 4 carbon atoms.
烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优 选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代。 Alkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano Base, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 ,-C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 ,-C 0-8alkyl -C(O)SR 14 ,-C 0-8alkyl -SC(O)R 15 ,-C 0-8alkyl -C( O)R 15 , -C 0-8 alkyl-OC(O)R 15 , -C 0-8 alkyl-P(O)(R 15 ) 2 , -C 0-8 alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C Substituents of (O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 .
“环烷基”或“碳环”指饱和或部分不饱和单环或多环环状烃取代基，所述部分不饱和环状烃是指环状烃可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，环烷基分为单环环烷基、多环环烷基，优选包括3至12个或3至8个或3至6个碳原子的环烷基，例如，“C 3-12环烷基”指包括3至12个碳原子的环烷基，“C 3-10环烷基”指包括3至10个碳原子的环烷基，“C 3-8环烷基”指包括3至8个碳原子的环烷基，“C 3-6环烷基”指包括3至6个碳原子的环烷基，其中： "Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π-electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 A cycloalkyl group of up to 6 carbon atoms, for example, "C 3-12 cycloalkyl" refers to a cycloalkyl group containing 3 to 12 carbon atoms, and "C 3-10 cycloalkyl" refers to a cycloalkyl group containing 3 to 10 carbon atoms atom, "C 3-8 cycloalkyl" refers to a cycloalkyl group comprising 3 to 8 carbon atoms, and "C 3-6 cycloalkyl" refers to a cycloalkyl group comprising 3 to 6 carbon atoms, in:
单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl et al.
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，螺环烷基包括但不限于：Multicyclic cycloalkyls include spiro, fused and bridged cycloalkyls. "Spirocycloalkyl" refers to polycyclic groups in which single rings share one carbon atom (called a spiro atom), these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has A fully conjugated π-electron system. According to the number of spiro atoms shared between rings, spirocycloalkyl groups are divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, spirocycloalkyl includes but not limited to:
Figure PCTCN2022130789-appb-000027
Figure PCTCN2022130789-appb-000027
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基包括但不限于："Fused cycloalkyl" means an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated π-electron system. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
Figure PCTCN2022130789-appb-000028
Figure PCTCN2022130789-appb-000028
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基包括但不限于："Bridged cycloalkyl" means an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated π-electron system. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Bridged cycloalkyl groups include but are not limited to:
Figure PCTCN2022130789-appb-000029
Figure PCTCN2022130789-appb-000029
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，包括但不限于茚满基、四氢萘基、苯并环庚烷基等。The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , Benzocycloheptyl, etc.
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代。 Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, Cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5 , - C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0- 8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C (O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 ) 2 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 alkyl- Substituents of C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 .
“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃取代基，所述部分不饱和环状烃是指环状烃可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，杂环基中一个或多个(优选1、2、3或4个)环原子选自N、O、N·O或S(O) r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个或3至8个或3至6个环原子的杂环基，例如，“3-6元杂环基”指包含3至6个环原子的杂环基，“3-8元杂环基”指包含3至8个环原子的杂环基，“4-8元杂环基”指包含4至8个环原子的杂环基，“4-10元杂环基”指包含4至10个环原子的杂环基，“5-8元杂环基”指包含5至8个环原子的杂环基，“3-12元杂环基”指包含3至12个环原子的杂环基。 "Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon can contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π-electron system, and one or more (preferably 1, 2, 3 or 4) ring atoms in the heterocyclyl group are selected from N, O, N O or a heteroatom of S(O) r (where r is an integer 0, 1, 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. A heterocyclic group comprising 3 to 12 or 3 to 8 or 3 to 6 ring atoms is preferred, for example, "3-6 membered heterocyclic group" refers to a heterocyclic group comprising 3 to 6 ring atoms, "3- 8-membered heterocyclic group" refers to a heterocyclic group containing 3 to 8 ring atoms, "4-8 membered heterocyclic group" refers to a heterocyclic group containing 4 to 8 ring atoms, and "4-10 membered heterocyclic group" Refers to a heterocyclic group containing 4 to 10 ring atoms, "5-8 membered heterocyclic group" refers to a heterocyclic group containing 5 to 8 ring atoms, "3-12 membered heterocyclic group" refers to a heterocyclic group containing 3 to 12 ring atom heterocyclyl.
单环杂环基包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、 高哌嗪基、氧杂环丁烷基、四氢呋喃基等。Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个(优选1、2、3或4个)环原子选自N、O、N·O或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键(优选1、2或3个)，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。螺杂环基包括但不限于： Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O , N·O or S(O) r (where r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system. According to the number of spiro atoms shared between the rings, spiroheterocyclyls are classified as single spiroheterocyclyls, double spiroheterocyclyls or polyspiroheterocyclyls. Spiroheterocyclyls include, but are not limited to:
Figure PCTCN2022130789-appb-000030
Figure PCTCN2022130789-appb-000030
“稠杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个(优选1、2、3或4个)环可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个(优选1、2、3或4个)环原子选自N、O、N·O或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基包括但不限于： "Fused heterocyclyl" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may be Contains one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π-electron system, where one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N·O or S(O) r (where r is an integer of 0, 1, 2) is a heteroatom, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups. The fused heterocyclyl groups include but are not limited to:
Figure PCTCN2022130789-appb-000031
Figure PCTCN2022130789-appb-000031
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个(优选1、2、3或4个)环原子选自N、O、N·O或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，桥杂环基包括但不限于： "Bridged heterocyclyl" means a polycyclic heterocyclic group in which any two rings share two atoms not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings Has a fully conjugated π-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N O or S(O) r (where r is an integer 0, 1 , 2), and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include but are not limited to:
Figure PCTCN2022130789-appb-000032
Figure PCTCN2022130789-appb-000032
所述杂环基环可以稠合于芳基、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，包括但不限于：The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring attached to the parent structure is a heterocyclyl, including but not limited to:
Figure PCTCN2022130789-appb-000033
Figure PCTCN2022130789-appb-000033
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代。 The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, Cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5 , - C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0- 8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C (O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 ) 2 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 alkyl- Substituents of C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 .
“芳基”或“芳环”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，优选含有6-10个或6-8个碳的全碳芳基，例如，“C 6-10芳基”指含有6-10个碳的全碳芳基，包括但不限于苯基和萘基，“C 6-8芳基”指含有6-8个碳的全碳芳基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，包括但不限于： "Aryl" or "aromatic ring" means an all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of For ring) groups of carbon atoms, preferably a full-carbon aryl group containing 6-10 or 6-8 carbons, for example, "C 6-10 aryl" refers to a full-carbon aryl group containing 6-10 carbons, Including but not limited to phenyl and naphthyl, "C 6-8 aryl" refers to a full carbon aryl group containing 6-8 carbons. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, including but not limited to:
Figure PCTCN2022130789-appb-000034
Figure PCTCN2022130789-appb-000034
“芳基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷 基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代。 "Aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano Base, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 ,-C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 ,-C 0-8alkyl -C(O)SR 14 ,-C 0-8alkyl -SC(O)R 15 ,-C 0-8alkyl -C( O)R 15 , -C 0-8 alkyl-OC(O)R 15 , -C 0-8 alkyl-P(O)(R 15 ) 2 , -C 0-8 alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C Substituents of (O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 .
“杂芳基”指包含一个或多个(优选1、2、3或4个)杂原子的杂芳族体系，所述杂原子包括N、O、N·O和S(O)r(其中r是整数0、1、2)的杂原子，优选含有5-10个或5-8个或5-6个环原子的杂芳族体系，例如，“5-8元杂芳基”指含有5-8个环原子的杂芳族体系，“5-10元杂芳基”指含有5-10个环原子的杂芳族体系，包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、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，包括但不限于："Heteroaryl" means a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms, including N, O, N.O and S(O)r (where r is an integer (0, 1, 2) heteroatom, preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered heteroaryl" means containing A heteroaromatic system with 5-8 ring atoms, "5-10 membered heteroaryl" refers to a heteroaromatic system with 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl , N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is a heteroaryl ring, including but not limited to:
Figure PCTCN2022130789-appb-000035
Figure PCTCN2022130789-appb-000035
“杂芳基”可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代。 "Heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, Halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 chain Alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5 , -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N= SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -P(O)(R 15 ) 2 , -C 0-8alkyl -NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 alkane Substituents of the group -C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 .
“链烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，优选含有2-10个或2-4个碳的直链或含支链烯基，例如，“C 2-10链烯基”指含有2-10个碳的直链或含支链烯基，“C 2-4链烯基”指含有2-4个碳的直链或含支链烯基。包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。 "Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight chain or branched alkenyl group containing 2-10 or 2-4 carbons For example, "C 2-10 alkenyl" refers to a straight-chain or branched alkenyl group containing 2-10 carbons, and "C 2-4 alkenyl" refers to a straight-chain or branched alkenyl group containing 2-4 carbons. branched alkenyl. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.
“链烯基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷 基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代。 "Alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, Cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5 , - C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0- 8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C (O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 ) 2 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 alkyl- Substituents of C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 .
“链炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，优选含有2-10个或2-4个碳的直链或含支链炔基，例如，“C 2-10链炔基”指含有2-10个碳的直链或含支链炔基，“C 2-4链炔基”指含有2-4个碳的直链或含支链炔基。包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。 "Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons, For example, "C 2-10 alkynyl" refers to a straight-chain or branched alkynyl group containing 2-10 carbons, and "C 2-4 alkynyl" refers to a straight-chain or branched alkynyl group containing 2-4 carbons. Alkynyl. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.
“链炔基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代。 "Alkynyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, Cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5 , - C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0- 8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C (O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 ) 2 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 alkyl- Substituents of C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 .
“烷氧基”指-O-烷基，其中烷基的定义如上所述，例如，“C 1-10烷氧基”指含1-10个碳的烷基氧基，“C 1-4烷氧基”指含1-4个碳的烷基氧基，“C 1-2烷氧基”指含1-2个碳的烷基氧基，包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。 "Alkoxy" refers to -O-alkyl, wherein the definition of alkyl is as above, for example, "C 1-10 alkoxy" refers to an alkyloxy group containing 1-10 carbons, "C 1-4 Alkoxy" refers to an alkyloxy group containing 1-4 carbons, and "C 1-2 alkoxy" refers to an alkyloxy group containing 1-2 carbons, including but not limited to methoxy, ethoxy , Propoxy, Butoxy, etc.
“烷氧基”可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代。 "Alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1, 2, 3 or 4) of the following groups, are independently selected from deuterium , halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5. -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N =SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , - C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkane -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -P(O)(R 15 ) 2 , -C 0-8alkyl- NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Substituents of alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 are substituted.
“环烷氧基”或“环烷基氧基”指-O-环烷基，其中环烷基的定义如上所述，例如，“C 3-12环烷氧基”指含3-12个碳的环烷基氧基，“C 3-6环烷氧基”指含3-6个碳的环烷 基氧基，包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。 "Cycloalkoxy" or "cycloalkyloxy" refers to -O-cycloalkyl, wherein the definition of cycloalkyl is as above, for example, "C 3-12 cycloalkoxy" refers to 3-12 Carbon cycloalkyloxy, "C 3-6 cycloalkoxy" refers to cycloalkyloxy containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy , Cyclohexyl and so on.
“环烷氧基”或“环烷基氧基”可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代。 "Cycloalkoxy" or "cycloalkyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) or less Groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, - C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 ,- C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O) 2 R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0- 8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 alkyl-C(O)R 15 , -C 0-8 alkyl-OC(O)R 15 , -C 0-8 alkyl-P(O)(R 15 ) 2 , -C 0-8 alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 ,-C 0-8 alkyl-N(R 16 )-C(=NR 17 ) Substituents of R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 are substituted.
“杂环氧基”或“杂环基氧基”指-O-杂环基，其中杂环基的定义如上所述，包括但不限于氮杂环丁基氧基、氧杂环丁基氧基、氮杂环戊基氧基、氮、氧杂环己基氧基等。"Heterocyclyloxy" or "heterocyclyloxy" refers to -O-heterocyclyl, where the definition of heterocyclyl is as above, including but not limited to azetidinyloxy, oxetanyloxy radical, azacyclopentyloxy, nitrogen, oxepyloxy, etc.
“杂环氧基”或“杂环基氧基”可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代。 "Heterocyclyloxy" or "heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) or less Groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, - C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 ,- C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O) 2 R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0- 8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 alkyl-C(O)R 15 , -C 0-8 alkyl-OC(O)R 15 , -C 0-8 alkyl-P(O)(R 15 ) 2 , -C 0-8 alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 ) Substituents of R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 are substituted.
“C 1-10烷酰基”指C 1-10烷基酸去掉羟基后剩下的一价原子团，通常也表示为“C 0-9烷基-C(O)-”，例如，“C 1烷基-C(O)-”是指乙酰基；“C 2烷基-C(O)-”是指丙酰基；“C 3烷基-C(O)-”是指丁酰基或异丁酰基。 "C 1-10 alkanoyl" refers to the monovalent atomic group left after C 1-10 alkanoic acid removes the hydroxyl group, and is usually expressed as "C 0-9 alkyl-C(O)-", for example, "C 1 Alkyl-C(O)-" refers to acetyl; "C 2 alkyl-C(O)-" refers to propionyl; "C 3 alkyl-C(O)-" refers to butyryl or isobutyryl Acyl.
“-C 0-8烷基-S(O)(＝N-R 10)R 11”指-S(O)(＝N-R 10)R 11中的硫原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-S(O)(=NR 10 )R 11 " means that the sulfur atom in -S(O)(=NR 10 )R 11 is connected to C 0-8 alkyl, where C 0-8 Alkyl is as defined above.
“-C 0-8烷基-N＝S(O)R 11R 12”指-N＝S(O)R 11R 12中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-N=S(O)R 11 R 12 "means that the nitrogen atom in -N=S(O)R 11 R 12 is connected to C 0-8 alkyl, where C 0- 8Alkyl is as defined above.
“-C 0-8烷基-N＝SR 11R 12”指-N＝SR 11R 12中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-N=SR 11 R 12 " means that the nitrogen atom in -N=SR 11 R 12 is connected to C 0-8 alkyl, wherein the definition of C 0-8 alkyl is as above .
“-C 0-8烷基-O-S(O) 2R 13”指-O-S(O) 2R 13中的氧原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-OS(O) 2 R 13 "means that the oxygen atom in -OS(O) 2 R 13 is connected to C 0-8 alkyl, wherein the definition of C 0-8 alkyl is as above mentioned.
“-C 0-8烷基-S(O) rR 13”指-S(O) rR 13中的硫原子连接在C 0-8烷基上，其中C 0-8烷 基的定义如上所述。 "-C 0-8 alkyl-S(O) r R 13 "means that the sulfur atom in -S(O) r R 13 is connected to C 0-8 alkyl, wherein the definition of C 0-8 alkyl is as above mentioned.
“-C 0-8烷基-O-R 14”指-O-R 14中的氧原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-OR 14 " means that the oxygen atom in -OR 14 is connected to C 0-8 alkyl, wherein the definition of C 0-8 alkyl is as above.
“-C 0-8烷基-C(O)OR 14”指-C(O)OR 14中的羰基连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(O)OR 14 " means that the carbonyl group in -C(O)OR 14 is connected to C 0-8 alkyl, wherein the definition of C 0-8 alkyl is as above.
“-C 0-8烷基-C(O)SR 14”指-C(O)SR 14中的羰基连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(O)SR 14 " means that the carbonyl group in -C(O)SR 14 is connected to C 0-8 alkyl, wherein the definition of C 0-8 alkyl is as above.
“-C 0-8烷基-S-C(O)R 15”指-S-C(O)R 15中的硫原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-SC(O)R 15 " means that the sulfur atom in -SC(O)R 15 is connected to C 0-8 alkyl, wherein the definition of C 0-8 alkyl is as above .
“-C 0-8烷基-C(O)R 15”指-C(O)R 15中的羰基连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(O)R 15 " means that the carbonyl group in -C(O)R 15 is connected to C 0-8 alkyl, wherein the definition of C 0-8 alkyl is as above.
“-C 0-8烷基-O-C(O)R 15”指-O-C(O)R 15中的氧原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-OC(O)R 15 " means that the oxygen atom in -OC(O)R 15 is connected to C 0-8 alkyl, wherein the definition of C 0-8 alkyl is as above .
“-C 0-8烷基-P(O)(R 15) 2”指-P(O)(R 15) 2中的磷原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-P(O)(R 15 ) 2 "means that the phosphorus atom in -P(O)(R 15 ) 2 is connected to C 0-8 alkyl, wherein C 0-8 alkyl The bases are defined as above.
“-C 0-8烷基-NR 16R 17”指-NR 16R 17中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-NR 16 R 17 " means that the nitrogen atom in -NR 16 R 17 is connected to C 0-8 alkyl, wherein the definition of C 0-8 alkyl is as above.
“-C 0-8烷基-C(＝NR 16)R 15”指-C(＝NR 16)R 15中的碳原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(=NR 16 )R 15 " means that the carbon atom in -C(=NR 16 )R 15 is connected to C 0-8 alkyl, wherein the C 0-8 alkyl defined above.
“-C 0-8烷基-N(R 16)-C(＝NR 17)R 15”指-N(R 16)-C(＝NR 17)R 15中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 " means that the nitrogen atom in -N(R 16 )-C(=NR 17 )R 15 is connected to C 0-8 On the alkyl, wherein C 0-8 alkyl is as defined above.
“-C 0-8烷基-C(O)NR 16R 17”指-C(O)NR 16R 17中的羰基连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(O)NR 16 R 17 "means that the carbonyl group in -C(O)NR 16 R 17 is connected to C 0-8 alkyl, where the definition of C 0-8 alkyl as above.
“-C 0-8烷基-N(R 16)-C(O)R 15”指-N(R 16)-C(O)R 15中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-N(R 16 )-C(O)R 15 " means that the nitrogen atom in -N(R 16 )-C(O)R 15 is connected to C 0-8 alkyl, Wherein the definition of C 0-8 alkyl is as above.
