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WO2024012449A1 - Compound containing trifluoromethyl group - Google Patents

Compound containing trifluoromethyl group Download PDF

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Publication number
WO2024012449A1
WO2024012449A1 PCT/CN2023/106784 CN2023106784W WO2024012449A1 WO 2024012449 A1 WO2024012449 A1 WO 2024012449A1 CN 2023106784 W CN2023106784 W CN 2023106784W WO 2024012449 A1 WO2024012449 A1 WO 2024012449A1
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Prior art keywords
alkyl
alkenyl
compound
optionally
membered
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PCT/CN2023/106784
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French (fr)
Chinese (zh)
Inventor
王斌
丰巍伟
汪纪楠
姚绎焱
盛化策
Original Assignee
正大天晴药业集团股份有限公司
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Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202380051966.5A priority Critical patent/CN119768402A/en
Publication of WO2024012449A1 publication Critical patent/WO2024012449A1/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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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 present application relates to compounds containing trifluoromethyl groups, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of tumor diseases.
  • Bcl-2 The B-cell lymphoma 2 (Bcl-2) protein family, composed of pro-apoptotic and anti-apoptotic members, plays a key role in determining cell fate by regulating the intrinsic apoptotic pathway.
  • Anti-apoptotic Bcl-2 family proteins (such as Bcl-2, Bcl-xL, Bcl-W, and Mcl-1) are upregulated in many cancers and are associated with tumor initiation, progression, and resistance to chemotherapy and targeted therapies. Sexually related. Since the growth of most solid tumors does not depend on BCL-2 protein, BCL-2 inhibitors alone have no obvious effect in the treatment of solid tumors.
  • the expression of BCL-XL protein is significantly increased in many leukemia cells and solid tumors. , studies have shown that BCL-XL expression in tumor tissues is positively correlated with tumor drug resistance, and targeting BCL-XL is a potential ideal anti-tumor molecular target.
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • E3 ubiquitin ligases Such compounds can induce the target protein to be recognized by the proteasome of the cell, causing the degradation of the targeted protein, and can effectively Reduce the content of target proteins in cells.
  • Each R 1 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S( O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS (O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1 -6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl,
  • n1 is selected from 1, 2, 3 or 4;
  • q is selected from 0, 1, 2, 3, 4, 5 or 6;
  • Each R 2 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1- 6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1 -6 alkylNHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O) NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered hetero Cycloalkyl, C 3
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • Ring A is selected from C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered hetero Aryl;
  • L is the connecting group
  • Each R 3 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1- 6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1 -6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O) NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS (O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 Alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C
  • p is selected from 0, 1, 2 or 3;
  • R 4 and R 5 are independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O- , C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S (O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS (O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalky
  • R 4 and R 5 are connected to each other and the connected carbon atoms together form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group;
  • X 1 is selected from CR b or N;
  • R a and R a ' may be the same or different, and are independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkylNHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl
  • R b is selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio Base, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkyl Base NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl,
  • R 1 , R 2 , ring A, R 3 , R 4 , R 5 , R a , R a′ or R b are optionally substituted by one or more substituents.
  • n1 is 1 or 2. In some embodiments, n1 is 1.
  • each R 1 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- 4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO-, C 1-4 alkyl C (O)O-, C 1-4 alkylNHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS(O)-, C 1 -4 alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1-4 alkyl S(O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membered heterocycloal
  • each R 1 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1- 3Alkoxy , C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO-, C 1-3 alkyl C (O)O-, C 1-3 alkylNHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS(O)-, C 1 -3 alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1-3 alkyl S(O) 2 NH-, (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloal
  • each R 1 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl , C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS ( O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH- or (C 1-6 alkyl) 2 NS(O) 2 -, and R 1 is optionally substituted by one or more substituents.
  • each R 2 is independently selected from halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl Oxygen group, C 1-4 alkylthio group, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO-, C 1-4 alkyl C(O )O-, C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS(O)-, C 1-4 Alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1-4 alkyl S(O) 2 NH- , (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membere
  • each R 2 is independently selected from halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkyl Oxygen group, C 1-3 alkylthio group, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO-, C 1-3 alkyl C(O )O-, C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1-3 alkyl S(O) 2 NH- , (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered hetero
  • each R 2 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy Base, C 1-6 alkylthio group, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O) O-, C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH- or (C 1-6 alkyl) 2 NS(O) 2 -, the R 2 is optionally substituted by one or more substituents.
  • each R 3 is independently selected from halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl Oxygen group, C 1-4 alkylthio group, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO-, C 1-4 alkyl C(O )O-, C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS(O)-, C 1-4 Alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1-4 alkyl S(O) 2 NH- , (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membere
  • each R 3 is independently selected from halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkyl Oxygen group, C 1-3 alkylthio group, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO-, C 1-3 alkyl C(O )O-, C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1-3 alkyl S(O) 2 NH- , (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered hetero
  • each R 3 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy Base, C 1-6 alkylthio group, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O) O-, C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH- or (C 1-6 alkyl) 2 NS(O) 2 -, the R 3 is optionally substituted by one or more substituents.
