WO2023098426A1 - Dérivés de 7-(naphtalén-1-yl)pyrido[4,3-d]pyrimidine, leur procédé de préparation et leur utilisation - Google Patents

Dérivés de 7-(naphtalén-1-yl)pyrido[4,3-d]pyrimidine, leur procédé de préparation et leur utilisation 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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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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    • 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.

Abstract

L'invention concerne des dérivés de 7-(naphtalén-1-yl)pyrido[4,3-d]pyrimidine, leur procédé de préparation et leur utilisation. En particulier, l'invention concerne des inhibiteurs de la mutation KRas G12D ayant la structure de formule (I), un procédé de préparation de ceux-ci, une composition pharmaceutique les contenant, une utilisation associée en tant qu'inhibiteur de la KRas G12D, et son utilisation dans le traitement et/ou la prévention du cancer ou de tumeurs associées à la mutation KRas G12D. Chaque substituant représenté par la formule (I) est tel que défini que dans la description.
PCT/CN2022/130789 2021-12-02 2022-11-09 Dérivés de 7-(naphtalén-1-yl)pyrido[4,3-d]pyrimidine, leur procédé de préparation et leur utilisation WO2023098426A1 (fr)

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WO2023220421A1 (fr) * 2022-05-13 2023-11-16 Ranok Therapeutics (Hangzhou) Co. Ltd. Inhibiteurs de kras (g12d)
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024041589A1 (fr) * 2022-08-25 2024-02-29 上海艾力斯医药科技股份有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et utilisation associée
WO2024054926A1 (fr) * 2022-09-07 2024-03-14 Bristol-Myers Squibb Company Inhibiteurs de kras g12d

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US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2023220421A1 (fr) * 2022-05-13 2023-11-16 Ranok Therapeutics (Hangzhou) Co. Ltd. Inhibiteurs de kras (g12d)
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WO2024054926A1 (fr) * 2022-09-07 2024-03-14 Bristol-Myers Squibb Company Inhibiteurs de kras g12d

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