“卤取代C 1-10烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷基团，包括但不限于二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。 "Halogen substituted C 1-10 alkyl" refers to 1-10 carbon alkyl groups whose hydrogen on the alkyl is optionally substituted by fluorine, chlorine, bromine, iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
“卤取代C 1-10烷氧基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷氧基团。包括但不限于二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。 "Halogen substituted C 1-10 alkoxy" refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally replaced by fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
“氘取代C 1-10烷基”指烷基上的氢任选的被氘原子取代的1-10个碳烷基团。包括但不限于一氘甲基、二氘甲基、三氘甲基等。 "Deuterium-substituted C 1-10 alkyl" refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl is optionally replaced by a deuterium atom. Including but not limited to mono-deuteromethyl, dide-deuteromethyl, tri-deuteromethyl, etc.
“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合，也即包括取代的或未取代的两种情形。例 如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes the occasion where the event or circumstance occurs or does not occur, that is, includes two situations of substitution or non-substitution . For example, a "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个“氢原子”彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，符合化学上的价键理论，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯烃)结合时可能是不稳定的。"Substituted" means that one or more "hydrogen atoms" in a group are independently substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, consistent with the valence bond theory in chemistry, and a person skilled in the art can determine (by experiment or theory) that it is possible or impossible without undue effort of the replacement. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond such as an alkene.
“立体异构体”，其英文名称为stereoisomer，是指由分子中原子在空间上排列方式不同所产生的异构体，它可分为顺反异构体、对映异构体两种，也可分为对映异构体和非对映异构体两大类。由于单键的旋转而引起的立体异构体称为构象异构体(conformational stereo-isomer)，有时也称为旋转异构体(rotamer)。因键长、键角、分子内有双键、有环等原因引起的立体异构体称为构型异构体(configuration stereo-isomer)，构型异构体又分为两类。其中因双键或成环碳原子的单键不能自由旋转而引起的异构体成为几何异构体(geometric isomer)，也称为顺反异构体(cis-trans isomer)，分为Z、E两种构型。例如：顺-2-丁烯和反-2-丁烯是一对几何异构体，因分子中没有反轴对称性而引起的具有不同旋光性能的立体异构体称为旋光异构体(optical isomer)，分为R、S构型。在本发明中所述“立体异构体”如未特别指明，可理解为包含上述对映异构体、构型异构体和构象异构体中的一种或几种。"Stereoisomer", its English name is stereoisomer, refers to the isomer produced by the different arrangement of atoms in the molecule in space, it can be divided into two kinds of cis-trans isomers and enantiomers, It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to the rotation of a single bond are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers caused by bond length, bond angle, double bonds in the molecule, rings, etc. are called configuration isomers (configuration stereo-isomers), and configuration isomers are divided into two categories. Among them, the isomers caused by double bonds or single bonds of ring-forming carbon atoms cannot freely rotate become geometric isomers (geometric isomers), also known as cis-trans isomers (cis-trans isomers), which are divided into Z, E two configurations. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and the stereoisomers with different optical rotation properties caused by the absence of anti-axis symmetry in the molecule are called optical isomers ( optical isomer), divided into R and S configurations. The "stereoisomer" mentioned in the present invention can be understood as including one or more of the above-mentioned enantiomers, configuration isomers and conformational isomers unless otherwise specified.
“药学上可接受盐”在本发明中是指药学上可接受的酸加成盐，包括无机酸盐和有机酸盐，这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which salts can be prepared by methods known in the art.
“前药”或“前体药物”在本发明中是指一种在展示其生理效应前，在生理条件下可被转化为或被溶剂分解为特定化合物或这类化合物的药学上可接受的盐的化合物。尽管不一定，前药在转化为特定化合物(也可称为母药或母体药物)之前通常是药理学非活性的。典型的是，前药的目的是改善化学稳定性、改善患者的接受性和顺应性、改善生物利用度、延长作用时间、改善器官选择性、提高水溶性和/或降低副作用等。前药的制备技术可运用现有技术中已知的方法，如Burger’s Medicinal Chemistry and Drug Chemistry,1,172-178,949-982(1995)等。"Prodrug" or "prodrug" in the present invention refers to a pharmaceutically acceptable compound that can be converted or solvolyzed into a specific compound or such compound under physiological conditions before exhibiting its physiological effect. Salt compounds. Prodrugs are generally, although not necessarily, pharmacologically inactive until converted to a specific compound (also known as a parent drug or parent drug). Typically, the purpose of the prodrug is to improve chemical stability, improve patient acceptance and compliance, improve bioavailability, prolong the duration of action, improve organ selectivity, increase water solubility and/or reduce side effects, etc. The preparation technology of prodrug can use the method known in the prior art, such as Burger's Medicinal Chemistry and Drug Chemistry, 1,172-178,949-982 (1995) etc.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。The present invention will be described in further detail and completely below in conjunction with the examples, but it is by no means limiting the present invention, and the present invention is not limited only to the content of the examples.
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker  AVANCE-400/500核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。 The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The determination of NMR is to use Bruker AVANCE-400/500 nuclear magnetic apparatus, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard For tetramethylsilane (TMS).
液质联用色谱LC-MS的测定用Agilent 6120质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。Agilent 6120 mass spectrometer was used for liquid chromatography-mass chromatography LC-MS determination. The determination of HPLC used Agilent 1200DAD high pressure liquid chromatography (Sunfire C18 150×4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150×4.6mm column).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度(℃)。Unless otherwise specified, all reactions in the present invention are carried out under continuous magnetic stirring, under dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the unit of reaction temperature is Celsius (° C.).
一、中间体的制备1. Preparation of intermediates
中间体A：((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷的制备Intermediate A: ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Preparation of base)naphthalene-1-yl)ethynyl)triisopropylsilane
Figure PCTCN2022130789-appb-000036
Figure PCTCN2022130789-appb-000036
第一步：(溴乙炔基)三异丙基硅烷的合成The first step: the synthesis of (bromoethynyl) triisopropylsilane
将乙炔基三异丙基硅烷(15g,82.2mmol)溶于丙酮(100mL)，分别加入硝酸银(1g,6.45mmol)，N-溴代丁二酰亚胺(15g,86.3mmol)。反应液氮气保护下室温反应1小时。减压浓缩除去溶剂，剩余物加入300mL石油醚，打浆，过滤，将滤液减压浓缩除去溶剂得到(溴乙炔基)三异丙基硅烷(21g,收率：97.7％)。Ethynyltriisopropylsilane (15g, 82.2mmol) was dissolved in acetone (100mL), and silver nitrate (1g, 6.45mmol) and N-bromosuccinimide (15g, 86.3mmol) were added respectively. React at room temperature for 1 hour under the protection of reaction liquid nitrogen. Concentrate under reduced pressure to remove the solvent, add 300 mL of petroleum ether to the residue, make a slurry, filter, and concentrate the filtrate under reduced pressure to remove the solvent to obtain (bromoethynyl)triisopropylsilane (21 g, yield: 97.7%).
1H NMR(400MHz,CDCl 3)δ1.10(m,21H). 1 H NMR (400MHz, CDCl 3 ) δ1.10 (m, 21H).
第二步：7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1,3-二醇的合成The second step: Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol
将7-氟萘-1,3-二醇(5g,28.1mmol)溶于1,4-二氧六环(200mL)，在氮气保护下分别加入(溴乙炔基)三异丙基硅烷(8.06g,30.8mmol)，二氯化钌，1-异丙基-4-甲基-苯(1.2g,1.96mmol)，乙酸钾(5.51g,56.2mmol)。氮气保护下反应液在110℃下反应18小时。反应液过滤，滤液减压浓缩除去溶剂，剩余物用快速硅胶柱分离得到7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1,3-二醇(9.1g,收率：90.4％)。ESI-MS：359 [M+1] +。 Dissolve 7-fluoronaphthalene-1,3-diol (5g, 28.1mmol) in 1,4-dioxane (200mL), and add (bromoethynyl)triisopropylsilane (8.06 g, 30.8 mmol), ruthenium dichloride, 1-isopropyl-4-methyl-benzene (1.2 g, 1.96 mmol), potassium acetate (5.51 g, 56.2 mmol). The reaction solution was reacted at 110° C. for 18 hours under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (9.1g, Yield: 90.4%). ESI-MS: 359 [M+1] + .
第三步：7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-醇的合成The third step: the synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol
将7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1,3-二醇(9g,25.1mmol)溶于无水二氯甲烷(200mL)，分别滴加N,N-二异丙基乙基胺(12.4mL,75.4mmol)，溴(甲氧基)甲烷(4.1g,32.6mmol)。氮气保护下反应液在室温反应1小时。反应液依次用饱和碳酸氢钠水溶液(100mL)，饱和氯化钠水溶液(100mL)洗涤。有机相用无水硫酸钠干燥，减压浓缩除去溶剂，剩余物用快速硅胶柱分离得到7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-醇(7.5g,收率：74.2％)。Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (9g, 25.1mmol) in anhydrous dichloromethane (200mL), add N, N-Diisopropylethylamine (12.4 mL, 75.4 mmol), bromo(methoxy)methane (4.1 g, 32.6 mmol). The reaction solution was reacted at room temperature for 1 hour under the protection of nitrogen. The reaction solution was washed successively with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphth-1-ol (7.5 g, yield: 74.2%).
1H NMR(400MHz,CDCl 3)δ9.12(s,1H),7.65(dd,J＝9.17,5.62Hz,1H),7.18(t,J＝8.74Hz,1H),6.96(d,J＝2.45Hz,1H),6.80(d,J＝1.83Hz,1H),5.24(s,2H),3.50(s,3H),1.17-1.23(m,21H). 1 H NMR (400MHz, CDCl 3 ) δ9.12(s, 1H), 7.65(dd, J=9.17, 5.62Hz, 1H), 7.18(t, J=8.74Hz, 1H), 6.96(d, J= 2.45Hz, 1H), 6.80(d, J=1.83Hz, 1H), 5.24(s, 2H), 3.50(s, 3H), 1.17-1.23(m, 21H).
第四步：7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基三氟甲磺酸的合成Step 4: Synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yltrifluoromethanesulfonic acid
将7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-醇(4g,9.94mmol)溶于无水二氯甲烷(60mL)，分别滴加N,N-二异丙基乙基胺(4.93mL,29.8mmol)。氮气保护下反应液降到-40℃。向反应液中缓慢滴加三氟甲磺酸酐(3.67g,14.9mmol)。反应液在-40℃下反应0.5小时。TLC检测会有少量原料剩余。反应液倒入200mL水。用100mL二氯甲烷萃取。有机相用饱和氯化钠水溶液(100mL)洗涤，无水硫酸钠干燥，减压浓缩除去溶剂，剩余物用快速硅胶柱分离得到7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基三氟甲磺酸(3.05g,收率：57.4％)。7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (4 g, 9.94 mmol) was dissolved in anhydrous dichloromethane ( 60mL), N,N-diisopropylethylamine (4.93mL, 29.8mmol) was added dropwise. The reaction liquid was lowered to -40°C under the protection of nitrogen. Trifluoromethanesulfonic anhydride (3.67 g, 14.9 mmol) was slowly added dropwise to the reaction solution. The reaction solution was reacted at -40°C for 0.5 hours. There will be a small amount of raw material remaining in TLC detection. The reaction solution was poured into 200 mL of water. Extract with 100 mL of dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain 7-fluoro-3-(methoxymethoxy)-8- ((Triisopropylsilyl)ethynyl)naphthalen-1-yltrifluoromethanesulfonic acid (3.05 g, yield: 57.4%).
第五步：((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷的合成The fifth step: ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Synthesis of yl)naphthalen-1-yl)ethynyl)triisopropylsilane
将7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基三氟甲磺酸(5.1g,9.54mmol)溶于无水甲苯(100mL)，分别加入双联频哪醇硼酸酯(4.84g,19.1mmol)，乙酸钾(2.81g,28.6mmol)，Pd(dppf)Cl 2(349mg,0.48mmol)。反应液130℃氮气保护下反应3小时。反应液用200mL乙酸乙酯稀释，饱和氯化钠水溶液(100mL*2)洗涤，有机相无水硫酸钠干燥，减压浓缩除去溶剂，剩余物用快速硅胶柱分离得到((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷(2.6g,收率：53.2％)。 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yltrifluoromethanesulfonic acid (5.1 g, 9.54 mmol) was dissolved in Anhydrous toluene (100 mL), double pinacol borate (4.84 g, 19.1 mmol), potassium acetate (2.81 g, 28.6 mmol), and Pd(dppf)Cl 2 (349 mg, 0.48 mmol) were added respectively. The reaction solution was reacted at 130° C. for 3 hours under nitrogen protection. The reaction solution was diluted with 200mL ethyl acetate, washed with saturated aqueous sodium chloride (100mL*2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain ((2-fluoro-6 -(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl) Triisopropylsilane (2.6 g, yield: 53.2%).
1H NMR(400MHz,CDCl 3)δ7.66(dd,J＝8.9,5.7Hz,1H),7.50(d,J＝2.3Hz,1H),7.37(d,J＝2.5Hz,1H),7.22(t,J＝8.8Hz,1H),5.27(s,2H),3.50(s,3H),1.43(s,12H),1.16(m,21H). 1 H NMR (400MHz, CDCl 3 ) δ7.66(dd, J=8.9,5.7Hz,1H),7.50(d,J=2.3Hz,1H),7.37(d,J=2.5Hz,1H),7.22 (t,J=8.8Hz,1H),5.27(s,2H),3.50(s,3H),1.43(s,12H),1.16(m,21H).
中间体B：1-(((4-硝基苯氧基)羰基)氧基)乙基特戊酰茚二酮酸酯的制备Intermediate B: Preparation of 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl pivaloylindanedionate
Figure PCTCN2022130789-appb-000037
Figure PCTCN2022130789-appb-000037
将1-氯乙基(4-硝基苯基)碳酸酯(100mg,0.41mmol)溶于无水二氯甲烷(5mL)中，加入特戊酸汞(245mg,0.81mmol)，特戊酸(0.09mL,0.81mmol)。混合液在50℃下反应18小时。反应液用二氯甲烷(20mL)稀释，经饱和氯化钠水溶液(10mL)洗涤，有机相通过无水硫酸钠干燥后减压浓缩除去溶剂得到1-(((4-硝基苯氧基)羰基)氧基)乙基特戊酰茚二酮酸酯(40mg,收率：31.6％)。Dissolve 1-chloroethyl (4-nitrophenyl) carbonate (100 mg, 0.41 mmol) in anhydrous dichloromethane (5 mL), add mercury pivalate (245 mg, 0.81 mmol), pivalic acid ( 0.09mL, 0.81mmol). The mixture was reacted at 50°C for 18 hours. The reaction solution was diluted with dichloromethane (20 mL), washed with saturated aqueous sodium chloride solution (10 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain 1-(((4-nitrophenoxy) Carbonyl)oxy)ethyl pivaloylindanedionate (40 mg, yield: 31.6%).
1H NMR(400MHz,DMSO-d 6)δ8.41-8.30(m,2H),7.68-7.53(m,2H),6.76-6.57(m,1H),1.86(d,J＝5.8Hz,3H),1.11(s,9H). 1 H NMR (400MHz,DMSO-d 6 )δ8.41-8.30(m,2H),7.68-7.53(m,2H),6.76-6.57(m,1H),1.86(d,J＝5.8Hz,3H ),1.11(s,9H).
中间体C1：叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯的制备Intermediate C1: tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) Preparation of pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2022130789-appb-000038
Figure PCTCN2022130789-appb-000038
第一步：叔丁基(2-氯-3-氟吡啶-4-基)氨基甲酸酯的合成The first step: the synthesis of tert-butyl (2-chloro-3-fluoropyridin-4-yl) carbamate
将2-氯-3-氟异尼古丁酸(90g,513mmol)溶于甲苯(675mL)和叔丁醇(675mL)，分别加入三乙胺(142mL,1.03mol)，叠氮磷酸二苯酯(116mL,538mmol)，Boc酸酐(11.0mL,51.3mmol)。反应液氮气保护下室温反应0.5小时，然后80℃下反应6小时。反应完成后，降到室温，用800mL水稀释，乙酸乙酯(500mL*2)萃取，有机相用硫酸镁干燥，减压浓缩除去溶剂。剩余物用快速硅胶柱分离得到叔丁基(2-氯-3-氟吡啶-4-基)氨基甲酸酯(105g,收率：83.0％)。ESI-MS：247[M+1] +。 Dissolve 2-chloro-3-fluoroisonicotinic acid (90g, 513mmol) in toluene (675mL) and tert-butanol (675mL), add triethylamine (142mL, 1.03mol), diphenylphosphoryl azide (116mL , 538mmol), Boc anhydride (11.0mL, 51.3mmol). The reaction was carried out at room temperature for 0.5 hours under the protection of reaction liquid nitrogen, and then at 80° C. for 6 hours. After the reaction was completed, it was lowered to room temperature, diluted with 800 mL of water, extracted with ethyl acetate (500 mL*2), the organic phase was dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated by flash silica gel column to obtain tert-butyl(2-chloro-3-fluoropyridin-4-yl)carbamate (105g, yield: 83.0%). ESI-MS: 247[M+1] + .
第二步：3-(叔丁基)-7-氯-8-氟吡啶并[4,3-d]嘧啶-2,4(1H,3H)-二酮的合成Step 2: Synthesis of 3-(tert-butyl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione
将叔丁基(2-氯-3-氟吡啶-4-基)氨基甲酸酯(30g,122mmol)溶于四氢呋喃(300mL)，在-78℃，氮气保护下滴加正丁基锂(121mL,304mmol)，滴加完成后，反应液缓慢升到-20℃，在此温度下反应1小时。然后在-20℃下向反应液中滴加叔丁基异氰酸酯(14.3mL,243mmol)，反应液缓慢升到室温反应1小试，然后加热到70℃反应过夜。反应液缓慢倒入饱和碳酸氢钠水溶液(300mL)，乙酸乙酯(500mL*2)萃取，有机相用硫酸镁干燥，减压浓缩除去溶剂。剩余物用快速硅胶柱分离得到3-(叔丁基)-7-氯-8-氟吡啶并[4,3-d]嘧啶-2,4(1H,3H)-二酮(248g,收率：72.6％)。Dissolve tert-butyl (2-chloro-3-fluoropyridin-4-yl) carbamate (30g, 122mmol) in tetrahydrofuran (300mL), add n-butyllithium (121mL) dropwise under nitrogen protection at -78°C ,304mmol), after the dropwise addition was completed, the reaction solution was slowly raised to -20°C, and reacted at this temperature for 1 hour. Then tert-butyl isocyanate (14.3 mL, 243 mmol) was added dropwise to the reaction solution at -20°C, the reaction solution was slowly raised to room temperature for 1 small test, and then heated to 70°C for overnight reaction. The reaction solution was slowly poured into saturated aqueous sodium bicarbonate solution (300 mL), extracted with ethyl acetate (500 mL*2), the organic phase was dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated by flash silica gel column to obtain 3-(tert-butyl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (248g, yield : 72.6%).