  • each R 4 or R 5 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO-, C 1-4 Alkyl C(O)O-, C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS(O)- , C 1-4 alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1-4 alkyl S( O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membered
  • R 4 and R 5 are connected to each other and the connected carbon atoms together form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group; the R 4 or R 5 is optionally substituted by one or more substituents replace.
  • each R 4 or R 5 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO-, C 1-3 alkyl C(O)O-, C 1-3 alkylNHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS(O)-, C 1-3 alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1-3 alkyl S(O) 2 NH-, (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloal
  • R 4 and R 5 are connected to each other and the connected carbon atoms together form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group; the R 4 or R 5 is optionally substituted by one or more substituents replace.
  • R 4 and R 5 are each independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkylNHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH- or (C 1-6 alkyl) 2 NS(O) 2 -, the R 4 or R 5 is optionally substituted by one or more substitu
  • R 4 and R 5 are each independently selected from C 1-3 alkyl, or R 4 and R 5 are connected to each other and the attached carbon atoms together to form a C 3-4 cycloalkyl or 3-4 membered Heterocycloalkyl. In some embodiments, R 4 and R 5 are each independently selected from methyl, or R 4 and R 5 are joined to each other and together with the attached carbon atom to form a C 3-4 cycloalkyl group. In some embodiments, R 4 and R 5 are each independently selected from methyl.
  • R a and R a' may be the same or different, and are each independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO- , C 1-4 alkyl C(O)O-, C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS (O)-, C 1-4 alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1-4 Alkyl S(O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10
  • R a and R a' may be the same or different, and are each independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2- 3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO- , C 1-3 alkyl C(O)O-, C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS (O)-, C 1-3 alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1-3 Alkyl S(O) 2 NH-, (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycl
  • R a and R a' may be the same or different, and are each independently selected from hydrogen or halogen.
  • R a and R a' are the same and each is independently selected from hydrogen.
  • R b is selected from hydrogen, halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO-, C 1-4 alkyl C(O)O- , C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS(O)-, C 1-4 alkyl S (O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS (O) 2 -, C 1-4 alkyl S(O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membered heterocycloal
  • R b is selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO-, C 1-3 alkyl C(O)O- , C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS(O)-, C 1-3 alkyl S (O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS (O) 2 -, C 1-3 alkyl S(O) 2 NH-, (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl
  • R b is selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O- , C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S (O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 Alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH- or (C 1-6 alkyl) 2 NS(O) 2 -, the R b is optionally replaced by one or more substituted by substituents.
  • R b is selected from hydrogen or halogen.
  • R b is selected from hydrogen.
  • Ring A is selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10 aryl Or 5-10 membered heteroaryl, the ring A is optionally substituted by one or more substituents.
  • the 3-4 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 3-12 membered heterocycloalkyl, 3-6 membered heterocycle Alkenyl, 3-10 membered heterocyclic alkenyl, 3-12 membered heterocyclic alkenyl, 5-10 membered heteroaryl and 5-12 membered heteroaryl each independently contain 1, 2 or 3 independently selected from Heteroatoms of N, O and S.
  • the R 1 , R 2 , Ring A, R 3 , R 4 , R 5 , R a , R a′ or R b are optionally substituted with one or more substituents selected from : -OH, -SH, halogen, -NH 2 , nitro group, nitroso group, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxyaldehyde group, sulfonate group Amine group, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo- Alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl
  • the compound of Formula I-0 or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of Formula I or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from hydrogen, halogen or C 1-3 alkyl
  • q is selected from 0, 1, 2, 3, 4, 5 or 6;
  • Each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • n 0, 1, 2 or 3;
  • Ring A is selected from C 4-10 cycloalkyl or 4-10 membered heterocycloalkyl
  • L is the connecting group
  • Each R 3 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • p is selected from 0, 1, 2 or 3;
  • X 1 is selected from CH or N;
  • R 1 , R 2 , ring A, R 3 , X or X 1 are optionally substituted by one or more substituents.
  • the compound of Formula I-0 and the compound of Formula I each independently include the following embodiments.
  • R 1 is selected from hydrogen, halogen or C 1-3 alkyl
  • q is selected from 0, 1, 2, 3, 4, 5 or 6;
  • Each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • n 0, 1, 2 or 3;
  • Ring A is selected from C 4-10 cycloalkyl or 4-10 membered heterocycloalkyl
  • L is the connecting group
  • Each R 3 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • p is selected from 0, 1, 2 or 3;
  • X 1 is selected from CH or N.
