WO2024021957A1 - Prmt5 inhibitor, preparation method therefor, and pharmaceutical use thereof - Google Patents

Prmt5 inhibitor, preparation method therefor, and pharmaceutical use thereof Download PDF

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WO2024021957A1
WO2024021957A1 PCT/CN2023/102508 CN2023102508W WO2024021957A1 WO 2024021957 A1 WO2024021957 A1 WO 2024021957A1 CN 2023102508 W CN2023102508 W CN 2023102508W WO 2024021957 A1 WO2024021957 A1 WO 2024021957A1
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alkyl
substituted
deuterium
halogen
group
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PCT/CN2023/102508
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French (fr)
Chinese (zh)
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邓海兵
刘建
杨飞
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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Publication of WO2024021957A1 publication Critical patent/WO2024021957A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a PRMT5 inhibitor, its preparation method and pharmaceutical application.
  • Epigenetic gene regulation is an important biological regulatory mechanism for protein synthesis and cell differentiation, and plays an important role in many human diseases.
  • Epigenetic regulation involves the modulation of inheritable genetic material without changing its nucleic acid sequence.
  • epigenetic regulation is controlled by selective and reversible modifications (such as methylation) of DNA and proteins (such as histones) to control the transition between transcriptionally active and inactive states in chromatin conformation. Modification of these covalent bonds can be controlled by enzymes such as methyltransferases (such as PRMT5), many of which are associated with specific genetic changes in many human disease-causing genes.
  • PRMT5 plays an important role in many diseases such as tumors, metabolic diseases and hematological diseases.
  • Homozygous deletions of tumor suppressor genes are tumor drivers and often result in deletions of passenger genes near the suppressor genes. Loss of these passenger genes creates tumor cell-specific vulnerabilities that can be targeted with targeted therapies.
  • Homozygous deletions of chromosome 9p21 which contains the well-known tumor suppressor gene CDKN2A, occur in 15% of tumors and often contain deletions of the passenger gene MTAP.
  • MTAP is a key enzyme in the methionine and adenine recycling pathway. The absence of MTAP leads to the accumulation of its substrate, MTA. MTA is structurally similar to S-adenosylmethionine (SAM), which is a methyl substrate donor for type II methyltransferase PRMT5.
  • SAM S-adenosylmethionine
  • PRMT5 is a very important gene for cells. Studies on conditional knockout of PRMT5 or siRNA knockout all suggest that inhibiting PRMT5 in normal tissues will have significant side effects. (For example, blood cell reduction, infertility, skeletal muscle loss, cardiac hypertrophy, etc.). Therefore, new strategies are needed to apply and explore this metabolic susceptibility, selectively targeting PRMT5 in MTAP-deficient tumors and avoiding the effects of PRMT5 in normal tissues (MTAP wild-type).
  • Small molecule inhibitors targeting PRMT5 that work together with MTA can selectively target only PRMT5 in the MTA-bound state, and this kind of PRMT5 is only enriched in tumor cells with MTAP deficiency, so in normal cells with intact MTAP When MTA levels are very low in cells, PRMT5 will not be targeted, providing a better therapeutic window.
  • the object of the present invention is to provide a PRMT5 inhibitor, its preparation method and pharmaceutical application.
  • the series of compounds of the present invention have a strong inhibitory effect on PRMT5 and can be widely used in the preparation of drugs for treating and/or preventing PRMT5-mediated diseases, thereby promising to develop a new generation of PRMT5 inhibitors.
  • a first aspect of the invention provides a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • X 1 is CR 6 or N
  • X 2 is CR 7 or N
  • X 3 is CR 8 or N
  • Ring A is C 4-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • Ring B is selected from a 4-10-membered nitrogen-containing heterocyclyl group or a 5-10-membered nitrogen-containing heteroaryl group, and the nitrogen atom is connected to a carbonyl group, wherein,
  • ring B is selected from a 4-membered nitrogen-containing heterocyclic group, an 8-10-membered nitrogen-containing heterocyclic group or an 8-10-membered nitrogen-containing heteroaryl group,
  • Ring C is C 3-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, and the C 3-12 cycloalkyl or 4-12 membered heterocycle
  • the base is optionally condensed on a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 6-10 aryl group or 5-10 membered heteroaryl group is optionally condensed on a C 3-12 cycloalkyl group or 4-12 membered heterocyclyl;
  • Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS( O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alky
  • ring B is selected from a 5-7 membered nitrogen-containing heterocyclyl group or a 5-7 membered nitrogen-containing heteroaryl group
  • Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O) R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alky
  • R 1 ' is selected from hydrogen, deuterium, 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, -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)R 11 and -C(O)NR 12 R 13 , the above-mentioned groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azide, 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 hetero Aryl,
  • Each R 1 ′′ is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS (O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , - C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl Base-OC(O)R 11 , -C 0-8 al
  • Y 6 , Y 7 , Y 8 and Y 9 are each independently CR 1 or N, and at least one is selected from CR 1 , wherein at least one R 1 is -C 0-8 alkyl -NR 14 R 15 or - OC 1-4 alkyl-NR 14 R 15 , each other R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-
  • Each R 2 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 -8alkyl -SF 5 , -C 0-8alkyl -OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0- 8alky
  • Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS( O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alky
  • R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl Base -OR 10 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl -C(O)SR 10 , -C 0-8 alkyl -SC(O)R 11 ,
  • R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl base, -C 0-8 alkyl -SF 5 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl -C(O)SR 10 , -C 0-8 alkyl -C(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 and -C 0-8 alkyl-C(O)NR 12 R 13 , or, R 14 and R 15
  • the nitrogen atom directly connected to it together forms a 4-10-membered heterocyclyl group or a 5-10-membered heteroaryl group, and the above-mentioned groups are independently optionally further optionally substituted by one or more members selected from the group consisting of deuterium,
  • Each r is independently 0, 1, or 2;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • p is selected from 0, 1, 2, 3, 4 or 5.
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, hydroxyl, 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 hetero ring base.
  • R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, and 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, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-
  • R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyanide base, 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 group, 5-8 membered heteroaryl group, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R
  • R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, 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- C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-P(O)( R 11 ) 2 and -C 0-4 alkyl -C(O)NR 12 R 13 , or R 14 and R 15 together with the nitrogen atom directly connected to form a 4-6 membered heterocyclic group or 5-8 membered Heteroaryl, the above groups are independently optionally further substituted by one or more selected from deuterium,
  • R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-4 alkyl , Halo-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, -SF 5 , -C(O)OR 10 , -C(O)SR 10 , -C(O)R 11 , -P(O)(R 11 ) 2 and -C(O)NR 12 R 13 ; where , R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • each R 5 is independently selected from hydrogen, 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 , -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl Base -OR 10 , -C 0-4 alkyl -C(O)OR 10 , -C 0-4 alkyl -C(O)SR 10 , -C 0-4 alkyl -SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -
  • each R 5 is independently selected from hydrogen, 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 Base, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted
  • each R 2 is 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 yuan Heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0- 4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O)SR 10 , -C 0-4 alkyl-SC(
  • ring B is selected from a 4-membered nitrogen-containing heterocyclic group
  • Ring C is C 3-6 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl, and the C 3-6 cycloalkyl or 4-8 membered heterocycle
  • the base is optionally fused to C 6-8 aryl or 5-8 membered heteroaryl
  • the C 6-8 aryl or 5-8 membered heteroaryl is optionally fused to C 3-6 cycloalkyl or 4-8 membered heterocyclyl;
  • Each R 1 is independently selected from hydrogen, 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -
  • R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • ring B is selected from an 8-10 membered nitrogen-containing heterocyclic group
  • Ring C is C 3-6 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl, and the C 3-6 cycloalkyl or 4-8 membered heterocycle
  • the base is optionally fused to C 6-8 aryl or 5-8 membered heteroaryl
  • the C 6-8 aryl or 5-8 membered heteroaryl is optionally fused to C 3-6 cycloalkyl or 4-8 membered heterocyclyl;
  • Each R 1 is independently selected from hydrogen, 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -
  • Ring B is selected from 5-7 membered nitrogen-containing heterocyclic groups, and ring C is formed together with -(R 1 ) m
  • Y 1 and Y 2 are each independently CR 1 or N
  • Y 3 is O
  • Y 4 and Y 5 are each independently CR 1 " or N;
  • Each R 1 is independently selected from hydrogen, 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -
  • Each R 1 ′′ is independently selected from hydrogen, 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, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl- C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O
  • R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • Ring B is selected from 5-7 membered nitrogen-containing heterocyclic groups, and ring C is formed together with -(R 1 ) m
  • Y 6 , Y 7 , Y 8 and Y 9 are each independently CR 1 or N, and at least one is CR 1 , wherein at least one R 1 is -C 0-4 alkyl -NR 14 R 15 or -OC 1-4 alkyl-NR 14 R 15 , each other R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 chain 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-OS(O) 2 R 9
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and r are as described for the compound of formula (I).
  • X 1 is CR 6 or N
  • X 2 is CR 7 or N
  • Each R 6 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
  • Each R 7 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
  • Each R 8 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
  • R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • the compound of formula (I) has the following compound structure of formula (II):
  • Y 1 and Y 2 are each independently CR 1 or N, and Y 3 is O, S or NR 1 ';
  • Ring A is C 4-8 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl;
  • Ring B together with -(R 2 ) p forms the following structure:
  • Each R 1 is independently selected from hydrogen, 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, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C (O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , - NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano group , C 1-4 al
  • Each R 2 is 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 group, C 3-6 cycloalkyl group, 3-6 membered heterocyclyl group, C 6-8 aryl group, 5-8 membered heteroaryl group, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC (O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
  • R 2 ' is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl base and 3-6 membered heterocyclyl;
  • Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl 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, - SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , - C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R
  • R 6 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 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, deuterium-substituted C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3 -6-membered heterocyclyl, 3-6-membered heterocyclicoxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, hydroxyl and -NR 12 R 13 ;
  • R 9 , R 10 , R 11 , R 12 , R 13 , n, p and r are as described in the compound of formula (I).
  • X 1 is CR 6 or N
  • X 2 is CH or N
  • Each R 6 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
  • R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • the compound of formula (I) has the following compound structure of formula (III 1 ) or formula (III 2 ):
  • Ring A together with its directly connected parts forms the following structure:
  • R 1 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethyl amino, dimethylamino-substituted methyl, dimethylamino-substituted ethyl, dimethylaminoethoxy, cyclopropyl, cyclobutyl, piperidyl, piperazinyl, morpholinyl, methyl base-substituted piperidinyl, ethyl-substituted piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazine and tetrahydropyranyl;
  • R 1 ' is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, dimethylamino-substituted methyl, dimethylamino-substituted ethyl, cyclopropyl , cyclobutyl, piperidinyl, methyl-substituted piperidinyl, ethyl-substituted Piperidinyl, cyclopropyl-substituted piperidinyl and tetrahydropyranyl;
  • Each R 2 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF 5 and hydroxyl;
  • Each R 5b is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF 5 and hydroxyl;
  • Each R is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF and hydroxyl;
  • p is selected from 0, 1 or 2.
  • Ring A together with its directly connected parts forms the following structure:
  • R 1 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methylamino, Dimethylamino-substituted ethyl, dimethylamino-substituted ethoxy, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted piperidinyl , cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazine and tetrahydropyranyl;
  • Each R 2 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5b is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 6 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, and cyclopropyl.
  • the compound of formula (I) has the following formula (IV 1 ), formula (IV 2 ), formula ( IV 3 ) or compound structure of formula (IV 4 ):
  • Each R 1 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methyl amino, dimethylamino-substituted ethyl, dimethylamino-substituted ethoxy, cyclopropyl, piperidyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted Piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazinyl and tetrahydropyranyl;
  • Each R 2a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 2b is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5b is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 6 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, and cyclopropyl.
  • the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt includes but is not limited to the following compounds:
  • a second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, which includes the following steps: reacting a compound of formula (Ia) with a compound of formula (Ib) to generate a compound of formula ( I) compound, the reaction formula is as follows:
  • X is hydroxyl or halogen
  • ring A, ring B, ring C, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , ) compound is defined.
  • the third aspect of the present invention provides a pharmaceutical composition, including a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides a use of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt in the preparation of drugs for treating MATP-related tumors.
  • the tumor is selected from the group consisting of cell tumor, lymphoma, leukemia, osteoma, malignant teratoma, intraepithelial carcinoma, adenoma, fibroma, melanoma, fallopian tube cancer, bladder cancer, and teratoma , embryonal carcinoma, choriocarcinoma, lipoma, liver cancer, cholangiocarcinoma, lung cancer, gastric cancer, hemangioma, gallbladder cancer, ampullary cancer, malignant melanoma, nevus, dysplastic nevus, myeloproliferative diseases, Hodgkin's disease, Chordoma, myxoma, rhabdomyomas, leiomyoma, hamartoma, mesothelioma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, viperoma, granuloma, xanthoma, de
  • the cell tumor is selected from the group consisting of granulosa-theca cell tumor, Sertoli cell tumor, germ cell tumor, nephroblastoma, seminoma, hepatoblastoma, malignant fibrous histiocytoma, chondroblastoma, blastoma, giant cell tumor, astrocytoma, medulloblastoma, glioblastoma multiforme, oligodendrogliomas, retinoblastoma, squamous cell carcinoma, clear cell carcinoma, transitional cell carcinoma , stromal cell carcinoma and basal cell carcinoma;
  • the lymphoma is selected from malignant lymphoma and non-Hodgkin lymphoma;
  • the leukemia is selected from the group consisting of acute and chronic myeloid leukemia, acute lymphoblastic leukemia and chronic lymphocytic leukemia;
  • the osteoma is selected from the group consisting of osteochondroma, benign enchondroma, osteoid osteoma, chondromatoid hamartoma, multiple myeloma and cranioma;
  • the adenoma is selected from the group consisting of fibroadenoma, adenomatoid tumor, hepatocellular adenoma, bronchial adenoma, tubular adenoma, villous adenoma, breast cancer, pancreatic cancer, endometrial adenocarcinoma, prostate cancer, ductal adenoma carcinoma and colorectal adenocarcinoma;
  • the fibroma is selected from the group consisting of fibroma, chondromyxofibroma, neurofibroma and spinal neurofibroma;
  • the myeloproliferative disease is selected from the group consisting of multiple myeloma and myelodysplastic syndrome;
  • the lung cancer is selected from bronchial lung cancer and alveolar cancer;
  • the sarcoma is selected from the group consisting of fibrosarcoma, botryoid sarcoma, angiosarcoma, Kaposi's sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma and meningiosarcoma.
  • the present invention also relates to the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, which is used as a PRMT5 inhibitor drug.
  • the present invention also relates to the use of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt in the preparation of medicaments for the treatment and/or prevention of PRMT5-mediated diseases.
  • the present invention also relates to a method for treating and/or preventing PRMT5-mediated diseases, which comprises administering to a patient in need a therapeutically effective amount of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof .
  • a PRMT5 inhibitor with the following formula (I) structure.
  • the series of compounds of the present invention can be widely used in the preparation of drugs for the treatment and/or prevention of PRMT5-mediated diseases. , is expected to be developed into a new generation of PRMT5 inhibitors. On this basis, the present invention was completed.
  • Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group, preferably including a linear alkyl group and a branched alkyl group of 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-methyl
  • C 1-10 alkyl refers to straight-chain alkyl groups and branched-chain alkyl groups having 1 to 10 carbon atoms
  • C 1-4 alkyl refers to straight-chain alkyl groups including 1 to 4 carbon atoms. Containing branched chain alkyl groups, "C 0-8 alkyl” refers to straight-chain alkyl groups containing 0 to 8 carbon atoms and branched-chain alkyl groups, and “C 0-4 alkyl groups” refers to containing 0 to 4 carbon atoms straight-chain alkyl groups and branched-chain alkyl groups.
  • the alkyl group may be optionally substituted or unsubstituted.
  • Cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ electron system.
  • the cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups with to 6 carbon atoms, for example, "C 3-12 cycloalkyl” refers to cycloalkyl groups including 3 to 12 carbon atoms, and "C 4-8 cycloalkyl” refers to cycloalkyl groups including 4 to 8 carbon atoms.
  • C 3-8 cycloalkyl refers to a cycloalkyl group including 3 to 8 carbon atoms
  • C 3-6 cycloalkyl refers to a cycloalkyl group including 3 to 6 carbon atoms, in:
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cycloctyl et al.
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between the single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no single ring has A fully conjugated ⁇ electron system. According to the number of shared spiro atoms between the rings, spirocycloalkyl groups are divided into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups. Spirocycloalkyl groups include but are not limited to:
  • Condensed cycloalkyl refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings 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 constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups.
  • the fused ring alkyl groups include but are not limited to:
  • Bridged cycloalkyl refers to an all-carbon polycyclic group in which any two rings share two non-directly connected carbon atoms. 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 constituent 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 connected to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.
  • Cycloalkyl or “carbocycle” may be optionally substituted or unsubstituted.
  • Heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may 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 heteroatoms of S(O) r (where r is an integer 0, 1, 2), excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • Preferred heterocyclyl groups include 3 to 12 or 3 to 8 or 3 to 6 ring atoms.
  • 3-6 membered heterocyclyl refers to heterocyclyl groups containing 3 to 6 ring atoms
  • 3- "8-membered heterocyclyl” refers to a heterocyclic group containing 3 to 8 ring atoms
  • 4-8-membered heterocyclyl refers to a heterocyclic group containing 4 to 8 ring atoms
  • “4-10-membered heterocyclyl” refers to a heterocyclic group containing 4 to 10 ring atoms
  • 5-8-membered heterocyclyl refers to a heterocyclic group containing 5 to 8 ring atoms
  • 3-12-membered heterocyclyl refers to a heterocyclic group containing 3 to 12 ring atoms.
  • Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
  • Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between single rings, 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) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but no ring has a fully conjugated pi electron system.
  • spiroheterocyclyl groups are divided into single spiroheterocyclyl groups, double spiroheterocyclyl groups or polyspiroheterocyclyl groups.
  • Spiroheterocyclyl groups include, but are not limited to:
  • Condensed heterocyclyl refers to a polycyclic heterocyclyl in which each ring in the system shares an adjacent pair of atoms with every other ring in the system group, one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a fully conjugated ⁇ electron system, where One or more (preferably 1, 2, 3 or 4) ring atoms are selected from heteroatoms of N, O, N ⁇ O or S(O) r (where r is an integer 0, 1, 2), and the remaining ring atoms for carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups.
  • the fused heterocyclic groups include but are not limited to:
  • Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings Having 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) heteroatoms, 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 heterocyclyl groups. Bridged heterocyclyl groups include but are not limited to:
  • the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
  • Heterocyclyl or “heterocycle” may be optionally substituted or unsubstituted.
  • Aryl or "aromatic ring” refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a common Polycyclic (i.e., rings with adjacent pairs of carbon atoms) groups of the yoke ⁇ electron system, preferably all-carbon aryl groups containing 6-10 or 6-8 carbons, for example, "C 6-10 aromatic "Basic” refers to an all-carbon aryl group containing 6-10 carbons, including but not limited to phenyl and naphthyl, and "C 6-8 aryl” refers to an all-carbon aryl group containing 6-8 carbons.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring, including but not limited to:
  • Aryl or "aromatic ring” may be substituted or unsubstituted.
  • Heteroaryl or “heteroaryl ring” refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms, including N, O, N ⁇ O and S (O) Heteroatom of r (where r is an integer 0, 1, 2), preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered”"Heteroaryl” refers to a heteroaromatic system containing 5-8 ring atoms, and "5-10-membered heteroaryl” refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl and thienyl.
  • heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
  • Heteroaryl or “heteroaryl ring” may be optionally substituted or unsubstituted.
  • Alkenyl refers to 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 to 10 or 2 to 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.
  • Alkenyl may be substituted or unsubstituted.
  • Alkynyl refers to 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.
  • Alkynyl may be substituted or unsubstituted.
  • Alkoxy refers to -O-alkyl, where alkyl is as defined 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 and ethoxy. , propoxy, butoxy, etc.
  • Alkoxy may be optionally substituted or unsubstituted.
  • Cycloalkoxy or “cycloalkyloxy” refers to -O-cycloalkyl, where cycloalkyl is as defined above, for example, “C 3-12 cycloalkoxy” refers to a group containing 3-12 Carbon cycloalkyloxy, “C 3-6 cycloalkoxy” refers to cycloalkyloxy containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy , cyclohexyloxy, etc.
  • Heterocyclyloxy or “heterocyclyloxy” refers to -O-heterocyclyl, wherein heterocyclyl is as defined above, including but not limited to azetidinyloxy, oxetanyloxy base, azetanyloxy group, nitrogen, oxanyloxy group, etc.
  • C 1-10 alkanoyl refers to the monovalent atomic group remaining after removing the hydroxyl group from C 1-10 alkyl acid. It is also usually expressed as “C 0-9 alkyl-C(O)-", for example, “C 1 "Alkyl-C(O)-” refers to acetyl; “C 2alkyl -C(O)-” refers to propionyl; “C 3alkyl -C(O)-” refers to butyryl or isobutyl acyl group.
  • -C 0-8 alkyl-C(O)SR 10 means that the carbonyl group in -C(O)SR 10 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl group is as defined above.
  • Halo-substituted C 1-10 alkyl refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • Halo-substituted C 1-10 alkoxy group refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.
  • Deuterium-substituted C 1-10 alkyl refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally replaced by a deuterium atom. Including but not limited to monodeuterium methyl, dideuterium methyl, trideuterium methyl, etc.
  • Halogen refers to fluorine, chlorine, bromine or iodine
  • EA refers to ethanol
  • PE refers to petroleum ether
  • EtOAc refers to ethyl acetate
  • MeOH methyl alcohol
  • DCM dichloromethane
  • DMSO dimethyl sulfoxide
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes situations where the event or circumstance does or does not occur, that is, whether it is substituted or not. .
  • a heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present. This description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
  • Substituted means that one or more "hydrogen atoms" in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with the chemical valence bond theory, which the person skilled in the art can determine without undue effort (either experimentally or theoretically) what is possible or impossible replacement. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond, such as an alkene.
  • Steps whose English name is stereoisomers, refer to isomers produced by the different spatial arrangements of atoms in the molecule. They can be divided into two types: cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers caused by the rotation of single bonds are called conformational 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). Configuration isomers are divided into two categories.
  • the isomers caused by the inability of the double bond or the single bond of the ring-forming carbon atoms to rotate freely become geometric isomers (geometric isomers), also called cis-trans isomers (cis-trans isomers), which are divided into Z, E two configurations.
  • geometric isomers also called cis-trans isomers (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.
  • the stereoisomers with different optical properties caused by the lack of anti-axial symmetry in the molecules are called optical isomers ( optical isomer), divided into R and S configurations.
  • the "stereoisomer" mentioned in the present invention can be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers.
  • “Pharmaceutically acceptable salts” in the present invention refer to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts. These salts can be prepared by methods known in the art.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. drug The purpose of the composition is to facilitate administration to the organism and facilitate the absorption of the active ingredients to exert biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm) units. NMR was measured using a Bruker AVANCE-400/500 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was It is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS tetramethylsilane
  • LC-MS was measured using an Agilent 6120 mass spectrometer.
  • HPLC was measured using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm column).
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 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 embodiments of the present invention are known and can be purchased on the market, or can be synthesized using or according to methods known in the art.
  • 2-Amino-4-chlorobenzenethiol (3.00g, 18.8mmol), 1-methylpiperidine-4-carboxylic acid (2.69g, 18.8mmol), N,N-diisopropylethylamine (6.55 mL, 37.6 mmol) and 50% 1-propylphosphonic anhydride (12.0 g, 18.8 mmol) were dissolved in a 100 mL round-bottomed flask, replaced with nitrogen three times and stirred at 100°C overnight.
  • Intermediates 2 to 6 can be prepared by referring to all or part of the synthesis method of intermediate 1 and selecting corresponding raw materials:
  • Step 2 Synthesis of tert-butyl 4-methyl-2-oxopiperidine-1-carboxylate
  • Step 4 Synthesis of tert-butyl 4-methyl-6-(2-methylbenzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate
  • Intermediates 8 to 15 can be prepared by referring to all or part of the synthesis method of intermediate 7 and selecting corresponding raw materials:
  • Step 1 Synthesis of tert-butyl 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate
  • Step 2 Synthesis of tert-butyl 5-(2-methylbenzo[d]thiazol-5-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate
  • Intermediates 17 to 19 can be prepared by referring to all or part of the synthesis method of intermediate 16 and selecting corresponding raw materials:
  • Step 1 Synthesis of methyl 4-amino-5-bromo-2-fluorobenzoate
  • Step 2 Synthesis of methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
  • Step 3 Synthesis of methyl 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate
  • Intermediates 21-26 can be prepared by selecting corresponding raw materials by referring to all or part of the synthesis method of intermediate 20:
  • the reaction solution was diluted with water and extracted with tert-butyl methyl ether.
  • the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation.
  • the crude product was separated by normal phase column to obtain methyl 4-methyl-5-oxopentanoate (6.22g, yield 47.6%).
  • Step 3 Synthesis of: (S)-1-((R)-2-hydroxy-1-phenylethyl)-5-methylpiperidin-2-one
  • Step 6 Synthesis of tert-butyl (S)-5-methyl-2-oxopiperidine-1-carboxylate
  • Step 8 Synthesis of tert-butyl (S)-6-(benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate
  • Embodiments 2 to 87 can be prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of Embodiments 1, 1-1, and 1-2:
  • HCT 116MTAP knockout and MTAP wild-type cells in a 96-well flat-bottom plate, and culture them in McCoy's 5A containing 10% fetal calf serum + 1% penicillin-streptomycin at 37°C and 5% CO2 . overnight.
  • the cell plate treated with the compound was continuously cultured at 37°C and 5% CO 2 for 6 days.
  • the series of compounds of the present invention have a strong inhibitory effect on the proliferation of human colon cancer HCT116 MTAP knockout cells at the cellular level.
  • the purpose of this test is to study the pharmacokinetic behavior of some compounds of the present invention.
  • the administration methods are: single oral administration (PO) to ICR mice, and the dosage is 10 mg/kg.
  • the compounds used in this test are derived from the specific example compounds of the present invention.
  • ICR mouse male N 3 Original source: Shanghai Sipur-Bika Experimental Animal Co., Ltd.
  • the blood collection time points are the 1st, 4th and 24th hour.
  • the samples are stored in a refrigerator at minus 20 degrees Celsius.
  • Kp is calculated from the AUC or concentration in brain or plasma measured by the above method. Kp refers to the relationship between drug concentrations in the brain and blood and is used to evaluate the ability of a drug to penetrate the blood-brain barrier. Kp after administration is calculated using the following formula:

Abstract

The present invention relates to a PRMT5 inhibitor, a preparation method therefor, and a pharmaceutical use thereof. In particular, the present invention relates to a PRMT5 inhibitor having a compound structure shown in formula (I), a preparation method therefor, a pharmaceutical composition containing same, a use thereof as a PRMT5 inhibitor, and a use thereof in treatment and/or prevention of a PRMT5-mediated disease. The definition of each substituent in the compound of formula (I) is the same as that in the description.

Description

一种PRMT5抑制剂及其制备方法和药学上的应用A PRMT5 inhibitor and its preparation method and pharmaceutical application 技术领域Technical field
本发明属于药物合成领域，具体涉一种PRMT5抑制剂及其制备方法和药学上的应用。The invention belongs to the field of drug synthesis, and specifically relates to a PRMT5 inhibitor, its preparation method and pharmaceutical application.
背景技术Background technique
表观遗传学的基因调控是蛋白质合成和细胞分化的重要生物调节机制，在很多人类疾病中扮演了重要的作用。Epigenetic gene regulation is an important biological regulatory mechanism for protein synthesis and cell differentiation, and plays an important role in many human diseases.
表观遗传学的调控包括对可继承的遗传物质的调节而不改变其核酸序列。通常，表观遗传学的调控是由选择性的可逆转的对DNA和蛋白(比如组蛋白)的修饰(比如甲基化)来控制染色质构象上转录活性状态和非活性状态的转换。这些共价键的修饰可以被酶来控制，比如甲基转移酶(比如PRMT5)，很多甲基转移酶和很多人类致病基因的特定基因变化相关。PRMT5在很多疾病比如肿瘤，代谢疾病和血液病中有重要的作用。Epigenetic regulation involves the modulation of inheritable genetic material without changing its nucleic acid sequence. Generally, epigenetic regulation is controlled by selective and reversible modifications (such as methylation) of DNA and proteins (such as histones) to control the transition between transcriptionally active and inactive states in chromatin conformation. Modification of these covalent bonds can be controlled by enzymes such as methyltransferases (such as PRMT5), many of which are associated with specific genetic changes in many human disease-causing genes. PRMT5 plays an important role in many diseases such as tumors, metabolic diseases and hematological diseases.
抑癌基因的纯合缺失是肿瘤的驱动子，经常会带来在抑制基因附近的乘客基因的缺失。这些乘客基因的缺失会带来肿瘤细胞特异性的弱点，能被针对性的治疗靶向到。染色体9p21位点的纯合缺失，包含了著名的抑癌基因CDKN2A,在15％的肿瘤中会出现，并且经常会包含乘客基因MTAP的缺失。MTAP是甲硫氨酸和腺嘌呤再利用途径中的一个关键酶。MTAP的缺失会导致它的底物，MTA的累积。MTA和S-腺苷甲硫氨酸(SAM)在结构上具有相似性，而后者是二型甲基转移酶PRMT5的甲基底物供体。由于MTAP缺失带来的MTA水平的升高，会选择性的和SAM竞争PRMT5的结合，将甲基转移酶处于一个失能的状态，更容易被PRMT5的抑制所影响。很多不同的基因组范围的应用大范围肿瘤细胞系的shRNA筛选已经表明，MTAP缺失和细胞系对于PRMT5的依赖性具有相关性，也就将这种代谢上的易感性的影响力置于聚光灯下。然而，PRMT5作为一个对于细胞非常重要的基因，条件性敲除PRMT5，或者siRNA敲除的研究都提示，在正常组织中抑制PRMT5会有显著的副作用。(比如，血细胞减少，不育，骨骼肌减少，心肌肥大等等)。因此，需要有新的策略来应用和探索这种代谢易感性，选择性地在MTAP缺失肿瘤中靶向PRMT5而在正常的组织(MTAP野生型)中避免对于PRMT5的作用。Homozygous deletions of tumor suppressor genes are tumor drivers and often result in deletions of passenger genes near the suppressor genes. Loss of these passenger genes creates tumor cell-specific vulnerabilities that can be targeted with targeted therapies. Homozygous deletions of chromosome 9p21, which contains the well-known tumor suppressor gene CDKN2A, occur in 15% of tumors and often contain deletions of the passenger gene MTAP. MTAP is a key enzyme in the methionine and adenine recycling pathway. The absence of MTAP leads to the accumulation of its substrate, MTA. MTA is structurally similar to S-adenosylmethionine (SAM), which is a methyl substrate donor for type II methyltransferase PRMT5. Due to the increase in MTA levels caused by the loss of MTAP, it will selectively compete with SAM for the binding of PRMT5, leaving the methyltransferase in a disabled state and more easily affected by the inhibition of PRMT5. A number of different genome-wide shRNA screens across a wide range of tumor cell lines have shown a correlation between MTAP loss and cell line dependence on PRMT5, bringing the impact of this metabolic susceptibility into the spotlight. However, PRMT5 is a very important gene for cells. Studies on conditional knockout of PRMT5 or siRNA knockout all suggest that inhibiting PRMT5 in normal tissues will have significant side effects. (For example, blood cell reduction, infertility, skeletal muscle loss, cardiac hypertrophy, etc.). Therefore, new strategies are needed to apply and explore this metabolic susceptibility, selectively targeting PRMT5 in MTAP-deficient tumors and avoiding the effects of PRMT5 in normal tissues (MTAP wild-type).
靶向和MTA共同协作的PRMT5的小分子抑制剂可以只选择性的靶向和MTA结合状态下的PRMT5，而这种PRMT5只在MTAP缺失的肿瘤细胞中被富集，因此在MTAP完整的正常细胞中，MTA水平非常低的时候，PRMT5就不会被靶向到，这样就可以提供一种更好的治疗窗口。Small molecule inhibitors targeting PRMT5 that work together with MTA can selectively target only PRMT5 in the MTA-bound state, and this kind of PRMT5 is only enriched in tumor cells with MTAP deficiency, so in normal cells with intact MTAP When MTA levels are very low in cells, PRMT5 will not be targeted, providing a better therapeutic window.
发明内容Contents of the invention
本发明的目的在于提供一种PRMT5抑制剂及其制备方法和药学上的应用。本发明系列化合物对PRMT5具有很强的抑制作用，可广泛应用于制备治疗和/或预防PRMT5介导疾病的药物，从而有望开发出新一代PRMT5抑制剂。The object of the present invention is to provide a PRMT5 inhibitor, its preparation method and pharmaceutical application. The series of compounds of the present invention have a strong inhibitory effect on PRMT5 and can be widely used in the preparation of drugs for treating and/or preventing PRMT5-mediated diseases, thereby promising to develop a new generation of PRMT5 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：
A first aspect of the invention provides a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:
其中，X1为CR6或N；X2为CR7或N；X3为CR8或N；Among them, X 1 is CR 6 or N; X 2 is CR 7 or N; X 3 is CR 8 or N;
环A为C4-12环烷基、4-12元杂环基、C6-10芳基或5-10元杂芳基；Ring A is C 4-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
环B选自4-10元含氮杂环基或5-10元含氮杂芳基，所述氮原子与羰基连接，其中，Ring B is selected from a 4-10-membered nitrogen-containing heterocyclyl group or a 5-10-membered nitrogen-containing heteroaryl group, and the nitrogen atom is connected to a carbonyl group, wherein,
1)当环B选自4元含氮杂环基、8-10元含氮杂环基或8-10元含氮杂芳基时，1) When ring B is selected from a 4-membered nitrogen-containing heterocyclic group, an 8-10-membered nitrogen-containing heterocyclic group or an 8-10-membered nitrogen-containing heteroaryl group,
环C为C3-12环烷基、4-12元杂环基、C6-10芳基或5-10元杂芳基，所述C3-12环烷基或4-12元杂环基任选稠合于C6-10芳基或5-10元杂芳基，所述C6-10芳基或5-10元杂芳基任选稠合于C3-12环烷基或4-12元杂环基；Ring C is C 3-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, and the C 3-12 cycloalkyl or 4-12 membered heterocycle The base is optionally condensed on a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 6-10 aryl group or 5-10 membered heteroaryl group is optionally condensed on a C 3-12 cycloalkyl group or 4-12 membered heterocyclyl;
每个R1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS( O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O )NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro base, azido group, C 1-10 alkyl group, halogen substituted C 1-10 alkyl group, deuterium substituted C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, 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-OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8alkyl -C(O) OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl Substituted by the substituents of -C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 ;
2)当环B选自5-7元含氮杂环基或5-7元含氮杂芳基时，2) When ring B is selected from a 5-7 membered nitrogen-containing heterocyclyl group or a 5-7 membered nitrogen-containing heteroaryl group,
环C与-(R1)m一起形成：其中，Ring C together with -(R 1 ) m forms: in,
a)当环C与-(R1)m一起形成时，Y1、Y2各自独立地为CR1或N，Y3为O、S或NR1’，Y4、Y5各自独立地为CR1”或N；a) When ring C is formed together with -(R 1 ) m When , Y 1 and Y 2 are each independently CR 1 or N, Y 3 is O, S or NR 1 ', Y 4 and Y 5 are each independently CR 1 " or N;
每个R1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、 -C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O) R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , - C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , 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, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl Base -SF 5 , -C 0-8 alkyl -OS(O) 2 R 9 , -C 0-8 alkyl -S(O) r R 9 , -C 0-8 alkyl -OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl -C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR Substituted by the substituents of 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 ;
R1’选自氢、氘、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)R11和-C(O)NR12R13，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；R 1 ' is selected from hydrogen, deuterium, 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, -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)R 11 and -C(O)NR 12 R 13 , the above-mentioned groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azide, 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 hetero Aryl, =O, =S, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9. -C 0-8 alkyl-OR 10 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl -C(O)SR 10 , -C 0-8 alkyl -SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O) (R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )- Substituted by C(O)R 11 substituent;
每个R1”各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 ″ is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS (O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , - C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl Base-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C( O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , 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, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl -SF 5 , -C 0- 8alkyl -OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8alkyl -C(O )OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , - C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 Substituted by the substituents of alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 ;
b)当环C与-(R1)m一起形成时，Y6、Y7、Y8和Y9各自独立地为CR1或N，且至少一个选自CR1，其中至少一个R1为-C0-8烷基-NR14R15或-O-C1-4烷基-NR14R15，其它每个R1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基 -P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；b) When ring C is formed together with -(R 1 ) m When , Y 6 , Y 7 , Y 8 and Y 9 are each independently CR 1 or N, and at least one is selected from CR 1 , wherein at least one R 1 is -C 0-8 alkyl -NR 14 R 15 or - OC 1-4 alkyl-NR 14 R 15 , each other R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0- 8alkyl -C(O)OR 10 , -C 0-8alkyl -C(O)SR 10 , -C 0-8alkyl -SC(O)R 11 , -C 0-8alkyl -C (O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alkyl -P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N (R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, and halogen 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 -OS(O) 2 R 9 , -C 0- 8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8alkyl -C(O)OR 10 , -C 0-8alkyl -C(O) SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8alkyl -P(O)(R 11 ) 2 , -C 0-8alkyl -NR 12 R 13 , -C 0-8alkyl -C(O)NR 12 R 13 and -C 0- 8Alkyl -N(R 12 )-C(O)R 11 substituent substituted;
每个R2各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，或者，当p≥2时，其中两个R2与其直接相连的部分一起形成一个C(O)；Each R 2 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 -8alkyl -SF 5 , -C 0-8alkyl -OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0- 8alkyl -C(O)R 11 , -C 0-8alkyl -OC(O)R 11 , -C 0-8alkyl -P(O)(R 11 ) 2 , -C 0-8alkyl -NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , or when p≥ When 2, two of the R 2s together with their directly connected parts form a C(O);
R3和R4各自独立地选自氢、氘、羟基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基和3-12元杂环基，或者，R3和R4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，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、羟基、＝O、＝S、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基和-NR12R13的取代基所取代；R 3 and R 4 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl and 3-12 membered heterocyclyl, or R 3 and R 4 together with the nitrogen atom directly connected to form a 4-10-membered heterocyclyl or 5-10-membered heteroaryl, and the above groups are independently optionally further substituted by one or more Selected from deuterium, halogen, cyano, hydroxyl, =O, =S, 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 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclic oxy and -Substituted by the substituent of NR 12 R 13 ;
每个R5各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS( O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O )NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro base, azido group, C 1-10 alkyl group, halogen substituted C 1-10 alkyl group, deuterium substituted C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, 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-OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8alkyl -C(O) OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl Substituted by the substituents of -C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 ;
R6、R7和R8各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11； R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl Base -OR 10 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl -C(O)SR 10 , -C 0-8 alkyl -SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8alkyl -NR 12 R 13 , -C 0-8alkyl -C(O)NR 12 R 13 and -C 0-8alkyl -N(R 12 )-C(O)R 11 ;
每个R9独立地选自氢、氘、羟基、C1-10烷基、C2-10链烯基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基和-NR12R13，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、C1-10烷基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR12R13的取代基所取代；Each R 9 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 aromatic group, 5-10 membered heteroaryl and -NR 12 R 13 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 1- 10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclic oxy, C 6-10 aryl, C 6-10 Substituted by aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 12 R 13 substituents;
每个R10独立地选自氢、氘、C1-10烷基、C2-10链烯基、C3-12环烷基、3-12元杂环基、C6-10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、C1-10烷基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR12R13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 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, the above-mentioned groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclic oxy, C 6-10 aryl, C 6-10 aryloxy, 5 Substituted by -10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 12 R 13 substituents;
每个R11独立地选自氢、氘、羟基、C1-10烷基、C1-10烷氧基、C2-10链烯基、C2-10链炔基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR12R13，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、C1-10烷基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR12R13的取代基所取代；Each R 11 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, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclic oxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 12 R 13 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =O, cyano group, C 1-10 alkyl group , C 1-10 alkoxy group, C 3-12 cycloalkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 aryl group, Substituted by C 6-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 12 R 13 substituent;
每个R12和R13各自独立地选自氢、氘、羟基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10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C1-10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、C1-10烷基、C2-10链烯基、C2-10链炔基、卤取代C1-10烷基、氘取代C1-10烷基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、C1-10烷基单取代氨基、C1-10烷基双取代氨基和C1-10烷酰基的取代基所取代，或者，Each R 12 and R 13 are 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 group, dimethylaminosulfonyl group and C 1-10 alkanoyl group, 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 group, 3-12 membered heterocyclyl group, 3-12 membered heterocyclic group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered Substituted with substituents of heteroaryloxy, amino, C 1-10 alkyl monosubstituted amino, C 1-10 alkyl disubstituted amino and C 1-10 alkanoyl, or,
R12和R13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、C1-10烷基、C2-10链烯基、C2-10链炔基、卤取代C1-10烷基、氘取代C1-10烷基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、C1-10烷基单取代氨基、C1-10烷基双取代氨基和C1-10烷酰基的取代基所取代；R 12 and R 13 together with the nitrogen atom to which they are directly connected form a 4-10-membered heterocyclyl or 5-10-membered heteroaryl, and the 4-10-membered heterocyclyl or 5-10-membered heteroaryl is optionally further Substituted 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 C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclic oxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, C 1-10 alkyl monosubstituted amino, C 1-10 alkyl bis Substituted with substituted amino and C 1-10 alkanoyl substituents;
R14和R15各自独立地选自氢、氘、C1-10烷基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-C(O)R11、-C0-8烷基-P(O)(R11)2和-C0-8烷基-C(O)NR12R13，或者，R14和R15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，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8 烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl base, -C 0-8 alkyl -SF 5 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl -C(O)SR 10 , -C 0-8 alkyl -C(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 and -C 0-8 alkyl-C(O)NR 12 R 13 , or, R 14 and R 15 The nitrogen atom directly connected to it together forms a 4-10-membered heterocyclyl group or a 5-10-membered heteroaryl group, and the above-mentioned groups are independently optionally further optionally substituted by one or more members selected from the group consisting of deuterium, halogen, cyano, nitro, Azide group, C 1-10 alkyl group, halogen substituted C 1-10 alkyl group, deuterium substituted C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 3-12 ring Alkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl -SF 5 , -C 0-8 alkyl -OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0- 8 Alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C Substituted by (O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 substituents;
每个r独立地为0、1或2；Each r is independently 0, 1, or 2;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
n选自0、1、2、3、4或5；且n is selected from 0, 1, 2, 3, 4 or 5; and
p选自0、1、2、3、4或5。p is selected from 0, 1, 2, 3, 4 or 5.
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，R3和R4各自独立地选自氢、氘、羟基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基和3-6元杂环基，或者，R3和R4与其直接相连的氮原子一起形成一个4-6元杂环基或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、氰基、羟基、＝O、＝S、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基和-NR12R13的取代基所取代；其中，R12和R13如式(I)化合物所述。As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 3 and R 4 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkane base, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, or R 3 and R 4 together with the nitrogen atom directly connected to them form a 4-6-membered heterocyclyl or 5-8-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more deuterium, halogen, cyano, hydroxyl, =O, =S, 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 1-4 alkoxy, C 3-6 ring Alkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclic oxy and -NR 12 R 13 substituents substituted; wherein, R 12 and R 13 are as in the formula ( I) compound described.
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，R3和R4各自独立地选自氢、氘、羟基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基和3-6元杂环基。As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 3 and R 4 are each independently selected from hydrogen, deuterium, hydroxyl, 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 hetero ring 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，R6、R7和R8各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11；其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, and 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, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl- C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0-4 alkyl-N(R 12 )-C(O)R 11 ; wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for 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，R6、R7和R8各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11；As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyanide base, 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 group, 5-8 membered heteroaryl group, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。Among them, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for 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，R14和R15各自独立地选自氢、氘、C1-4烷基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-C(O)R11、-C0-4烷基-P(O)(R11)2和-C0-4烷基-C(O)NR12R13，或者，R14和R15与其直接相连的氮原子一起形成一个4-6元杂环基或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、氰基、硝基、叠氮基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、 -C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, 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- C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-P(O)( R 11 ) 2 and -C 0-4 alkyl -C(O)NR 12 R 13 , or R 14 and R 15 together with the nitrogen atom directly connected to form a 4-6 membered heterocyclic group or 5-8 membered Heteroaryl, the above groups 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 aryl, 5-8 Metaheteroaryl, =O, =S, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 Alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C (O)NR 12 R 13 and -C 0-4 alkyl-N(R 12 )-C(O)R 11 substituents; wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for compounds 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，R14和R15各自独立地选自氢、氘、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-C(O)OR10、-C(O)SR10、-C(O)R11、-P(O)(R11)2和-C(O)NR12R13；其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-4 alkyl , Halo-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, -SF 5 , -C(O)OR 10 , -C(O)SR 10 , -C(O)R 11 , -P(O)(R 11 ) 2 and -C(O)NR 12 R 13 ; where , R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for 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，每个R5各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 5 is independently selected from hydrogen, 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 , -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl Base -OR 10 , -C 0-4 alkyl -C(O)OR 10 , -C 0-4 alkyl -C(O)SR 10 , -C 0-4 alkyl -SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4 alkyl-P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0-4alkyl -N(R 12 )-C(O)R 11 , as mentioned above The group is independently optionally further substituted by one or more selected from the group consisting 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, - C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl- OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4alkyl -C(O)R 11 , -C 0-4alkyl -OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0- The substituents of 4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0-4alkyl -N(R 12 )-C(O)R 11 Substitution; wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for 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，每个R5各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 5 is independently selected from hydrogen, 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 Base, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted 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 hetero Aryl, =O, =S, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 substituents; wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for 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，每个R2各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，或者，当p≥2时，其中两个R2与其直接相连的部分一起形成一个C(O)；其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。 As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 2 is 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 yuan Heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0- 4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O) SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0- 4Alkyl -N(R 12 )-C(O)R 11 , or, when p ≥ 2, two R 2s together with their directly connected parts form a C(O); where, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for 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，环B选自4元含氮杂环基；As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, ring B is selected from a 4-membered nitrogen-containing heterocyclic group;
环C为C3-6环烷基、4-8元杂环基、C6-8芳基或5-8元杂芳基，所述C3-6环烷基或4-8元杂环基任选稠合于C6-8芳基或5-8元杂芳基，所述C6-8芳基或5-8元杂芳基任选稠合于C3-6环烷基或4-8元杂环基；Ring C is C 3-6 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl, and the C 3-6 cycloalkyl or 4-8 membered heterocycle The base is optionally fused to C 6-8 aryl or 5-8 membered heteroaryl, and the C 6-8 aryl or 5-8 membered heteroaryl is optionally fused to C 3-6 cycloalkyl or 4-8 membered heterocyclyl;
每个R1各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 is independently selected from hydrogen, 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and - C 0-4 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , -C 0 -4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O )SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , - C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0 -4Alkyl -N(R 12 )-C(O)R 11 substituent substituted;
其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。Among them, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for 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，环B选自8-10元含氮杂环基；As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, ring B is selected from an 8-10 membered nitrogen-containing heterocyclic group;
环C为C3-6环烷基、4-8元杂环基、C6-8芳基或5-8元杂芳基，所述C3-6环烷基或4-8元杂环基任选稠合于C6-8芳基或5-8元杂芳基，所述C6-8芳基或5-8元杂芳基任选稠合于C3-6环烷基或4-8元杂环基；Ring C is C 3-6 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl, and the C 3-6 cycloalkyl or 4-8 membered heterocycle The base is optionally fused to C 6-8 aryl or 5-8 membered heteroaryl, and the C 6-8 aryl or 5-8 membered heteroaryl is optionally fused to C 3-6 cycloalkyl or 4-8 membered heterocyclyl;
每个R1各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。Each R 1 is independently selected from hydrogen, 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and - C 0-4 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , -C 0 -4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O )SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , - C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0 -4alkyl -N(R 12 )-C(O)R 11 is substituted by the substituent; wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for 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， 环B选自5-7元含氮杂环基，环C与-(R1)m一起形成其中Y1、Y2各自独立地为CR1或N，Y3为O、S或NR1’，Y4、Y5各自独立地为CR1”或N；As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, Ring B is selected from 5-7 membered nitrogen-containing heterocyclic groups, and ring C is formed together with -(R 1 ) m Among them, Y 1 and Y 2 are each independently CR 1 or N, Y 3 is O, S or NR 1 ', Y 4 and Y 5 are each independently CR 1 " or N;
每个R1各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 is independently selected from hydrogen, 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and - C 0-4 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , -C 0 -4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O )SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , - C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0 -4Alkyl -N(R 12 )-C(O)R 11 substituent substituted;
R1’选自氢、氘、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)R11和-C(O)NR12R13，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；R 1 ' is 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, -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)R 11 and -C(O)NR 12 R 13 , the above-mentioned groups are independently optionally further substituted 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, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 Alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4 alkyl-P(O)(R 11 ) 2 , - of C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0-4alkyl -N(R 12 )-C(O)R 11 Substituted by substituents;
每个R1”各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 ″ is independently selected from hydrogen, 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, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl- C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0-4 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, Halo-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 -OS(O) 2 R 9 , -C 0-4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C( O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C Substituted with 0-4 alkyl-N(R 12 )-C(O)R 11 substituents;
其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。Among them, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for 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， 环B选自5-7元含氮杂环基，环C与-(R1)m一起形成其中Y6、Y7、Y8和Y9各自独立地为CR1或N，且至少一个为CR1，其中，至少一个R1为-C0-4烷基-NR14R15或-O-C1-4烷基-NR14R15，其它每个R1各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, Ring B is selected from 5-7 membered nitrogen-containing heterocyclic groups, and ring C is formed together with -(R 1 ) m Wherein Y 6 , Y 7 , Y 8 and Y 9 are each independently CR 1 or N, and at least one is CR 1 , wherein at least one R 1 is -C 0-4 alkyl -NR 14 R 15 or -OC 1-4 alkyl-NR 14 R 15 , each other R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 chain 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-OS(O) 2 R 9 , -C 0-4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O) OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4 alkyl-P(O)(R 11 ) 2 , -C 0-4 alkyl-NR 12 R 13 , -C 0-4 alkyl -C(O)NR 12 R 13 and -C 0-4 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen , cyano group, 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 ring Alkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0- 4alkyl -OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl- Substituted with substituents of C(O)NR 12 R 13 and -C 0-4 alkyl-N(R 12 )-C(O)R 11 ;
其中，R9、R10、R11、R12、R13、R14、R15和r如式(I)化合物所述。Among them, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and r are as described for 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，每个R9独立地选自氢、氘、羟基、C1-4烷基、C2-4链烯基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基和-NR12R13，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、C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR12R13的取代基所取代；As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 9 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, 5-8 membered heteroaryl and -NR 12 R 13 , the above groups are independent is optionally further selected from one or more deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy base, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxygen group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group Substituted with -NR 12 R 13 substituents;
每个R10独立地选自氢、氘、C1-4烷基、C2-4链烯基、C3-6环烷基、3-6元杂环基、C6-8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、C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR12R13的取代基所取代；Each R 10 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 independently optionally further substituted by one or more 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 membered heterocyclyl, 3-6 membered heterocyclic oxy, C 6-8 aryl, C 6-8 aryloxy, 5 Substituted by -8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 12 R 13 substituents;
每个R11独立地选自氢、氘、羟基、C1-4烷基、C1-4烷氧基、C2-4链烯基、C2-4链炔基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR12R13，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、C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR12R13的取代基所取代；Each R 11 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, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclic oxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 12 R 13 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =O, cyano group, C 1-4 alkyl group , C 1-4 alkoxy group, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl group, Substituted by C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 12 R 13 substituents;
每个R12和R13各自独立地选自氢、氘、羟基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8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C1-4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、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、氘取代C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷 氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、C1-4烷基单取代氨基、C1-4烷基双取代氨基和C1-4烷酰基的取代基所取代，或者，Each R 12 and R 13 are 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 heterocyclyl, C 6-8 aryl, 5-8-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl and C 1-4 alkanoyl, the above groups are independently optionally further selected from one or more 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 cycloalkanes Oxygen group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxygen group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryl oxygen group Substituted with substituents of base, amino, C 1-4 alkyl monosubstituted amino, C 1-4 alkyl disubstituted amino and C 1-4 alkanoyl, or,
R12和R13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、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、氘取代C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、C1-4烷基单取代氨基、C1-4烷基双取代氨基和C1-4烷酰基的取代基所取代。R 12 and R 13 together with the nitrogen atom to which they are directly connected form a 4-8-membered heterocyclyl or 5-8-membered heteroaryl, and the 4-8-membered heterocyclyl or 5-8-membered heteroaryl is optionally further Substituted 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 C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclic oxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, C 1-4 alkyl monosubstituted amino, C 1-4 alkyl bis Substituted with substituted amino and C 1-4 alkanoyl substituents.
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，环A与其直接相连的部分一起形成如下结构：