第三步：2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶的合成Step 3: Synthesis of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine
将3-(叔丁基)-7-氯-8-氟吡啶并[4,3-d]嘧啶-2,4(1H,3H)-二酮(24g,88.3mmol)分批缓慢加入三氯氧磷(300mL)，缓慢滴加N,N-二异丙基乙基胺(43.8mL,265mmol)。110℃反应过夜。减压蒸去大部分的三氯氧磷。剩余物缓慢倒入冰的饱和碳酸氢钠 水溶液(300mL)，乙酸乙酯(500mL*2)萃取。有机相用饱和氯化钠水溶液(100mL)洗涤，无水硫酸钠干燥，减压浓缩除去溶剂，剩余物在200mL石油醚里打浆，过滤，滤饼干燥得到2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(14.8g,收率：66.6％)。3-(tert-butyl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (24g, 88.3mmol) was slowly added to trichloro Oxon (300mL), N,N-diisopropylethylamine (43.8mL, 265mmol) was slowly added dropwise. React overnight at 110°C. Most of the phosphorus oxychloride was evaporated under reduced pressure. The residue was slowly poured into ice-saturated saturated sodium bicarbonate aqueous solution (300 mL), and extracted with ethyl acetate (500 mL*2). The organic phase was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was slurried in 200 mL of petroleum ether, filtered, and the filter cake was dried to obtain 2,4,7-trichloro-8 -Fluoropyrido[4,3-d]pyrimidine (14.8 g, yield: 66.6%).
1H NMR(400MHz,DMSO-d 6)δ8.94(s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ8.94(s,1H).
第四步：叔丁基3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯的合成The fourth step: tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Synthesis of octane-8-carboxylate
将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(4.99g,14.8mmol)溶于无水二氯甲烷(800mL)，冷却到-40℃，氮气保护下分别加入叔丁基3,8-二氮杂二环[3.2.1]辛-8-羧酸酯(3.15g,14.8mmol)和N,N-二异丙基乙基胺(12.3mL,74.2mmol)。在-40℃下反应0.5小时。LC-MS显示82％的产物。反应液倒入200mL水。用100mL二氯甲烷萃取。有机相用饱和氯化钠水溶液(100mL)洗涤，无水硫酸钠干燥，减压浓缩除去溶剂，剩余物用快速硅胶柱分离得到叔丁基3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯(6g,收率：94.5％)。ESI-MS：428[M+1] +。 Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4.99g, 14.8mmol) in anhydrous dichloromethane (800mL), cool to -40°C, under nitrogen protection Add tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.15g, 14.8mmol) and N,N-diisopropylethylamine (12.3mL, 74.2 mmol). The reaction was carried out at -40°C for 0.5 hours. LC-MS showed 82% product. The reaction solution was poured into 200 mL of water. Extract with 100 mL of dichloromethane. The organic phase was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain tert-butyl 3-(2,7-dichloro-8-fluoropyridine Con[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6 g, yield: 94.5%). ESI-MS: 428[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ9.07(s,1H),4.48(s,2H),4.27(s,2H),3.70(s,2H),1.89-1.72(m,2H),1.62(d,J＝7.5Hz,2H),1.47(s,9H). 1 H NMR (400MHz,DMSO-d 6 )δ9.07(s,1H),4.48(s,2H),4.27(s,2H),3.70(s,2H),1.89-1.72(m,2H), 1.62(d,J=7.5Hz,2H),1.47(s,9H).
第五步：叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯的合成The fifth step: tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) Synthesis of pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将叔丁基3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯(5.5g,12.8mmol)溶于无水四氢呋喃(80mL)，分别加入叔丁醇钠(2.47g,25.7mmol)，((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲醇(2.04g,12.8mmol)。反应液0℃氮气保护下反应1小时。LC-MS显示95％的产物。反应液倒入200mL水。用100mL乙酸乙酯萃取。有机相用饱和氯化钠水溶液(100mL)洗涤，无水硫酸钠干燥，减压浓缩除去溶剂，剩余物用快速硅胶柱分离得到叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯(5g,收率：70.6％)。ESI-MS：551[M+1] +。 tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8 -Carboxylate (5.5g, 12.8mmol) was dissolved in anhydrous tetrahydrofuran (80mL), sodium tert-butoxide (2.47g, 25.7mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrole (oxazin-7a-yl)methanol (2.04g, 12.8mmol). The reaction solution was reacted at 0° C. under nitrogen protection for 1 hour. LC-MS showed 95% product. The reaction solution was poured into 200 mL of water. Extract with 100 mL ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain tert-butyl 3-(7-chloro-8-fluoro-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-di Azabicyclo[3.2.1]oct-8-carboxylate (5 g, yield: 70.6%). ESI-MS: 551 [M+1] + .
中间体C2～C3可参照中间体C1全部或部分合成方法选择相应的原料进行制备:Intermediates C2-C3 can be prepared by referring to all or part of the synthesis method of intermediate C1 and selecting corresponding raw materials:
Figure PCTCN2022130789-appb-000039
Figure PCTCN2022130789-appb-000039
Figure PCTCN2022130789-appb-000040
Figure PCTCN2022130789-appb-000040
中间体D1：4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的制备Intermediate D1: 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro Preparation of -1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
Figure PCTCN2022130789-appb-000041
Figure PCTCN2022130789-appb-000041
第一步：叔丁基3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯的合成The first step: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8-carboxylate synthesis
将叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯(651mg,1.27mmol)，溶于1,4-二氧六环(15mL)和水(5mL)的混合溶剂，分别加入磷酸钾(539mg,2.54mmol)，金刚烷二代钯催化剂(42.5mg,0.06mmol)。氮气保护下，上述混合液85℃反应1小时。反应1小时。反应液用乙酸乙酯(30mL)稀释，经饱和氯化钠水溶液(30mL)洗涤，有机相通过无水硫酸钠干燥后减压浓缩除去溶剂，剩余物用快速硅胶柱分离得到叔丁基3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯(690mg,收率：60.3％)。ESI-MS：901[M+1] +。 Tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[ 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (651mg, 1.27mmol), dissolved in 1,4-dioxahexa To a mixed solvent of ring (15mL) and water (5mL), potassium phosphate (539mg, 2.54mmol) and adamantane palladium catalyst (42.5mg, 0.06mmol) were added respectively. Under nitrogen protection, the above mixed solution was reacted at 85° C. for 1 hour. React for 1 hour. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated aqueous sodium chloride solution (30 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain tert-butyl 3- (8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Bicyclo[3.2.1]octyl-8-carboxylate (690 mg, yield: 60.3%). ESI-MS: 901 [M+1] + .
第二步：4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇的合成The second step: 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)acetylene Base) Synthesis of Naphthalene-2-ol
将叔丁基3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4- 基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯(690mg,0.20mmol)溶于乙腈(20mL)，溶液冷却到0℃，氮气保护下滴加盐酸的1,4-二氧六环溶液(5mL,20mmol)。0℃下反应1小时。反应液直接减压浓缩除去溶剂得到粗产品4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(570mg,收率：98.3％)，直接用于下一步反应。ESI-MS：757[M+1] +。 Tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3 , 8-diazabicyclo[3.2.1]octane-8-carboxylate (690mg, 0.20mmol) was dissolved in acetonitrile (20mL), the solution was cooled to 0°C, and 1,4-hydrochloric acid was added dropwise under nitrogen protection. Dioxane solution (5 mL, 20 mmol). React at 0°C for 1 hour. The reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain the crude product 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triiso Propylsilyl)ethynyl)naphthalene-2-ol (570mg, yield: 98.3%) was directly used in the next reaction. ESI-MS: 757 [M+1] + .
第三步：4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成The third step: 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro Synthesis of -1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
将4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(570mg,0.65mmol)溶于N,N-二甲基甲酰胺(15mL)，加入氟化铯(1.99g,13.1mmol)。室温反应1小时。LC-MS显示原料剩余，额外补加30个当量的氟化铯，反应1小时。LC-MS显示反应完成。反应液过滤，滤液减压浓缩除去溶剂，剩余物用反相柱分离得到4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(196.8mg,收率：49.0％)。ESI-MS：601[M+1] +。 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene -2-ol (570 mg, 0.65 mmol) was dissolved in N,N-dimethylformamide (15 mL), and cesium fluoride (1.99 g, 13.1 mmol) was added. React at room temperature for 1 hour. LC-MS showed that the raw material remained, and an additional 30 equivalents of cesium fluoride was added and reacted for 1 hour. LC-MS showed the reaction was complete. The reaction solution was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated by a reverse-phase column to obtain 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- Ethynyl-6-fluoronaphthalen-2-ol (196.8 mg, yield: 49.0%). ESI-MS: 601 [M+1] + .
1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.03(s,1H),7.97(dd,J＝6.0,9.1Hz,1H),7.46(t,J＝9.0Hz,1H),7.39(d,J＝2.3Hz,1H),7.17(d,J＝1.9Hz,1H),5.40-5.15(m,1H),4.47(d,J＝12.1Hz,1H),4.31(d,J＝12.1Hz,1H),4.15-4.07(m,1H),4.00(dd,J＝2.2,10.4Hz,1H),3.92(s,1H),3.63(d,J＝12.5Hz,1H),3.56(s,3H),3.08(d,J＝8.6Hz,2H),3.01(s,1H),2.89-2.78(m,1H),2.12(s,1H),2.07-1.96(m,2H),1.88-1.74(m,3H),1.70-1.55(m,4H). 1 H NMR (400MHz, DMSO-d 6 )δ10.18(s, 1H), 9.03(s, 1H), 7.97(dd, J=6.0, 9.1Hz, 1H), 7.46(t, J=9.0Hz, 1H), 7.39(d, J=2.3Hz, 1H), 7.17(d, J=1.9Hz, 1H), 5.40-5.15(m, 1H), 4.47(d, J=12.1Hz, 1H), 4.31( d,J=12.1Hz,1H),4.15-4.07(m,1H),4.00(dd,J=2.2,10.4Hz,1H),3.92(s,1H),3.63(d,J=12.5Hz,1H ),3.56(s,3H),3.08(d,J＝8.6Hz,2H),3.01(s,1H),2.89-2.78(m,1H),2.12(s,1H),2.07-1.96(m, 2H),1.88-1.74(m,3H),1.70-1.55(m,4H).
中间体D2可参照中间体D1全部或部分合成方法选择相应的原料进行制备:Intermediate D2 can be prepared by selecting corresponding raw materials with reference to all or part of the synthetic method of intermediate D1:
Figure PCTCN2022130789-appb-000042
Figure PCTCN2022130789-appb-000042
中间体E1:叔丁基3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2的制备 Intermediate E1: Preparation of tert-butyl 3,8-diazabicyclo[3.2.1]oct-8-carboxylate-1,5-d 2
Figure PCTCN2022130789-appb-000043
Figure PCTCN2022130789-appb-000043
第一步：叔丁基3-三苯甲基-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯的合成Step 1: Synthesis of tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]octyl-8-carboxylate
将叔丁基3,8-二氮杂二环[3.2.1]辛-8-羧酸酯(3g,14.1mmol)和三苯基氯甲烷(4.33g,15.5mmol)溶入二氯甲烷(20mL)中，加入三乙胺(2.35mL,16.9mmol)，反应液在25℃下搅拌18小时。反应液倒入100mL水中，用二氯甲烷(200mL)萃取，有机相通过无水硫酸镁干燥后减压浓缩除去溶剂，剩余物用快速硅胶柱分离得到叔丁基3-三苯甲基-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯(6g,收率：93.4％)。Dissolve tert-butyl 3,8-diazabicyclo[3.2.1]oct-8-carboxylate (3 g, 14.1 mmol) and triphenylchloromethane (4.33 g, 15.5 mmol) in dichloromethane ( 20 mL), triethylamine (2.35 mL, 16.9 mmol) was added, and the reaction solution was stirred at 25° C. for 18 hours. The reaction solution was poured into 100 mL of water, extracted with dichloromethane (200 mL), the organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain tert-butyl 3-trityl-3 , 8-diazabicyclo[3.2.1]octane-8-carboxylate (6 g, yield: 93.4%).
1H NMR(400MHz,CDCl 3)δ7.37-7.24(m,12H),7.20-7.14(m,3H),4.24-4.12(m,1H),4.05(s,1H),2.99(d,J＝10.9Hz,2H),2.46-2.32(m,2H),2.04-1.95(m,2H),1.89-1.69(m,2H),1.27(s,9H). 1 H NMR (400MHz, CDCl 3 )δ7.37-7.24(m,12H),7.20-7.14(m,3H),4.24-4.12(m,1H),4.05(s,1H),2.99(d,J ＝10.9Hz,2H),2.46-2.32(m,2H),2.04-1.95(m,2H),1.89-1.69(m,2H),1.27(s,9H).
第二步：叔丁基3-三苯甲基-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2的合成 The second step: Synthesis of tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]oct-8-carboxylate-1,5- d2
将叔丁基3-三苯甲基-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯(1g,2.20mmol)和TMEDA(1.66mL,10.9mmol)溶入四氢呋喃(20mL)中，氮气保护下向上述溶液中滴加叔丁基锂(8.46mL,10.9mmol)。滴加完成后，0℃搅拌0.5小时。之后往反应液里加入氘水(0.8mL,44.0mmol)，滴加完成后，0℃搅拌0.5小时。将反应液用饱和氯化铵水溶液(20mL)淬灭，用乙酸乙酯(60mL)萃取，有机相通过无水硫酸镁干燥后减压浓缩除去溶剂得到叔丁基3-三苯甲基-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2(650mg,收率：65.0％)。 Dissolve tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]oct-8-carboxylate (1 g, 2.20 mmol) and TMEDA (1.66 mL, 10.9 mmol) in THF (20 mL), tert-butyllithium (8.46 mL, 10.9 mmol) was added dropwise to the above solution under nitrogen protection. After the dropwise addition was completed, the mixture was stirred at 0° C. for 0.5 hours. Then deuterium water (0.8mL, 44.0mmol) was added to the reaction solution, and after the dropwise addition was completed, it was stirred at 0°C for 0.5 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (60 mL), the organic phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent to obtain tert-butyl 3-trityl-3 ,8-diazabicyclo[3.2.1]oct-8-carboxylate-1,5-d 2 (650 mg, yield: 65.0%).
1H NMR(400MHz,CDCl 3)δ7.35-7.24(m,12H),7.20-7.12(m,3H),2.99(d,J＝11.1Hz,2H),2.37(d,J＝6.8Hz,2H),2.00(d,J＝7.5Hz,2H),1.87-1.72(m,2H),1.30-1.25(m,9H). 1 H NMR (400MHz, CDCl 3 ) δ7.35-7.24(m, 12H), 7.20-7.12(m, 3H), 2.99(d, J=11.1Hz, 2H), 2.37(d, J=6.8Hz, 2H), 2.00(d, J=7.5Hz, 2H), 1.87-1.72(m, 2H), 1.30-1.25(m, 9H).
第三步：叔丁基3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2合成 Step 3: Synthesis of tert-butyl 3,8-diazabicyclo[3.2.1]oct-8-carboxylate-1,5-d 2
将叔丁基3-三苯甲基-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2(650mg,1.42mmol)溶入二氧六环(6mL)中，加入盐酸二氧六环(1.5mL,6mmol)，反应液在25℃下搅拌1小时。反应液直接减压浓缩除去溶剂得到叔丁基3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2(770mg,粗品)。ESI-MS：215[M+1] +。 Dissolve tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate-1,5-d 2 (650mg, 1.42mmol) in dioxane Dioxane hydrochloride (1.5 mL, 6 mmol) was added to a ring (6 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain tert-butyl 3,8-diazabicyclo[3.2.1]oct-8-carboxylate-1,5-d 2 (770mg, crude product). ESI-MS: 215[M+1] + .
中间体E2～E5可参照中间体E1全部或部分合成方法选择相应的原料进行制备:Intermediates E2-E5 can be prepared by referring to the whole or part of the synthesis method of intermediate E1 and selecting corresponding raw materials:
Figure PCTCN2022130789-appb-000044
Figure PCTCN2022130789-appb-000044
Figure PCTCN2022130789-appb-000045
Figure PCTCN2022130789-appb-000045
二、具体实施例的制备Two, the preparation of specific embodiment
实施例1：4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基-1,5-d 2)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的制备 Example 1: 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 )-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- Preparation of 2-ol
Figure PCTCN2022130789-appb-000046
Figure PCTCN2022130789-appb-000046
第一步：叔丁基3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2的合成 The first step: tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Synthesis of octane-8-carboxylate-1,5-d 2
将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(471mg,1.40mmol)溶于二氯甲烷(3mL)中，加入N,N-二异丙基乙胺(0.69mL,4.20mmol)，在-78℃下搅拌10分钟，然后在氮气保护下加入叔丁基3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯-1,5-d 2(300mg,1.40mmol)，反应液在-78℃下搅拌1小时。将反应液倒入10mL水中，用二氯甲烷(30mL)萃取，有机相通过无水硫酸镁干燥后减压浓缩除去溶剂，剩余物用快速硅胶柱分离得到叔丁基3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2(330mg,收率：54.7％)。ESI-MS 430[M+1] +。 Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (471 mg, 1.40 mmol) in dichloromethane (3 mL), add N,N-diisopropylethylamine (0.69mL, 4.20mmol), stirred at -78°C for 10 minutes, then added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate-1 under nitrogen protection ,5-d 2 (300mg, 1.40mmol), the reaction solution was stirred at -78°C for 1 hour. The reaction solution was poured into 10 mL of water, extracted with dichloromethane (30 mL), the organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to obtain tert-butyl 3-(2,7- Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate-1,5-d 2 (330 mg, yield: 54.7%). ESI-MS 430[M+1] + .