  • each R 1 is independently selected from hydrogen, halogen, or C 1-3 alkyl, and said R 1 is optionally substituted with one or more substituents.
  • each R 1 is independently selected from hydrogen, halogen, or C 1-2 alkyl, and said R 1 is optionally substituted with one or more substituents.
  • each R 1 is independently selected from hydrogen, fluorine, chlorine, bromine, or methyl, and said R 1 is optionally substituted with one or more substituents.
  • each R 1 is independently selected from hydrogen, chlorine, or methyl, and said R 1 is optionally substituted with one or more substituents.
  • R 1 is selected from hydrogen, halogen, or C 1-3 alkyl.
  • R 1 is selected from hydrogen, halogen, or C 1-2 alkyl.
  • R1 is selected from hydrogen, fluorine, chlorine, bromine, or methyl.
  • R1 is selected from hydrogen, chlorine, or methyl.
  • R1 is hydrogen
  • q is selected from 0, 1, 2, or 3. In some embodiments, q is selected from 0, 1, or 2. In some embodiments, q is 1.
  • each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl, or C 1-3 alkoxy, and the R 2 is optionally replaced by one or more substituted by substituents.
  • each R 2 is independently selected from CN, halogen, or C 1-3 alkyl, and the R 2 is optionally substituted with one or more substituents.
  • each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl, or C 1-3 alkoxy.
  • each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-2 alkyl, or C 1-2 alkoxy.
  • each R is independently selected from CN, halogen, or C 1-3 alkyl.
  • each R 2 is independently selected from CN, halogen, or C 1-2 alkyl.
  • m is selected from 0, 1, 2, or 3.
  • n is selected from 0, 1, or 2. In some embodiments, m is selected from 0 or 1. In some embodiments, m is 0.
  • Ring A is selected from C 4-10 cycloalkyl or 4-10 membered heterocycloalkyl.
  • Ring A is selected from C 4-8 cycloalkyl or 4-8 membered heterocycloalkyl.
  • Ring A is selected from C 4-6 cycloalkyl or 4-6 membered heterocycloalkyl.
  • Ring A is selected from C 5-6 cycloalkyl or 5-6 membered heterocycloalkyl.
  • Ring A is selected from C 6 cycloalkyl or 6 membered heterocycloalkyl.
  • Ring A is selected from C 6 cycloalkyl or 6 membered N-containing heterocycloalkyl.
  • Ring A is selected from cyclohexyl or piperidinyl.
  • Ring A is selected from
  • L is selected from -Cy-L 1 - or -L 2 -; wherein Cy is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 cycloalkyl Alkyl or 3-10 membered heterocycloalkyl is optionally substituted by one or more substituents;
  • -L 1 - or -L 2 - are each independently selected from 1 or more -CH 2 - optionally selected from -O-, phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 1-20 alkyl-, 1 or more -CH 2 - optionally selected from -O- , phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-20 alkenyl-, or 1 or more -CH 2 - optionally selected from -O -, phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 2-20 alkenyl -, or -C 2-20 alkynyl- optionally substituted by one or more substitu
  • the -L 1 - or -L 2 - are each independently selected from 1 or more -CH 2 - optionally selected from -O-, phenyl (e.g. ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 1-15 alkyl-, 1 or more -CH 2 - optionally selected from -O- , phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-15 alkenyl-, or 1 or more -CH 2 - optionally selected from -O -, phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-15 alkynyl-, the -C 1-15 alkyl-, -C 2-15 alkenyl -, or -C 2-15 alkynyl - optionally substituted
  • -L 1 - or -L 2 - are each independently selected from -1 or more -CH 2 - optionally selected from -O-, phenyl (e.g. ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 1-12 alkyl-, 1 or more -CH 2 - optionally selected from -O- , phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-12 alkenyl-, or 1 or more -CH 2 - optionally selected from -O -, phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-12 alkynyl-, the -C 1-12 alkyl-, -C 2-12 alkenyl -, or -C 2-12 alkynyl - optionally substituted
  • the Cy is selected from C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl.
  • the Cy is selected from C 5-6 cycloalkyl or 5-6 membered heterocycloalkyl.
  • the Cy is selected from 5-6 membered heterocycloalkyl.
  • the Cy is selected from 6-membered heterocycloalkyl.
  • the Cy is selected from piperidinyl or piperazinyl.
  • the Cy is selected from In some embodiments, the Cy is selected from
  • the structural fragment - Cy-L 1 - is selected from In some embodiments, the structural fragment -Cy- L1- is
  • the -L 1 - is selected from 1 or more -CH 2 - optionally selected from phenyl (e.g. ), or -N(C 1-6 alkyl)-substituted -C 1-20 alkyl-, -C 1-19 alkyloxy-, -C 1-19 alkylthio-, -C 1 -19 alkylamino-, -C 2-20 alkenyl- or -C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 1-19 alkyloxy-, -C 1 -19alkylthio- , -C1-19alkylamino- , -C2-20alkenyl- or -C2-20alkynyl- is optionally substituted by one or more substituents.