As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, ring A and its directly connected part together form the following structure:

其中，X1为CR6或N；X2为CR7或N；Among them, X 1 is CR 6 or N; X 2 is CR 7 or N;
每个R5a各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 5a is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5- 8-membered heteroaryl, -SF 5 and -OR 10 , the above groups are independently optionally further substituted with one or more C 1-4 alkyl selected from deuterium, halogen, cyano, C 1-4 alkyl, and halogen base, 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 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C (O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C( Substituted by the substituents of O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
每个R5b各自独立地选自氢、氘、C1-4烷基、C3-6环烷基、3-6元杂环基和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 5b is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and -OR 10 , and the above groups are independently optionally further supplemented by a 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 chain Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC The substituents of (O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 replace;
每个R5c各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、 -C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 5c is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5- 8-membered heteroaryl, -SF 5 and -OR 10 , the above groups are independently optionally further substituted with one or more C 1-4 alkyl selected from deuterium, halogen, cyano, C 1-4 alkyl, and halogen base, 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 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C (O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , Substituted by the substituents of -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
每个R6各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基、3-6元杂环基、-SF5和-O-R10；Each R 6 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
每个R7各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基、3-6元杂环基、-SF5和-O-R10；Each R 7 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
每个R8各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基、3-6元杂环基、-SF5和-O-R10；Each R 8 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。Among them, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for 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)化合物具有如下式(Ⅱ)化合物结构：
As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) has the following compound structure of formula (II):
其中，Y1、Y2各自独立地为CR1或N，Y3为O、S或NR1’；Among them, Y 1 and Y 2 are each independently CR 1 or N, and Y 3 is O, S or NR 1 ';
环A为C4-8环烷基、4-8元杂环基、C6-8芳基或5-8元杂芳基；Ring A is C 4-8 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl;
环B与-(R2)p一起形成如下结构：
Ring B together with -(R 2 ) p forms the following structure:
每个R1各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 1 is independently selected from hydrogen, 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, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C (O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , - NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano group , 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 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O) Substituted by the substituents of (R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
R1’选自氢、氘、羟基、C1-4烷基、C1-4烷氧基、C2-4链烯基、C2-4链炔基、C3-6环烷基和3-6元杂环基，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和 -N(R12)-C(O)R11的取代基所取代；R 1 ' is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, the above groups are independently optionally further substituted 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 Base, =O, =S, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and Substituted with the substituent -N(R 12 )-C(O)R 11 ;
每个R2各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11；Each R 2 is 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 group, C 3-6 cycloalkyl group, 3-6 membered heterocyclyl group, C 6-8 aryl group, 5-8 membered heteroaryl group, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC (O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
R2’选自氢、氘、羟基、C1-4烷基、C1-4烷氧基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基和3-6元杂环基；R 2 ' is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl base and 3-6 membered heterocyclyl;
每个R5各自独立地选自氢、氘、卤素、氰基、C1-4烷基、羟基取代C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11；Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl 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, - SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , - C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C (O)R 11 ;
R6选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C1-4烷氧基、卤取代C1-4烷氧基、氘取代C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、羟基和-NR12R13；R 6 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 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, deuterium-substituted C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3 -6-membered heterocyclyl, 3-6-membered heterocyclicoxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, hydroxyl and -NR 12 R 13 ;
其中，R9、R10、R11、R12、R13、n、p和r式(I)化合物所述。Among them, R 9 , R 10 , R 11 , R 12 , R 13 , n, p and r are as described 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，环A与其直接相连的部分一起形成如下结构：
As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, ring A and its directly connected part together form the following structure:
其中，X1为CR6或N；X2为CH或N；Among them, X 1 is CR 6 or N; X 2 is CH or N;
每个R5a各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 5a is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5- 8-membered heteroaryl, -SF 5 and -OR 10 , the above groups are independently optionally further substituted with one or more C 1-4 alkyl selected from deuterium, halogen, cyano, C 1-4 alkyl, and halogen base, 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 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C (O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C( Substituted by the substituents of O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
每个R5b各自独立地选自氢、氘、C1-4烷基、C3-6环烷基、3-6元杂环基和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元 杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 5b is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and -OR 10 , and the above groups are independently optionally further supplemented by a 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 chain Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered Heteroaryl, =O, =S, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 Substituted by substituents of R 13 and -N(R 12 )-C(O)R 11 ;
每个R5c各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 5c is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5- 8-membered heteroaryl, -SF 5 and -OR 10 , the above groups are independently optionally further substituted with one or more C 1-4 alkyl selected from deuterium, halogen, cyano, C 1-4 alkyl, and halogen base, 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 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C (O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C( Substituted by the substituents of O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
每个R6各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基、3-6元杂环基、-SF5和-O-R10；Each R 6 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
其中，R9、R10、R11、R12、R13和r如式(I)化合物所述。Among them, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for 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)化合物具有如下式(Ⅲ1)或式(Ⅲ2)化合物结构：
As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) has the following compound structure of formula (Ⅲ 1 ) or formula (Ⅲ 2 ):
其中，所述式(Ⅲ1)或式(Ⅲ2)化合物结构中结构为 Wherein, in the structure of the compound of formula (Ⅲ 1 ) or formula (Ⅲ 2 ) The structure is
环A与其直接相连的部分一起形成如下结构：
Ring A together with its directly connected parts forms the following structure:
R1选自氢、氘、氟、氯、甲基、乙基、异丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、氨基、甲基氨基、二甲基氨基、二甲基氨基取代的甲基、二甲基氨基取代的乙基、二甲基氨基乙氧基、环丙基、环丁基、哌啶基、哌嗪基、吗啉基、甲基取代的哌啶基、乙基取代的哌啶基、环丙基取代的哌啶基、甲基取代的哌嗪基、环丙基取代的哌嗪和四氢吡喃基；R 1 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethyl amino, dimethylamino-substituted methyl, dimethylamino-substituted ethyl, dimethylaminoethoxy, cyclopropyl, cyclobutyl, piperidyl, piperazinyl, morpholinyl, methyl base-substituted piperidinyl, ethyl-substituted piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazine and tetrahydropyranyl;
R1’选自氢、氘、甲基、乙基、异丙基、三氟甲基、三氘甲基、二甲基氨基取代的甲基、二甲基氨基取代的乙基、环丙基、环丁基、哌啶基、甲基取代的哌啶基、乙基取代的 哌啶基、环丙基取代的哌啶基和四氢吡喃基；R 1 ' is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, dimethylamino-substituted methyl, dimethylamino-substituted ethyl, cyclopropyl , cyclobutyl, piperidinyl, methyl-substituted piperidinyl, ethyl-substituted Piperidinyl, cyclopropyl-substituted piperidinyl and tetrahydropyranyl;
每个R2各自独立地选自氢、氘、氟、氯、甲基、乙基、异丙基、三氟甲基、三氘甲基和环丙基；Each R 2 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
每个R5a各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、三氟甲基、三氘甲基、环丙基、-SF5和羟基；Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF 5 and hydroxyl;
每个R5b各自独立地选自氢、氘、甲基、乙基、异丙基、三氟甲基、三氘甲基和环丙基；Each R 5b is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
每个R5c各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、三氟甲基、三氘甲基、环丙基、-SF5和羟基；Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF 5 and hydroxyl;
每个R6各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、三氟甲基、三氘甲基、环丙基、-SF5和羟基；Each R is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF and hydroxyl;
p选自0、1或2。p is selected from 0, 1 or 2.
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，所述式(Ⅲ1)或式(Ⅲ2)化合物结构中结构为 As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, in the structure of the compound of formula (Ⅲ 1 ) or formula (Ⅲ 2 ) The structure is
环A与其直接相连的部分一起形成如下结构：
Ring A together with its directly connected parts forms the following structure:
其中，R1选自氢、氘、氟、氯、甲基、乙基、异丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、氨基、甲基氨基、二甲基氨基取代的乙基、二甲基氨基取代的乙氧基、环丙基、哌啶基、哌嗪基、吗啉基、甲基取代的哌啶基、乙基取代的哌啶基、环丙基取代的哌啶基、甲基取代的哌嗪基、环丙基取代的哌嗪和四氢吡喃基；Wherein, R 1 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methylamino, Dimethylamino-substituted ethyl, dimethylamino-substituted ethoxy, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted piperidinyl , cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazine and tetrahydropyranyl;
每个R2各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 2 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
每个R5a各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
每个R5b各自独立地选自氢、氘、甲基、三氟甲基、三氘甲基和环丙基；Each R 5b is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
每个R5c各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
每个R6各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基。Each R 6 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, and cyclopropyl.
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)化合物具有如下式(Ⅳ1)、式(Ⅳ2)、式(Ⅳ3)或式(Ⅳ4)化合物结构：
As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) has the following formula (IV 1 ), formula (IV 2 ), formula ( Ⅳ 3 ) or compound structure of formula (Ⅳ 4 ):
其中，in,
每个R1各自独立地选自氢、氘、氟、氯、甲基、乙基、异丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、氨基、甲基氨基、二甲基氨基取代的乙基、二甲基氨基取代的乙氧基、环丙基、哌啶基、哌嗪基、吗啉基、甲基取代的哌啶基、乙基取代的哌啶基、环丙基取代的哌啶基、甲基取代的哌嗪基、环丙基取代的哌嗪基和四氢吡喃基；Each R 1 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methyl amino, dimethylamino-substituted ethyl, dimethylamino-substituted ethoxy, cyclopropyl, piperidyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted Piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazinyl and tetrahydropyranyl;
每个R2a各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 2a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
每个R2b各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 2b is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
每个R5a各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
每个R5b各自独立地选自氢、氘、甲基、三氟甲基、三氘甲基和环丙基；Each R 5b is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
每个R5c各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
每个R6各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基。Each R 6 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, and cyclopropyl.
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 version, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt includes but is not limited to the following compounds:






本发明第二方面提供一种式(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：式(Ia)化合物与式(Ib)化合物反应生成式(I)化合物，反应式如下：
A second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, which includes the following steps: reacting a compound of formula (Ia) with a compound of formula (Ib) to generate a compound of formula ( I) compound, the reaction formula is as follows:
其中，X为羟基或卤素；环A、环B、环C、R1、R2、R3、R4、R5、X1、X2、X3、m、n和p如式(I)化合物所定义。Among them, X is hydroxyl or halogen; ring A, ring B, ring C, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , ) compound is defined.
本发明第三方面提供一种药物组合物，包括式(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, including a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
本发明第四方面提供一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗MATP相关肿瘤药物中的应用。The fourth aspect of the present invention provides a use of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt in the preparation of drugs for treating MATP-related tumors.
作为进一步优选的方案，所述的肿瘤选自细胞瘤、淋巴瘤、白血病、骨瘤、恶性畸胎瘤、上皮内癌、腺瘤、纤维瘤、黑色素瘤、输卵管癌、膀胱癌、畸胎瘤、胚胎癌、绒毛膜癌、脂肪瘤、肝癌、胆管癌、肺癌、胃癌、血管瘤、胆囊癌、壶腹癌、恶性黑色素瘤、痣、发育不良痣、骨髓增生性疾病、霍奇金病、脊索瘤、粘液瘤、横纹肌瘤、平滑肌瘤、错构瘤、间皮瘤、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、毒蛇瘤、肉芽肿、黄色瘤、变形性骨炎、室管膜瘤、神经鞘瘤、先天性肿瘤、脑膜瘤、胶质瘤、皮肤癌、头颈癌和肉瘤。 As a further preferred option, the tumor is selected from the group consisting of cell tumor, lymphoma, leukemia, osteoma, malignant teratoma, intraepithelial carcinoma, adenoma, fibroma, melanoma, fallopian tube cancer, bladder cancer, and teratoma , embryonal carcinoma, choriocarcinoma, lipoma, liver cancer, cholangiocarcinoma, lung cancer, gastric cancer, hemangioma, gallbladder cancer, ampullary cancer, malignant melanoma, nevus, dysplastic nevus, myeloproliferative diseases, Hodgkin's disease, Chordoma, myxoma, rhabdomyomas, leiomyoma, hamartoma, mesothelioma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, viperoma, granuloma, xanthoma, deformation Osteitis, ependymomas, schwannomas, congenital tumors, meningiomas, gliomas, skin cancers, head and neck cancers, and sarcomas.
作为进一步优选的方案，所述细胞瘤选自颗粒-卵泡膜细胞瘤、睾丸支持细胞瘤、生殖细胞瘤、肾母细胞瘤、精原细胞瘤、肝母细胞瘤、恶性纤维组织细胞瘤、软骨母细胞瘤、巨细胞瘤、星形细胞瘤、髓母细胞瘤、多形胶质母细胞瘤、少突胶质细胞瘤、视网膜母细胞瘤、鳞状细胞癌、透明细胞癌、移行细胞癌、间质细胞癌和基底细胞癌；As a further preferred solution, the cell tumor is selected from the group consisting of granulosa-theca cell tumor, Sertoli cell tumor, germ cell tumor, nephroblastoma, seminoma, hepatoblastoma, malignant fibrous histiocytoma, chondroblastoma, blastoma, giant cell tumor, astrocytoma, medulloblastoma, glioblastoma multiforme, oligodendrogliomas, retinoblastoma, squamous cell carcinoma, clear cell carcinoma, transitional cell carcinoma , stromal cell carcinoma and basal cell carcinoma;
所述淋巴瘤选自恶性淋巴瘤和非霍奇金淋巴瘤；The lymphoma is selected from malignant lymphoma and non-Hodgkin lymphoma;
所述白血病选自急慢性髓系白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病；The leukemia is selected from the group consisting of acute and chronic myeloid leukemia, acute lymphoblastic leukemia and chronic lymphocytic leukemia;
所述骨瘤选自骨软骨瘤、良性软骨瘤、骨样骨瘤、软骨瘤样错构瘤、多发性骨髓瘤和颅骨瘤；The osteoma is selected from the group consisting of osteochondroma, benign enchondroma, osteoid osteoma, chondromatoid hamartoma, multiple myeloma and cranioma;
所述腺瘤选自纤维腺瘤、腺瘤样瘤、肝细胞腺瘤、支气管腺瘤、管状腺瘤、绒毛状腺瘤、乳腺癌、胰腺癌、子宫内膜腺癌、前列腺癌、导管腺癌和大肠腺癌；The adenoma is selected from the group consisting of fibroadenoma, adenomatoid tumor, hepatocellular adenoma, bronchial adenoma, tubular adenoma, villous adenoma, breast cancer, pancreatic cancer, endometrial adenocarcinoma, prostate cancer, ductal adenoma carcinoma and colorectal adenocarcinoma;
所述纤维瘤选自纤维瘤、软骨粘液纤维瘤、神经纤维瘤和脊髓神经纤维瘤；The fibroma is selected from the group consisting of fibroma, chondromyxofibroma, neurofibroma and spinal neurofibroma;
所述骨髓增生性疾病选自多发性骨髓瘤和骨髓增生异常综合征；The myeloproliferative disease is selected from the group consisting of multiple myeloma and myelodysplastic syndrome;
所述肺癌选自支气管肺癌和肺泡癌；The lung cancer is selected from bronchial lung cancer and alveolar cancer;
所述肉瘤选自纤维肉瘤、葡萄状肉瘤、血管肉瘤、卡波西肉瘤、骨肉瘤、软骨肉瘤、尤因氏肉瘤、横纹肌肉瘤、脂肪肉瘤、平滑肌肉瘤和脑膜肉瘤。The sarcoma is selected from the group consisting of fibrosarcoma, botryoid sarcoma, angiosarcoma, Kaposi's sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma and meningiosarcoma.
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PRMT5抑制剂药物。The present invention also relates to the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, which is used as a PRMT5 inhibitor drug.
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PRMT5介导的疾病的药物中的用途。The present invention also relates to the use of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt in the preparation of medicaments for the treatment and/or prevention of PRMT5-mediated diseases.
本发明还涉及一种治疗和/或预防PRMT5介导的疾病的方法，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 PRMT5-mediated diseases, which comprises administering to a patient in need a therapeutically effective amount of the 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如下式(Ⅰ)结构的PRMT5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PRMT5介导的疾病的药物，有望开发成新一代PRMT5抑制剂。在此基础上，完成了本发明。After extensive and in-depth research, the inventor of the present application has developed for the first time a PRMT5 inhibitor with the following formula (I) structure. The series of compounds of the present invention can be widely used in the preparation of drugs for the treatment and/or prevention of PRMT5-mediated diseases. , is expected to be developed into a new generation of PRMT5 inhibitors. On this basis, the present invention was completed.
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。“C1-10烷基”指包括1至10个碳原子的直链烷基和含支链烷基，“C1-4烷基”指包括1至4个碳原子的直链烷基和含支链烷基，“C0-8烷基”指包括0至8个碳原子的直链烷基和含支链烷基，“C0-4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 linear or branched saturated aliphatic hydrocarbon group, preferably including a linear alkyl group and a branched alkyl group of 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 base, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, etc. “C 1-10 alkyl” refers to straight-chain alkyl groups and branched-chain alkyl groups having 1 to 10 carbon atoms, and “C 1-4 alkyl” refers to straight-chain alkyl groups including 1 to 4 carbon atoms. Containing branched chain alkyl groups, "C 0-8 alkyl" refers to straight-chain alkyl groups containing 0 to 8 carbon atoms and branched-chain alkyl groups, and "C 0-4 alkyl groups" refers to containing 0 to 4 carbon atoms straight-chain alkyl groups and branched-chain alkyl groups.
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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代。The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) the following groups, independently selected from deuterium, halogen, cyanide 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 0-8alkyl -OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8alkyl -C (O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0 Substituted with -8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 substituents.
“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，“C3-12环烷基”指包括3至12个碳原子的环烷基，“C4-8环烷基”指包括4至8个碳原子的环烷基，“C3-8环烷基”指包括3至8个碳原子的环烷基，“C3-6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 refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π electron system. The cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups with to 6 carbon atoms, for example, "C 3-12 cycloalkyl" refers to cycloalkyl groups including 3 to 12 carbon atoms, and "C 4-8 cycloalkyl" refers to cycloalkyl groups including 4 to 8 carbon atoms. cycloalkyl group of atoms, "C 3-8 cycloalkyl" refers to a cycloalkyl group including 3 to 8 carbon atoms, "C 3-6 cycloalkyl" refers to a cycloalkyl group including 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 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cycloctyl 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：
Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between the single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no single ring has A fully conjugated π electron system. According to the number of shared spiro atoms between the rings, spirocycloalkyl groups are divided into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups. Spirocycloalkyl groups include but are not limited to:
“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：
"Condensed cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings 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 constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups. The fused ring alkyl groups include but are not limited to:
“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" refers to an all-carbon polycyclic group in which any two rings share two non-directly connected carbon atoms. 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 constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Bridged cycloalkyl groups include but are not limited to:
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 connected to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.
“环烷基”或“碳环”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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代。"Cycloalkyl" or "carbocycle" may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently is 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , - C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl Base -C(O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alkyl -P(O)(R 11 ) 2 , -C 0-8 alkyl- Substituted with the substituents of NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 .
“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 refers to a cyclic hydrocarbon that may 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 heteroatoms of S(O) r (where r is an integer 0, 1, 2), excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferred heterocyclyl groups include 3 to 12 or 3 to 8 or 3 to 6 ring atoms. For example, "3-6 membered heterocyclyl" refers to heterocyclyl groups containing 3 to 6 ring atoms, "3- "8-membered heterocyclyl" refers to a heterocyclic group containing 3 to 8 ring atoms, "4-8-membered heterocyclyl" refers to a heterocyclic group containing 4 to 8 ring atoms, "4-10-membered heterocyclyl" refers to a heterocyclic group containing 4 to 10 ring atoms, "5-8-membered heterocyclyl" refers to a heterocyclic group containing 5 to 8 ring atoms, and "3-12-membered heterocyclyl" refers to a heterocyclic group containing 3 to 12 ring atoms. Heterocyclyl group of ring atoms.
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 heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between single rings, 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) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but no ring has a fully conjugated pi electron system. According to the number of shared spiro atoms between rings, spiroheterocyclyl groups are divided into single spiroheterocyclyl groups, double spiroheterocyclyl groups or polyspiroheterocyclyl groups. Spiroheterocyclyl groups include, but are not limited to:
“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：
"Condensed heterocyclyl" refers to a polycyclic heterocyclyl in which each ring in the system shares an adjacent pair of atoms with every other ring in the system group, one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a fully conjugated π electron system, where One or more (preferably 1, 2, 3 or 4) ring atoms are selected from heteroatoms of N, O, N·O or S(O) r (where r is an integer 0, 1, 2), and the remaining ring atoms for carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups. The fused heterocyclic groups include but are not limited to:
“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" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings Having 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) heteroatoms, 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 heterocyclyl groups. Bridged heterocyclyl groups include but are not limited to:
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 can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
“杂环基”或“杂环”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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代的取代基所取代。"Heterocyclyl" or "heterocycle" may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently is 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , - C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl Base -C(O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alkyl -P(O)(R 11 ) 2 , -C 0-8 alkyl- Substituents substituted by the substituents of NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 replaced.
“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，“C6-10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，“C6-8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" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a common Polycyclic (i.e., rings with adjacent pairs of carbon atoms) groups of the yoke π electron system, preferably all-carbon aryl groups containing 6-10 or 6-8 carbons, for example, "C 6-10 aromatic "Basic" refers to an all-carbon aryl group containing 6-10 carbons, including but not limited to phenyl and naphthyl, and "C 6-8 aryl" refers to an all-carbon aryl group containing 6-8 carbons. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring, including but not limited to:
“芳基”或“芳环”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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代。"Aryl" or "aromatic ring" may be substituted or unsubstituted. When substituted, the substituent is 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0- 8alkyl -C(O)OR 10 , -C 0-8alkyl -C(O)SR 10 , -C 0-8alkyl -SC(O)R 11 , -C 0-8alkyl -C (O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 substituents.
“杂芳基”或“杂芳环”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" or "heteroaryl ring" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms, including N, O, N·O and S (O) Heteroatom of r (where r is an integer 0, 1, 2), preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered""Heteroaryl" refers to a heteroaromatic system containing 5-8 ring atoms, and "5-10-membered heteroaryl" refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl and thienyl. , pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
“杂芳基”或“杂芳环”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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基 -NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代。"Heteroaryl" or "heteroaryl ring" may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) 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- 8alkyl -SF 5 , -C 0-8alkyl -OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 Alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl Substituted with -NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 substituents.
“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，“C2-10链烯基”指含有2-10个碳的直链或含支链烯基，“C2-4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" refers to 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 to 10 or 2 to 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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代。"Alkenyl" may be substituted or unsubstituted. When substituted, the substituent is 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl- C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C Substituted with the substituents of 0-8alkyl -C(O)NR 12 R 13 and -C 0-8alkyl -N(R 12 )-C(O)R 11 .
“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，“C2-10链炔基”指含有2-10个碳的直链或含支链炔基，“C2-4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" refers to 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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代。"Alkynyl" may be substituted or unsubstituted. When substituted, the substituent is 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl- C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C Substituted with the substituents of 0-8alkyl -C(O)NR 12 R 13 and -C 0-8alkyl -N(R 12 )-C(O)R 11 .
“烷氧基”指-O-烷基，其中烷基的定义如上所述，例如，“C1-10烷氧基”指含1-10个碳的烷基氧基，“C1-4烷氧基”指含1-4个碳的烷基氧基，“C1-2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, where alkyl is as defined 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 and 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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代。"Alkoxy" may be optionally substituted or unsubstituted. When substituted, the substituent, preferably one or more (preferably 1, 2, 3 or 4) of the following groups, is 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-OS(O) 2 R 9 , -C 0-8 alkyl -S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 Alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C( O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 substituents.
“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，“C3-12环烷氧基”指含3-12个碳的环烷基氧基，“C3-6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, where cycloalkyl is as defined above, for example, "C 3-12 cycloalkoxy" refers to a group containing 3-12 Carbon cycloalkyloxy, "C 3-6 cycloalkoxy" refers to cycloalkyloxy containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy , cyclohexyloxy, etc.
“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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代。"Cycloalkoxy" or "cycloalkyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably Be 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 aromatic Base, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl -SF 5 , -C 0-8 alkyl -OS(O) 2 R 9 , -C 0-8 alkyl -S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 Alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl -N(R 12 )-C(O)R 11 substituent.
“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, wherein heterocyclyl is as defined above, including but not limited to azetidinyloxy, oxetanyloxy base, azetanyloxy group, nitrogen, oxanyloxy group, 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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代。"Heterocyclyloxy" or "heterocyclyloxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) or less. Group, 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl- OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8alkyl -C(O)R 11 , -C 0-8alkyl -OC(O)R 11 , -C 0-8alkyl -P(O)(R 11 ) 2 , -C 0- The substituents of 8- alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 replace.
“C1-10烷酰基”指C1-10烷基酸去掉羟基后剩下的一价原子团，通常也表示为“C0-9烷基-C(O)-”，例如，“C1烷基-C(O)-”是指乙酰基；“C2烷基-C(O)-”是指丙酰基；“C3烷基-C(O)-”是指丁酰基或异丁酰基。"C 1-10 alkanoyl" refers to the monovalent atomic group remaining after removing the hydroxyl group from C 1-10 alkyl acid. It is also usually expressed as "C 0-9 alkyl-C(O)-", for example, "C 1 "Alkyl-C(O)-" refers to acetyl; "C 2alkyl -C(O)-" refers to propionyl; "C 3alkyl -C(O)-" refers to butyryl or isobutyl acyl group.
“-C0-8烷基-O-S(O)2R9”指-O-S(O)2R9中的氧原子连接在C0-8烷基上，其中C0-8烷基的定义如上所述。"-C 0-8 alkyl-OS(O) 2 R 9 " means that the oxygen atom in -OS(O) 2 R 9 is connected to the C 0-8 alkyl group, where the C 0-8 alkyl group is as defined above described.
“-C0-8烷基-S(O)rR9”指-S(O)rR9中的硫原子连接在C0-8烷基上，其中C0-8烷基的定义如上所述。"-C 0-8 alkyl-S(O) r R 9 " means that the sulfur atom in -S(O) r R 9 is connected to the C 0-8 alkyl group, where the C 0-8 alkyl group is as defined above described.
“-C0-8烷基-O-R10”指-O-R10中的氧原子连接在C0-8烷基上，其中C0-8烷基的定义如上所述。"-C 0-8 alkyl-OR 10 " means that the oxygen atom in -OR 10 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl group is as defined above.
“-C0-8烷基-C(O)OR10”指-C(O)OR10中的羰基连接在C0-8烷基上，其中C0-8烷基的定义如上所述。"-C 0-8 alkyl-C(O)OR 10 " means that the carbonyl group in -C(O)OR 10 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl group is as defined above.
“-C0-8烷基-C(O)SR10”指-C(O)SR10中的羰基连接在C0-8烷基上，其中C0-8烷基的定义如上所述。"-C 0-8 alkyl-C(O)SR 10 " means that the carbonyl group in -C(O)SR 10 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl group is as defined above.
“-C0-8烷基-S-C(O)R11”指-S-C(O)R11中的硫原子连接在C0-8烷基上，其中C0-8烷基的定义如上所述。"-C 0-8 alkyl-SC(O)R 11 " means that the sulfur atom in -SC(O)R 11 is connected to the C 0-8 alkyl group, where the C 0-8 alkyl group is as defined above .
“-C0-8烷基-C(O)R11”指-C(O)R11中的羰基连接在C0-8烷基上，其中C0-8烷基的定义如上所述。"-C 0-8 alkyl-C(O)R 11 " means that the carbonyl group in -C(O)R 11 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl group is as defined above.
“-C0-8烷基-O-C(O)R11”指-O-C(O)R11中的氧原子连接在C0-8烷基上，其中C0-8烷基的定义如上所述。"-C 0-8 alkyl-OC(O)R 11 " means that the oxygen atom in -OC(O)R 11 is connected to the C 0-8 alkyl group, where the C 0-8 alkyl group is as defined above .
“-C0-8烷基-P(O)(R11)2”指-P(O)(R11)2中的磷原子连接在C0-8烷基上，其中C0-8烷基的定义如上所述。"-C 0-8 alkyl-P(O)(R 11 ) 2 " means that the phosphorus atom in -P(O)(R 11 ) 2 is connected to the C 0-8 alkyl group, where C 0-8 alkyl The basis is defined as above.
“-C0-8烷基-NR12R13”指-NR12R13中的氮原子连接在C0-8烷基上，其中C0-8烷基的定义 如上所述。"-C 0-8 alkyl-NR 12 R 13 " means that the nitrogen atom in -NR 12 R 13 is connected to the C 0-8 alkyl group, where the definition of C 0-8 alkyl group As mentioned above.
“-C0-8烷基-C(O)NR12R13”指-C(O)NR12R13中的羰基连接在C0-8烷基上，其中C0-8烷基的定义如上所述。"-C 0-8 alkyl-C(O)NR 12 R 13 " means that the carbonyl group in -C(O)NR 12 R 13 is connected to the C 0-8 alkyl group, where the definition of C 0-8 alkyl group As mentioned above.
“-C0-8烷基-N(R12)-C(O)R11”指-N(R12)-C(O)R11中的氮原子连接在C0-8烷基上，其中C0-8烷基的定义如上所述。"-C 0-8 alkyl-N(R 12 )-C(O)R 11 " means that the nitrogen atom in -N(R 12 )-C(O)R 11 is connected to the C 0-8 alkyl group, Wherein C 0-8 alkyl is defined as above.
“卤取代C1-10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。"Halo-substituted C 1-10 alkyl" refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
“卤取代C1-10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。"Halo-substituted C 1-10 alkoxy group" refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.
“氘取代C1-10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 group is optionally replaced by a deuterium atom. Including but not limited to monodeuterium methyl, dideuterium methyl, trideuterium methyl, etc.
“卤素”指氟、氯、溴或碘，“EA”指乙醇，“PE”指石油醚，“EtOAc”指乙酸乙脂，“MeOH”指甲醇，“DCM”指二氯甲烷，“DMSO”指二甲基亚砜。"Halogen" refers to fluorine, chlorine, bromine or iodine, "EA" refers to ethanol, "PE" refers to petroleum ether, "EtOAc" refers to ethyl acetate, "MeOH" methyl alcohol, "DCM" refers to dichloromethane, "DMSO" Refers to dimethyl sulfoxide.
“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 situations where the event or circumstance does or does not occur, that is, whether it is substituted or not. . For example, "a heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but need not be present. This description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
“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 a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with the chemical valence bond theory, which the person skilled in the art can determine without undue effort (either experimentally or theoretically) what is possible or impossible replacement. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with 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。"Stereoisomers", whose English name is stereoisomers, refer to isomers produced by the different spatial arrangements of atoms in the molecule. They can be divided into two types: cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers caused by the rotation of single bonds are called conformational 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). Configuration isomers are divided into two categories. Among them, the isomers caused by the inability of the double bond or the single bond of the ring-forming carbon atoms to rotate freely become geometric isomers (geometric isomers), also called 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. The stereoisomers with different optical properties caused by the lack of anti-axial symmetry in the molecules are called optical isomers ( optical isomer), divided into R and S configurations. Unless otherwise specified, the "stereoisomer" mentioned in the present invention can be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers.
“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 salts" in the present invention refer to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts. These salts can be prepared by methods known in the art.
“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 physiologically/pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. drug The purpose of the composition is to facilitate administration to the organism and facilitate the absorption of the active ingredients to 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 further described in detail and completely with reference to the examples below, but in no way limits the present invention, and the present invention is not limited to the contents 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-d6)，氘代甲醇(CD3OD)和氘代氯仿(CDCl3)，内标为四甲基硅烷(TMS)。The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm) units. NMR was measured using a Bruker AVANCE-400/500 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was It is 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)。LC-MS was measured using an Agilent 6120 mass spectrometer. HPLC was measured using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6mm column) and Waters 2695-2996 high-pressure liquid chromatograph (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。Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 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 embodiments of the present invention are known and can be purchased on the market, or can be synthesized using or according to 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 of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius (°C).
Ⅰ.中间体的制备Ⅰ. Preparation of intermediates
中间体1:2-(1-甲基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯并[d]噻唑的制备第一步：5-氯-2-(1-甲基哌啶-4-基)苯并[d]噻唑的合成
Intermediate 1: 2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) The first step in the preparation of benzo[d]thiazole: synthesis of 5-chloro-2-(1-methylpiperidin-4-yl)benzo[d]thiazole
将2-氨基-4-氯苯硫醇(3.00g，18.8mmol)、1-甲基哌啶-4-羧酸(2.69g，18.8mmol)、N,N-二异丙基乙胺(6.55mL，37.6mmol)和50％的1-丙基磷酸酐(12.0g，18.8mmol)溶于100mL圆底烧瓶中，氮气置换三次并在100℃搅拌过夜。反应液冷却至室温，饱和碳酸氢钠溶液调节pH至9～10，乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液旋蒸浓缩得到5-氯-2-(1-甲基哌啶-4-基)苯并[d]噻唑(4.50g，收率：90％)。MS m/z(ESI):267[M+H]+。2-Amino-4-chlorobenzenethiol (3.00g, 18.8mmol), 1-methylpiperidine-4-carboxylic acid (2.69g, 18.8mmol), N,N-diisopropylethylamine (6.55 mL, 37.6 mmol) and 50% 1-propylphosphonic anhydride (12.0 g, 18.8 mmol) were dissolved in a 100 mL round-bottomed flask, replaced with nitrogen three times and stirred at 100°C overnight. The reaction solution was cooled to room temperature, and the pH was adjusted to 9-10 with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation to obtain 5-chloro-2-(1-methylpiperidine- 4-yl)benzo[d]thiazole (4.50 g, yield: 90%). MS m/z(ESI):267[M+H] + .
第二步：2-(1-甲基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯并[d]噻唑的合成
Step 2: 2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Synthesis of benzo[d]thiazole
将5-氯-2-(1-甲基哌啶-4-基)苯并[d]噻唑(1.80g，6.75mmol)和联硼酸频那醇酯(2.57g，10.12mmol)溶于二氧六环(40mL)，加入乙酸钾(1.66g，16.87mmol)、三环己基膦(305mg，1.09mmol)和双(二亚芐基丙酮)钯(313mg，0.54mmol)，氮气置换三次并在105℃搅拌过夜。 反应结束后过滤，乙酸乙酯洗涤滤饼，滤液旋蒸浓缩。残留物经柱层析分离得到2-(1-甲基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯并[d]噻唑(1.93g，收率：80％)。MS m/z(ESI):359[M+H]+。Dissolve 5-chloro-2-(1-methylpiperidin-4-yl)benzo[d]thiazole (1.80g, 6.75mmol) and pinacol diborate (2.57g, 10.12mmol) in dioxygen Six rings (40 mL), add potassium acetate (1.66g, 16.87mmol), tricyclohexylphosphine (305mg, 1.09mmol) and bis(dibenzylideneacetone)palladium (313mg, 0.54mmol), replace with nitrogen three times and incubate at 105 °C and stir overnight. After the reaction, filter, wash the filter cake with ethyl acetate, and concentrate the filtrate by rotary evaporation. The residue was separated by column chromatography to obtain 2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane- 2-yl)benzo[d]thiazole (1.93g, yield: 80%). MS m/z(ESI):359[M+H] + .
中间体2～6可参照中间体1全部或部分合成方法选择相应的原料进行制备:
Intermediates 2 to 6 can be prepared by referring to all or part of the synthesis method of intermediate 1 and selecting corresponding raw materials:
中间体7：2-甲基-5-(4-甲基哌啶-2-基)苯并[d]噻唑的制备
Intermediate 7: Preparation of 2-methyl-5-(4-methylpiperidin-2-yl)benzo[d]thiazole
第一步：4-甲基哌啶-2-酮的合成
Step 1: Synthesis of 4-methylpiperidin-2-one
将4-甲基吡啶-2(1H)-酮(25.0g，0.23mol)溶于醋酸(30mL)，加入10％的钯碳(4.88g)，反应液在氢气氛围中70℃搅拌24小时。反应结束后过滤，滤液直接旋蒸浓缩得到4-甲基哌啶-2-酮粗品(25.4g)。MS m/z(ESI):114[M+H]+。4-methylpyridin-2(1H)-one (25.0g, 0.23mol) was dissolved in acetic acid (30mL), 10% palladium on carbon (4.88g) was added, and the reaction solution was stirred at 70°C for 24 hours in a hydrogen atmosphere. After the reaction, it was filtered, and the filtrate was directly concentrated by rotary evaporation to obtain crude 4-methylpiperidin-2-one (25.4g). MS m/z(ESI):114[M+H] + .
第二步：叔-丁基4-甲基-2-氧代哌啶-1-羧酸酯的合成
Step 2: Synthesis of tert-butyl 4-methyl-2-oxopiperidine-1-carboxylate
将4-甲基哌啶-2-酮(23.0g，0.20mol)溶于四氢呋喃(30mL)，加入二碳酸二叔丁酯(47.8mL，0.22mol)，4-二甲氨基吡啶(4.97g，40.6mmol)和三乙胺(28.2mL，0.20mol)，室温搅拌24小时。反应液用乙酸乙酯和水稀释，分液，有机相旋蒸浓缩，残留物经柱层析得到叔-丁基4-甲基-2-氧代哌啶-1-羧酸酯(7.0g，收率：16％)。MS m/z(ESI):158[M-56+H]+。第三步：叔-丁基4-甲基-6-(((三氟甲基)磺酰基)氧基)-3,4-二氢吡啶-1(2H)-羧酸酯的合成
Dissolve 4-methylpiperidin-2-one (23.0g, 0.20mol) in tetrahydrofuran (30mL), add di-tert-butyl dicarbonate (47.8mL, 0.22mol), 4-dimethylaminopyridine (4.97g, 40.6 mmol) and triethylamine (28.2 mL, 0.20 mol), stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate and water, separated, and the organic phase was concentrated by rotary evaporation. The residue was subjected to column chromatography to obtain tert-butyl 4-methyl-2-oxopiperidine-1-carboxylate (7.0g). , Yield: 16%). MS m/z(ESI):158[M-56+H] + . Step 3: Synthesis of tert-butyl 4-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate
将叔-丁基4-甲基-2-氧代哌啶-1-羧酸酯(1.00g，4.69mmol)溶于干燥四氢呋喃(40mL)，冷却至零下78℃，缓慢加入双(三甲基硅烷基)氨基钾的四氢呋喃溶液(6.1mL，6.10mmol)。加完后继续零下78℃搅拌反应1小时，加入N-苯基双(三氟甲烷磺酰)亚胺(2.177g，6.10mmol)，反应液继续-78℃搅拌反应2小时。反应液用乙酸乙酯和水稀释，分液，有机相旋蒸浓缩，残留物经柱层析得到叔-丁基4-甲基-6-(((三氟甲基)磺酰基)氧基)-3,4-二氢吡啶-1(2H)-羧酸酯(900mg，收率：54％)。MS m/z(ESI):290[M-56+H]+。Dissolve tert-butyl 4-methyl-2-oxopiperidine-1-carboxylate (1.00g, 4.69mmol) in dry tetrahydrofuran (40mL), cool to minus 78°C, and slowly add bis(trimethyl A solution of potassium silyl)amide in tetrahydrofuran (6.1 mL, 6.10 mmol). After the addition was completed, the stirring reaction was continued at -78°C for 1 hour. N-phenylbis(trifluoromethanesulfonyl)imide (2.177g, 6.10mmol) was added, and the reaction solution was continued to stir at -78°C for 2 hours. The reaction solution was diluted with ethyl acetate and water, separated, and the organic phase was concentrated by rotary evaporation. The residue was subjected to column chromatography to obtain tert-butyl 4-methyl-6-(((trifluoromethyl)sulfonyl)oxy). )-3,4-dihydropyridine-1(2H)-carboxylate (900 mg, yield: 54%). MS m/z(ESI):290[M-56+H] + .
第四步：叔-丁基4-甲基-6-(2-甲基苯并[d]噻唑-5-基)-3,4-二氢吡啶-1(2H)-羧酸酯的合成
Step 4: Synthesis of tert-butyl 4-methyl-6-(2-methylbenzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate
将叔-丁基4-甲基-6-(((三氟甲基)磺酰)氧基)-3,4-二氢吡啶-1(2H)-羧酸酯(319mg，1.16mmol)和2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d]噻唑(400mg，1.16mmol)溶于二氧六环(9mL)和水(3mL)中，加入碳酸钠(368mg，3.48mmol)和1,1-双(二苯基膦)二荗铁二氯化钯(85mg，0.12mmol)，氮气置换三次并在90℃搅拌过夜。反应结束后用水稀释，并用乙酸乙酯萃取两次，合并有机相并旋蒸浓缩。残留物柱层析得到叔-丁基4-甲基-6-(2-甲基苯并[d]噻唑-5-基)-3,4-二氢吡啶-1(2H)-羧酸酯(180mg，收率：45％)。MS m/z(ESI):345[M+H]+。tert-Butyl 4-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (319 mg, 1.16 mmol) and 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (400 mg, 1.16 mmol) Dissolve in dioxane (9mL) and water (3mL), add sodium carbonate (368mg, 3.48mmol) and 1,1-bis(diphenylphosphine)diphenyliron palladium dichloride (85mg, 0.12mmol) , replaced with nitrogen three times and stirred at 90°C overnight. After the reaction, it was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and concentrated by rotary evaporation. Column chromatography of the residue yielded tert-butyl 4-methyl-6-(2-methylbenzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate (180 mg, yield: 45%). MS m/z(ESI):345[M+H] + .
第五步：2-甲基-5-(4-甲基-3,4,5,6-四氢吡啶-2-基)苯并[d]噻唑的合成
Step 5: Synthesis of 2-methyl-5-(4-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole
将叔-丁基4-甲基-6-(2-甲基苯并[d]噻唑-5-基)-3,4-二氢吡啶-1(2H)-羧酸酯(180mg，0.52mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(2mL)，室温反应1小时。反应结束后浓缩除去溶剂。残留物用二氯甲烷稀释，饱和碳酸钠溶液调pH至8～9，二氯甲烷萃取两次。合并有机相，旋蒸浓缩得到2-甲基-5-(4-甲基-3,4,5,6-四氢吡啶-2-基)苯并[d]噻唑(127mg，收率：100％)。MS m/z(ESI):245[M+H]+。tert-Butyl 4-methyl-6-(2-methylbenzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate (180 mg, 0.52 mmol ) was dissolved in dichloromethane (2mL), added trifluoroacetic acid (2mL), and reacted at room temperature for 1 hour. After the reaction was completed, the solvent was concentrated to remove. The residue was diluted with dichloromethane, the pH was adjusted to 8-9 with saturated sodium carbonate solution, and extracted twice with dichloromethane. The organic phases were combined and concentrated by rotary evaporation to obtain 2-methyl-5-(4-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole (127 mg, yield: 100 %). MS m/z(ESI):245[M+H] + .
第六步：2-甲基-5-(5-甲基哌啶-2-基)苯并[d]噻唑的合成
Step 6: Synthesis of 2-methyl-5-(5-methylpiperidin-2-yl)benzo[d]thiazole
将2-甲基-5-(5-甲基-3,4,5,6-四氢吡啶-2-基)苯并[d]噻唑(128mg，0.52mmol)溶于甲醇(5mL)中，冰浴冷却，加入硼氢化钠(53mg，1.57mmol)，冰浴下搅拌反应1小时。反应结束后浓缩除去溶剂。残留物柱层析得到2-甲基-5-(5-甲基哌啶-2-基)苯并[d]噻唑(95mg，收率：74％)。MS m/z(ESI):247[M+H]+。Dissolve 2-methyl-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole (128 mg, 0.52 mmol) in methanol (5 mL), Cool in an ice bath, add sodium borohydride (53 mg, 1.57 mmol), and stir for 1 hour in an ice bath. After the reaction was completed, the solvent was concentrated to remove. Column chromatography of the residue gave 2-methyl-5-(5-methylpiperidin-2-yl)benzo[d]thiazole (95 mg, yield: 74%). MS m/z(ESI):247[M+H] + .
中间体8～15可参照中间体7全部或部分合成方法选择相应的原料进行制备:

Intermediates 8 to 15 can be prepared by referring to all or part of the synthesis method of intermediate 7 and selecting corresponding raw materials:

中间体16：3-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)吗啉的制备
Intermediate 16: Preparation of 3-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)morpholine
第一步：叔-丁基5-((二苯氧基磷酰基)氧基)-2,3-二氢-4H-1,4-噁嗪-4-羧酸酯的合成
Step 1: Synthesis of tert-butyl 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate
将叔-丁基3-氧代吗啉-4-羧酸酯(1.00g，4.97mmol)溶于干燥四氢呋喃(40mL)，冷却至零下40℃，缓慢加入双(三甲基硅烷基)氨基锂的四氢呋喃溶液(5.47mL，5.47mmol)。加完后继续零下40℃搅拌反应1小时，加入磷氯化酸二苯酯(1.09mL，5.22mmol)，反应液继续-40℃搅拌反应2小时。反应液用乙酸乙酯和饱和氯化铵溶液稀释，分液，有机相旋蒸浓缩，残留物经柱层析分离得到叔-丁基5-((二苯氧基磷酰基)氧基)-2,3-二氢-4H-1,4-噁嗪-4-羧酸酯(1550mg，收率：72％)。MS m/z(ESI):334[M-Boc+H]+。Dissolve tert-butyl 3-oxomorpholine-4-carboxylate (1.00g, 4.97mmol) in dry tetrahydrofuran (40mL), cool to minus 40°C, and slowly add lithium bis(trimethylsilyl)amide of tetrahydrofuran solution (5.47mL, 5.47mmol). After the addition was completed, the reaction was continued with stirring at -40°C for 1 hour, diphenyl phosphorus chloride (1.09 mL, 5.22 mmol) was added, and the reaction solution was continued with stirring at -40°C for 2 hours. The reaction solution was diluted with ethyl acetate and saturated ammonium chloride solution, separated, and the organic phase was concentrated by rotary evaporation. The residue was separated by column chromatography to obtain tert-butyl 5-((diphenoxyphosphoryl)oxy)- 2,3-Dihydro-4H-1,4-oxazine-4-carboxylate (1550 mg, yield: 72%). MS m/z(ESI):334[M-Boc+H] + .
第二步：叔-丁基5-(2-甲基苯并[d]噻唑-5-基)-2,3-二氢-4H-1,4-噁嗪-4-羧酸酯的合成
Step 2: Synthesis of tert-butyl 5-(2-methylbenzo[d]thiazol-5-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate
将叔-丁基5-((二苯氧基磷酰基)氧基)-2,3-二氢-4H-1,4-噁嗪-4-羧酸酯(750mg，1.38mmol)和2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d]噻唑(381mg，1.38mmol)溶于二氧六环(15mL)和水(3mL)中，加入碳酸钠(587mg，5.54mmol)和1,1-双(二苯基膦)二荗铁二氯化钯(101mg，0.14mmol)，氮气置换三次并在95℃搅拌过夜。反应结束后用水稀释，并用乙酸乙酯萃取两次，合并有机相并旋蒸浓缩。残留物柱层析分离得到叔-丁基5-(2-甲基苯并[d]噻唑-5-基)-2,3-二氢-4H-1,4-噁嗪-4-羧酸酯(400mg，收率：87％)。MS m/z(ESI):333[M+H]+。Combine tert-butyl 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (750 mg, 1.38 mmol) and 2- Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (381 mg, 1.38 mmol) was dissolved in To dioxane (15 mL) and water (3 mL), add sodium carbonate (587 mg, 5.54 mmol) and 1,1-bis(diphenylphosphine)diphenyliron palladium dichloride (101 mg, 0.14 mmol), nitrogen Displaced three times and stirred at 95°C overnight. After the reaction, it was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and concentrated by rotary evaporation. The residue was separated by column chromatography to obtain tert-butyl 5-(2-methylbenzo[d]thiazol-5-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid. Ester (400 mg, yield: 87%). MS m/z(ESI):333[M+H] + .
第三步：5-(2-甲基苯并[d]噻唑-5-基)-3,6-二氢-2H-1,4-噁嗪的合成
Step 3: Synthesis of 5-(2-methylbenzo[d]thiazol-5-yl)-3,6-dihydro-2H-1,4-oxazine
将叔-丁基5-(2-甲基苯并[d]噻唑-5-基)-2,3-二氢-4H-1,4-噁嗪-4-羧酸酯(390mg，1.17mmol)溶于二氯甲烷(5mL)中，加入三氟乙酸(3mL)，室温反应3小时。反应液用二氯甲烷稀释，饱和碳酸钠溶液调pH至8～9，二氯甲烷萃取两次。合并有机相，旋蒸浓缩得到5-(2-甲基苯并[d]噻唑-5-基)-3,6-二氢-2H-1,4-噁嗪(270mg，收率：84％，纯度：85％)。MS m/z(ESI):233[M+H]+。tert-Butyl 5-(2-methylbenzo[d]thiazol-5-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (390 mg, 1.17 mmol ) was dissolved in dichloromethane (5 mL), added trifluoroacetic acid (3 mL), and reacted at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, the pH was adjusted to 8-9 with saturated sodium carbonate solution, and extracted twice with dichloromethane. The organic phases were combined, concentrated by rotary evaporation to obtain 5-(2-methylbenzo[d]thiazol-5-yl)-3,6-dihydro-2H-1,4-oxazine (270 mg, yield: 84% , purity: 85%). MS m/z(ESI):233[M+H] + .
第四步：3-(2-甲基苯并[d]噻唑-5-基)吗啉的合成
Step 4: Synthesis of 3-(2-methylbenzo[d]thiazol-5-yl)morpholine
将5-(2-甲基苯并[d]噻唑-5-基)-3,6-二氢-2H-1,4-噁嗪(270mg，纯度：85％，0.99mmol)溶于甲醇(10mL)中，加入硼氢化钠(100mg，2.97mmol)，室温搅拌反应1小时。反应结束后浓缩除去溶剂。残留物柱层析得到3-(2-甲基苯并[d]噻唑-5-基)吗啉(205mg，收率：86％)。MS m/z(ESI):235[M+H]+。5-(2-Methylbenzo[d]thiazol-5-yl)-3,6-dihydro-2H-1,4-oxazine (270 mg, purity: 85%, 0.99 mmol) was dissolved in methanol ( 10 mL), add sodium borohydride (100 mg, 2.97 mmol), stir and react at room temperature for 1 hour. After the reaction was completed, the solvent was concentrated to remove. Column chromatography of the residue gave 3-(2-methylbenzo[d]thiazol-5-yl)morpholine (205 mg, yield: 86%). MS m/z(ESI):235[M+H] + .
中间体17～19可参照中间体16全部或部分合成方法选择相应的原料进行制备:
Intermediates 17 to 19 can be prepared by referring to all or part of the synthesis method of intermediate 16 and selecting corresponding raw materials:
中间体20：4-氨基-7-氟-1-甲基-1H-吡唑并[4,3-c]喹啉-8-羧酸的制备
Intermediate 20: Preparation of 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid
第一步：甲基4-氨基-5-溴-2-氟苯酸酯的合成
Step 1: Synthesis of methyl 4-amino-5-bromo-2-fluorobenzoate
将甲基4-氨基-2-氟苯酸酯(20.8g，123.0mmol)溶于氯仿(500mL)中，0℃下加入N-溴代丁二酰亚胺(21.89g，123.0mmol)，20℃搅拌反应16小时。反应液旋蒸浓缩，粗品经正相柱分离得到甲基4-氨基-5-溴-2-氟苯酸酯(27.9g，收率91％)。MS m/z(ESI):248,250[M+H]+。Dissolve methyl 4-amino-2-fluorobenzoate (20.8g, 123.0mmol) in chloroform (500mL), add N-bromosuccinimide (21.89g, 123.0mmol) at 0°C, 20 The reaction was stirred for 16 hours. The reaction solution was concentrated by rotary evaporation, and the crude product was separated by normal phase column to obtain methyl 4-amino-5-bromo-2-fluorobenzoate (27.9 g, yield 91%). MS m/z(ESI):248,250[M+H] + .
1H NMR(400MHz,CDCl3)δ8.04(d,J＝7.2Hz,1H),6.46(d,J＝12.2Hz,1H),4.62(s,2H),3.88(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.04 (d, J = 7.2 Hz, 1H), 6.46 (d, J = 12.2 Hz, 1H), 4.62 (s, 2H), 3.88 (s, 3H).
第二步：甲基4-氨基-2-氟-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯酸酯的合成
Step 2: Synthesis of methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
将甲基4-氨基-5-溴-2-氟苯酸酯(27.9g，112.5mmol)和联硼酸频那醇酯(35mL，135mmol)溶于二氧六环(300mL)中，加入醋酸钾(33.12g，337.4mmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(8.23g，11.2mmol)。混合物在100℃下搅拌反应18小时。反应液过滤后旋干。粗品用水稀释，乙酸乙酯萃取三遍，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液旋蒸浓缩。粗品经正相柱分离得到甲基4-氨基-2-氟-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯酸酯(25.2g，76％)。MS m/z(ESI):296[M+H]+。Dissolve methyl 4-amino-5-bromo-2-fluorobenzoate (27.9g, 112.5mmol) and pinacol diborate (35mL, 135mmol) in dioxane (300mL), add potassium acetate (33.12 g, 337.4 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (8.23 g, 11.2 mmol). The mixture was stirred for 18 hours at 100°C. The reaction solution was filtered and spun dry. The crude product was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. The crude product was separated by normal phase column to obtain methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. Ester (25.2g, 76%). MS m/z(ESI):296[M+H] + .
1H NMR(400MHz,CDCl3)δ8.25(d,J＝9.2Hz,1H),6.24(d,J＝13.2Hz,1H),5.29(s,2H),3.86(s,3H),1.34(s,12H). 1 H NMR (400MHz, CDCl 3 ) δ8.25 (d, J = 9.2Hz, 1H), 6.24 (d, J = 13.2Hz, 1H), 5.29 (s, 2H), 3.86 (s, 3H), 1.34 (s,12H).
第三步：甲基4-氨基-7-氟-1-甲基-1H-吡唑并[4,3-c]喹啉-8-羧酸酯的合成
Step 3: Synthesis of methyl 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate
将5-溴-1-甲基-1H-吡唑-4-甲腈(9.1g，48.9mmol)，甲基4-氨基-2-氟-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯酸酯(14.4g，48.9mmol)，碳酸钾(27.04g，195.7mmol)和四(三苯基膦)钯(7.35g，6.4mmol)加入1,4-二氧六环(100mL)和水(100mL)中，并在氮气保护下100℃反应16小时。减压蒸去有机溶剂，过滤，滤饼用乙醇(50mL)洗涤，滤饼干燥得到甲基4-氨基-7-氟-1-甲基-1H-吡唑并[4,3-c]喹啉-8-羧酸酯(13.28g，收率99％)。MS m/z(ESI):275[M+H]+。5-Bromo-1-methyl-1H-pyrazole-4-carbonitrile (9.1g, 48.9mmol), methyl4-amino-2-fluoro-5-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)benzoate (14.4g, 48.9mmol), potassium carbonate (27.04g, 195.7mmol) and tetrakis(triphenylphosphine)palladium (7.35g , 6.4 mmol) was added to 1,4-dioxane (100 mL) and water (100 mL), and reacted at 100°C for 16 hours under nitrogen protection. The organic solvent was evaporated under reduced pressure, filtered, the filter cake was washed with ethanol (50 mL), and the filter cake was dried to obtain methyl 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quin. Phenoline-8-carboxylate (13.28g, yield 99%). MS m/z(ESI):275[M+H] + .
第四步：4-氨基-7-氟-1-甲基-1H-吡唑并[4,3-c]喹啉-8-羧酸的合成
Step 4: Synthesis of 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid
甲基4-氨基-7-氟-1-甲基-1H-吡唑并[4,3-c]喹啉-8-羧酸酯(13.28g,48.4mmol)加入四氢呋喃(100mL)和水(100mL)中，然后加入一水合氢氧化锂(4.06g,96.8mmol)并在50℃条件下反应16小时。反应完成后旋干有机相并加水稀释，乙酸乙酯(200mL*6)萃取。水相用饱和硫酸氢钾调至pH＝2，有大量固体析出，过滤并用水(100mL)和乙腈(100mL)洗涤滤饼，滤饼干燥后得到4-氨基-7-氟-1-甲基-1H-吡唑并[4,3-c]喹啉-8-羧酸(6.7g，收率53％)。MS m/z(ESI):261[M+H]+。Methyl 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (13.28g, 48.4mmol) was added with tetrahydrofuran (100mL) and water ( 100 mL), then add lithium hydroxide monohydrate (4.06 g, 96.8 mmol) and react at 50°C for 16 hours. After the reaction is completed, spin the organic phase to dryness, dilute with water, and extract with ethyl acetate (200 mL*6). Adjust the water phase to pH=2 with saturated potassium hydrogen sulfate. A large amount of solid precipitates. Filter and wash the filter cake with water (100 mL) and acetonitrile (100 mL). After drying the filter cake, 4-amino-7-fluoro-1-methyl is obtained. -1H-Pyrazolo[4,3-c]quinoline-8-carboxylic acid (6.7g, yield 53%). MS m/z(ESI):261[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.73(d,J＝8.0Hz,1H),8.27(s,1H),7.54(s,2H),7.27(d,J＝13.2Hz,1H),4.38(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.73(d,J＝8.0Hz,1H),8.27(s,1H),7.54(s,2H),7.27(d,J＝13.2Hz,1H) ,4.38(s,3H).
中间体21-26可参照中间体20全部或部分合成方法选择相应的原料进行制备:
Intermediates 21-26 can be prepared by selecting corresponding raw materials by referring to all or part of the synthesis method of intermediate 20:
中间体27：5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑的制备
Intermediate 27: Preparation of 5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole
第一步：甲基4-甲基-5-氧代戊酸酯的合成
Step 1: Synthesis of methyl 4-methyl-5-oxopentanoate
在冰水浴下，六氢吡啶(14.66g，172.2mmol)，碳酸钾(4.76g，34.43mmol)中加入丙醛(5.0g,86.09mmol)，该混合物在室温下剧烈搅拌18小时。过滤，母液用无水硫酸钠干燥，再次过滤，滤液浓缩后溶于乙腈(50mL)，缓慢滴加丙烯酰酸甲酯(14.82g,172.2mmol)。反应液加热回流24小时。加入冰醋酸(10.34g,172.2mmol)和水(50mL),再回流24小时。反应液加水稀释后，用叔丁基甲醚萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液旋蒸浓缩。粗品经正相柱分离得到甲基4-甲基-5-氧代戊酸酯(6.22g，收率47.6％)。Under an ice-water bath, propionaldehyde (5.0g, 86.09mmol) was added to hexahydropyridine (14.66g, 172.2mmol) and potassium carbonate (4.76g, 34.43mmol), and the mixture was stirred vigorously at room temperature for 18 hours. Filter, dry the mother liquor over anhydrous sodium sulfate, filter again, concentrate the filtrate and dissolve it in acetonitrile (50 mL), and slowly add methyl acrylate (14.82g, 172.2mmol) dropwise. The reaction solution was heated to reflux for 24 hours. Add glacial acetic acid (10.34g, 172.2mmol) and water (50mL), and reflux for another 24 hours. The reaction solution was diluted with water and extracted with tert-butyl methyl ether. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. The crude product was separated by normal phase column to obtain methyl 4-methyl-5-oxopentanoate (6.22g, yield 47.6%).
1H NMR(400MHz,CDCl3)δ9.63(d,J＝1.6Hz,1H),3.68(s,3H),2.48-2.40(m,1H),2.41-2.35(m,2H),2.10-2.02(m,1H),1.71(dq,J＝14.3,7.3Hz,1H),1.14(d,J＝7.2Hz,3H).第二步：(3R,8S)-8-甲基-3-苯基六氢并-5H-噁唑并[3,2-a]吡啶-5-酮的合成
 1 H NMR (400MHz, CDCl 3 ) δ9.63 (d, J = 1.6Hz, 1H), 3.68 (s, 3H), 2.48-2.40 (m, 1H), 2.41-2.35 (m, 2H), 2.10- 2.02(m,1H),1.71(dq,J＝14.3,7.3Hz,1H),1.14(d,J＝7.2Hz,3H). Second step: (3R,8S)-8-methyl-3- Synthesis of phenylhexahydro-5H-oxazolo[3,2-a]pyridin-5-one
向甲基4-甲基-5-氧代戊酸酯(6.222g，43.16mmol)的甲苯(100mL)中加入(R)-2-氨基-2-苯基乙烷-1-醇(5.92g,43.16mmol)，该混合物加热回流24小时，并用分水器除水。反应液浓缩，粗品经正相柱分离得到(3R,8S)-8-甲基-3-苯基六氢并-5H-噁唑并[3,2-a]吡啶-5-酮(4.866g,收率46.3％)。MS m/z(ESI):232[M+H]+。To methyl 4-methyl-5-oxopentanoate (6.222 g, 43.16 mmol) in toluene (100 mL) was added (R)-2-amino-2-phenylethan-1-ol (5.92 g , 43.16 mmol), the mixture was heated to reflux for 24 hours, and water was removed with a water separator. The reaction solution was concentrated, and the crude product was separated by normal phase column to obtain (3R,8S)-8-methyl-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridin-5-one (4.866g , yield 46.3%). MS m/z(ESI):232[M+H] + .
1H NMR(400MHz,CDCl3)δ7.33-7.20(m,5H),4.93(dd,J＝6.8,1.3Hz,1H),4.44(d,J＝8.8Hz,1H),4.17-4.08(m,2H),4.01(dd,J＝9.0,1.3Hz,1H),2.46-2.28(m,2H),2.02-1.87(m,2H),1.60-1.45(m,1H),1.21(d,J＝6.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.33-7.20 (m, 5H), 4.93 (dd, J = 6.8, 1.3Hz, 1H), 4.44 (d, J = 8.8Hz, 1H), 4.17-4.08 ( m,2H),4.01(dd,J＝9.0,1.3Hz,1H),2.46-2.28(m,2H),2.02-1.87(m,2H),1.60-1.45(m,1H),1.21(d, J＝6.4Hz,3H).
第三步：(S)-1-((R)-2-羟基-1-苯基乙基)-5-甲基哌啶-2-酮的合成
Step 3: Synthesis of: (S)-1-((R)-2-hydroxy-1-phenylethyl)-5-methylpiperidin-2-one