1H NMR(400MHz,CDCl 3)δ8.86(s,1H),4.55(s,2H),3.73(d,J＝14.6Hz,2H),2.00(d,J＝8.5Hz,2H),1.69(d,J＝7.0Hz,2H),1.54(s,9H). 1 H NMR (400MHz, CDCl 3 )δ8.86(s,1H),4.55(s,2H),3.73(d,J=14.6Hz,2H),2.00(d,J=8.5Hz,2H),1.69 (d,J=7.0Hz,2H),1.54(s,9H).
第二步：叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2的合成 The second step: tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) Synthesis of pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-carboxylate-1,5-d 2
将叔丁基3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2(100mg,0.23mmol)和((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲醇(37mg,0.23mmol)溶于四氢呋喃(2mL)，在0℃氮气保护下分批缓慢加入叔丁醇钠(44.59mg,0.46mmol),加完后，0℃下搅拌1小时。将反应液倒入10mL水中，用乙酸乙酯(20mL)萃取，有机相通过无水硫酸镁干燥后减压浓缩除去溶剂得到叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2(120mg,收率：93.3％)。ESI-MS 553[M+1] +。 tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8 -Carboxylate-1,5-d 2 (100mg, 0.23mmol) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (37mg, 0.23mmol) in THF (2mL), sodium tert-butoxide (44.59mg, 0.46mmol) was slowly added in batches under nitrogen protection at 0°C, and after the addition was complete, it was stirred at 0°C for 1 hour. The reaction solution was poured into 10 mL of water, extracted with ethyl acetate (20 mL), the organic phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent to obtain tert-butyl 3-(7-chloro-8-fluoro-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Heterobicyclo[3.2.1]octyl-8-carboxylate-1,5-d 2 (120 mg, yield: 93.3%). ESI-MS 553[M+1] + .
第三步：叔丁基3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2的合成 The third step: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8-carboxylate-1,5-d 2 synthesis
将叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯-1,5-d 2(120mg,0.22mmol)和((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷(111mg,0.22mmol)溶于1,4-二氧六环(6mL)和水(2mL)中，在氮气保护下分别缓慢加入磷酸钾(92.1mg,0.43mmol),[(二(1-金刚烷基)-N-丁基膦)-2-(2-氨基联苯)氯化钯(II)(7.25mg,0.01mmol)。该混合物90℃下反应3小时。将反应液倒入20mL水中，用乙酸乙酯(40mL)萃取，有机相通过无水硫酸镁干燥后过滤减压浓缩除去溶剂，剩余物用快速硅胶柱分离得到叔丁基3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯-1,5-d 2(100mg,收率：51％)。ESI-MS 903[M+1] +。 Tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[ 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate-1,5-d 2 (120mg, 0.22mmol) and ( (2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1 -yl)ethynyl)triisopropylsilane (111mg, 0.22mmol) was dissolved in 1,4-dioxane (6mL) and water (2mL), and potassium phosphate (92.1mg, 0.43 mmol), [(bis(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)palladium(II) chloride (7.25 mg, 0.01 mmol). The mixture was reacted at 90°C for 3 hours. The reaction solution was poured into 20 mL of water, extracted with ethyl acetate (40 mL), the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated with a fast silica gel column to obtain tert-butyl 3-(8-fluoro -7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 .1] Octane-8-carboxylate-1,5-d 2 (100 mg, yield: 51%). ESI-MS 903[M+1] + .
第四步：4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基-1,5-d 2)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇的合成 The fourth step: 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 )-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triiso Synthesis of Propylsilyl)ethynyl)naphthalene-2-ol
将叔丁基3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2(100mg,0.11mmol)溶于乙腈(2mL)中，加入盐酸二氧六环(1mL)，0℃反应1小时。反应液直接减压浓缩除去溶剂得到4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基-1,5-d 2)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(100mg,粗品)。ESI-MS 759[M+1] +。 Tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3 ,8-diazabicyclo[3.2.1]octane-8-carboxylate-1,5-d 2 (100mg, 0.11mmol) was dissolved in acetonitrile (2mL), and dioxane hydrochloride (1mL) was added , react at 0°C for 1 hour. The reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 )-8-fluoro-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5 -((triisopropylsilyl)ethynyl)naphthalen-2-ol (100 mg, crude). ESI-MS 759[M+1] + .
第五步：4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基-1,5-d 2)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成 The fifth step: 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 )-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- Synthesis of 2-alcohols
将4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基-1,5-d 2)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(100mg,0.13mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入氟化铯(2g,13.2mmol)，25℃反应1小时。反应液过滤，滤液减压浓缩除去溶剂，剩余物用反相柱分离得到4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基-1,5-d 2)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(7.4mg,收率：9.17％，纯度：98.60％)。ESI-MS 603[M+1] +。 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 )-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylmethyl Silyl)ethynyl)naphthalene-2-ol (100mg, 0.13mmol) was dissolved in N,N-dimethylformamide (10mL), cesium fluoride (2g, 13.2mmol) was added, and reacted at 25°C for 1 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated by a reverse-phase column to obtain 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 ) -8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (7.4 mg, yield: 9.17%, purity: 98.60%). ESI-MS 603[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.04(s,1H),7.98(dd,J＝6.0,8.9 Hz,1H),7.47(t,J＝9.0Hz,1H),7.39(d,J＝2.4Hz,1H),7.18(s,1H),5.41-5.15(m,1H),4.46(d,J＝14.2Hz,1H),4.31(d,J＝12.3Hz,1H),4.16-4.07(m,1H),4.05-3.97(m,1H),3.93(s,1H),3.67-3.52(m,2H),3.17-2.97(m,3H),2.83(d,J＝7.1Hz,1H),2.13(s,1H),2.09-1.97(m,2H),1.92-1.72(m,3H),1.65(m,4H). 1 H NMR (400MHz, DMSO-d 6 )δ10.18(s, 1H), 9.04(s, 1H), 7.98(dd, J=6.0, 8.9 Hz, 1H), 7.47(t, J=9.0Hz, 1H), 7.39(d, J=2.4Hz, 1H), 7.18(s, 1H), 5.41-5.15(m, 1H), 4.46(d, J=14.2Hz, 1H), 4.31(d, J=12.3 Hz,1H),4.16-4.07(m,1H),4.05-3.97(m,1H),3.93(s,1H),3.67-3.52(m,2H),3.17-2.97(m,3H),2.83( d,J＝7.1Hz,1H),2.13(s,1H),2.09-1.97(m,2H),1.92-1.72(m,3H),1.65(m,4H).
实施例2～6可参照实施例1全部或部分合成方法选择相应的原料进行制备:Embodiment 2～6 can select corresponding raw material to prepare with reference to all or part of the synthetic method of embodiment 1:
Figure PCTCN2022130789-appb-000047
Figure PCTCN2022130789-appb-000047
上述实施例制备得到的化合物的核磁数据如下：The NMR data of the compound prepared by the above-mentioned examples are as follows:
Figure PCTCN2022130789-appb-000048
Figure PCTCN2022130789-appb-000048
实施例7：甲基3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯的制备Example 7: Methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 - Preparation of carboxylate
Figure PCTCN2022130789-appb-000049
Figure PCTCN2022130789-appb-000049
第一步：3-(7-(8-乙炔基-7-氟-3-((甲酯基(甲氧羰基))氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸的合成The first step: 3-(7-(8-ethynyl-7-fluoro-3-((methoxycarbonyl))oxy)naphthalene-1-yl)-8-fluoro-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Synthesis of Heterobicyclo[3.2.1]octane-8-carboxylic Acid
将4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(100mg,0.166mmol)溶于二氯甲烷(5mL)，加入三乙胺(50.5mg,0.50mmol)。溶液冷却到0℃，氮气保护下滴加二碳酸二甲酯(33.5mg,0.25mmol)，室温下反应过夜。LC-MS显示反应产物是接上去一个碳酸甲酯和两个碳酸甲酯的混合物。反应液直接用于下一步反应。ESI-MS：716[M+1] +。 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (100mg, 0.166mmol) To dichloromethane (5 mL), triethylamine (50.5 mg, 0.50 mmol) was added. The solution was cooled to 0°C, and dimethyl dicarbonate (33.5 mg, 0.25 mmol) was added dropwise under nitrogen protection, and reacted overnight at room temperature. LC-MS showed that the reaction product was a mixture of one methyl carbonate followed by two methyl carbonates. The reaction solution was directly used in the next reaction. ESI-MS: 716 [M+1] + .
第二步：甲基3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯的合成The second step: Methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 -Synthesis of Carboxylate
向上一步的反应液中加入5mL水和1mL甲醇。然后加入碳酸钾(68.8mg,0.50mmol)，室温反应0.5小时。反应液用二氯甲烷(20mL)稀释，过滤，滤液经减压浓缩除去溶剂，剩余物用反相柱分离得到甲基3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8- 氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯(19.5mg,收率：16.8％)。ESI-MS：658[M+1] +。 Add 5 mL of water and 1 mL of methanol to the reaction solution of the previous step. Then potassium carbonate (68.8mg, 0.50mmol) was added and reacted at room temperature for 0.5 hours. The reaction solution was diluted with dichloromethane (20mL), filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated with a reversed-phase column to obtain methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene -1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19.5 mg, yield: 16.8%). ESI-MS: 658 [M+1] + .
1H NMR(400MHz,DMSO-d 6)δ9.06(s,1H),8.02-7.93(m,1H),7.46(t,J＝8.9Hz,1H),7.38(s,1H),7.18(d,J＝1.5Hz,1H),5.38-5.19(m,1H),4.58(d,J＝11.5Hz,1H),4.46-4.36(m,3H),4.17-4.10(m,1H),4.07-4.00(m,1H),3.93(s,1H),3.69(s,3H),3.68-3.60(m,2H),3.13-3.06(m,2H),3.06-2.99(m,1H),2.88-2.78(m,1H),2.14(d,J＝3.3Hz,1H),2.06(d,J＝1.5Hz,1H),2.02(d,J＝7.4Hz,1H),1.90-1.82(m,3H),1.81-1.75(m,4H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.06(s, 1H), 8.02-7.93(m, 1H), 7.46(t, J=8.9Hz, 1H), 7.38(s, 1H), 7.18( d,J=1.5Hz,1H),5.38-5.19(m,1H),4.58(d,J=11.5Hz,1H),4.46-4.36(m,3H),4.17-4.10(m,1H),4.07 -4.00(m,1H),3.93(s,1H),3.69(s,3H),3.68-3.60(m,2H),3.13-3.06(m,2H),3.06-2.99(m,1H),2.88 -2.78(m,1H),2.14(d,J=3.3Hz,1H),2.06(d,J=1.5Hz,1H),2.02(d,J=7.4Hz,1H),1.90-1.82(m, 3H),1.81-1.75(m,4H).
实施例8～25、54、55可参照实施例7全部或部分合成方法选择相应的原料进行制备:Embodiments 8-25, 54, 55 can be prepared by referring to all or part of the synthetic method of embodiment 7 to select corresponding raw materials:
Figure PCTCN2022130789-appb-000050
Figure PCTCN2022130789-appb-000050
Figure PCTCN2022130789-appb-000051
Figure PCTCN2022130789-appb-000051
Figure PCTCN2022130789-appb-000052
Figure PCTCN2022130789-appb-000052
Figure PCTCN2022130789-appb-000053
Figure PCTCN2022130789-appb-000053
Figure PCTCN2022130789-appb-000054
Figure PCTCN2022130789-appb-000054
上述实施例制备得到的化合物的核磁数据如下：The NMR data of the compound prepared by the above-mentioned examples are as follows:
Figure PCTCN2022130789-appb-000055
Figure PCTCN2022130789-appb-000055
Figure PCTCN2022130789-appb-000056
Figure PCTCN2022130789-appb-000056
实施例26：4-(4-(8-苯甲基-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的制备Example 26: 4-(4-(8-Benzyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 - Preparation of alcohol
Figure PCTCN2022130789-appb-000057
Figure PCTCN2022130789-appb-000057
第一步：4-(4-(8-苯甲基-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷 基)乙炔基)萘-2-醇的合成The first step: 4-(4-(8-benzyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl Synthesis of (yl)ethynyl)naphthalen-2-ol
将4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(100mg,0.13mmol)溶于无水二氯甲烷(3mL)中，分别加入苯甲醛(17.9uL,0.17mmol)，三乙酰氧基硼氢化钠(71.1mg,0.34mmol)，三乙胺(0.03mL,0.23mmol)。氮气保护下，上述混合液25℃反应16小时。反应液用二氯甲烷(10mL)稀释，经饱和氯化钠水溶液(10mL)洗涤，有机相通过无水硫酸钠干燥后减压浓缩除去溶剂得到4-(4-(8-苯甲基-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(70mg,粗品)。ESI-MS：845[M+1] +。 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2- Alcohol (100mg, 0.13mmol) was dissolved in anhydrous dichloromethane (3mL), benzaldehyde (17.9uL, 0.17mmol), sodium triacetoxyborohydride (71.1mg, 0.34mmol), triethylamine ( 0.03mL, 0.23mmol). Under nitrogen protection, the above mixed solution was reacted at 25° C. for 16 hours. The reaction solution was diluted with dichloromethane (10 mL), washed with saturated aqueous sodium chloride solution (10 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain 4-(4-(8-benzyl-3 ,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methyl Oxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (70 mg, crude). ESI-MS: 845 [M+1] + .
第二步：4-(4-(8-苯甲基-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成The second step: 4-(4-(8-benzyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS) The synthesis
将4-(4-(8-苯甲基-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(70mg,粗品)溶于N,N-二甲基甲酰胺(2mL)，加入氟化铯(1.26g,8.26mmol)，混合液在25℃反应2小时，LC-MS显示反应完成。反应液过滤，滤液减压浓缩除去溶剂，剩余物用反相柱分离得到4-(4-(8-苯甲基-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(12.2mg,收率：20.1％)。ESI-MS：691[M+1] +。 4-(4-(8-Benzyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)acetylene Base) naphthalene-2-ol (70mg, crude product) was dissolved in N,N-dimethylformamide (2mL), cesium fluoride (1.26g, 8.26mmol) was added, and the mixture was reacted at 25°C for 2 hours, LC- MS showed the reaction was complete. The reaction solution was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated by a reverse-phase column to obtain 4-(4-(8-benzyl-3,8-diazabicyclo[3.2.1]oct-3-yl )-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (12.2 mg, yield: 20.1%). ESI-MS: 691 [M+1] + .
1H NMR(400MHz,DMSO-d 6)δ10.18(br s,1H),9.05(s,1H),7.97(dd,J＝5.9,9.2Hz,1H),7.50-7.42(m,3H),7.41-7.33(m,3H),7.31-7.25(m,1H),7.18(d,J＝2.0Hz,1H),5.40-5.17(m,1H),4.48(d,J＝12.5Hz,1H),4.34(d,J＝12.3Hz,1H),4.12(dd,J＝3.5,10.3Hz,1H),4.01(dd,J＝2.8,10.5Hz,1H),3.94(s,1H),3.77-3.63(m,2H),3.58(s,2H),3.33-3.30(m,1H),3.09(d,J＝7.8Hz,2H),3.01(s,1H),2.89-2.76(m,1H),2.17-2.10(m,1H),2.08-1.95(m,4H),1.89-1.74(m,3H),1.69-1.59(m,2H),1.03-0.88(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.18(br s,1H),9.05(s,1H),7.97(dd,J=5.9,9.2Hz,1H),7.50-7.42(m,3H) ,7.41-7.33(m,3H),7.31-7.25(m,1H),7.18(d,J=2.0Hz,1H),5.40-5.17(m,1H),4.48(d,J=12.5Hz,1H ),4.34(d,J=12.3Hz,1H),4.12(dd,J=3.5,10.3Hz,1H),4.01(dd,J=2.8,10.5Hz,1H),3.94(s,1H),3.77 -3.63(m,2H),3.58(s,2H),3.33-3.30(m,1H),3.09(d,J＝7.8Hz,2H),3.01(s,1H),2.89-2.76(m,1H ),2.17-2.10(m,1H),2.08-1.95(m,4H),1.89-1.74(m,3H),1.69-1.59(m,2H),1.03-0.88(m,1H).
实施例27～44、52、53可参照实施例26全部或部分合成方法选择相应的原料进行制备:Embodiments 27-44, 52, 53 can be prepared by referring to all or part of the synthetic method of embodiment 26 and selecting corresponding raw materials:
Figure PCTCN2022130789-appb-000058
Figure PCTCN2022130789-appb-000058
Figure PCTCN2022130789-appb-000059
Figure PCTCN2022130789-appb-000059
Figure PCTCN2022130789-appb-000060
Figure PCTCN2022130789-appb-000060
Figure PCTCN2022130789-appb-000061
Figure PCTCN2022130789-appb-000061
Figure PCTCN2022130789-appb-000062
Figure PCTCN2022130789-appb-000062
上述实施例制备得到的化合物的核磁数据如下：The NMR data of the compound prepared by the above-mentioned examples are as follows:
Figure PCTCN2022130789-appb-000063
Figure PCTCN2022130789-appb-000063
Figure PCTCN2022130789-appb-000064
Figure PCTCN2022130789-appb-000064
Figure PCTCN2022130789-appb-000065
Figure PCTCN2022130789-appb-000065
实施例45:1-(异丁氧基)乙基3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2的制备 Example 45: 1-(isobutoxy)ethyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo [3.2.1] Preparation of octane-8-carboxylate-1,5- d2
Figure PCTCN2022130789-appb-000066
Figure PCTCN2022130789-appb-000066
将4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基-1,5-d 2)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(150mg,0.25mmol)和1-(((4-硝基苯氧基)羰基)氧基)乙基异丁酸酯(73.9mg,0.25mmol)溶于二氯甲烷(5mL)中，加入三乙胺(75.5mg,0.75mmol)，25℃反应2小时。反应液直接减压浓缩除去溶剂，剩余物用反相柱分离得到1-(异丁氧基)乙基3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2(23.3mg,收率：11.4％)。ESI-MS：761[M+1] +。 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 )-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (150mg, 0.25mmol) and 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl isobutyrate (73.9mg, 0.25mmol) were dissolved in dichloromethane (5mL), added three Ethylamine (75.5mg, 0.75mmol) was reacted at 25°C for 2 hours. The reaction solution was directly concentrated under reduced pressure to remove the solvent, and the residue was separated by a reverse-phase column to obtain 1-(isobutoxy)ethyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl )-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4 -yl)-3,8-diazabicyclo[3.2.1]oct-8-carboxylate-1,5-d 2 (23.3 mg, yield: 11.4%). ESI-MS: 761 [M+1] + .