  • phenyl e.g.
  • the -L 1 - is selected from 1 or more -CH 2 - optionally selected from phenyl (e.g. ), or -N(C 1-6 alkyl)-substituted -C 1-15 alkyl-, -C 1-14 alkyloxy-, -C 1-14 alkylthio-, -C 1 -14 alkylamino-, -C 2-15 alkenyl- or -C 2-15 alkynyl-, the -C 1-15 alkyl-, -C 1-14 alkyloxy-, -C 1 -14alkylthio- , -C1-14alkylamino- , -C2-15alkenyl- or -C2-15alkynyl- is optionally substituted by one or more substituents.
  • phenyl e.g.
  • the -L 1 - is selected from 1 or more -CH 2 - optionally selected from phenyl (e.g. ), or -N(C 1-6 alkyl)-substituted -C 1-12 alkyl-, -C 1-11 alkyloxy-, -C 1-11 alkylthio-, -C 1 -11 alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkynyl-, the -C 1-12 alkyl-, -C 1-11 alkyloxy-, -C 1 -11 Alkylthio-, -C 1-11 alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkynyl- is optionally substituted by one or more substituents.
  • phenyl e.g.
  • -L 1 - or -L 2 - are each independently selected from -(CH 2 ) n O-, -(CH 2 ) n S-, -C(O)-(CH 2 ) n O-, -C(O)-(CH 2 ) n S-, -(CH 2 ) n C ⁇ C-, -C(O)-(CH 2 ) n C ⁇ C-, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n C ⁇ C-, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n O-, -CH 2 N(CH 3 )-(CH 2 ) n C ⁇ C-, -CH 2 N(CH 3 )-(CH 2 ) n O-, -(CH 2 N(CH 3 )-(CH 2 ) n C ⁇ C-, -CH 2 N(CH 3 )-(CH 2 ) n O-, -(CH
  • -L 1 - or -L 2 - are each independently selected from -(CH 2 ) n NH- or -CH 2 -phenyl-(CH 2 ) n O-, where n is selected from 1-12. In some embodiments, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.
  • -L 1 - is selected from -(CH 2 ) n O-, -(CH 2 ) n S-, -C(O)-(CH 2 ) n O-, -C(O )-(CH 2 ) n S-, -(CH 2 ) n C ⁇ C- or -C(O)-(CH 2 ) n C ⁇ C-, where n is selected from 1-12.
  • -L 1 - is selected from -(CH 2 ) n NH-, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n C ⁇ C-, or -CH 2 - Phenyl-(CH 2 ) n O-, where n is selected from 1-12.
  • -L 1 - is selected from -(CH 2 ) n NH-, -(CH 2 ) n O-, -(CH 2 ) n S-, -(CH 2 ) n C ⁇ C -, -(CH 2 ) 3 N(CH 3 )-(CH 2 ) n C ⁇ C- or -CH 2 -phenyl-(CH 2 ) n O-, where n is selected from 1-12.
  • -L 1 - is selected from -(CH 2 ) n O-, -(CH 2 ) n S-, or -(CH 2 ) n C ⁇ C-, where n is selected from 1-12 .
  • n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two. In some embodiments, n is selected from 3-7. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.
  • -L 2 - is selected from -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n C ⁇ C-, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n O-, -CH 2 N(CH 3 )-(CH 2 ) n C ⁇ C-, -CH 2 N(CH 3 )-(CH 2 ) n O-, -(CH 2 ) 3 N( CH 3 )-(CH 2 ) n C ⁇ C- or -(CH 2 ) 3 N(CH 3 )-(CH 2 ) n O-, where n is selected from 1-12.
  • the -L2- is selected from -( CH2 ) nO- , -( CH2 ) nS- , -( CH2 ) nNH- , -( CH2 ) nC ⁇ C -, -(CH 2 ) n N(CH 3 )(CH 2 ) n C ⁇ C- or -(CH 2 ) n -phenyl-(CH 2 ) n O-, where n is selected from 1-12.
  • n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two.
  • n is 3-5.
  • n is 3-7.
  • n is 3-9. In some embodiments, n is 3-10.
  • L is selected from -Cy-L 3 -X 2 - or -L 2 -, wherein Cy and L 2 are as described above;
  • X 2 is selected from bond, O or S.
  • L is selected from -Cy-L 3 -X 2 - or -L 2 -, wherein Cy and L 2 are as described above; L 3 is selected from 1 or more -CH 2 - optionally Ground is selected from -O-, phenyl (e.g.
  • X 2 is selected from bond, O or S.