向(3R,8S)-8-甲基-3-苯基六氢并-5H-噁唑并[3,2-a]吡啶-5-酮(4.866g，21.04mmol)的无水二氯甲烷溶液中(200mL)中加入三乙基硅烷(7.34g,63.12mmol)和四氯化钛(17.96g,94.68mmol)，该混合物在50℃条件下反应24小时。再补加三乙基硅烷(7.34g,63.12mmol)和四氯化钛(17.96g,94.68mmol)，在50℃条件下继续反应24小时。反应液缓慢倒入饱和碳酸氢钠溶液(500mL)中，水相过滤后用二氯甲烷萃取。有机相用无水硫酸钠干燥，过滤，滤液浓缩。粗品经正相柱分离得到(S)-1-((R)-2-羟基-1-苯基乙基)-5-甲基哌啶-2-酮(1.54g,收率31.4％)。MS m/z(ESI):234[M+H]+。To (3R,8S)-8-methyl-3-phenylhexahydro-5H-oxazolo[3,2-a]pyridin-5-one (4.866g, 21.04mmol) in anhydrous dichloromethane Triethylsilane (7.34g, 63.12mmol) and titanium tetrachloride (17.96g, 94.68mmol) were added to the solution (200mL), and the mixture was reacted at 50°C for 24 hours. Triethylsilane (7.34g, 63.12mmol) and titanium tetrachloride (17.96g, 94.68mmol) were added, and the reaction was continued at 50°C for 24 hours. The reaction solution was slowly poured into saturated sodium bicarbonate solution (500 mL), the aqueous phase was filtered and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by normal phase column to obtain (S)-1-((R)-2-hydroxy-1-phenylethyl)-5-methylpiperidin-2-one (1.54g, yield 31.4%). MS m/z(ESI):234[M+H] + .
第四步：(S)-5-甲基-1-(1-苯基乙烯基)哌啶-2-酮的合成
Step 4: Synthesis of (S)-5-methyl-1-(1-phenylvinyl)piperidin-2-one
向(S)-1-((R)-2-羟基-1-苯基乙基)-5-甲基哌啶-2-酮(10.3g，44.15mmol)的DMSO(150mL)溶液中加入单水氢氧化锂(37.05g,882.9mmol)。该混合物在135℃条件下反应4天。倒入水中，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到(S)-5-甲基-1-(1-苯基乙烯基)哌啶-2-酮(7.383g,收率66.0％)。MS m/z(ESI):216.3[M+H]+。To a solution of (S)-1-((R)-2-hydroxy-1-phenylethyl)-5-methylpiperidin-2-one (10.3 g, 44.15 mmol) in DMSO (150 mL) was added Lithium hydroxide in water (37.05g, 882.9mmol). The mixture was reacted at 135°C for 4 days. Pour into water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain (S)-5-methyl-1-(1-phenylvinyl)piperidin-2-one ( 7.383g, yield 66.0%). MS m/z(ESI):216.3[M+H] + .
第五步：(S)-5-甲基哌啶-2-酮的合成
Step 5: Synthesis of (S)-5-methylpiperidin-2-one
向(S)-5-甲基-1-(1-苯基乙烯基)哌啶-2-酮(7.28g，33.81mmol)的二氯甲烷(30mL)溶液中加入TFA(30mL)和水(3mL)。在40℃条件下反应过夜。浓缩后用反相柱分离得到粗品，冻干后加入氨水(3mL)，再浓缩干，用乙酸乙酯打浆过滤得到(S)-5-甲基哌啶-2-酮(2.52g,收率62.6％)。MS m/z(ESI):114[M+H]+。To a solution of (S)-5-methyl-1-(1-phenylvinyl)piperidin-2-one (7.28 g, 33.81 mmol) in dichloromethane (30 mL) was added TFA (30 mL) and water ( 3mL). React overnight at 40°C. After concentration, use a reverse-phase column to separate the crude product. After lyophilizing, add ammonia water (3mL), concentrate to dryness, beat with ethyl acetate and filter to obtain (S)-5-methylpiperidin-2-one (2.52g, yield 62.6%). MS m/z(ESI):114[M+H] + .
1H NMR(400MHz,MeOD)δ3.30-3.24(m,1H),2.86(dd,J＝12.2,10.1Hz,1H),2.39-2.26(m,2H),1.96-1.80(m,2H),1.54-1.40(m,1H),1.01(d,J＝6.5Hz,3H). 1 H NMR (400MHz, MeOD) δ3.30-3.24(m,1H),2.86(dd,J＝12.2,10.1Hz,1H),2.39-2.26(m,2H),1.96-1.80(m,2H) ,1.54-1.40(m,1H),1.01(d,J＝6.5Hz,3H).
第六步：叔-丁基(S)-5-甲基-2-氧代哌啶-1-羧酸酯的合成
Step 6: Synthesis of tert-butyl (S)-5-methyl-2-oxopiperidine-1-carboxylate
向(S)-5-甲基哌啶-2-酮(2.02g，17.85mmol)的四氢呋喃(25mL)溶液中加入DMAP(327mg,2.68mmol)和二碳酸二叔丁酯(6.22g，26.78mmol)。在25℃条件下反应过夜。反应液浓缩后用二氯甲烷稀释，5％硫酸氢钾溶液洗涤。有机相用无水硫酸钠干燥，过滤，滤液浓缩得到叔-丁基(S)-5-甲基-2-氧代哌啶-1-羧酸酯(3.48g,12.55mmol,70.3％)。MS m/z(ESI):214[M+H]+。To a solution of (S)-5-methylpiperidin-2-one (2.02g, 17.85mmol) in tetrahydrofuran (25mL) was added DMAP (327mg, 2.68mmol) and di-tert-butyl dicarbonate (6.22g, 26.78mmol) ). React overnight at 25°C. The reaction solution was concentrated, diluted with methylene chloride, and washed with 5% potassium hydrogen sulfate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain tert-butyl (S)-5-methyl-2-oxopiperidine-1-carboxylate (3.48g, 12.55mmol, 70.3%). MS m/z(ESI):214[M+H] + .
1H NMR(400MHz,CDCl3)δ3.83-3.75(m,1H),3.11(dd,J＝12.7,10.4Hz,1H),2.63-2.53(m,1H),2.53-2.41(m,1H),2.01-1.93(m,1H),1.92-1.83(m,1H),1.53(s,9H),1.46-1.40(m,1H),1.04(d,J＝6.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ3.83-3.75(m,1H),3.11(dd,J＝12.7,10.4Hz,1H),2.63-2.53(m,1H),2.53-2.41(m,1H) ),2.01-1.93(m,1H),1.92-1.83(m,1H),1.53(s,9H),1.46-1.40(m,1H),1.04(d,J＝6.6Hz,3H).
第七步：叔-丁基(S)-3-甲基-6-(((三氟甲基)磺酰)氧基)-3,4-二氢吡啶-1(2H)-羧酸酯的合成
Step 7: tert-Butyl (S)-3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate Synthesis
在-78℃条件下，往叔-丁基(S)-5-甲基-2-氧代哌啶-1-羧酸酯(1.00g，4.69mmol)的无水四氢呋喃(25mL)溶液中加入双(三甲基硅基)氨基钠(3.52mL,7.03mmol)。反应液在该温度下反应1小时。然后加入N-苯基双(三氟甲磺酰亚胺)(2.18g，6.10mmol)。反应液缓慢升温，在室温下搅拌3.5小时。反应液用乙酸乙酯稀释，饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩。粗品经正相柱分离得到叔-丁基(S)-3-甲基-6-(((三氟甲基)磺酰)氧基)-3,4-二氢吡啶-1(2H)-羧酸酯(1.05g,收率62.4％)。MS m/z(ESI):290[M+H-56]+。To a solution of tert-butyl (S)-5-methyl-2-oxopiperidine-1-carboxylate (1.00 g, 4.69 mmol) in anhydrous tetrahydrofuran (25 mL) at -78°C was added Sodium bis(trimethylsilyl)amide (3.52 mL, 7.03 mmol). The reaction solution was reacted at this temperature for 1 hour. Then N-phenylbis(trifluoromethanesulfonimide) (2.18 g, 6.10 mmol) was added. The reaction solution was slowly heated up and stirred at room temperature for 3.5 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by normal phase column to obtain tert-butyl (S)-3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)- Carboxylic acid ester (1.05g, yield 62.4%). MS m/z(ESI):290[M+H-56] + .
1H NMR(400MHz,CDCl3)δ5.25(t,J＝3.8Hz,1H),3.87(dd,J＝12.8,3.3Hz,1H),3.00(dd,J＝12.7,9.1Hz,1H),2.44-2.34(m,1H),1.98-1.88(m,1H),1.88-1.78(m,1H),1.49(s,9H),0.99(d,J＝6.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ5.25 (t, J = 3.8 Hz, 1H), 3.87 (dd, J = 12.8, 3.3 Hz, 1H), 3.00 (dd, J = 12.7, 9.1 Hz, 1H) ,2.44-2.34(m,1H),1.98-1.88(m,1H),1.88-1.78(m,1H),1.49(s,9H),0.99(d,J＝6.6Hz,3H).
第八步：叔-丁基(S)-6-(苯并[d]噻唑-5-基)-3-甲基-3,4-二氢吡啶-1(2H)-羧酸酯的合成
Step 8: Synthesis of tert-butyl (S)-6-(benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate
将叔-丁基(S)-3-甲基-6-(((三氟甲基)磺酰)氧基)-3,4-二氢吡啶-1(2H)-羧酸酯(1.39g，4.02mmol)，5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯并[d]噻唑(1.00g，3.83mmol)，碳酸钠(1.01g，9.57mmol)和1,1'-双二苯基膦二茂铁二氯化钯(140mg，0.191mmol)加入1,4-二氧六环(30mL)和水(10mL)中，并在氮气保护下90℃反应18小时。反应液用乙酸乙酯稀释，饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩。粗品经正相柱分离得到叔-丁基(S)-6-(苯并[d]噻唑-5-基)-3-甲基-3,4-二氢吡啶-1(2H)-羧酸酯(1.01g,收率74.9％)。MS m/z(ESI):331[M+H]+。tert-Butyl (S)-3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (1.39g , 4.02mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (1.00g, 3.83mmol), Sodium carbonate (1.01g, 9.57mmol) and 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (140mg, 0.191mmol) were added to 1,4-dioxane (30mL) and water (10mL) in, and reacted at 90°C for 18 hours under nitrogen protection. The reaction solution was diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by normal phase column to obtain tert-butyl (S)-6-(benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylic acid Ester (1.01g, yield 74.9%). MS m/z(ESI):331[M+H] + .
第九步：(S)-5-(5-甲基-3,4,5,6-四氢吡啶-2-基)苯并[d]噻唑的合成
Step 9: Synthesis of (S)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole
向叔-丁基(S)-6-(苯并[d]噻唑-5-基)-3-甲基-3,4-二氢吡啶-1(2H)-羧酸酯(1.01g，3.05mmol)的二氯甲烷(9mL)溶液中加入三氟乙酸(3mL,2.68mmol)。在25℃条件下反应过夜。反应液浓缩后加水稀释，用氨水调pH到8,用二氯甲烷萃取。有机相用无水硫酸钠干 燥，过滤，滤液浓缩得到(S)-5-(5-甲基-3,4,5,6-四氢吡啶-2-基)苯并[d]噻唑(0.70g,收率91.7％)。MS m/z(ESI):231[M+H]+。To tert-butyl(S)-6-(benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate (1.01g, 3.05 To a solution of dichloromethane (9 mL) was added trifluoroacetic acid (3 mL, 2.68 mmol). React overnight at 25°C. The reaction solution was concentrated, diluted with water, adjusted to pH 8 with ammonia, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate Dry, filter, and concentrate the filtrate to obtain (S)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole (0.70g, yield 91.7%) . MS m/z(ESI):231[M+H] + .
第十步：5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑的合成
Step 10: Synthesis of 5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole
冰水浴下，向(S)-5-(5-甲基-3,4,5,6-四氢吡啶-2-基)苯并[d]噻唑(0.70g，3.04mmol)的甲醇(5mL)溶液中加入硼氢化钠(308mg,9.12mmol)。反应液在室温下搅拌45分钟。反应液浓缩后加水稀释，用氨水调pH到8,用二氯甲烷萃取。有机相用无水硫酸钠干燥，过滤，滤液浓缩得到5-((2R,5S)-5-甲基哌啶-2-基)苯并[d]噻唑(0.69g,收率97.6％)。MS m/z(ESI):233[M+H]+。Under an ice-water bath, add (S)-5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole (0.70g, 3.04mmol) in methanol (5mL ) solution, add sodium borohydride (308 mg, 9.12 mmol). The reaction solution was stirred at room temperature for 45 minutes. The reaction solution was concentrated, diluted with water, adjusted to pH 8 with ammonia, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 5-((2R,5S)-5-methylpiperidin-2-yl)benzo[d]thiazole (0.69g, yield 97.6%). MS m/z(ESI):233[M+H] + .
1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.15(d,J＝1.7Hz,1H),7.88(d,J＝8.3Hz,1H),7.56(dd,J＝8.3,1.7Hz,1H),3.78(dd,J＝11.4,2.6Hz,1H),3.22-3.13(m,1H),2.48(t,J＝11.4Hz,1H),1.97-1.87(m,2H),1.86-1.68(m,2H),1.30-1.19(m,1H),0.92(d,J＝6.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.98 (s, 1H), 8.15 (d, J = 1.7Hz, 1H), 7.88 (d, J = 8.3Hz, 1H), 7.56 (dd, J = 8.3, 1.7Hz,1H),3.78(dd,J＝11.4,2.6Hz,1H),3.22-3.13(m,1H),2.48(t,J＝11.4Hz,1H),1.97-1.87(m,2H), 1.86-1.68(m,2H),1.30-1.19(m,1H),0.92(d,J=6.6Hz,3H).
Ⅱ.实施例的制备Ⅱ. Preparation of Examples
实施例1：(4-氨基-7-氟-1-甲基-1H-吡唑并[4,3-c]喹啉-8-基)(2-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)甲酮的制备
Example 1: (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(2-(1-methylpiperidine) Preparation of -4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)methanone
将2-(1-甲基哌啶-4-基)-5-(哌啶-2-基)苯并[d]噻唑(74mg，0.15mmol)和4-氨基-7-氟-1-甲基-1H-吡唑并[4,3-c]喹啉-8-羧酸(40mg，0.15mmol)溶于N,N-二甲基甲酰胺(3mL)中，加入三乙胺(71mg，0.70mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(80mg，0.21mmol)，氮气置换三次室温搅拌过夜。反应液直接经反相分离得到(4-氨基-7-氟-1-甲基-1H-吡唑并[4,3-c]喹啉-8-基)(2-(2-(1-甲基哌啶-4-基)苯并[d]噻唑-5-基)哌啶-1-基)甲酮(13mg，收率：15％)。MS m/z(ESI):558[M+H]+。2-(1-methylpiperidin-4-yl)-5-(piperidin-2-yl)benzo[d]thiazole (74 mg, 0.15 mmol) and 4-amino-7-fluoro-1-methyl 1H-Pyrazolo[4,3-c]quinoline-8-carboxylic acid (40mg, 0.15mmol) was dissolved in N,N-dimethylformamide (3mL), and triethylamine (71mg, 0.70mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (80mg, 0.21mmol), replaced with nitrogen three times and stirred at room temperature overnight. The reaction solution is directly separated by reversed phase to obtain (4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl) (2-(2-(1- Methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)methanone (13 mg, yield: 15%). MS m/z(ESI):558[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.33-7.72(m,4H),7.49-7.35(m,2H),7.29(s,2H),6.09-5.08(m,1H),4.60-4.42(m,3H),3.80-3.48(m,1H),3.17-2.58(m,6H),2.20(s,3H),2.10-2.00(m,4H),1.88-1.76(m,2H),1.70-1.40(m,4H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.33-7.72(m,4H),7.49-7.35(m,2H),7.29(s,2H),6.09-5.08(m,1H),4.60-4.42 (m,3H),3.80-3.48(m,1H),3.17-2.58(m,6H),2.20(s,3H),2.10-2.00(m,4H),1.88-1.76(m,2H),1.70 -1.40(m,4H).
将按照上述制备方法得到的实施例1化合物(940mg,1.69mmol)经手性SFC制备拆分(柱型:AS-H 4.6*100mm,5um；流动相:甲醇[0.2％氨(7M in甲醇)]/乙腈＝30％；流速:3.0mL/min；柱温:40℃；检测波长:214nm)得到实施例1-1(411mg峰1,保留时间：1.391min)和实施例1-2((448mg,峰2,保留时间:1.890min)。

The compound of Example 1 (940mg, 1.69mmol) obtained according to the above preparation method was prepared and separated by chiral SFC (column type: AS-H 4.6*100mm, 5um; mobile phase: methanol [0.2% ammonia (7M in methanol)] /acetonitrile=30%; flow rate: 3.0mL/min; column temperature: 40°C; detection wavelength: 214nm) to obtain Example 1-1 (411mg peak 1, retention time: 1.391min) and Example 1-2 ((448mg , Peak 2, retention time: 1.890min).

实施例2～87可参照实施例1、1-1、1-2全部或部分合成方法选择相应的原料进行制备:

















Embodiments 2 to 87 can be prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of Embodiments 1, 1-1, and 1-2:

















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 compounds prepared in the above examples are as follows:


生物学测试评价Biological test evaluation
一、人结肠癌HCT116细胞增殖抑制试验1. Human colon cancer HCT116 cell proliferation inhibition test
1、将HCT 116MTAP敲除和MTAP野生型细胞铺在96孔平底板中，用含有10％胎牛血清+1％青霉素-链霉素的McCoy’s 5A培养基于37℃、5％CO2条件下培养过夜。1. Plate HCT 116MTAP knockout and MTAP wild-type cells in a 96-well flat-bottom plate, and culture them in McCoy's 5A containing 10% fetal calf serum + 1% penicillin-streptomycin at 37°C and 5% CO2 . overnight.
2、第二天，用DMSO溶解化合物，依次用DMSO和培养基稀释化合物并转移至细胞板，化合物终浓度为10μM，4倍稀释，9个浓度梯度外加DMSO对照。2. The next day, dissolve the compound with DMSO, dilute the compound with DMSO and culture medium in sequence and transfer to the cell plate. The final concentration of the compound is 10 μM, 4-fold dilution, 9 concentration gradients plus DMSO control.
3、取出未用化合物处理的细胞，用CellTiter-Glo Luminescent Cell Viability Assay(Promega)检测细胞活性，操作参照试剂盒说明书，然后将细胞板置于EnVision Multilabel Reader上检测冷光信号。3. Remove the cells that have not been treated with compounds and use CellTiter-Glo Luminescent Cell Viability Assay (Promega) to detect cell viability. Follow the instructions of the kit and then place the cell plate on the EnVision Multilabel Reader to detect the luminescence signal.
4、同时将加入化合物处理的细胞板至于37℃、5％CO2条件下连续培养6天。4. At the same time, the cell plate treated with the compound was continuously cultured at 37°C and 5% CO 2 for 6 days.
5、然后，同样用CellTiter-Glo检测细胞活性。5. Then, also use CellTiter-Glo to detect cell viability.
6、最后，用GraphPad Prism v 9.2.0软件的四参数剂量反应曲线模块绘制剂量反应曲线并计算增殖抑制IC50(单位：nM)。

6. Finally, use the four-parameter dose-response curve module of GraphPad Prism v 9.2.0 software to draw a dose-response curve and calculate the proliferation inhibition IC 50 (unit: nM).