1H NMR(400MHz,DMSO-d 6)δ9.05(s,1H),7.95(dd,J＝9.0,6.0Hz,1H),7.45(t,J＝9.0Hz,1H),7.36(d,J＝2.1Hz,1H),7.17(s,1H),6.73(q,J＝5.0Hz,1H),5.38-5.18(m,1H),4.63-4.53(m,1H),4.50-4.35(m,1H),4.16-4.08(m,1H),4.03(d,J＝10.5Hz,1H),3.92(s,1H),3.77-3.42(m,2H),3.15-2.97(m,3H),2.82(d,J＝6.8Hz,1H),2.17-1.98(m,3H),1.91-1.70(m,7H),1.48(s,3H),1.09(d,J＝6.8Hz,6H). 1 H NMR (400MHz, DMSO-d 6 )δ9.05(s, 1H), 7.95(dd, J=9.0, 6.0Hz, 1H), 7.45(t, J=9.0Hz, 1H), 7.36(d, J＝2.1Hz, 1H), 7.17(s, 1H), 6.73(q, J＝5.0Hz, 1H), 5.38-5.18(m, 1H), 4.63-4.53(m, 1H), 4.50-4.35(m ,1H),4.16-4.08(m,1H),4.03(d,J＝10.5Hz,1H),3.92(s,1H),3.77-3.42(m,2H),3.15-2.97(m,3H), 2.82(d,J=6.8Hz,1H),2.17-1.98(m,3H),1.91-1.70(m,7H),1.48(s,3H),1.09(d,J=6.8Hz,6H).
实施例46～48、56～58、62可参照实施例45全部或部分合成方法选择相应的原料进行制备:Embodiments 46-48, 56-58, and 62 can be prepared by referring to all or part of the synthetic method of embodiment 45 and selecting corresponding raw materials:
Figure PCTCN2022130789-appb-000067
Figure PCTCN2022130789-appb-000067
Figure PCTCN2022130789-appb-000068
Figure PCTCN2022130789-appb-000068
Figure PCTCN2022130789-appb-000069
Figure PCTCN2022130789-appb-000069
上述实施例制备得到的化合物的核磁数据如下：The NMR data of the compound prepared by the above-mentioned examples are as follows:
Figure PCTCN2022130789-appb-000070
Figure PCTCN2022130789-appb-000070
实施例49:4-((3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-基-1,5-d 2)甲基)-5-甲基-1,3-二噁唑-2-酮的制备 Example 49: 4-((3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane Preparation of -8-yl-1,5-d 2 )methyl)-5-methyl-1,3-dioxazol-2-one
Figure PCTCN2022130789-appb-000071
Figure PCTCN2022130789-appb-000071
将4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基-1,5-d 2)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(200mg,0.33mmol)和4-(氯甲基)-5-甲基-1,3-二噁唑-2-酮(49.2mg,0.33mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入碳酸氢钾(66.4mg,0.66mmol)，25℃反应18小时。反应液过滤，滤液减压浓缩除去溶剂，剩余物用反相柱分离得到4-((3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-基-1,5-d 2)甲基)-5-甲基-1,3-二噁唑-2-酮(8.5mg,甲酸盐,收率：3.39％)。ESI-MS：715[M+1] +。 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 )-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (200mg, 0.33mmol) and 4-(chloromethyl)-5-methyl-1,3-dioxazol-2-one (49.2mg, 0.33mmol) were dissolved in N,N-dimethylformamide ( 10 mL), potassium bicarbonate (66.4 mg, 0.66 mmol) was added, and the reaction was carried out at 25°C for 18 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated by a reverse-phase column to obtain 4-((3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]oct-8-yl-1,5-d 2 )methyl)-5-methyl-1,3-dioxazol-2-one (8.5mg , formate, yield: 3.39%). ESI-MS: 715 [M+1] + .
1H NMR(400MHz,DMSO-d 6)δ10.19(br s,1H),9.04(s,1H),8.19(s,1H),7.98(dd,J＝5.8,9.0Hz,1H),7.47(t,J＝9.0Hz,1H),7.39(d,J＝2.5Hz,1H),7.18(s,1H),5.40-5.15(m,1H),4.49(d,J＝12.1Hz,1H),4.31(d,J＝11.3Hz,1H),4.15-4.08(m,1H),4.01(d,J＝10.3Hz,1H),3.95(s,1H),3.70(d,J＝12.8Hz,1H),3.62(d,J＝11.3Hz,1H),3.11(s,3H),3.02(s,1H),2.84(s,2H),2.18-2.11(m,4H),2.07-1.98(m,2H),1.93(d,J＝10.3Hz,2H),1.88-1.73(m,3H),1.63(d,J＝9.8Hz,2H). 1 H NMR (400MHz,DMSO-d 6 )δ10.19(br s,1H),9.04(s,1H),8.19(s,1H),7.98(dd,J＝5.8,9.0Hz,1H),7.47 (t,J=9.0Hz,1H),7.39(d,J=2.5Hz,1H),7.18(s,1H),5.40-5.15(m,1H),4.49(d,J=12.1Hz,1H) ,4.31(d,J=11.3Hz,1H),4.15-4.08(m,1H),4.01(d,J=10.3Hz,1H),3.95(s,1H),3.70(d,J=12.8Hz, 1H), 3.62(d, J=11.3Hz, 1H), 3.11(s, 3H), 3.02(s, 1H), 2.84(s, 2H), 2.18-2.11(m, 4H), 2.07-1.98(m ,2H),1.93(d,J=10.3Hz,2H),1.88-1.73(m,3H),1.63(d,J=9.8Hz,2H).
实施例59～61可参照实施例49全部或部分合成方法选择相应的原料进行制备:Embodiments 59-61 can be prepared by referring to all or part of the synthetic method of embodiment 49 and selecting corresponding raw materials:
Figure PCTCN2022130789-appb-000072
Figure PCTCN2022130789-appb-000072
Figure PCTCN2022130789-appb-000073
Figure PCTCN2022130789-appb-000073
实施例50:((异丙氧基羰基)氧基)甲基3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2的制备 Example 50: ((isopropoxycarbonyl)oxy)methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Preparation of heterobicyclo[3.2.1]oct-8-carboxylate-1,5-d 2
Figure PCTCN2022130789-appb-000074
Figure PCTCN2022130789-appb-000074
第一步：碘甲基异丙基碳酸酯的合成The first step: the synthesis of iodomethyl isopropyl carbonate
将氯甲基异丙基碳酸酯(5g,32.7mmol)溶于乙腈(50mL)，在25℃条件下加入碘化钠(14.74g,98.32mmol)。60℃条件下反应3小时。反应液过滤，滤液减压浓缩除去溶剂，所得固体用无水二氯甲烷溶解，饱和硫代硫酸钠洗涤，硫酸钠干燥，再过滤除去固体，滤液减压浓缩除去溶剂得到碘甲基异丙基碳酸酯(6.5g,粗品)。Chloromethyl isopropyl carbonate (5 g, 32.7 mmol) was dissolved in acetonitrile (50 mL), and sodium iodide (14.74 g, 98.32 mmol) was added at 25°C. React at 60°C for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, the obtained solid was dissolved in anhydrous dichloromethane, washed with saturated sodium thiosulfate, dried over sodium sulfate, and then filtered to remove the solid, the filtrate was concentrated under reduced pressure to remove the solvent to obtain iodomethyl isopropyl Carbonate (6.5 g, crude).
1H NMR(400MHz,CDCl 3)δ5.94(s,2H),4.94(td,J＝6.3,12.5Hz,1H),1.32(d,J＝6.3Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ5.94(s, 2H), 4.94(td, J=6.3, 12.5Hz, 1H), 1.32(d, J=6.3Hz, 6H).
第二步：((异丙氧基羰基)氧基)甲基3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2的合成 The second step: ((isopropoxycarbonyl)oxy)methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Synthesis of Heterobicyclo[3.2.1]oct-8-carboxylate-1,5-d 2
将碘甲基异丙基碳酸酯(50mg,0.08mmol)溶于DMF(2mL)，在25℃条件下加入碳酸铯(67.5mg,0.21mmol)，向混合物中加入5个固体二氧化碳并在25℃条件下反应50分钟。向反应液中缓慢加入4-(4-(3,8-二氮杂二环[3.2.1]辛-3-基-1,5-d 2)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5- 乙炔基-6-氟萘-2-醇(20.2mg,0.08mmol)，在25℃条件下反应18小时。反应液用水(20mL)淬灭，乙酸乙酯(20mL*2)萃取，无水氯化钠(10mL*2)洗涤，无水硫酸钠干燥，减压浓缩除去溶剂，剩余物用反相柱分离得到((异丙氧基羰基)氧基)甲基3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2(10.7mg,收率：16.16％)。ESI-MS：763[M+1] +。 Dissolve iodomethyl isopropyl carbonate (50mg, 0.08mmol) in DMF (2mL), add cesium carbonate (67.5mg, 0.21mmol) at 25°C, add 5 solid carbon dioxide to the mixture and warm at 25°C Under the condition of reaction for 50 minutes. Slowly add 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-1,5-d 2 )-8-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphthalene-2-ol (20.2mg, 0.08mmol) was reacted at 25°C for 18 hours. The reaction solution was quenched with water (20mL), extracted with ethyl acetate (20mL*2), washed with anhydrous sodium chloride (10mL*2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated by a reverse-phase column ((isopropoxycarbonyl)oxy)methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo [3.2.1] Octan-8-carboxylate-1,5-d 2 (10.7 mg, yield: 16.16%). ESI-MS: 763 [M+1] + .
1H NMR(400MHz,DMSO-d 6)δ10.17(s,1H),9.05(s,1H),7.98(dd,J＝6.1,9.2Hz,1H),7.47(t,J＝9.0Hz,1H),7.39(d,J＝2.5Hz,1H),7.18(s,1H),5.75(s,2H),5.38-5.18(m,1H),4.83(td,J＝6.2,12.4Hz,1H),4.59(d,J＝12.5Hz,1H),4.43(d,J＝14.1Hz,1H),4.12(d,J＝10.8Hz,1H),4.06-4.00(m,1H),3.94(s,1H),3.64(s,2H),3.09(d,J＝8.0Hz,2H),3.01(s,1H),2.83(d,J＝6.3Hz,1H),2.13(s,1H),2.05(s,1H),2.01(s,1H),1.88(d,J＝9.5Hz,2H),1.78(d,J＝10.0Hz,4H),1.25(d,J＝6.3Hz,6H). 1 H NMR (400MHz, DMSO-d 6 )δ10.17(s, 1H), 9.05(s, 1H), 7.98(dd, J=6.1, 9.2Hz, 1H), 7.47(t, J=9.0Hz, 1H), 7.39(d, J=2.5Hz, 1H), 7.18(s, 1H), 5.75(s, 2H), 5.38-5.18(m, 1H), 4.83(td, J=6.2, 12.4Hz, 1H ),4.59(d,J=12.5Hz,1H),4.43(d,J=14.1Hz,1H),4.12(d,J=10.8Hz,1H),4.06-4.00(m,1H),3.94(s ,1H),3.64(s,2H),3.09(d,J=8.0Hz,2H),3.01(s,1H),2.83(d,J=6.3Hz,1H),2.13(s,1H),2.05 (s,1H),2.01(s,1H),1.88(d,J=9.5Hz,2H),1.78(d,J=10.0Hz,4H),1.25(d,J=6.3Hz,6H).
实施例51：((叔-丁氧基羰基)氧基)甲基3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2的制备 Example 51: ((tert-Butoxycarbonyl)oxy)methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-di Preparation of azabicyclo[3.2.1]octane-8-carboxylate-1,5-d 2
Figure PCTCN2022130789-appb-000075
Figure PCTCN2022130789-appb-000075
实施例51化合物((叔-丁氧基羰基)氧基)甲基3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛-8-羧酸酯-1,5-d 2可按照实施例50的合成方法选择相应的原料制备得到。ESI-MS：777[M+1] +。 Example 51 Compound ((tert-butoxycarbonyl)oxy)methyl 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylate-1,5-d 2 can be prepared by selecting corresponding raw materials according to the synthesis method in Example 50. ESI-MS: 777 [M+1] + .
1H NMR(400MHz,DMSO-d 6)δ10.17(s,1H),9.06(s,1H),7.98(dd,J＝6.0,9.2Hz,1H),7.55-7.37(m,2H),7.18(d,J＝1.8Hz,1H),5.72(s,2H),5.42-5.20(m,1H),4.67-4.54(m,1H),4.51-4.37(m,1H),4.20-3.99(m,2H),3.94(s,1H),3.77-3.50(m,2H),3.13-3.00(m,3H),2.92-2.80(m,1H),2.15(s,1H),2.10-2.01(m,2H),1.92-1.83(m,3H),1.82-1.71(m,4H),1.49-1.42(m,9H). 1 H NMR (400MHz,DMSO-d 6 )δ10.17(s,1H),9.06(s,1H),7.98(dd,J=6.0,9.2Hz,1H),7.55-7.37(m,2H), 7.18(d,J=1.8Hz,1H),5.72(s,2H),5.42-5.20(m,1H),4.67-4.54(m,1H),4.51-4.37(m,1H),4.20-3.99( m,2H),3.94(s,1H),3.77-3.50(m,2H),3.13-3.00(m,3H),2.92-2.80(m,1H),2.15(s,1H),2.10-2.01( m,2H),1.92-1.83(m,3H),1.82-1.71(m,4H),1.49-1.42(m,9H).
生物学测试评价Biology Test Evaluation
一、KRAS G12D/cRAF结合测试 1. KRAS G12D /cRAF binding test
1、化合物制备1. Compound preparation
将化合物溶解在100％DMSO中，开始浓度为5mM，3倍梯度稀释于DMSO中，共稀释8个浓度点。每个浓度点的化合物或者DMSO取1μL加入到99μL的实验缓冲液中制成10X储备溶液。The compound was dissolved in 100% DMSO with an initial concentration of 5 mM, and was serially diluted 3 times in DMSO, and a total of 8 concentration points were diluted. Add 1 μL of compound or DMSO at each concentration point to 99 μL of assay buffer to make a 10X stock solution.
2、测试步骤2. Test steps
1)向384孔板中加入4μL带有His标签的KRAS G12D和GMPPNP的工作混合溶液。 1) Add 4 μL of working mixture solution of His-tagged KRAS G12D and GMPPNP to a 384-well plate.
2)向384孔板中加入10X化合物储备溶液或者1％DMSO。2) Add 10X compound stock solution or 1% DMSO to the 384-well plate.
3)将板以1000rpm离心1分钟。3) Centrifuge the plate at 1000 rpm for 1 minute.
4)向384孔板中加入4μL带有GST标签的cRAF溶液。4) Add 4 μL of cRAF solution with GST label to the 384-well plate.
5)将板以1000rpm离心1分钟。5) Centrifuge the plate at 1000 rpm for 1 minute.
6)将板在室温下孵育15分钟。6) Incubate the plate at room temperature for 15 minutes.
7)向384孔板中添加10μL检测工作溶液。7) Add 10 μL detection working solution to the 384-well plate.
8)将板以1000rpm离心1分钟。8) Centrifuge the plate at 1000 rpm for 1 minute.
9)将板在室温下孵育60分钟。9) Incubate the plate at room temperature for 60 minutes.
10)将384孔板放入Envision并获取测定数据。10) Put the 384-well plate into Envision and acquire the measurement data.
3、数据处理3. Data processing
根据每个分析板中包含的DMSO对照组的信号和各个化合物孔中的Alphalisa信号，计算每个化合物浓度下的比值。通过测试化合物的浓度和比值的值，使用四参数对数剂量反应方程式确定抑制50％(IC 50)所需的化合物浓度。在每个实验中评估参考化合物的终点值(IC 50)，作为质量控制措施。如果终点值在预期值的三倍以内，则认为该实验可以接受。 Ratios at each compound concentration were calculated based on the signal from the DMSO control contained in each assay plate and the Alphalisa signal from the individual compound wells. The concentration of compound required for 50% inhibition ( IC50 ) was determined using the four parameter logarithmic dose response equation from the concentration of test compound and the value of the ratio. Endpoint values ( IC50 ) of reference compounds were assessed in each experiment as a quality control measure. The experiment was considered acceptable if the endpoint value was within three times the expected value.
表1：生物学测试结果Table 1: Biological Test Results
Figure PCTCN2022130789-appb-000076
Figure PCTCN2022130789-appb-000076
Figure PCTCN2022130789-appb-000077
Figure PCTCN2022130789-appb-000077
本申请生物学测试评价所用“阳性化合物”为WO2021041671A1中实施例252(以下抗增殖2D CTG测试和小鼠药代动力学实验所用阳性化合物与此相同)，化学结构如下：The "positive compound" used in the biological test evaluation of this application is Example 252 in WO2021041671A1 (the positive compound used in the following anti-proliferation 2D CTG test and mouse pharmacokinetic experiment is the same), and the chemical structure is as follows:
Figure PCTCN2022130789-appb-000078
Figure PCTCN2022130789-appb-000078
二、抗增殖2D CTG测试2. Anti-proliferation 2D CTG test
1、实验步骤：1. Experimental steps:
1.1.第0天 铺板1.1. Day 0 planking
当细胞汇合约为80％时，用0.25％胰蛋白酶分离细胞。将分离的细胞重悬于5mL新鲜细胞培养基中并离心以收集细胞。同时计算细胞数量。然后将细胞悬浮于中等浓度的培养基中。将细胞放入96孔板中，AGS为1000细胞/孔，GP2D为1000 细胞/孔。96孔板置于37℃的培养箱中，孵育过夜。When the cells were approximately 80% confluent, detach the cells with 0.25% trypsin. The detached cells were resuspended in 5 mL of fresh cell culture medium and centrifuged to collect the cells. Simultaneously count the number of cells. Cells were then suspended in medium concentration medium. Cells were placed in a 96-well plate with 1000 cells/well for AGS and 1000 cells/well for GP2D. The 96-well plate was placed in a 37°C incubator and incubated overnight.