  • L is selected from -Cy-L 3 -X 2 - or -L 2 -, where Cy is selected from 3-10 membered heterocycloalkyl and L 3 is selected from 1 or more -CH 2 - Optionally selected from -O-, phenyl (e.g. ), -NH-, -N(C 1-4 alkyl)- or -S- substituted -C 1-20 alkyl- or -C 2-20 alkynyl-, L 2 is selected from -C 1-20 Alkyl NH-; X 2 is selected from bond, O, S or NH.
  • L is selected from -Cy-L 3 -X 2 - or -L 2 -, where Cy is selected from 3-6 membered heterocycloalkyl and L 3 is selected from 1 or more -CH 2 - Optionally selected from phenyl (e.g. ) or -N(C 1-4 alkyl)-substituted -C 3-15 alkyl-or -C 3-15 alkynyl-, L 2 is selected from -C 3-15 alkyl NH-; X 2 is selected Self bond, O, S or NH.
  • L is selected from -Cy-L 3 -X 2 - or -L 2 -, where Cy is selected from 6-membered heterocycloalkyl and L 3 is selected from 1 or more -CH 2 - Optionally selected from phenyl (e.g. ) or -N(C 1-3 alkyl)-substituted -C 3-10 alkyl-or -C 5-11 alkynyl-, L 2 is selected from -C 3-10 alkyl NH-; X 2 is selected Self bond, O, S or NH.
  • the moiety -Cy- L3 - X2- is selected from -piperidinyl-( CH2 ) 3S- , -piperidinyl-( CH2 ) 4S- , -piperidinyl- (CH 2 ) 5 S-, -piperidinyl-(CH 2 ) 6 S-, -piperidinyl-(CH 2 ) 7 S-, -piperidinyl-(CH 2 ) 8 S-, -piperidinyl Base-(CH 2 ) 9 S-, -piperidyl-(CH 2 ) 3 O-, -piperidyl-(CH 2 ) 4 O-, -piperidyl-(CH 2 ) 5 O-, - Piperidinyl-(CH 2 ) 6 O-, -piperidinyl-(CH 2 ) 7 O-, -piperidinyl-(CH 2 ) 8 O-, -piperidinyl-(CH 2
  • moiety -L3 - X2- or -L2- is selected from -( CH2 ) 3NH- , -( CH2 ) 4NH- , -( CH2 ) 5NH- , - (CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 6 O-, -(CH 2 ) 7 O-, -(CH 2 ) 8 O-, -(CH 2 ) 9 O-, -(CH 2 ) 10 O-, -(CH 2 ) 3 S-, -(CH 2 ) 4 S-, -(CH 2 ) 5 S-, -( CH 2 ) 6 S-, -(CH 2 ) 7 S-, -(CH 2 ) 8 S-, -(CH 2 ) 9 S-, -( CH 2 ) 3 C ⁇ C-, -(CH 2 ) 4 C ⁇ C-, -(CH 2 ) 4
  • moiety -L3 - X2- or -L2- is selected from -( CH2 ) 3O- , -( CH2 ) 4O- , -( CH2 ) 5O- , - (CH 2 ) 6 O-, -(CH 2 ) 7 O-, -(CH 2 ) 8 O-, -(CH 2 ) 9 O-, -(CH 2 ) 10 O-, -(CH 2 ) 3 S-, -(CH 2 ) 4 S-, -(CH 2 ) 5 S-, -(CH 2 ) 6 S-, -(CH 2 ) 7 S-, -(CH 2 ) 8 S-, -( CH 2 ) 9 S-, -(CH 2 ) 3 C ⁇ C-, -(CH 2 ) 4 C ⁇ C-, -(CH 2 ) 5 C ⁇ C-, -(CH 2 ) 6 C ⁇ C- , -(CH 2 ) 7 C ⁇
  • L is selected from
  • L is selected from The definition of n is as mentioned above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10. In some embodiments, L is selected from The definition of n is as mentioned above. In some embodiments, L is selected from The definition of n is as mentioned above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.
  • L is selected from The definition of n is as mentioned above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.
  • L is selected from -(CH 2 ) n -NH-or
  • n is as mentioned above.
  • n is 3-5.
  • n is 3-7.
  • n is 3-9.
  • n is 3-10.
  • n is selected from The definition of n is as mentioned above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.
  • each R 3 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl, or C 1-3 alkoxy.
  • each R 3 is independently selected from OH, NH 2 , CN, halogen, C 1-2 alkyl, or C 1-2 alkoxy. In some embodiments, each R 3 is independently selected from OH, NH 2 , fluorine, chlorine, or methyl. In some embodiments, each R 3 is independently selected from fluorine.
  • p is selected from 0, 1, or 2. In some embodiments, p is selected from 0 or 1. In some embodiments, p is selected from 0.
  • X1 is selected from CH or N.