从具体实施例化合物生物活性数据来看，本发明系列化合物在细胞水平上对人结肠癌HCT116 MTAP敲除细胞增殖具有很强的抑制作用。Judging from the biological activity data of the compounds in specific examples, the series of compounds of the present invention have a strong inhibitory effect on the proliferation of human colon cancer HCT116 MTAP knockout cells at the cellular level.
二、小鼠药代动力学测定2. Mouse pharmacokinetics determination
1.研究目的1. Research purpose
本试验目的为研究本发明部分化合物的药代动力学行为，给药方式分别为：ICR小鼠经单次口服(PO)，给药剂量：10mg/kg。The purpose of this test is to study the pharmacokinetic behavior of some compounds of the present invention. The administration methods are: single oral administration (PO) to ICR mice, and the dosage is 10 mg/kg.
2.试验方案2.Test plan
2.1试验药品2.1 Experimental 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 derived from the specific example compounds of the present invention.
2.2试验动物2.2 Experimental 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 mouse male N=3 Original source: Shanghai Sipur-Bika Experimental Animal Co., Ltd.
2.3药物配制与给药2.3 Drug Preparation and Administration
称取化合物分别溶于20％PG+10％Solutol HS15+70％pH3 citrate buffer的溶媒中，摇匀、超声，配成无色澄清溶液或悬浊液。9只小鼠，禁食一夜后口服。给药剂量为10mg/kg。Weigh the compounds and dissolve them in the solvent of 20% PG + 10% Solutol HS15 + 70% pH3 citrate buffer, shake well, ultrasonicate, and prepare a colorless clear solution or suspension. 9 mice were fed orally after fasting overnight. The dosage is 10mg/kg.
2.4样品采集：2.4 Sample collection:
1)约90μL/时间点经颌下静脉取血，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度)。1) Take about 90 μL/time point of blood through the submandibular vein, anticoagulate with heparin sodium, place it on ice after collection, and centrifuge to separate the plasma within 1 hour (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 degrees ).
2)采血时间点为第1,4,24小时。样品放于负20度冰箱保存。2) The blood collection time points are the 1st, 4th and 24th hour. The samples are stored in a refrigerator at minus 20 degrees Celsius.
3)血浆样品40μL，加入160μL含有内标的冰冷乙腈，涡旋3分钟，11000转/分钟离心5分钟。3) For 40 μL of plasma sample, add 160 μL of ice-cold acetonitrile containing internal standard, vortex for 3 minutes, and centrifuge at 11,000 rpm for 5 minutes.
4)取上清液100μL加入到100μL水中，取5μL进样到LC/MS/MS进行分析。4) Add 100 μL of supernatant to 100 μL of water, and inject 5 μL into LC/MS/MS for analysis.
三、小鼠中的血脑屏障穿透分析 3. Blood-brain barrier penetration analysis in mice
通过上述方法测得的脑或血浆中的AUC或者浓度来计算Kp。Kp是指脑和血液中药物浓度之间的关系，用于评估药物穿透血脑屏障的能力。给药后的Kp通过以下的公式进行计算：Kp is calculated from the AUC or concentration in brain or plasma measured by the above method. Kp refers to the relationship between drug concentrations in the brain and blood and is used to evaluate the ability of a drug to penetrate the blood-brain barrier. Kp after administration is calculated using the following formula:
Kp＝[AUC(脑)/AUC(血浆)]，或者，Kp＝[药物浓度(脑)/药物浓度(血浆)]。Kp=[AUC (brain)/AUC (plasma)], or, Kp=[drug concentration (brain)/drug concentration (plasma)].
表2：实施例化合物及对比化合物的Kp的数据
Table 2: Kp data of example compounds and comparative compounds
由上述数据可知，本发明实施例82和83化合物具有很高的Kp，具有优异的血脑屏障穿透特性。It can be seen from the above data that the compounds of Examples 82 and 83 of the present invention have high Kp and excellent blood-brain barrier penetration properties.
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 to the same extent as if each individual document was 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 can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims (24)

  1. 式(I)化合物、其立体异构体或其药学上可接受盐：
    Compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof:
    其中，X1为CR6或N；X2为CR7或N；X3为CR8或N；Among them, X 1 is CR 6 or N; X 2 is CR 7 or N; X 3 is CR 8 or N;
    环A为C4-12环烷基、4-12元杂环基、C6-10芳基或5-10元杂芳基；Ring A is C 4-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    环B选自4-10元含氮杂环基或5-10元含氮杂芳基，所述氮原子与羰基连接，其中，Ring B is selected from a 4-10-membered nitrogen-containing heterocyclyl group or a 5-10-membered nitrogen-containing heteroaryl group, and the nitrogen atom is connected to a carbonyl group, wherein,
    1)当环B选自4元含氮杂环基、8-10元含氮杂环基或8-10元含氮杂芳基时，1) When ring B is selected from a 4-membered nitrogen-containing heterocyclic group, an 8-10-membered nitrogen-containing heterocyclic group or an 8-10-membered nitrogen-containing heteroaryl group,
    环C为C3-12环烷基、4-12元杂环基、C6-10芳基或5-10元杂芳基，所述C3-12环烷基或4-12元杂环基任选稠合于C6-10芳基或5-10元杂芳基，所述C6-10芳基或5-10元杂芳基任选稠合于C3-12环烷基或4-12元杂环基；Ring C is C 3-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, and the C 3-12 cycloalkyl or 4-12 membered heterocycle The base is optionally condensed on a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 6-10 aryl group or 5-10 membered heteroaryl group is optionally condensed on a C 3-12 cycloalkyl group or 4-12 membered heterocyclyl;
    每个R1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS( O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O )NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro base, azido group, C 1-10 alkyl group, halogen substituted C 1-10 alkyl group, deuterium substituted C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, 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-OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8alkyl -C(O) OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl Substituted by the substituents of -C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 ;
    2)当环B选自5-7元含氮杂环基或5-7元含氮杂芳基时，2) When ring B is selected from a 5-7 membered nitrogen-containing heterocyclyl group or a 5-7 membered nitrogen-containing heteroaryl group,
    环C与-(R1)m一起形成：其中，Ring C together with -(R 1 ) m forms: in,
    a)当环C与-(R1)m一起形成时，Y1、Y2各自独立地为CR1或N，Y3为O、S或NR1’，Y4、Y5各自独立地为CR1”或N； a) When ring C is formed together with -(R 1 ) m When , Y 1 and Y 2 are each independently CR 1 or N, Y 3 is O, S or NR 1 ', Y 4 and Y 5 are each independently CR 1 " or N;
    每个R1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS( O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O )NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro base, azido group, C 1-10 alkyl group, halogen substituted C 1-10 alkyl group, deuterium substituted C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, 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-OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8alkyl -C(O) OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl Substituted by the substituents of -C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 ;
    R1’选自氢、氘、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)R11和-C(O)NR12R13，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；R 1 ' is selected from hydrogen, deuterium, 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, -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)R 11 and -C(O)NR 12 R 13 , the above-mentioned groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azide, 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 hetero Aryl, =O, =S, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9. -C 0-8 alkyl-OR 10 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl -C(O)SR 10 , -C 0-8 alkyl -SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O) (R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )- Substituted by C(O)R 11 substituent;
    每个R1”各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 ″ is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS (O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , - C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl Base-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C( O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , 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, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl -SF 5 , -C 0- 8alkyl -OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8alkyl -C(O )OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , - C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 Substituted by the substituents of alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 ;
    b)当环C与-(R1)m一起形成时，Y6、Y7、Y8和Y9各自独立地为CR1或N，且至少一个选自CR1，其中，至少一个R1为-C0-8烷基-NR14R15或-O-C1-4烷基-NR14R15，其它每个R1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8 烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；b) When ring C is formed together with -(R 1 ) m When , Y 6 , Y 7 , Y 8 and Y 9 are each independently CR 1 or N, and at least one is selected from CR 1 , wherein at least one R 1 is -C 0-8 alkyl-NR 14 R 15 or -OC 1-4 alkyl-NR 14 R 15 , each other R 1 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-OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8alkyl -C(O) OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl -C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , 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 alkyne Base, 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O) R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , - Substituted by the substituents of C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 ;
    每个R2各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，或者，当p≥2时，其中两个R2与其直接相连的部分一起形成一个C(O)；Each R 2 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 -8alkyl -SF 5 , -C 0-8alkyl -OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0- 8alkyl -C(O)R 11 , -C 0-8alkyl -OC(O)R 11 , -C 0-8alkyl -P(O)(R 11 ) 2 , -C 0-8alkyl -NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , or when p≥ 2, two of the R 2s together with their directly connected parts form a C(O);
    R3和R4各自独立地选自氢、氘、羟基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基和3-12元杂环基，或者，R3和R4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，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、羟基、＝O、＝S、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基和-NR12R13的取代基所取代；R 3 and R 4 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl and 3-12 membered heterocyclyl, or R 3 and R 4 together with the nitrogen atom directly connected to form a 4-10-membered heterocyclyl or 5-10-membered heteroaryl, and the above groups are independently optionally further substituted by one or more Selected from deuterium, halogen, cyano, hydroxyl, =O, =S, 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 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclic oxy and -Substituted by the substituent of NR 12 R 13 ;
    每个R5各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；Each R 5 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-OS( O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O )NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro base, azido group, C 1-10 alkyl group, halogen substituted C 1-10 alkyl group, deuterium substituted C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, 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-OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8alkyl -C(O) OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl Substituted by the substituents of -C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 ;
    R6、R7和R8各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基 -C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11；R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl Base -OR 10 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl -C(O)SR 10 , -C 0-8 alkyl -SC(O)R 11 , -C 0-8 alkyl -C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 ;
    每个R9独立地选自氢、氘、羟基、C1-10烷基、C2-10链烯基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基和-NR12R13，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、C1-10烷基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR12R13的取代基所取代；Each R 9 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 aromatic group, 5-10 membered heteroaryl and -NR 12 R 13 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 1- 10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclic oxy, C 6-10 aryl, C 6-10 Substituted by aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 12 R 13 substituents;
    每个R10独立地选自氢、氘、C1-10烷基、C2-10链烯基、C3-12环烷基、3-12元杂环基、C6-10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、C1-10烷基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR12R13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 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, the above-mentioned groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclic oxy, C 6-10 aryl, C 6-10 aryloxy, 5 Substituted by -10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 12 R 13 substituents;
    每个R11独立地选自氢、氘、羟基、C1-10烷基、C1-10烷氧基、C2-10链烯基、C2-10链炔基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR12R13，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、C1-10烷基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR12R13的取代基所取代；Each R 11 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, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclic oxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 12 R 13 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =O, cyano group, C 1-10 alkyl group , C 1-10 alkoxy group, C 3-12 cycloalkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 aryl group, Substituted by C 6-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 12 R 13 substituents;
    每个R12和R13各自独立地选自氢、氘、羟基、C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10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C1-10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、C1-10烷基、C2-10链烯基、C2-10链炔基、卤取代C1-10烷基、氘取代C1-10烷基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、C1-10烷基单取代氨基、C1-10烷基双取代氨基和C1-10烷酰基的取代基所取代，或者，Each R 12 and R 13 are 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 group, dimethylaminosulfonyl group and C 1-10 alkanoyl group, 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 group, 3-12 membered heterocyclyl group, 3-12 membered heterocyclic group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered Substituted with substituents of heteroaryloxy, amino, C 1-10 alkyl monosubstituted amino, C 1-10 alkyl disubstituted amino and C 1-10 alkanoyl, or,
    R12和R13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、C1-10烷基、C2-10链烯基、C2-10链炔基、卤取代C1-10烷基、氘取代C1-10烷基、C1-10烷氧基、C3-12环烷基、C3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C6-10芳基、C6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、C1-10烷基单取代氨基、C1-10烷基双取代氨基和C1-10烷酰基的取代基所取代；R 12 and R 13 together with the nitrogen atom to which they are directly connected form a 4-10-membered heterocyclyl or 5-10-membered heteroaryl, and the 4-10-membered heterocyclyl or 5-10-membered heteroaryl is optionally further Substituted 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 C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclic oxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, C 1-10 alkyl monosubstituted amino, C 1-10 alkyl bis Substituted with substituted amino and C 1-10 alkanoyl substituents;
    R14和R15各自独立地选自氢、氘、C1-10烷基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳基、-C0-8烷基-SF5、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-C(O)R11、-C0-8烷基-P(O)(R11)2和-C0-8烷基-C(O)NR12R13，或者，R14和R15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，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、C1-10烷基、卤取代C1-10烷基、氘取代C1-10烷基、C2-10链烯基、C2-10链炔基、C3-12环烷基、3-12元杂环基、C6-10芳基、5-10元杂芳 基、＝O、＝S、-C0-8烷基-SF5、-C0-8烷基-O-S(O)2R9、-C0-8烷基-S(O)rR9、-C0-8烷基-O-R10、-C0-8烷基-C(O)OR10、-C0-8烷基-C(O)SR10、-C0-8烷基-S-C(O)R11、-C0-8烷基-C(O)R11、-C0-8烷基-O-C(O)R11、-C0-8烷基-P(O)(R11)2、-C0-8烷基-NR12R13、-C0-8烷基-C(O)NR12R13和-C0-8烷基-N(R12)-C(O)R11的取代基所取代；R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl base, -C 0-8 alkyl -SF 5 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl -C(O)SR 10 , -C 0-8 alkyl -C(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 and -C 0-8 alkyl-C(O)NR 12 R 13 , or, R 14 and R 15 The nitrogen atom directly connected to it together forms a 4-10-membered heterocyclyl group or a 5-10-membered heteroaryl group, and the above-mentioned groups are independently optionally further optionally substituted by one or more members selected from the group consisting of deuterium, halogen, cyano, nitro, Azide group, C 1-10 alkyl group, halogen substituted C 1-10 alkyl group, deuterium substituted C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 3-12 ring Alkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl Base, =O, =S, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl- SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alkyl-P(O)( R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C (O) Substituted by a substituent of R 11 ;
    每个r独立地为0、1或2；Each r is independently 0, 1, or 2;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    n选自0、1、2、3、4或5；且n is selected from 0, 1, 2, 3, 4 or 5; and
    p选自0、1、2、3、4或5。p is selected from 0, 1, 2, 3, 4 or 5.
  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，R3和R4各自独立地选自氢、氘、羟基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基和3-6元杂环基，或者，R3和R4与其直接相连的氮原子一起形成一个4-6元杂环基或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、氰基、羟基、＝O、＝S、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基和-NR12R13的取代基所取代；其中，R12和R13如权利要求1所述；The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R 3 and R 4 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, or R 3 and R 4 are formed together with the nitrogen atom directly connected to them A 4-6-membered heterocyclyl or 5-8-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more deuterium, halogen, cyano, hydroxyl, =O, =S, 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 1-4 alkoxy, C 3-6 Substituted by the substituents of cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and -NR 12 R 13 ; wherein, R 12 and R 13 are as defined by the rights As stated in requirement 1;
    优选地，R3和R4各自独立地选自氢、氘、羟基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基和3-6元杂环基。Preferably, R 3 and R 4 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkene base, C 2-4 alkynyl group, C 3-6 cycloalkyl group and 3-6 membered heterocyclyl group.
  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，R6、R7和R8各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11；The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyanide base, 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-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl -C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O) R 11 , -C 0-4 alkyl-P(O)(R 11 ) 2 , -C 0-4 alkyl-NR 12 R 13 , -C 0-4 alkyl-C(O)NR 12 R 13 and -C 0-4alkyl -N(R 12 )-C(O)R 11 ;
    优选地，R6、R7和R8各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11；Preferably, R 6 , R 7 and R 8 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 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C( O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O )R 11 ;
    其中，R9、R10、R11、R12、R13和r如权利要求1所述。Wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described in claim 1 .
  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，R14和R15各自独立地选自氢、氘、C1-4烷基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-C(O)R11、-C0-4烷基-P(O)(R11)2和-C0-4烷基-C(O)NR12R13，或者，R14和R15与其直接相连的氮原子一起形成一个4-6元杂环基或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、氰基、硝基、叠氮基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-4 alkyl , 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 -C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-P(O) (R 11 ) 2 and -C 0-4 alkyl-C(O)NR 12 R 13 , or R 14 and R 15 together with the nitrogen atom directly connected to form a 4-6 membered heterocyclic group or 5-8 Yuanheteroaryl, 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- chain 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 0-4alkyl -OS(O) 2 R 9 , -C 0-4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0- 4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O)SR 10 , -C 0-4alkyl -SC(O)R 11 , -C 0-4alkyl -C (O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4 alkyl-P(O)(R 11 ) 2 , -C 0-4 alkyl-NR 12 R 13 , substituted by the substituents of -C 0-4 alkyl-C(O)NR 12 R 13 and -C 0-4 alkyl-N(R 12 )-C(O)R 11 ;
    优选地，R14和R15各自独立地选自氢、氘、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-C(O)OR10、-C(O)SR10、-C(O)R11、-P(O)(R11)2和-C(O)NR12R13；Preferably, R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl group, 5-8 membered heteroaryl group, -SF 5 , -C(O)OR 10 , -C(O)SR 10 , -C(O)R 11 , -P(O)(R 11 ) 2 and -C(O)NR 12 R 13 ;
    其中，R9、R10、R11、R12、R13和r如权利要求1所述。Wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described in claim 1 .
  5. 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R5各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that each R 5 is independently selected from hydrogen, 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 base, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , -C 0-4 alkyl -S(O) r R 9 , -C 0-4 Alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4 alkyl-P(O)(R 11 ) 2 , - C 0-4 alkyl-NR 12 R 13 , -C 0-4 alkyl-C(O)NR 12 R 13 and -C 0-4 alkyl-N(R 12 )-C(O)R 11 , The above-mentioned groups are independently optionally further substituted by one or more selected from the group consisting 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, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl -OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , - C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4 alkyl-P(O)(R 11 ) 2 , -C 0 Substituents of -4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0-4alkyl -N(R 12 )-C(O)R 11 replaced;
    优选地，每个R5各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Preferably, each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 aryl group, 5-8 membered heteroaryl group, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2. -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen , cyano group, 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 ring Alkyl group, 3-6 membered heterocyclyl group, C 6-8 aryl group, 5-8 membered heteroaryl group, =O, =S, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P Substituted by the substituents of (O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
    其中，R9、R10、R11、R12、R13和r如权利要求1所述。Wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described in claim 1 .
  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，每个R2各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基 -C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，或者，当p≥2时，其中两个R2与其直接相连的部分一起形成一个C(O)；The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that each R 2 is 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , -C 0 -4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O)SR 10 , -C 0-4alkyl -SC(O)R 11 , -C 0-4alkyl -C(O) R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4 alkyl-P(O)(R 11 ) 2 , -C 0-4 alkyl-NR 12 R 13 , - C 0-4alkyl -C(O)NR 12 R 13 and -C 0-4alkyl -N(R 12 )-C(O)R 11 , or, when p≥2, two of R 2 Together with its directly connected parts, they form a C(O);
    其中，R9、R10、R11、R12、R13和r如权利要求1所述。Wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described 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，环B选自4元含氮杂环基；The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that ring B is selected from a 4-membered nitrogen-containing heterocyclic group;
    环C为C3-6环烷基、4-8元杂环基、C6-8芳基或5-8元杂芳基，所述C3-6环烷基或4-8元杂环基任选稠合于C6-8芳基或5-8元杂芳基，所述C6-8芳基或5-8元杂芳基任选稠合于C3-6环烷基或4-8元杂环基；Ring C is C 3-6 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl, and the C 3-6 cycloalkyl or 4-8 membered heterocycle The base is optionally fused to C 6-8 aryl or 5-8 membered heteroaryl, and the C 6-8 aryl or 5-8 membered heteroaryl is optionally fused to C 3-6 cycloalkyl or 4-8 membered heterocyclyl;
    每个R1各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 is independently selected from hydrogen, 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and - C 0-4 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , -C 0 -4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O )SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , - C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0 -4Alkyl -N(R 12 )-C(O)R 11 substituent substituted;
    其中，R9、R10、R11、R12、R13和r如权利要求1所述。Wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described in claim 1 .
  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，环B选自8-10元含氮杂环基；The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that ring B is selected from 8-10 membered nitrogen-containing heterocyclic groups;
    环C为C3-6环烷基、4-8元杂环基、C6-8芳基或5-8元杂芳基，所述C3-6环烷基或4-8元杂环基任选稠合于C6-8芳基或5-8元杂芳基，所述C6-8芳基或5-8元杂芳基任选稠合于C3-6环烷基或4-8元杂环基；Ring C is C 3-6 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl, and the C 3-6 cycloalkyl or 4-8 membered heterocycle The base is optionally fused to C 6-8 aryl or 5-8 membered heteroaryl, and the C 6-8 aryl or 5-8 membered heteroaryl is optionally fused to C 3-6 cycloalkyl or 4-8 membered heterocyclyl;
    每个R1各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4 烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 is independently selected from hydrogen, 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and - C 0-4 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , -C 0 -4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O )SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , - C 0-4 Alkyl-P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0-4alkyl Substituted with the substituent -N(R 12 )-C(O)R 11 ;
    其中，R9、R10、R11、R12、R13和r如权利要求1所述。Wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described in claim 1 .
  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，环B选自5-7元含氮杂环基，环C与-(R1)m一起形成其中Y1、Y2各自独立地为CR1或N，Y3为O、S或NR1’，Y4、Y5各自独立地为CR1”或N；The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that ring B is selected from 5-7 membered nitrogen-containing heterocyclic groups, ring C and -(R 1 ) m form together Among them, Y 1 and Y 2 are each independently CR 1 or N, Y 3 is O, S or NR 1 ', Y 4 and Y 5 are each independently CR 1 " or N;
    每个R1各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 is independently selected from hydrogen, 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and - C 0-4 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted 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, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , -C 0 -4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O )SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , - C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0 -4Alkyl -N(R 12 )-C(O)R 11 substituent substituted;
    R1’选自氢、氘、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)R11和-C(O)NR12R13，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；R 1 ' is 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, -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)R 11 and -C(O)NR 12 R 13 , the above-mentioned groups are independently optionally further substituted 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, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 Alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4 alkyl-P(O)(R 11 ) 2 , - of C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0-4alkyl -N(R 12 )-C(O)R 11 Substituted by substituents;
    每个R1”各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、 -C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；Each R 1 ″ is independently selected from hydrogen, 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, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl- C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C(O)NR 12 R 13 and -C 0-4 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, Halo-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 -OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 Alkyl-OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl -C Substituted by (O)NR 12 R 13 and -C 0-4 alkyl-N(R 12 )-C(O)R 11 substituents;
    其中，R9、R10、R11、R12、R13和r如权利要求1所述。Wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described 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，环B选自5-7元含氮杂环基，环C与-(R1)m一起形成其中Y6、Y7、Y8和Y9各自独立地为CR1或N，且至少一个为CR1，其中，至少一个R1为-C0-4烷基-NR14R15或-O-C1-4烷基-NR14R15，其它每个R1各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-C0-4烷基-SF5、-C0-4烷基-O-S(O)2R9、-C0-4烷基-S(O)rR9、-C0-4烷基-O-R10、-C0-4烷基-C(O)OR10、-C0-4烷基-C(O)SR10、-C0-4烷基-S-C(O)R11、-C0-4烷基-C(O)R11、-C0-4烷基-O-C(O)R11、-C0-4烷基-P(O)(R11)2、-C0-4烷基-NR12R13、-C0-4烷基-C(O)NR12R13和-C0-4烷基-N(R12)-C(O)R11的取代基所取代；The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that ring B is selected from 5-7 membered nitrogen-containing heterocyclic groups, ring C and -(R 1 ) m form together Wherein Y 6 , Y 7 , Y 8 and Y 9 are each independently CR 1 or N, and at least one is CR 1 , wherein at least one R 1 is -C 0-4 alkyl -NR 14 R 15 or -OC 1-4 alkyl-NR 14 R 15 , each other R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 chain 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-OS(O) 2 R 9 , -C 0-4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O) OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4 alkyl-P(O)(R 11 ) 2 , -C 0-4 alkyl-NR 12 R 13 , -C 0-4 alkyl -C(O)NR 12 R 13 and -C 0-4 alkyl-N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen , cyano group, 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 ring Alkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0- 4alkyl -OC(O)R 11 , -C 0-4alkyl -P(O)(R 11 ) 2 , -C 0-4alkyl -NR 12 R 13 , -C 0-4alkyl- Substituted with substituents of C(O)NR 12 R 13 and -C 0-4 alkyl-N(R 12 )-C(O)R 11 ;
    其中，R9、R10、R11、R12、R13、R14、R15和r如权利要求1所述。Wherein, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and r are as described in claim 1 .
  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，每个R9独立地选自氢、氘、羟基、C1-4烷基、C2-4链烯基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基和-NR12R13，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、C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR12R13的取代基所取代；The compound of formula (I) according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, characterized in that each R 9 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, 5-8 membered heteroaryl and -NR 12 R 13 , the above groups are independent is optionally further selected from one or more deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy base, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxygen group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group Substituted with -NR 12 R 13 substituents;
    每个R10独立地选自氢、氘、C1-4烷基、C2-4链烯基、C3-6环烷基、3-6元杂环基、C6-8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、C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR12R13的取代基所取代；Each R 10 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 independently optionally further substituted by one or more 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 membered heterocyclyl, 3-6 membered heterocyclic oxy, C 6-8 aryl, C 6-8 aryloxy, 5 Substituted by -8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 12 R 13 substituents;
    每个R11独立地选自氢、氘、羟基、C1-4烷基、C1-4烷氧基、C2-4链烯基、C2-4链炔基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR12R13，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、C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6 元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR12R13的取代基所取代；Each R 11 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, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclic oxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 12 R 13 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =O, cyano group, C 1-4 alkyl group , C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 Substituted with substituents of heteroaryloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 12 R 13 ;
    每个R12和R13各自独立地选自氢、氘、羟基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8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C1-4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、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、氘取代C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、C1-4烷基单取代氨基、C1-4烷基双取代氨基和C1-4烷酰基的取代基所取代，或者，Each R 12 and R 13 are 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 heterocyclyl, C 6-8 aryl, 5-8-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl and C 1-4 alkanoyl, the above groups are independently optionally further selected from one or more 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 heterocyclyl, 3-6-membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered Substituted with heteroaryloxy, amino, C 1-4 alkyl monosubstituted amino, C 1-4 alkyl disubstituted amino and C 1-4 alkanoyl substituents, or,
    R12和R13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、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、氘取代C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、C1-4烷基单取代氨基、C1-4烷基双取代氨基和C1-4烷酰基的取代基所取代。R 12 and R 13 together with the nitrogen atom to which they are directly connected form a 4-8-membered heterocyclyl or 5-8-membered heteroaryl, and the 4-8-membered heterocyclyl or 5-8-membered heteroaryl is optionally further Substituted 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 C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclic oxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, C 1-4 alkyl monosubstituted amino, C 1-4 alkyl bis Substituted with substituted amino and C 1-4 alkanoyl substituents.
  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，环A与其直接相连的部分一起形成如下结构：