1.2.第1天 化合物处理1.2. Day 1 Compound treatment
从10mM储备液中按1：5的比例连续稀释10点。将10X含化合物的培养基转移到96孔的相应孔中。最终最高点化合物浓度为10μM，DMSO最终浓度为0.1％。96孔板置于37℃培养箱中，AGS细胞孵育3天，GP2D细胞孵育4天。Serial 10-point dilutions were made 1:5 from the 10 mM stock solution. Transfer 10X compound-containing media to corresponding wells of the 96-well. The final peak compound concentration was 10 [mu]M and the final DMSO concentration was 0.1%. The 96-well plate was placed in a 37°C incubator, AGS cells were incubated for 3 days, and GP2D cells were incubated for 4 days.
1.3.第4天 基线读数1.3. Day 4 Baseline readings
1.4.读取信号1.4. Read signal
AGS细胞中加入50μL/孔的检测试剂(CTG)，在Envision机器中读取信号。Add 50 μL/well detection reagent (CTG) to the AGS cells, and read the signal in the Envision machine.
1.5.第5天 读取信号1.5. Day 5 Read the signal
GP2D细胞中加入50μL/孔的检测试剂(CTG)，在Envision机器中读取信号。Add 50 μL/well detection reagent (CTG) to GP2D cells, and read the signal in the Envision machine.
2、数据处理2. Data processing
根据每个分析板中包含的HPE和ZPE对照孔中的信号和各个化合物孔中的荧光信号，计算每个化合物浓度下的抑制百分比(％)。ZPE对照孔含酶和底物的抑制率为0％，HPE对照孔仅含底物的抑制率为100％。通过测试化合物的浓度和抑制百分数的值，使用四参数对数剂量反应方程式确定抑制50％(IC 50)所需的化合物浓度。在每个实验中评估参考化合物的终点值(IC 50)，作为质量控制措施。如果终点值在预期值的三倍以内，则认为该实验可以接受。 The percent inhibition (%) at each compound concentration was calculated from the signal in the HPE and ZPE control wells contained in each assay plate and the fluorescence signal in the individual compound wells. ZPE control wells containing enzyme and substrate had an inhibition rate of 0%, and HPE control wells containing only substrate had an inhibition rate of 100%. The concentration of compound required for 50% inhibition ( IC50 ) was determined using the four parameter logarithmic dose response equation from the concentration of test compound and the value of percent inhibition. Endpoint values ( IC50 ) of reference compounds were assessed in each experiment as a quality control measure. The experiment was considered acceptable if the endpoint value was within three times the expected value.
表2：生物学测试结果Table 2: Biological Test Results
Figure PCTCN2022130789-appb-000079
Figure PCTCN2022130789-appb-000079
Figure PCTCN2022130789-appb-000080
Figure PCTCN2022130789-appb-000080
从具体实施例化合物活性数据来看，本发明系列化合物对KRAS细胞活性具有较强的抑制作用。在相同测试条件下，部分实施例化合物或前药化合物细胞抑制活性甚至与阳性化合物相当，或有一定程度的提高。According to the activity data of the compounds in the specific examples, the series of compounds of the present invention have strong inhibitory effect on KRAS cell activity. Under the same test conditions, the cytostatic activity of some of the compounds or prodrug compounds of the examples is even comparable to that of the positive compounds, or improved to a certain extent.
三、小鼠药代动力学实验3. Pharmacokinetic experiments in mice
1.试验药品1. Test drugs
本试验用化合物来自本发明具体实施例化合物。The compounds used in this test are from the compounds of the specific examples of the present invention.
2.试验动物2. Test animals
ICR小鼠 雄性N＝3原始来源：上海西普尔-必凯实验动物有限公司。ICR mice Male N=3 Original source: Shanghai Xipuer-Bikay Experimental Animal Co., Ltd.
3.药物配制与给药3. Drug preparation and administration
称取化合物分别加入到0.5％CMC+1％Tween 80的溶媒中，摇匀、超声得到淡黄色悬浊液。3只小鼠，禁食一夜后口服。给药剂量为10mg/kg。给药方式分别为ICR小鼠经单次口服(PO)。The compounds were weighed and added to the solvent of 0.5% CMC+1% Tween 80, shake well, and ultrasonic to obtain a light yellow suspension. 3 mice were given orally after fasting overnight. The dosage is 10mg/kg. The way of administration was single oral administration (PO) in ICR mice respectively.
4.样品采集：4. Sample collection:
约90μL/时间点经眼眶取血，肝素钠抗凝，采集后放置冰上，并于1小时之内离心分离血浆(离心条件：8000转/分钟，6分钟，2-8℃)。采血时间点为0,0.25,0.5,1,2,4,6,8,24小时。样品放于-20℃冰箱保存。At about 90 μL/time point, blood was drawn from the orbit, anticoagulated with heparin sodium, placed on ice after collection, and centrifuged within 1 hour to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C). The blood collection time points are 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. The samples were stored in a -20°C refrigerator.
血浆样品40μL，加入160μL含有内标的冰冷乙腈，涡旋1分钟，18000转/分钟离心10分钟。将上清液转移至96孔板中，取5μL进样到LC-MS/MS进行分析。对实施例45，46，48，49，50和51等前药化合物，分析过程中同时检测其母药化合物(即实施例1)。For 40 μL of plasma sample, add 160 μL of ice-cold acetonitrile containing internal standard, vortex for 1 minute, and centrifuge at 18,000 rpm for 10 minutes. The supernatant was transferred to a 96-well plate, and 5 μL was injected into LC-MS/MS for analysis. For prodrug compounds such as Examples 45, 46, 48, 49, 50 and 51, the parent drug compound (ie, Example 1) was detected simultaneously during the analysis.
表3：药代动力学数据Table 3: Pharmacokinetic data
Figure PCTCN2022130789-appb-000081
Figure PCTCN2022130789-appb-000081
从以上具体实施例化合物的药代动力学数据来看，本发明系列化合物经单次口服(10mg/kg)吸收进入小鼠体内，具有非常好的PK数据。相比阳性化合物，部分实施例化合物的AUC提高十几倍、甚至数十倍，试验证明，本发明系列化合物具有非常好的开发前景，有望解决阳性化合物pK差，不适于口服的问题。Judging from the pharmacokinetic data of the compounds in the above specific examples, the series of compounds of the present invention are absorbed into mice after a single oral administration (10 mg/kg), and have very good PK data. Compared with the positive compounds, the AUC of some of the compounds in the examples is increased by more than ten times, even dozens of times. The test proves that the series of compounds of the present invention have very good development prospects and are expected to solve the problem that the positive compounds have poor pK and are not suitable for oral administration.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述公开内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above disclosure of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (23)

  1. 式(I)化合物、其立体异构体或其药学上可接受盐：Compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof:
    Figure PCTCN2022130789-appb-100001
    Figure PCTCN2022130789-appb-100001
    其中，R 1选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基和-C 0-4烷基-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基的取代基所取代； Wherein, R 1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and -C 0-4 alkyl-NR 16 R 17 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1 -10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl The substituent of the group is substituted;
    每个R 2各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15； Each R is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0 -8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0 -8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O) 2 R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkane -OR 14 , -C 0-8alkyl -C(O)OR 14 , -C 0-8alkyl -C(O)SR 14 , -C 0-8alkyl -SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 ) 2 , -C 0-8 alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 ;
    R 3选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15； R3 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl- SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl- N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8Alkyl -OC(O)R 15 , -C 0-8Alkyl -P(O)(R 15 ) 2 , -C 0-8Alkyl -NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0- 8 alkyl-C (O) NR 16 R 17 and -C 0-8 alkyl-N (R 16 )-C (O) R 15 ;
    R 4选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、 -C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15； R is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl- SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl- N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8Alkyl -OC(O)R 15 , -C 0-8Alkyl -P(O)(R 15 ) 2 , -C 0-8Alkyl -NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0- 8 alkyl-C (O) NR 16 R 17 and -C 0-8 alkyl-N (R 16 )-C (O) R 15 ;
    R 5a和R 5b各自独立地选自氢、氘、卤素、C 1-10烷氧基、卤取代C 1-10烷氧基和氘取代C 1-10烷氧基； R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-10 alkoxy, halogen substituted C 1-10 alkoxy and deuterium substituted C 1-10 alkoxy;
    R 6a、R 6b、R 6c和R 6d各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15，或者， R 6a , R 6b , R 6c and R 6d are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered Heteroaryl, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)SR 14 , -C 0-8 alkyl- SC(O)R 15 , -C 0-8alkyl -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -P(O)( R 15 ) 2 , -C 0-8alkyl -NR 16 R 17 , -C 0-8alkyl -C(=NR 16 )R 15 , -C 0-8alkyl -N(R 16 )-C (=NR 17 )R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 , or,
    R 6a、R 6b、R 6c和R 6d其中两个与其直接相连的部分原子一起形成一个C 3-10环烷基和3-10元杂环基，另两个如前所定义，所述C 3-10环烷基和3-10元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代； Two of R 6a , R 6b , R 6c and R 6d form a C 3-10 cycloalkyl group and a 3-10 membered heterocyclic group together with some of the atoms directly connected to them, and the other two are as defined above, and the C The 3-10 cycloalkyl group and the 3-10 membered heterocyclic group are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , - C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 ,- C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C (O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 alkyl-P(O)(R 15 ) 2 , -C 0-8 alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 ,- C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C (O) R 15 substituents are substituted;
    R 7选自氢、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(S)NR 16R 17、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基 -N(R 16)-C(O)R 15的取代基所取代，上述基团独立地任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代，条件是，当R 7为氢、-C(O)O-叔丁基、-C(O)O-芳基、-C(O)-C 1-6烷基或-C(O)O-C 1-4烷基-O-C(O)-C 1-21烷基时，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子，或者，R 4为-C 0-8烷基-S-R 13； R 7 is selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)SR 14 , -C 0-8 alkane -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -P(O)(R 15 ) 2 , -C 0-8alkyl- NR 16 R 17 , -C 0-8 alkyl-C(S)NR 16 R 17 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 , the above groups are independently optionally further selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, - C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 ,- C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O) 2 R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0- 8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 alkyl-C(O)R 15 , -C 0-8 alkyl-OC(O)R 15 , -C 0-8 alkyl-P(O)(R 15 ) 2 , -C 0-8 alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 , -C 0-8 alkyl-N(R 16 )-C(=NR 17 ) Substituents of R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 are substituted, the above groups are independently Optionally, one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O , =S, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)SR 14 , -C 0-8 alkyl- SC(O)R 15 , -C 0-8alkyl -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -P(O)( R 15 ) 2 , -C 0-8alkyl -NR 16 R 17 , -C 0-8alkyl -C(=NR 16 )R 15 , -C 0-8alkyl -N(R 16 )-C (=NR 17 )R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 are substituted by substituents , with the proviso that when R 7 is hydrogen, -C(O)O-tert-butyl, -C(O)O-aryl, -C(O)-C 1-6 alkyl or -C(O)OC When 1-4 alkyl-OC(O)-C 1-21 alkyl, R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom, or, R 4 is -C 0-8 alkyl-SR 13 ;
    R 8a和R 8b各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-10环烷基和3-10元杂环基，所述C 3-10环烷基和3-10元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF 5 , -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O) 2 R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 alkyl-C(O)R 15 , -C 0-8 alkyl-OC(O)R 15 , -C 0-8 alkyl-P(O)(R 15 ) 2 ,- C 0-8 alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 ,-C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15. -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 , or, R 8a and R 8b are directly connected to it The carbon atoms together form a C 3-10 cycloalkyl group and a 3-10 membered heterocyclic group, and the C 3-10 cycloalkyl group and the 3-10 membered heterocyclic group are independently optionally further selected by one or more From deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl -SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl -N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0- 8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 ) 2 , -C 0-8 Alkane -NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0 Substituents of -8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 ;
    每个R 9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15， 或者，相邻的两个R 9与其直接相连的部分一起形成一个环烷基和杂环基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、＝S、-C 0-8烷基-SF 5、-C 0-8烷基-S(O)(＝N-R 10)R 11、-C 0-8烷基-N＝S(O)R 11R 12、-C 0-8烷基-N＝SR 11R 12、-C 0-8烷基-O-S(O) 2R 13、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)SR 14、-C 0-8烷基-S-C(O)R 15、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-P(O)(R 15) 2、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17和-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代； Each R 9 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S( O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkane -OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-OR 14 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)SR 14 , -C 0-8 alkyl-SC(O)R 15 , -C 0-8 alkyl-C(O)R 15 , -C 0 -8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 ) 2 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl -C(=NR 16 )R 15 , -C 0-8alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0-8alkyl -C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 , or, two adjacent R 9 and the part directly connected together form a cycloalkyl group and a heterocyclic group, and the above groups are independently Optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O)(=NR 10 )R 11 , -C 0-8 alkyl-N=S(O)R 11 R 12 , -C 0-8 alkyl-N=SR 11 R 12 , -C 0-8 alkyl-OS(O) 2 R 13 , -C 0-8 alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC (O)R 15 , -C 0-8alkyl -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -P(O)(R 15 ) 2 , -C 0-8alkyl -NR 16 R 17 , -C 0-8alkyl -C(=NR 16 )R 15 , -C 0-8alkyl -N(R 16 )-C( =NR 17 )R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 and -C 0-8 alkyl-N(R 16 )-C(O)R 15 are substituted by substituents;
    每个R 10各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)R 15或-C 0-8烷基-C(O)NR 16R 17，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17或-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代； Each R 10 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycle base, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-S(O) r R 13 , -C 0-8 alkyl-C(O)OR 14 , -C 0-8 alkyl-C(O)R 15 or -C 0-8 alkyl-C(O)NR 16 R 17 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, Nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3 -10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 alkyl-NR 16 R 17 , -C 0-8 alkyl-C(=NR 16 )R 15 ,-C 0-8 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 alkyl-C(O)NR 16 R 17 or -C 0-8 alkyl-N(R 16 )-C(O)R 15 are substituted by substituents;
    每个R 11和R 12各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，或者，R 11和R 12与其直接相连的硫原子一起形成3-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-S(O) rR 13、-C 0-8烷基-O-R 14、-C 0-8烷基-C(O)OR 14、-C 0-8烷基-C(O)R 15、-C 0-8烷基-O-C(O)R 15、-C 0-8烷基-NR 16R 17、-C 0-8烷基-C(＝NR 16)R 15、-C 0-8烷基-N(R 16)-C(＝NR 17)R 15、-C 0-8烷基-C(O)NR 16R 17或-C 0-8烷基-N(R 16)-C(O)R 15的取代基所取代； Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3 -10-membered heterocyclic group, C 6-10 aryl or 5-10-membered heteroaryl group, or, R 11 and R 12 form a 3-10-membered heterocyclic group together with the sulfur atom directly connected to it, the above-mentioned groups are optional Further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1- 10 alkyl, deuterium substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkane -S(O) r R 13 , -C 0-8alkyl -OR 14 , -C 0-8alkyl -C(O)OR 14 , -C 0-8alkyl -C(O)R 15 , -C 0-8alkyl -OC(O)R 15 , -C 0-8alkyl -NR 16 R 17 , -C 0-8alkyl -C(=NR 16 )R 15 , -C 0- 8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 or -C 0-8 Alkyl-N(R 16 )- C(O)R 15 is replaced by a substituent;
    每个R 13独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 16R 17的取代基所取代； Each R 13 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl group, 5-10 membered heteroaryl group and -NR 16 R 17 , the above groups are independently optionally further selected from one or more deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 1- 10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 heterocyclic, 3-12 heterocyclic, C 6-10 aryl, C 6-10 Substituted by aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 ;
    每个R 14独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12 元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 16R 17的取代基所取代； Each R 14 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the above-mentioned groups are optionally further independently selected from one or more of deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclyl group, C 6-10 aryl group, C 6-10 aryloxy group, 5 Substituents of -10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 16 R 17 ;
    每个R 15独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 16R 17的取代基所取代； Each R 15 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 ring Alkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heteroaryl group group, 5-10 membered heteroaryloxy group and -NR 16 R 17 , the above groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl , C 1-10 alkoxy group, C 3-12 cycloalkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 aryl group, Substituents of C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 ;
    每个R 16和R 17各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基和C 1-10烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Each R 16 and R 17 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, C 6-10 aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl and C 1-10 alkanoyl, the above groups are independently optionally further selected from one or more of deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3- 12 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryl group Heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl substituents;
    或者，R 16和R 17与其直接相连的氮原子一起形成一个4-10元杂环基或5-10元杂芳基，所述4-10元杂环基或5-10元杂芳基任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Alternatively, R 16 and R 17 form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group together with the nitrogen atom directly connected to it, and any of the 4-10 membered heterocyclic group or 5-10 membered heteroaryl group is further selected by one or more selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, Deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group , C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 alkylamino, two C 1-10 alkane Substituents of amino group and C 1-10 alkanoyl;
    m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
    n为0、1、2、3、4、5或6；且n is 0, 1, 2, 3, 4, 5 or 6; and
    每个r独立地为0、1或2。Each r is independently 0, 1 or 2.