  • X1 is selected from CH. In some embodiments, X1 is selected from N.
  • R1 is hydrogen; structural fragment for m is 0; L is selected from -(CH 2 ) n -NH-or n is 3-5 or 3-9 or 3-10; q is 1 or 2; and the structural fragment Selected from
  • R1 is hydrogen; structural fragment for m is 0; L is selected from q is 1 or 2; and the structure fragment Selected from
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from the compounds of formula II, II-A or II-B or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , m, L, R 3 , p or X are defined as described in this application;
  • X 3 and X 4 are independently selected from N, NH, CH or CH 2 ;
  • R 1 , R 2 , R 3 , X, X 3 and X 4 are optionally substituted with one or more substituents.
  • the compound of Formula I, II, II-A or II-B, or a pharmaceutically acceptable salt thereof wherein R 1 , R 2 , m, L, R 3 , p or X is defined As described herein, X 3 and X 4 are each independently selected from N, NH, CH or CH 2 .
  • X 3 and X 4 are each independently selected from NH or CH 2 .
  • the present application relates to a compound of formula III or a pharmaceutically acceptable salt thereof,
  • Each R 11 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH- , (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl ) 2 NS(O) 2 -, C 3-12 cycloalkyl,
  • k is selected from 0, 1, 2 or 3;
  • L is selected from -Cy-L 1 -; wherein, Cy is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, said C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl optionally substituted with one or more substituents;
  • each R 11 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-4 alkyl, haloC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO -, C 1-4 alkyl C(O)O-, C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl Base NHS(O)-, C 1-4 alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1 -4 alkyl S(O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cyclo
  • each R 11 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, haloC 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO -, C 1-3 alkyl C(O)O-, C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl Base NHS(O)-, C 1-3 alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1 -3 alkyl S(O) 2 NH-, (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalky
  • each R 11 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, haloC 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO -, C 1-3 alkyl C(O)O-, C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl Base NHS(O)-, C 1-3 alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1 -3 alkyl S(O) 2 NH- or (C 1-3 alkyl) 2 NS(O) 2 -, the R 11 is optionally substituted
  • each R 11 is independently selected from halogen or C 1-3 alkyl, which is optionally substituted with one or more substituents. In some embodiments, each R 11 is independently selected from halogen or C 1-3 alkyl, which is optionally substituted with one or more halogens.
  • each R 11 is independently selected from fluorine, chlorine, or methyl, with the methyl optionally substituted by one or more halogens.
  • each R 11 is independently selected from chlorine or methyl, optionally substituted with one or more fluorine or chlorine. In some embodiments, R 11 is selected from chloro, methyl, or trifluoromethyl.
  • R 4 and R 5 are each independently selected from C 1-3 alkyl, or R 4 and R 5 are connected to each other and the attached carbon atoms together to form a C 3-6 cycloalkyl or 3-6 membered Heterocycloalkyl, the C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more substituents.
  • R 4 and R 5 are each independently selected from C 1-3 alkyl, or R 4 and R 5 are connected to each other and the attached carbon atoms together to form a C 3-4 cycloalkyl or 3-4 membered Heterocycloalkyl. In some embodiments, R 4 and R 5 are each independently selected from methyl, or R 4 and R 5 are joined to each other and together with the attached carbon atom to form a C 3-4 cycloalkyl group. In some embodiments, R 4 and R 5 are each independently selected from methyl.
  • k is selected from 0, 1, or 2. In some embodiments, k is selected from 1.
  • the Cy is as defined herein.
  • the structural fragment - Cy-L 1 - is selected from
  • -L1- is as defined herein.
  • the -L 1 - is selected from 1 or more -CH 2 -phenyl groups (e.g. ), and optionally one or more -CH 2 -are replaced by -N(C 1-6 alkyl)-: -C 1-20 alkyl-, -C 1-19 alkyl Oxy-, -C 1-19 alkylthio-, -C 1-19 alkylamino-, -C 2-20 alkenyl- or -C 2-20 alkynyl-, the -C 1-20 Alkyl-, -C 1-19 alkyloxy-, -C 1-19 alkylthio-, -C 1-19 alkylamino-, -C 2-20 alkenyl- or -C 2-20 Alkynyl - optionally substituted with one or more substituents.
  • -N(C 1-6 alkyl)- -C 1-20 alkyl-, -C 1-19 alkyl Oxy-, -C 1-19 alkylthio
  • the -L 1 - is selected from 1 or more -CH 2 -phenyl groups (e.g. ), and optionally one or more -CH 2 -are replaced by -N(C 1-6 alkyl)-: -C 1-15 alkyl-, -C 1-14 alkyl Oxy-, -C 1-14 alkylthio-, -C 1-14 alkylamino-, -C 2-15 alkenyl- or -C 2-15 alkynyl-, the -C 1-15 Alkyl-, -C 1-14 alkyloxy-, -C 1-14 alkylthio-, -C 1-14 alkylamino-, -C 2-15 alkenyl- or -C 2-15 Alkynyl - optionally substituted with one or more substituents.