    The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that ring A and its directly connected part together form the following structure:

    其中，X1为CR6或N；X2为CR7或N；Among them, X 1 is CR 6 or N; X 2 is CR 7 or N;
    每个R5a各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 5a is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5- 8-membered heteroaryl, -SF 5 and -OR 10 , the above groups are independently optionally further substituted with one or more C 1-4 alkyl selected from deuterium, halogen, cyano, C 1-4 alkyl, and halogen base, 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 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C (O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C( Substituted by the substituents of O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
    每个R5b各自独立地选自氢、氘、C1-4烷基、C3-6环烷基、3-6元杂环基和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代； Each R 5b is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and -OR 10 , and the above groups are independently optionally further supplemented by a 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 chain Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC The substituents of (O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 replace;
    每个R5c各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 5c is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5- 8-membered heteroaryl, -SF 5 and -OR 10 , the above groups are independently optionally further substituted with one or more C 1-4 alkyl selected from deuterium, halogen, cyano, C 1-4 alkyl, and halogen base, 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 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C (O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C( Substituted by the substituents of O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
    每个R6各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基、3-6元杂环基、-SF5和-O-R10；Each R 6 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
    每个R7各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基、3-6元杂环基、-SF5和-O-R10；Each R 7 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
    每个R8各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基、3-6元杂环基、-SF5和-O-R10；Each R 8 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
    其中，R9、R10、R11、R12、R13和r如权利要求1所述。Wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described in claim 1 .
  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)化合物具有如下式(II)化合物结构：
    The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound of formula (I) has the following compound structure of formula (II):
    其中，Y1、Y2各自独立地为CR1或N，Y3为O、S或NR1’；Among them, Y 1 and Y 2 are each independently CR 1 or N, and Y 3 is O, S or NR 1 ';
    环A为C4-8环烷基、4-8元杂环基、C6-8芳基或5-8元杂芳基；Ring A is C 4-8 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl;
    环B与-(R2)p一起形成如下结构：
    Ring B together with -(R 2 ) p forms the following structure:
    每个R1各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、 -C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 1 is independently selected from hydrogen, 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, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C (O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , - NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano group , 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 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 Substituted by the substituents of , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
    R1’选自氢、氘、羟基、C1-4烷基、C1-4烷氧基、C2-4链烯基、C2-4链炔基、C3-6环烷基和3-6元杂环基，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；R 1 ' is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, the above groups are independently optionally further substituted 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 Base, =O, =S, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 Substituted with the substituent -N(R 12 )-C(O)R 11 ;
    每个R2各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11；Each R 2 is 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 group, C 3-6 cycloalkyl group, 3-6 membered heterocyclyl group, C 6-8 aryl group, 5-8 membered heteroaryl group, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC (O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
    R2’选自氢、氘、羟基、C1-4烷基、C1-4烷氧基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基和3-6元杂环基；R 2 ' is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl base and 3-6 membered heterocyclyl;
    每个R5各自独立地选自氢、氘、卤素、氰基、C1-4烷基、羟基取代C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11；Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl 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, - SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , - C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C (O)R 11 ;
    R6选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C1-4烷氧基、卤取代C1-4烷氧基、氘取代C1-4烷氧基、C3-6环烷基、C3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C6-8芳基、C6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、羟基和-NR12R13；R 6 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 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, deuterium-substituted C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3 -6-membered heterocyclyl, 3-6-membered heterocyclicoxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, hydroxyl and -NR 12 R 13 ;
    其中，R9、R10、R11、R12、R13、n、p和r如权利要求1所述。Wherein, R 9 , R 10 , R 11 , R 12 , R 13 , n, p and r are as described 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，环A与其直接相连的部分一起形成如下结构：
    The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that ring A and its directly connected part together form the following structure:
    其中，X1为CR6或N；X2为CH或N；Among them, X 1 is CR 6 or N; X 2 is CH or N;
    每个R5a各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C3-6环烷基、3-6元杂环基、 C6-8芳基、5-8元杂芳基、-SF5和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 5a is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 and -OR 10 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkane base, 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 heterocycle group, C 6-8 aryl group, 5-8 membered heteroaryl group, =O, =S, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , - C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , Substituted by the substituents of -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
    每个R5b各自独立地选自氢、氘、C1-4烷基、C3-6环烷基、3-6元杂环基和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 5b is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and -OR 10 , and the above groups are independently optionally further supplemented by a 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 chain Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC The substituents of (O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 replace;
    每个R5c各自独立地选自氢、氘、卤素、氰基、C1-4烷基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、-SF5和-O-R10，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、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C6-8芳基、5-8元杂芳基、＝O、＝S、-SF5、-O-S(O)2R9、-S(O)rR9、-O-R10、-C(O)OR10、-C(O)SR10、-S-C(O)R11、-C(O)R11、-O-C(O)R11、-P(O)(R11)2、-NR12R13、-C(O)NR12R13和-N(R12)-C(O)R11的取代基所取代；Each R 5c is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5- 8-membered heteroaryl, -SF 5 and -OR 10 , the above groups are independently optionally further substituted with one or more C 1-4 alkyl selected from deuterium, halogen, cyano, C 1-4 alkyl, and halogen base, 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 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C (O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C( Substituted by the substituents of O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
    每个R6各自独立地选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、氘取代C1-4烷基、C3-6环烷基、3-6元杂环基、-SF5和-O-R10；Each R 6 is 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 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
    其中，R9、R10、R11、R12、R13和r如权利要求1所述。Wherein, R 9 , R 10 , R 11 , R 12 , R 13 and r are as described in claim 1 .
  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)化合物具有如下式(III1)或式(III2)化合物结构：
    The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound of formula (I) has the following compound structure of formula (III 1 ) or formula (III 2 ) :
    其中，所述式(III1)或式(III2)化合物结构中结构为 Wherein, in the compound structure of formula (III 1 ) or formula (III 2 ) The structure is
    环A与其直接相连的部分一起形成如下结构：
    Ring A together with its directly connected parts forms the following structure:
    R1选自氢、氘、氟、氯、甲基、乙基、异丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、氨基、甲基氨基、二甲基氨基、二甲基氨基取代的甲基、二甲基氨基取代的乙基、二甲基氨基乙氧基、环丙基、环丁基、哌啶基、哌嗪基、吗啉基、甲基取代的哌啶基、乙基取代的哌啶基、环丙基取代的哌啶基、甲基取代的哌嗪基、环丙基取代的哌嗪和四氢吡喃基；R 1 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethyl amino, dimethylamino-substituted methyl, dimethylamino-substituted ethyl, dimethylaminoethoxy, cyclopropyl, cyclobutyl, piperidyl, piperazinyl, morpholinyl, methyl base-substituted piperidinyl, ethyl-substituted piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazine and tetrahydropyranyl;
    R1’选自氢、氘、甲基、乙基、异丙基、三氟甲基、三氘甲基、二甲基氨基取代的甲基、二甲基氨基取代的乙基、环丙基、环丁基、哌啶基、甲基取代的哌啶基、乙基取代的哌啶基、环丙基取代的哌啶基和四氢吡喃基；R 1 ' is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, dimethylamino-substituted methyl, dimethylamino-substituted ethyl, cyclopropyl , cyclobutyl, piperidinyl, methyl-substituted piperidinyl, ethyl-substituted piperidinyl, cyclopropyl-substituted piperidinyl and tetrahydropyranyl;
    每个R2各自独立地选自氢、氘、氟、氯、甲基、乙基、异丙基、三氟甲基、三氘甲基和环丙基；Each R 2 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
    每个R5a各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、三氟甲基、三氘甲基、环丙基、-SF5和羟基；Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF 5 and hydroxyl;
    每个R5b各自独立地选自氢、氘、甲基、乙基、异丙基、三氟甲基、三氘甲基和环丙基；Each R 5b is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
    每个R5c各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、三氟甲基、三氘甲基、环丙基、-SF5和羟基；Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF 5 and hydroxyl;
    每个R6各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、三氟甲基、三氘甲基、环丙基、-SF5和羟基；Each R is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF and hydroxyl;
    p选自0、1或2。p is selected from 0, 1 or 2.
  16. 根据权利要求15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，所述式(III1)或式(III2)化合物结构中结构为 The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 15, characterized in that, in the structure of the compound of formula (III 1 ) or formula (III 2 ) The structure is
    环A与其直接相连的部分一起形成如下结构：
    Ring A together with its directly connected parts forms the following structure:
    其中，R1选自氢、氘、氟、氯、甲基、乙基、异丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、氨基、甲基氨基、二甲基氨基取代的乙基、二甲基氨基取代的乙氧基、环丙 基、哌啶基、哌嗪基、吗啉基、甲基取代的哌啶基、乙基取代的哌啶基、环丙基取代的哌啶基、甲基取代的哌嗪基、环丙基取代的哌嗪和四氢吡喃基；Wherein, R 1 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methylamino, Dimethylamino-substituted ethyl, dimethylamino-substituted ethoxy, cyclopropyl base, piperidinyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl Substituted piperazine and tetrahydropyranyl;
    每个R2各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 2 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
    每个R5a各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
    每个R5b各自独立地选自氢、氘、甲基、三氟甲基、三氘甲基和环丙基；Each R 5b is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
    每个R5c各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
    每个R6各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基。Each R 6 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, and cyclopropyl.
  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)化合物具有如下式(IV1)、式(IV2)、式(IV3)或式(IV4)化合物结构：
    The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound of formula (I) has the following formula (IV 1 ), formula (IV 2 ), formula (IV 3 ) or formula (IV 4 ) compound structure:
    其中，in,
    每个R1各自独立地选自氢、氘、氟、氯、甲基、乙基、异丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、氨基、甲基氨基、二甲基氨基取代的乙基、二甲基氨基取代的乙氧基、环丙基、哌啶基、哌嗪基、吗啉基、甲基取代的哌啶基、乙基取代的哌啶基、环丙基取代的哌啶基、甲基取代的哌嗪基、环丙基取代的哌嗪基和四氢吡喃基；Each R 1 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methyl amino, dimethylamino-substituted ethyl, dimethylamino-substituted ethoxy, cyclopropyl, piperidyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted Piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazinyl and tetrahydropyranyl;
    每个R2a各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 2a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
    每个R2b各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 2b is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
    每个R5a各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
    每个R5b各自独立地选自氢、氘、甲基、三氟甲基、三氘甲基和环丙基；Each R 5b is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
    每个R5c各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基；Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
    每个R6各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基和环丙基。 Each R 6 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, and cyclopropyl.
  18. 根据权利要求1-17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：





    The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 17, characterized in that it is selected from the following compounds:





  19. 一种权利要求1所述的式(I)化合物、其立体异构体、或其药学上可接受盐的制备方法，其特征在于，包括如下步骤：式(Ia)化合物与式(Ib)化合物反应生成式(I)化合物，反应式如下：
    A method for preparing the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it includes the following steps: a compound of formula (Ia) and a compound of formula (Ib) The reaction generates the compound of formula (I), and the reaction formula is as follows:
    其中，X为羟基或卤素；环A、环B、环C、R1、R2、R3、R4、R5、X1、X2、X3、m、n和p如权利要求1所述。Wherein, X is hydroxyl or halogen; ring A, ring B, ring C, R 1 , R 2 , R 3 , R 4 , R 5 , described.
  20. 一种药物组合物，其包括权利要求1-18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 to 18, its stereoisomer or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  21. 权利要求1-18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MATP相关肿瘤药物中的应用。 Use of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 18 in the preparation of a drug for treating MATP-related tumors.
  22. 根据权利要求21所述的应用，其特征在于，所述的肿瘤选自细胞瘤、淋巴瘤、白血病、骨瘤、恶性畸胎瘤、上皮内癌、腺瘤、纤维瘤、黑色素瘤、输卵管癌、膀胱癌、畸胎瘤、胚胎癌、绒毛膜癌、脂肪瘤、肝癌、胆管癌、肺癌、胃癌、血管瘤、胆囊癌、壶腹癌、恶性黑色素瘤、痣、发育不良痣、骨髓增生性疾病、霍奇金病、脊索瘤、粘液瘤、横纹肌瘤、平滑肌瘤、错构瘤、间皮瘤、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、毒蛇瘤、肉芽肿、黄色瘤、变形性骨炎、室管膜瘤、神经鞘瘤、先天性肿瘤、脑膜瘤、胶质瘤、皮肤癌、头颈癌和肉瘤。The application according to claim 21, wherein the tumor is selected from the group consisting of cell tumor, lymphoma, leukemia, osteoma, malignant teratoma, intraepithelial carcinoma, adenoma, fibroma, melanoma, and fallopian tube cancer. , bladder cancer, teratoma, embryonal carcinoma, choriocarcinoma, lipoma, liver cancer, cholangiocarcinoma, lung cancer, gastric cancer, hemangioma, gallbladder cancer, ampullary cancer, malignant melanoma, nevus, dysplastic nevus, myeloproliferative Disease, Hodgkin's disease, chordoma, myxoma, rhabdomyomas, leiomyoma, hamartoma, mesothelioma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, viperoma, granuloma tumors, xanthomas, osteitis deformans, ependymomas, schwannomas, congenital tumors, meningiomas, gliomas, skin cancers, head and neck cancers and sarcomas.
  23. 根据权利要求22所述的应用，其特征在于，所述细胞瘤选自颗粒-卵泡膜细胞瘤、睾丸支持细胞瘤、生殖细胞瘤、肾母细胞瘤、精原细胞瘤、肝母细胞瘤、恶性纤维组织细胞瘤、软骨母细胞瘤、巨细胞瘤、星形细胞瘤、髓母细胞瘤、多形胶质母细胞瘤、少突胶质细胞瘤、视网膜母细胞瘤、鳞状细胞癌、透明细胞癌、移行细胞癌、间质细胞癌和基底细胞癌；The application according to claim 22, characterized in that the cell tumor is selected from the group consisting of granulosa-theca cell tumor, Sertoli cell tumor, germ cell tumor, nephroblastoma, seminoma, hepatoblastoma, Malignant fibrous histiocytoma, chondroblastoma, giant cell tumor, astrocytoma, medulloblastoma, glioblastoma multiforme, oligodendroglioma, retinoblastoma, squamous cell carcinoma, Clear cell carcinoma, transitional cell carcinoma, stromal cell carcinoma, and basal cell carcinoma;
    所述淋巴瘤选自恶性淋巴瘤和非霍奇金淋巴瘤；The lymphoma is selected from malignant lymphoma and non-Hodgkin lymphoma;
    所述白血病选自急慢性髓系白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病；The leukemia is selected from the group consisting of acute and chronic myeloid leukemia, acute lymphoblastic leukemia and chronic lymphocytic leukemia;
    所述骨瘤选自骨软骨瘤、良性软骨瘤、骨样骨瘤、软骨瘤样错构瘤、多发性骨髓瘤和颅骨瘤；The osteoma is selected from the group consisting of osteochondroma, benign enchondroma, osteoid osteoma, chondromatoid hamartoma, multiple myeloma and cranioma;
    所述腺瘤选自纤维腺瘤、腺瘤样瘤、肝细胞腺瘤、支气管腺瘤、管状腺瘤、绒毛状腺瘤、乳腺癌、胰腺癌、子宫内膜腺癌、前列腺癌、导管腺癌和大肠腺癌；The adenoma is selected from the group consisting of fibroadenoma, adenomatoid tumor, hepatocellular adenoma, bronchial adenoma, tubular adenoma, villous adenoma, breast cancer, pancreatic cancer, endometrial adenocarcinoma, prostate cancer, ductal adenoma carcinoma and colorectal adenocarcinoma;
    所述纤维瘤选自纤维瘤、软骨粘液纤维瘤、神经纤维瘤和脊髓神经纤维瘤；The fibroma is selected from the group consisting of fibroma, chondromyxofibroma, neurofibroma and spinal neurofibroma;
    所述骨髓增生性疾病选自多发性骨髓瘤和骨髓增生异常综合征；The myeloproliferative disease is selected from the group consisting of multiple myeloma and myelodysplastic syndrome;
    所述肺癌选自支气管肺癌和肺泡癌；The lung cancer is selected from bronchial lung cancer and alveolar cancer;
    所述肉瘤选自纤维肉瘤、葡萄状肉瘤、血管肉瘤、卡波西肉瘤、骨肉瘤、软骨肉瘤、尤因氏肉瘤、横纹肌肉瘤、脂肪肉瘤、平滑肌肉瘤和脑膜肉瘤。The sarcoma is selected from the group consisting of fibrosarcoma, botryoid sarcoma, angiosarcoma, Kaposi's sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma and meningiosarcoma.
  24. 根据权利要求1-18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，其用作PRMT5抑制剂。 The compound of formula (I) according to any one of claims 1 to 18, its stereoisomer or a pharmaceutically acceptable salt thereof, is used as a PRMT5 inhibitor.
PCT/CN2023/102508 2022-07-26 2023-06-26 Prmt5 inhibitor, preparation method therefor, and pharmaceutical use thereof WO2024021957A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021163344A1 (en) * 2020-02-12 2021-08-19 Amgen Inc. Novel prmt5 inhibitors
WO2022132914A1 (en) * 2020-12-16 2022-06-23 Amgen Inc. Prmts inhibitors
WO2023034786A1 (en) * 2021-08-30 2023-03-09 Amgen Inc. Process for synthesizing naphthyridine derivatives and intermediates thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021163344A1 (en) * 2020-02-12 2021-08-19 Amgen Inc. Novel prmt5 inhibitors
WO2022132914A1 (en) * 2020-12-16 2022-06-23 Amgen Inc. Prmts inhibitors
WO2023034786A1 (en) * 2021-08-30 2023-03-09 Amgen Inc. Process for synthesizing naphthyridine derivatives and intermediates thereof

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