  2. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 1选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基和-C 0-4烷基-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基的取代基所取代； The compound of formula (I) according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, R is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group and -C 0-4 alkyl-NR 16 R 17 , the above groups are independently optionally further selected from one or more deuterium, halogen, cyano , nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C Substituents of 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl and 5-8 membered heteroaryl;
    每个R 2各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、 -C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15； Each R is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0 -4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0 -4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O) 2 R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkane -OR 14 , -C 0-4alkyl -C(O)OR 14 , -C 0-4alkyl -C(O)SR 14 , -C 0-4alkyl -SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -P(O)(R 15 ) 2 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 ;
    R 3选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15； R is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl- SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl- N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4Alkyl -OC(O)R 15 , -C 0-4Alkyl -P(O)(R 15 ) 2 , -C 0-4Alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0- 4 alkyl-C (O) NR 16 R 17 and -C 0-4 alkyl-N (R 16 )-C (O) R 15 ;
    R 4选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15； R is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl- SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl- N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4Alkyl -OC(O)R 15 , -C 0-4Alkyl -P(O)(R 15 ) 2 , -C 0-4Alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0- 4 alkyl-C (O) NR 16 R 17 and -C 0-4 alkyl-N (R 16 )-C (O) R 15 ;
    R 5a和R 5b各自独立地选自氢、氘、卤素、C 1-4烷氧基、卤取代C 1-4烷氧基和氘取代C 1-4烷氧基； R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy and deuterium substituted C 1-4 alkoxy;
    R 6a、R 6b、R 6c和R 6d各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15，或者，R 6a、R 6b、R 6c和R 6d其中两个与其直接相连的部分原子一起形成一个C 3-6环烷基和3-6元杂环基，另两个如前所定义，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4 烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代； R 6a , R 6b , R 6c and R 6d are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered Heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl-N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 alkyl-C(O)OR 14 , -C 0-4 alkyl-C(O)SR 14 , -C 0-4 alkyl- SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -P(O)( R 15 ) 2 , -C 0-4alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C (=NR 17 )R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 , or, R 6a , R 6b , R 6c and R 6d , two of which are directly connected to some atoms together form a C 3-6 cycloalkyl group and a 3-6 membered heterocyclic group, and the other two are as defined above, and the C 3- The 6- cycloalkyl group and the 3-6-membered heterocyclic group are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1- 4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aromatic radical, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0 -4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O) 2 R 13 , -C 0 -4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O )SR 14 , -C 0-4alkyl -SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 ,- C 0-4 alkyl-P(O)(R 15 ) 2 , -C 0-4 alkyl-NR 16 R 17 , -C 0-4 alkyl-C(=NR 16 )R 15 , -C 0 -4alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0-4alkyl -C(O)NR 16 R 17 and -C 0-4alkyl -N(R 16 ) -C(O)R 15 is replaced by a substituent;
    R 7选自氢、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(S)NR 16R 17、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代，上述基团独立地任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代，条件是，当R 7为氢、-C(O)O-叔丁基、-C(O)O-芳基、-C(O)-C 1-6烷基或-C(O)O-C 1-4烷基-O-C(O)-C 1-21烷基时，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子，或者，R 4为-S-R 13； R 7 is selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 alkyl-C(O)OR 14 , -C 0-4 alkyl-C(O)SR 14 , -C 0-4 alkane -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -P(O)(R 15 ) 2 , -C 0-4alkyl- NR 16 R 17 , -C 0-4 alkyl-C(S)NR 16 R 17 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 , the above groups are independently optionally further selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, - C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 ,- C 0-4 alkyl-N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0- 4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 alkyl-C(O)R 15 , -C 0-4 alkyl-OC(O)R 15 , -C 0-4 alkyl-P(O)(R 15 ) 2 , -C 0-4 alkyl-NR 16 R 17 , -C 0-4 alkyl-C(=NR 16 )R 15 , -C 0-4 alkyl-N(R 16 )-C(=NR 17 ) Substituents of R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 are substituted, the above groups are independently Optionally, one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O , =S, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl-N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 alkyl-C(O)OR 14 , -C 0-4 alkyl-C(O)SR 14 , -C 0-4 alkyl- SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -P(O)( R 15 ) 2 , -C 0-4alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C (=NR 17 )R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 are substituted by substituents , with the proviso that when R 7 is hydrogen, -C(O)O-tert-butyl, -C(O)O-aryl, -C(O)-C 1-6 alkyl or -C(O)OC When 1-4 alkyl-OC(O)-C 1-21 alkyl, R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom, or, R 4 is -SR 13 ;
    R 8a和R 8b各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、 5-8元杂芳基、＝O、＝S、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O) 2 R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 alkyl-C(O)R 15 , -C 0-4 alkyl-OC(O)R 15 , -C 0-4 alkyl-P(O)(R 15 ) 2 ,- C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15. -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 , or, R 8a and R 8b are directly connected to it The carbon atoms together form a C 3-6 cycloalkyl group and a 3-6 membered heterocyclic group, and the C 3-6 cycloalkyl group and the 3-6 membered heterocyclic group are independently optionally further selected by one or more From deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl -N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0- 4Alkyl -C(O)R 15 , -C 0-4Alkyl -OC(O)R 15 , -C 0-4Alkyl -P(O)(R 15 ) 2 , -C 0-4Alkane -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0 Substituents of -4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 ;
    每个R 9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15，或者，相邻的两个R 9与其直接相连的部分一起形成一个环烷基和杂环基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-C 0-4烷基-SF 5、-C 0-4烷基-S(O)(＝N-R 10)R 11、-C 0-4烷基-N＝S(O)R 11R 12、-C 0-4烷基-N＝SR 11R 12、-C 0-4烷基-O-S(O) 2R 13、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)SR 14、-C 0-4烷基-S-C(O)R 15、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-P(O)(R 15) 2、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17和-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代； Each R is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0 -4 Alkyl-SF 5 , -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0 -4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O) 2 R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkane -OR 14 , -C 0-4alkyl -C(O)OR 14 , -C 0-4alkyl -C(O)SR 14 , -C 0-4alkyl -SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -P(O)(R 15 ) 2 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl-N(R 16 )-C(O)R 15 , or, two adjacent R 9 directly The connected parts together form a cycloalkyl group and a heterocyclic group, and the above-mentioned groups are independently and optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, Halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl-N=S(O)R 11 R 12 , -C 0-4 alkyl-N=SR 11 R 12 , -C 0-4 alkyl-OS(O) 2 R 13 , -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 alkyl-C(O)OR 14 , -C 0-4 alkane -C(O)SR 14 , -C 0-4alkyl -SC(O)R 15 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O )R 15 , -C 0-4alkyl -P(O)(R 15 ) 2 , -C 0-4alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0-4 alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 alkyl-C(O)NR 16 R 17 and -C 0-4 alkyl- Substituents of N(R 16 )-C(O)R 15 ;
    其中，R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17和r如权利要求1中所定义。 Wherein, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in claim 1.
  3. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，每个R 10各自独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)R 15或-C 0-4烷基-C(O)NR 16R 17，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17或-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代； The compound of formula (I) according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, each R 10 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0 -4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)R 15 or -C 0-4 Alkyl -C(O)NR 16 R 17 , the above groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenes Base, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl , 5-8 membered heteroaryl, -C 0-4 alkyl-S(O) r R 13 , -C 0-4 alkyl-OR 14 , -C 0-4 alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkane -C(=NR 16 )R 15 , -C 0-4alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0-4alkyl -C(O)NR 16 R 17 Or -C 0-4 alkyl-N(R 16 )-C(O)R 15 substituents substituted;
    每个R 11和R 12各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基或5-8元杂芳基，或者，R 11和R 12与其直接相连的硫原子一起形成3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-S(O) rR 13、-C 0-4烷基-O-R 14、-C 0-4烷基-C(O)OR 14、-C 0-4烷基-C(O)R 15、-C 0-4烷基-O-C(O)R 15、-C 0-4烷基-NR 16R 17、-C 0-4烷基-C(＝NR 16)R 15、-C 0-4烷基-N(R 16)-C(＝NR 17)R 15、-C 0-4烷基-C(O)NR 16R 17或-C 0-4烷基-N(R 16)-C(O)R 15的取代基所取代； Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclic group, C 6-8 aryl group or 5-8 membered heteroaryl group, or, R 11 and R 12 form a 3-6 membered heterocyclic group together with the sulfur atom directly connected to it, the above-mentioned groups are optional Further by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1- 4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkane -S(O) r R 13 , -C 0-4alkyl -OR 14 , -C 0-4alkyl -C(O)OR 14 , -C 0-4alkyl -C(O)R 15 , -C 0-4alkyl -OC(O)R 15 , -C 0-4alkyl -NR 16 R 17 , -C 0-4alkyl -C(=NR 16 )R 15 , -C 0- 4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 or -C 0-4 Alkyl-N(R 16 )- C(O)R 15 is replaced by a substituent;
    每个R 13独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17的取代基所取代； Each R 13 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl group, 5-8 membered heteroaryl group and -NR 16 R 17 , the above-mentioned groups are independently optionally further selected from deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 1- 4 alkoxyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 heterocyclyl, 3-6 heterocyclyl, C 6-8 aryl, C 6-8 Substituents of aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 ;
    每个R 14独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17的取代基所取代； Each R is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, the above-mentioned groups are optionally further independently selected from one or more of deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5 -8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 16 R 17 substituents;
    每个R 15独立地选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17的取代基所取代； Each R is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring Alkyl group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group group, 5-8 membered heteroaryloxy group and -NR 16 R 17 , the above groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl , C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 heterocyclic, 3-6 heterocyclic, C 6-8 aryl, Substituents of C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 ;
    每个R 16和R 17各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基和C 1-4烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代； Each R 16 and R 17 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, C 6-8 aryl group, 5-8 membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, amino group Sulfonyl, dimethylaminosulfonyl and C 1-4 alkanoyl, the above groups are independently optionally further selected from one or more of deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3- 6- cycloalkoxy, 3-6-membered heterocyclic group, 3-6-membered heterocyclic epoxy group, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered Heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl substituents;
    或者，R 16和R 17与其直接相连的氮原子一起形成一个4-8元杂环基或5-8元杂芳基，所述4-8元杂环基或5-8元杂芳基任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷 基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代。 Alternatively, R 16 and R 17 form a 4-8 membered heterocyclic group or a 5-8 membered heteroaryl group together with the nitrogen atom directly connected to it, and the 4-8 membered heterocyclic group or 5-8 membered heteroaryl group is any is further selected by one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, Deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 heterocyclic, 3-6 heterocyclic , C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkane Substituted by substituents of amino group and C 1-4 alkanoyl group.
  4. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅱ)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (II):
    Figure PCTCN2022130789-appb-100002
    Figure PCTCN2022130789-appb-100002
    其中，R 1选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基的取代基所取代； Wherein, R 1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group and -NR 16 R 17 , the above groups are independently any selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C Substituents of 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl;
    R 2a、R 2b、R 2c和R 2d各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15； R 2a , R 2b , R 2c and R 2d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O )(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and - N(R 16 )-C(O)R 15 ;
    R 3选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15； R is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 ;
    R 4选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15； R 4 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 ;
    R 5a和R 5b各自独立地选自氢、氘、卤素、C 1-4烷氧基、卤取代C 1-4烷氧基和氘取代C 1-4烷氧基； R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy and deuterium substituted C 1-4 alkoxy;
    R 6a、R 6b、R 6c和R 6d各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代 C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15； R 6a , R 6b , R 6c and R 6d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O )(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and - N(R 16 )-C(O)R 15 ;
    R 7选自氢、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(S)NR 16R 17、-C(O)NR 16R 17和-N(R 16)-C(O)R 15，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代，上述基团独立地任选再进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、C 0-2烷基-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代，条件是，当R 7为氢、-C(O)O-叔丁基、-C(O)O-芳基、-C(O)-C 1-6烷基或-C(O)O-C 1-4烷基-O-C(O)-C 1-21烷基时，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子，或者，R 4为-S-C 1-4烷基； R 7 is selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , - C(S)NR 16 R 17 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , the above groups are independently optionally further selected from one or more of deuterium, Halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl , 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C (O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C( =NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 are substituted by substituents, the above groups are independently optionally further replaced by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , C 0-2 alkyl-OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 is substituted with the proviso that when R 7 is hydrogen, -C(O)O-tert-butyl, -C(O)O-aryl, -C(O)- When C 1-6 alkyl or -C(O)OC 1-4 alkyl-OC(O)-C 1-21 alkyl, among R 5a , R 5b , R 6a , R 6b , R 6c and R 6d Contains at least one deuterium atom, or, R 4 is -SC 1-4 alkyl;
    R 8a和R 8b各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenes Base, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O) (=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )- C(O)R 15 , or, R 8a and R 8b form a C 3-6 cycloalkyl group and a 3-6 membered heterocyclic group together with the carbon atoms directly connected to them, and the C 3-6 cycloalkyl group and 3 -6-membered heterocyclic group is optionally further independently selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , - S(O) rR 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O) Substituents of NR 16 R 17 and -N(R 16 )-C(O)R 15 ;
    R 9a、R 9b、R 9c、R 9d和R 9e各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂 环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15，或者，R 9d和R 9e与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，另三个如前所定义，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代； R 9a , R 9b , R 9c , R 9d and R 9e are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O ) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , - P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 9d and R 9e form a C 3-6 cycloalkyl group and a 3-6 membered heterocyclic group together with the carbon atoms directly connected to them, and the other three As defined above, the C 3-6 cycloalkyl and 3-6 membered heterocyclyl are independently optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, halogen Substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , - N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O) R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 ) Substituents of -C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 ;
    其中，R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17和r如权利要求1中所定义。 Wherein, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in claim 1.
  5. 根据权利要求4所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 1选自氢、氘、氟、氰基、甲基、乙基、异丙基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、环丙甲基、环丙基、氧杂环丁基、氧杂环戊基、氮杂环丁基、氮杂环戊基、氨基和二甲氨基； The compound of formula (I) according to claim 4, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, R is selected from hydrogen, deuterium, fluorine, cyano, methyl, ethyl, iso Propyl, difluoromethyl, trifluoromethyl, dideuteriomethyl, trideuteromethyl, cyclopropylmethyl, cyclopropyl, oxetanyl, oxolyl, azetidinyl, Azacyclopentyl, amino and dimethylamino;
    R 2a、R 2b、R 2c和R 2d各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-S-R 13和-O-R 14； R 2a , R 2b , R 2c and R 2d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
    其中，R 13和R 14如权利要求4中所定义。 Wherein, R 13 and R 14 are as defined in claim 4.
  6. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅲ)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (III):
    Figure PCTCN2022130789-appb-100003
    Figure PCTCN2022130789-appb-100003
    其中，R 2a选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-S-R 13和-O-R 14； Wherein, R 2a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
    R 3选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-S-R 13和-O-R 14； R is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
    R 4选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、 C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-S-R 13和-O-R 14； R is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
    R 5a和R 5b各自独立地选自氢、氘、卤素、C 1-4烷氧基、卤取代C 1-4烷氧基和氘取代C 1-4烷氧基； R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy and deuterium substituted C 1-4 alkoxy;
    R 6a、R 6b、R 6c和R 6d各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-S-R 13和-O-R 14； R 6a , R 6b , R 6c and R 6d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SR 13 and -OR 14 ;
    R 7选自氢、C 1-4烷基、C 3-6环烷基、3-6元杂环基、-S(O) rR 13、-C(O)OR 14、-P(O)(R 15) 2、-C(O)R 15、-C(S)NR 16R 17和-C(O)NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代，上述基团独立地任选再进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、C 0-2烷基-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代，条件是，当R 7为氢、-C(O)O-叔丁基、-C(O)O-芳基、-C(O)-C 1-6烷基或-C(O)O-C 1-4烷基-O-C(O)-C 1-21烷基时，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子，或者，R 4为-S-C 1-4烷基； R 7 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -S(O) r R 13 , -C(O)OR 14 , -P(O )(R 15 ) 2 , -C(O)R 15 , -C(S)NR 16 R 17 and -C(O)NR 16 R 17 , the above groups are independently optionally further selected from one or more Deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )- C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 are substituted by substituents, the above groups are independently optionally further replaced by one or Multiple selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne base, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S(O)(= NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , C 0-2 alkyl -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)( R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N( R 16 )-C(O)R 15 is substituted with the proviso that when R 7 is hydrogen, -C(O)O-tert-butyl, -C(O)O-aryl, -C(O )-C 1-6 alkyl or -C(O)OC 1-4 alkyl-OC(O)-C 1-21 alkyl, R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contains at least one deuterium atom, or, R 4 is -SC 1-4 alkyl;
    R 8a和R 8b各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基和3-6元杂环基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、＝O、＝S、C 3-6环烷基和3-6元杂环基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenes group, C 2-4 alkynyl group, C 3-6 cycloalkyl group and 3-6 membered heterocyclyl group, or, R 8a and R 8b together form a C 3-6 cycloalkyl group and their directly connected carbon atoms 3-6 membered heterocyclic group, the C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, halogen, cyano, C 1-4 alkyl , halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, =O, =S, C 3-6 cycloalkyl and 3 -substituted by a substituent of a 6-membered heterocyclic group;
    R 9a选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基和3-6元杂环基； R 9a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
    其中，R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17和r如权利要求1中所定义。 Wherein, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in claim 1.
  7. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅳ1)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (IV1):
    Figure PCTCN2022130789-appb-100004
    Figure PCTCN2022130789-appb-100004
    其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
    R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 5a选自氢、氘、三氘甲氧基、二氘甲氧基和三氘乙氧基； R is selected from the group consisting of hydrogen, deuterium, trideuteriomethoxy, diduteriomethoxy and trideuteroethoxy;
    R 5b选自氢、氘、三氘甲氧基、二氘甲氧基和三氘乙氧基； R is selected from the group consisting of hydrogen, deuterium, trideuteriomethoxy, dideriomethoxy and trideuteroethoxy;
    R 6a选自氢、氘、三氘甲基、二氘甲基、一氘甲基、三氘甲氧基、二氘甲氧基和三氘乙氧基； R is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuteriomethyl, monodeuteromethyl, trideuteriomethoxy, dideuuteriomethoxy and trideuteroethoxy;
    R 6b选自氢、氘、三氘甲基、二氘甲基、一氘甲基、三氘甲氧基、二氘甲氧基和三氘乙氧基； R6b is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuteriomethyl, monodeuteromethyl, trideuteriomethoxy, diduteriomethoxy and trideuteroethoxy;
    R 6c选自氢、氘、三氘甲基、二氘甲基、一氘甲基、三氘甲氧基、二氘甲氧基和三氘乙氧基； R is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuuteromethyl, monodeuteromethyl, trideuteromethoxy, dideuuteriomethoxy and trideuteroethoxy;
    R 6d选自氢、氘、三氘甲基、二氘甲基、一氘甲基、三氘甲氧基、二氘甲氧基和三氘乙氧基； R is selected from the group consisting of hydrogen, deuterium, trideuteromethyl, dideuteriomethyl, monodeuteromethyl, trideuteriomethoxy, dideuuteriomethoxy and trideuteroethoxy;
    R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立 地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
    R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
    条件是，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子。 Provided that R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom.