  • the -L 1 - is selected from 1 or more -CH 2 -phenyl
  • the following groups are replaced, and optionally 1 or more -CH 2 - are replaced by -N(C 1-6 alkyl)-: -C 1-12 alkyl-, -C 1-11 alkyloxy Base-, -C 1-11 alkylthio-, -C 1-11 alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkynyl-, the -C 1-12 alkyl Base-, -C 1-11 alkyloxy-, -C 1-11 alkylthio-, -C 1-11 alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkyne Group - optionally substituted by one or more substituents.
  • -L 1 - is selected from -CH 2 -phenyl-(CH 2 ) n O-, where n is selected from 1-12. In some embodiments, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two. In some embodiments, n is selected from 1-8.
  • L is selected from -Cy-L 3 -X 2 -, wherein Cy is as described above; L 3 is selected from 1 or more -CH 2 - by C 6-10 aryl or 5-10
  • L is selected from -Cy-L 3 -X 2 -, where Cy is selected from 3-10 membered heterocycloalkyl and L 3 is selected from 1 or more -CH 2 -C 6 aryl or 5-6 membered heteroaryl substituted, and optionally 1 or more -CH 2 -selected from -O-, -NH-, -N(C 1-4 alkyl)- or -S- The following groups: -C 1-20 alkyl- or -C 2-20 alkynyl-; X 2 is selected from bond, O, S or NH.
  • L is selected from -Cy-L 3 -X 2 -, where Cy is selected from 3-6 membered heterocycloalkyl and L 3 is selected from 1 or more -CH 2 - by C 6 aryl or 6-membered heteroaryl substituted, and optionally 1 or more -CH 2 -selected from -N(C 1-4 alkyl)-substituted with the following groups: -C 3-15 alkyl- or -C 3-15 alkynyl-; X 2 is selected from bond, O, S or NH.
  • L is selected from -Cy-L 3 -X 2 -, where Cy is selected from 6-membered heterocycloalkyl, L 3 is selected from 1 or more -CH 2 - replaced by phenyl, and any Optionally 1 or more -CH 2 - are selected from -N(C 1-3 alkyl)- replaced by the following groups: -C 3-10 alkyl-; X 2 is selected from bond, O, S or NH.
  • the moiety -Cy- L3 - X2- is selected from -piperidinyl- CH2 -phenyl-( CH2 ) nO- , n is as defined herein. In some embodiments, the moiety -Cy- L3 - X2- is selected from -piperidinyl- CH2 -phenyl- CH2O- .
  • moiety -L3 - X2- is selected from -CH2 -phenyl- CH2O- . In some embodiments, L is selected from
  • L is selected from The definition of n is as mentioned above.
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
  • n 1, 2, 3, 4, 5, 6, 7 or 8.
  • the present application relates to a compound of formula I-0, or a pharmaceutically acceptable salt thereof, wherein R 1 , n, q, R 2 , m, ring A, L, R 3 , p, R 4 , R 5 ,
  • R 1 , n, q, R 2 , m, ring A, L, R 3 , p, R 4 , R 5 The definitions of X , Optionally substituted by one or more substituents.
  • the structural fragments in the structure shown in the compound of formula I-0 is optionally substituted by one or more substituents.
  • the structural fragments in the structure shown in the compound of formula I-0 is optionally substituted with one or more substituents.
  • the present application relates to a pharmaceutical composition, which contains the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application also includes pharmaceutically acceptable excipients.
  • the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a condition treated by degrading a target protein bound to a targeting ligand.
  • the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a condition treated by binding to a cerebellar protein in vivo.
  • the present application relates to the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for preventing or treating diseases related to BCL-XL.
  • the present application relates to a method for treating or preventing a condition in a mammal treated by degrading a target protein bound to a targeting ligand, which includes administering a therapeutically effective amount of the above compound of the present application or its application to a mammal in need of such treatment, preferably a human.
  • Pharmaceutically acceptable salts, or pharmaceutical compositions thereof are provided.
  • the present application relates to methods for treating or preventing diseases treated by binding to cerebellar proteins in vivo, which include administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof to a mammal, preferably a human, in need of such treatment. or pharmaceutical compositions thereof.
  • the present application relates to a method for treating mammals and BCL-XL-related diseases, which includes administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment, preferably a human. or pharmaceutical compositions thereof.
  • the present application relates to the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a condition treated by degrading a target protein bound to a targeting ligand.
  • the present application relates to the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating a disorder treated by binding to cerebellar protein in vivo.
  • the present application relates to the above compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating diseases related to BCL-XL.
  • the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disorder treated by degrading a target protein bound to a targeting ligand.