  8. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅴ1)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (V1):
    Figure PCTCN2022130789-appb-100005
    Figure PCTCN2022130789-appb-100005
    其中，R 5a为氢或氘；R 5b为氢或氘；R 6a为氢或氘；R 6b为氢或氘；R 6c为氢或氘；R 6d为氢或氘； Wherein, R 5a is hydrogen or deuterium; R 5b is hydrogen or deuterium; R 6a is hydrogen or deuterium; R 6b is hydrogen or deuterium; R 6c is hydrogen or deuterium; R 6d is hydrogen or deuterium;
    条件是，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子，优选包含1、2、4或6个氘原子。 The proviso is that R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom, preferably 1, 2, 4 or 6 deuterium atoms.
  9. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅳ2)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (IV2):
    Figure PCTCN2022130789-appb-100006
    Figure PCTCN2022130789-appb-100006
    其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
    R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 6a选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6b选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6c选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6d选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 7a和R 7b各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、C 2-4链炔基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C(O)OR 14和-C(O)NR 16R 17，或者，R 7a和R 7b与其直接相连的碳原子一起形成一个C 3-6环烷基或3-6元杂环基，上述基团独立地任选再进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-O-R 14、-NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代； R 7a and R 7b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkane Base, C 2-4 alkynyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C(O)OR 14 and -C(O)NR 16 R 17 , or, R 7a and R 7b form a C 3-6 cycloalkyl group or a 3-6 membered heterocyclic group together with the directly connected carbon atoms, and the above-mentioned groups are independently optionally further selected from one or more deuterium , halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -OR 14 , -NR 16 R 17 and -N(R 16 ) -C(O)R 15 is replaced by a substituent;
    R 7c选自氢、氘、卤素、氰基、卤取代C 1-4烷基和氘取代C 1-4烷基； R 7c is selected from hydrogen, deuterium, halogen, cyano, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
    R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
    R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
    其中，R 14、R 15、R 16和R 17如权利要求1中所定义。 Wherein, R 14 , R 15 , R 16 and R 17 are as defined in claim 1.
  10. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅴ2)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (V2):
    Figure PCTCN2022130789-appb-100007
    Figure PCTCN2022130789-appb-100007
    其中，R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； Wherein, R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy , Dideriomethoxy, Trifluoroethoxy and Trideuteroethoxy;
    R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 7a和R 7b各自独立地选自氢、氘、氟、氯、甲基、乙基、乙炔基、一氟甲基、二氟甲基、三氟甲基、环丙基和
    Figure PCTCN2022130789-appb-100008
    或者，R 7a和R 7b与其直接相连的碳原子一起形成一个环丙基，上述基团独立地任选再进一步被一个或多个选自氘、氟、氯、氰基、羟基、甲氧基、甲基、乙基、一氟甲基、二氟甲基、三氟甲基、二甲氨基、甲氧基取代的甲基和苯基的取代基所取代；     R 7a and R 7b are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, ethynyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl and
    Figure PCTCN2022130789-appb-100008
    Alternatively, R 7a and R 7b form a cyclopropyl group together with their directly connected carbon atoms, and the above-mentioned groups are independently optionally further replaced by one or more selected from deuterium, fluorine, chlorine, cyano, hydroxyl, and methoxy , methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, dimethylamino, methoxy substituted methyl and phenyl substituents;
    R 7c为氢、氘或氟； R 7c is hydrogen, deuterium or fluorine;
    优选地，R 5a选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； Preferably, R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy and dideudemethoxy;
    R 5b选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧 基； R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
    R 7a和R 7b各自独立地选自氢、氘、氟、氯、甲基、乙基、一氟甲基、二氟甲基、三氟甲基和
    Figure PCTCN2022130789-appb-100009
    上述基团独立地任选再进一步被一个或多个选自氘、氟、氯、氰基、羟基、甲基、乙基、一氟甲基、二氟甲基、三氟甲基、甲氧基取代的甲基和苯基的取代基所取代；     R 7a and R 7b are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl and
    Figure PCTCN2022130789-appb-100009
    The above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy Substituents of methyl and phenyl substituents substituted by radicals;
    R 7c为氢、氘或氟。 R 7c is hydrogen, deuterium or fluorine.
  11. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅳ3)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (IV3):
    Figure PCTCN2022130789-appb-100010
    Figure PCTCN2022130789-appb-100010
    其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
    R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲 氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 6a选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6b选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6c选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6d选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 7d为C 1-2烷基，上述C 1-2烷基任选进一步被一个或多个选自氘、卤素、氰基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、
    Figure PCTCN2022130789-appb-100011
    ＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-O-C(O)R 15a、-S-C(O)R 15、-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代；     R 7d is C 1-2 alkyl, the above C 1-2 alkyl is optionally further selected from one or more of deuterium, halogen, cyano, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkane Base, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl,
    Figure PCTCN2022130789-appb-100011
    =O, =S, -SF 5 , -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , -OR 14 , -C(O)OR 14 , -C(O)SR 14 , -OC(O)R 15a , -SC(O)R 15 , -C( O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C Substituents of (O)NR 16 R 17 and -N(R 16 )-C(O)R 15 ;
    R 15a选自氢、氘、羟基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17的取代基所取代； R 15a is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy , 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 16 R 17 , the above groups are independently optionally further selected from one or more of deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3 -6 cycloalkyl group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 Substituents of heteroaryl, 5-8-membered heteroaryloxy and -NR 16 R 17 ;
    R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
    R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
    其中，R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17和r如权利要求1中所定义。 Wherein, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in claim 1.
  12. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅴ3)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (V3):
    Figure PCTCN2022130789-appb-100012
    Figure PCTCN2022130789-appb-100012
    其中，R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethyl, Deuteromethyl, Dideuteriomethyl, One-Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy , Trifluoromethoxy, Difluoromethoxy, Trideuteromethoxy, Dideriomethoxy, Trifluoroethoxy, Trideuteroethoxy, Cyclopropoxy, Cyclobutoxy, Methylthio and ethylthio;
    R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 7d为甲基或乙基，上述甲基或乙基任选进一步被一个或多个选自氘、氟、氯、氰基、羟基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基、三氘甲基、 环丙基、甲氧基、苯基、
    Figure PCTCN2022130789-appb-100013
    的取代基所取代。     R 7d is methyl or ethyl, and the above-mentioned methyl or ethyl is optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, hydroxyl, monofluoromethyl, difluoromethyl, trifluoromethyl , a deuteromethyl, dide deuteromethyl, trideuteromethyl, cyclopropyl, methoxy, phenyl,
    Figure PCTCN2022130789-appb-100013
    replaced by substituents.
  13. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅳ4)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (IV4):
    Figure PCTCN2022130789-appb-100014
    Figure PCTCN2022130789-appb-100014
    其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
    R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 6a选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁 基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6b选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6c选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6d选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 7e和R 7f各自独立地选自羟基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基和3-6元杂环氧基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 16R 17的取代基所取代； R 7e and R 7f are each independently selected from hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocycle and 3-6 membered heterooxyl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkane Oxygen, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 heterocyclic, 3-6 heterocyclic, C 6-8 aryl, C 6-8 aryloxy Substituents of base, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 ;
    R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
    R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基 R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl
    其中，R 16和R 17如权利要求1中所定义。 Wherein, R 16 and R 17 are as defined in claim 1.
  14. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐， 其特征在于，式(I)化合物为如下式(Ⅴ4)化合物：The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that, the compound of formula (I) is the compound of formula (V4):
    Figure PCTCN2022130789-appb-100015
    Figure PCTCN2022130789-appb-100015
    其中，R 5a选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； Wherein, R 5a is selected from hydrogen, deuterium, methoxyl group, trifluoromethoxyl group, difluoromethoxyl group, trideuterium methoxy group and didereter methoxy group;
    R 5b选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
    R 7e和R 7f各自独立地选自羟基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、环丙基、环丁基、环丙氧基、环丁氧基、氧杂环丙基和氧杂环丁基，上述基团独立地任选进一步被一个或多个选自氘、氟、氯、羟基、＝O、氰基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、环丙基、环丁基、环丙氧基、环丁氧基、氧杂环丙基、氧杂环丁基、氨基和二甲基氨基的取代基所取代。 R 7e and R 7f are each independently selected from hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopropoxy , cyclobutoxy, oxirane and oxetanyl, the above groups are independently optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, =O, cyano, methyl, Ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopropoxy, cyclobutoxy, oxirane, oxetane Butyl, amino and dimethylamino substituents are substituted.
  15. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅳ5)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (IV5):
    Figure PCTCN2022130789-appb-100016
    Figure PCTCN2022130789-appb-100016
    其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
    R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三 氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基 R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio
    R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 6a选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6b选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6c选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    条件是，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子； The condition is that R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom;
    R 7g为C 1-4烷基；R 7h为C 1-4烷基； R 7g is C 1-4 alkyl; R 7h is C 1-4 alkyl;
    R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
    R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基。 R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl.
  16. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅴ5)化合物：The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, is characterized in that, the compound of formula (I) is the compound of formula (V5):
    Figure PCTCN2022130789-appb-100017
    Figure PCTCN2022130789-appb-100017
    其中，R 5a选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； Wherein, R 5a is selected from hydrogen, deuterium, methoxyl group, trifluoromethoxyl group, difluoromethoxyl group, trideuterium methoxy group and didereter methoxy group;
    R 5b选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
    R 7g为氢、甲基或乙基；R 7h为氢、甲基、乙基、丙基、丁基、异丙基、叔丁基或异丁基； R 7g is hydrogen, methyl or ethyl; R 7h is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl or isobutyl;
    条件是，R 5a、R 5b、R 6a、R 6b、R 6c和R 6d中至少包含一个氘原子。 Provided that R 5a , R 5b , R 6a , R 6b , R 6c and R 6d contain at least one deuterium atom.
  17. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅳ6)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (IV6):
    Figure PCTCN2022130789-appb-100018
    Figure PCTCN2022130789-appb-100018
    其中，R 2a选自氢、氘、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R 2a is selected from hydrogen, deuterium, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , Trideuteromethyl, Dideuteromethyl, One Deuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropyl Oxygen, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, diduteriomethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methyl Thio and ethylthio;
    R 3选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 5a选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 5b选自氢、氘、氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基和三氘乙氧基； R 5b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, di Deuteromethoxy, trifluoroethoxy and trideuteroethoxy;
    R 6a选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6b选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 6c选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl Dideuteromethyl, Dideuteromethyl, Cyclopropyl, Cyclobutyl, Oxetanyl, Azetidinyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Tri Fluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, trifluoroethoxy, trideuteroethoxy, cyclopropoxy, cyclobutoxy, methylthio and ethyl Thio group;
    R 7k选自氢、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、6-8元杂芳基和-NR 16R 17，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、＝S、-SF 5、-S(O)(＝N-R 10)R 11、-N＝S(O)R 11R 12、-N＝SR 11R 12、-O-S(O) 2R 13、-S(O) rR 13、-O-R 14、-C(O)OR 14、-C(O)SR 14、-S-C(O)R 15、-C(O)R 15、-O-C(O)R 15、-P(O)(R 15) 2、-NR 16R 17、-C(＝NR 16)R 15、-N(R 16)-C(＝NR 17)R 15、-C(O)NR 16R 17和-N(R 16)-C(O)R 15的取代基所取代； R 7k is selected from hydrogen, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 6-8 membered heteroaryl and -NR 16 R 17 , the above groups are independently any selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -S (O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 , -N=SR 11 R 12 , -OS(O) 2 R 13 , -S(O) r R 13 , - OR 14 , -C(O)OR 14 , -C(O)SR 14 , -SC(O)R 15 , -C(O)R 15 , -OC(O)R 15 , -P(O)(R 15 ) 2 , -NR 16 R 17 , -C(=NR 16 )R 15 , -N(R 16 )-C(=NR 17 )R 15 , -C(O)NR 16 R 17 and -N(R 16 )-C (O) R 15 substituents are substituted;
    R 8a和R 8b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、 异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基，或者，R 8a和R 8b与其直接相连的碳原子一起形成一个C 3-6环烷基和3-6元杂环基，所述C 3-6环烷基和3-6元杂环基独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、＝O、＝S、环丙基、环丁基、氧杂环丁基和氮杂环丁基的取代基所取代； R 8a and R 8b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl , trideuteromethyl, dideuteriomethyl, monodeuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R 8a and R 8b together with the carbon atom directly attached to it Form a C 3-6 cycloalkyl and 3-6 membered heterocyclic group, said C 3-6 cycloalkyl and 3-6 membered heterocyclic group are independently optionally further selected from one or more deuterium, fluorine , Chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trideuteromethyl, dideuteriomethyl, one deuteromethyl , =O, =S, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl substituents;
    R 9a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基和氮杂环丁基； R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trideuteromethyl, Dideuteromethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;
    其中，R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17和r如权利要求1中所定义。 Wherein, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined in claim 1.
  18. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅴ6)化合物：The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, is characterized in that, the compound of formula (I) is the compound of formula (V6):
    Figure PCTCN2022130789-appb-100019
    Figure PCTCN2022130789-appb-100019
    其中，R 4选自氢、氘、氟、氯、溴、氰基、羟基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、三氘甲基、二氘甲基、一氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基、三氟乙氧基、三氘乙氧基、环丙氧基、环丁氧基、甲硫基和乙硫基； Wherein, R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethyl, Deuteromethyl, dideuteriomethyl, monodeuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy , Trifluoromethoxy, Difluoromethoxy, Trideuteromethoxy, Dideuteromethoxy, Trifluoroethoxy, Trideuteroethoxy, Cyclopropoxy, Cyclobutoxy, Methylthio and ethylthio;
    R 5a选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideudemethoxy;
    R 5b选自氢、氘、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基和二氘甲氧基； R is selected from the group consisting of hydrogen, deuterium, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideteriomethoxy;
    R 7k选自氢、环丙基、环丁基、氧杂环丙基、氧杂环丁基和苯基，上述基团独立地任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、丙基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基、三氘甲基、＝O和＝S的取代基所取代。 R 7k is selected from hydrogen, cyclopropyl, cyclobutyl, oxirane propyl, oxetanyl and phenyl, and the above-mentioned groups are independently optionally further selected from deuterium, fluorine, chlorine, Substituents of cyano, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteromethyl, dideuteriomethyl, trideuteromethyl, =O and =S replaced.
  19. 根据权利要求1-18中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：According to the compound of formula (I) described in any one of claims 1-18, its stereoisomer or pharmaceutically acceptable salt thereof, it is characterized in that, be selected from the following compounds:
    Figure PCTCN2022130789-appb-100020
    Figure PCTCN2022130789-appb-100020
    Figure PCTCN2022130789-appb-100021
    Figure PCTCN2022130789-appb-100021
    Figure PCTCN2022130789-appb-100022
    Figure PCTCN2022130789-appb-100022
    Figure PCTCN2022130789-appb-100023
    Figure PCTCN2022130789-appb-100023
    Figure PCTCN2022130789-appb-100024
    Figure PCTCN2022130789-appb-100024
  20. 一种药物组合物，其包含根据权利要求1-19中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1-19, its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  21. 根据权利要求1-19中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防与KRas G12D相关的癌症或肿瘤的药物中的用途。According to the compound of formula (I) described in any one of claims 1-19, its stereoisomer or its pharmaceutically acceptable salt in the medicine of preparation treatment and/or prevention and KRas G12D relevant cancer or tumor use.
  22. 根据权利要求1-19中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗与KRas G12D相关的肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤、畸胎瘤；支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、肺泡(细支气管癌)癌、支气管腺瘤、淋巴瘤、软骨瘤样错构瘤、间皮瘤；食管癌(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(淋巴瘤、平滑肌肉瘤)、胰腺癌(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、血管活性肠肽瘤)、小肠癌(腺癌、淋巴瘤、类癌瘤、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠癌(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤)；肾脏癌(腺癌、肾母细胞瘤(肾胚细胞瘤)、淋巴瘤、白血病)、膀胱和尿道癌(鳞状细胞癌、移行细胞癌、腺癌)、前列腺癌(腺癌、肉瘤)、睾丸癌(精原细胞瘤、畸胎瘤、胚胎性癌、畸胎上皮癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤)；肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤；胆囊癌、壶腹癌、胆管癌；骨原性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨外生骨)、良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤和 巨细胞瘤；颅骨癌(骨瘤、血管瘤、肉芽肿、黄色瘤、畸形性骨炎)、脑膜癌(脑膜瘤、脑膜肉瘤、神经胶瘤病)、脑癌(星形细胞瘤、神经管胚细胞瘤、神经胶质瘤、室管膜瘤、胚细胞瘤(松果体瘤)、多形神经胶母细胞瘤、寡树突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤)；子宫癌(子宫内膜癌(浆液性囊腺癌、粘液性囊腺癌、未分类的癌瘤)、粒层泡膜细胞瘤、塞特利氏-雷迪格细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴癌(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道癌(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎性横纹肌肉瘤))、输卵管(癌瘤)；血液癌(骨髓性白血病(急性及慢性)、急性淋巴母细胞白血病、慢性淋巴细胞性白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤)；恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤、牛皮癣及肾上腺瘤或神经母细胞瘤的药物中的用途。According to the compound of formula (I) described in any one of claims 1-19, its stereoisomer or its pharmaceutically acceptable salt in preparation prevention and/or the sarcoma (angiosarcoma, fibrosarcoma) relevant with KRas G12D , rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroid, lipoma, teratoma; bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole carcinoma ) carcinoma, bronchial adenoma, lymphoma, chondromatoid hamartoma, mesothelioma; esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, smooth Myoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); kidney cancer (adenocarcinoma, nephroblastoma) tumor (nephroblastoma), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma fetal tumor, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, mesenchymal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer (hepatocellular carcinoma), cholangiocarcinoma, liver Blastoma, angiosarcoma, hepatocellular adenoma, hemangioma; gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, Malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exogenous bone), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid bone tumor and giant cell tumor; skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meningeal cancer (meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma, Medulloblastoma, glioma, ependymoma, blastoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma , congenital neoplasms, spinal neurofibroma, meningioma, glioma, sarcoma); uterine cancer (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa Theca cell tumor, Setley-Rediger cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma); blood cancers (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia , myeloproliferative disorder, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi Use in medicine for sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis and adrenal adenoma or neuroblastoma.
  23. 根据权利要求1-19中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防与KRas G12D相关的癌症或肿瘤的用途。According to the compound of formula (I) described in any one of claims 1-19, its stereoisomer or pharmaceutically acceptable salt thereof, it is used for treating and/or preventing the purposes of the cancer or tumor relevant with KRas G12D .
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