  • the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disorder treated by binding to cerebellar proteins in vivo.
  • the present application relates to the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in preventing or treating diseases related to BCL-XL.
  • the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating cancer.
  • the present application relates to the use of the above-mentioned compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in preventing or treating cancer.
  • the present application relates to the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating cancer.
  • the present application relates to a method for treating or preventing mammalian cancer, which includes administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a medicament thereof to a mammal in need of such treatment, preferably a human. combination.
  • the above-mentioned BCL-XL-related diseases are selected from conditions treated by degrading and/or inhibiting proteins that bind to BCL-XL target protein ligands; in some specific embodiments, the above-mentioned BCL-XL-related diseases Selected from conditions treated by binding to cerebellar protein in vivo; in some embodiments, the disease or condition is selected from cancer.
  • the conditions treated by binding to cerebellar proteins in vivo are selected from BCL-XL-related diseases; in some embodiments, the BCL-XL-related diseases are selected from cancer.
  • the cancer is selected from leukemia; in some embodiments, the cancer is selected from lymphoid leukemia.
  • the "one or more” is selected from one, two, three, four, five, or six. In some embodiments, the “one or more” is selected from one, two, or three. In some embodiments, the “one or more” is selected from one, or two.
  • the substituent in "optionally substituted by one or more substituents” is selected from hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, carboxyl, aldehyde, C 1-12 alkyl, halo-C 1-12 alkyl, 3-12-membered cycloalkyl, halo-3-12-membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 Alkenyl, 3-12-membered cycloalkenyl, halogenated-3-12-membered cycloalkenyl, C 2-12 alkynyl, halogenated-C 2-12 alkynyl, 8-12-membered cycloalkynyl, halogenated- 8-12 membered ring alkynyl, C 1-12 heteroalkyl, halo-C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10
  • this application encompasses the variables defined above and embodiments thereof, as well as any combinations thereof.
  • the compound of the present application has a proliferation inhibitory effect on RS4;11 cells and MOLT-4 cells; it can degrade BCL-XL protein, such as BCL-XL protein in MOLT-4 cells; it has binding inhibitory activity on BCL-XL/BAK; in vitro (such as Human, monkey, dog, rat or mouse liver microsomes) metabolically stable; and has good in vivo (mouse, rat or dog) pharmacokinetic properties, as well as in vivo pharmacodynamic data; low platelet toxicity (canine or human platelets), with low toxic and side effects.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • the term "optionally” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and absence of the stated event or circumstance.
  • the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), or poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.
  • Substituent as used herein includes all substituents mentioned in the context of this article, including but not limited to the terms “alkyl”, “alkoxy”, “heteroalkyl”, “alkenyl” mentioned below , “alkynyl”, “cycloalkenyl”, “cycloalkyl”, “heterocycloalkyl”, “heterocycloalkenyl”, “heterocyclyl”, “Heteroaryl” and the like, and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent” include deuterium, tritium, -OH, -SH, halogen, -NH 2 , nitro , nitroso group, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxyaldehyde group, imine group, alkyl group, halogenated-alkyl group, cycloalkane base
  • C mn as used herein means that the part has an integer number of carbon atoms in the given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • C 1-3 means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.
  • the substituent is selected from the group consisting of hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azide group, sulfoxide group, sulfone group, and sulfonamide group , carboxyl group, aldehyde group, imine group, C 1-12 alkyl group, halogenated-C 1-12 alkyl group, 3-12-membered cycloalkyl group, halogenated-3-12-membered cycloalkyl group, C 2- 12- alkenyl, halo-C 2-12 alkenyl, 3-12-membered cycloalkenyl, halogen-3-12-membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8-12-membered cycloalkynyl, halogenated-8-12-membered cycloalkynyl, C 1-12 heteroalky
  • One or more in this article refers to an integer ranging from one to ten. For example, “one or more” refers to one, two, three, four, five, six, seven, eight, nine or ten; or “one or more” refers to one, two , three, four, five or six; alternatively, "one or more” means one, two or three.
  • any variable e.g., R
  • its definition in each instance is independent. For example, if a group contains 2 R's, there will be separate options for each R.
  • a bond When a bond is cross-connected to two atoms of a ring (including a single ring, a parallel ring, or a spiro ring), such a bond can be bonded to any atom on the ring (including a single ring, a parallel ring, or a spiro ring).
  • ring A means that the bonds on both sides can be connected to any two different atoms on ring A;
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to the -OH group.
  • amino refers to the -NH 2 group.
  • cyano refers to the -CN group.
  • mercapto refers to the -SH group.
  • nitro refers to the -NO group.
  • heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, sulfur, silicon and phosphorus. exist In one embodiment, the heteroatoms are selected from N, O, and S. In some embodiments, the number of heteroatoms is 1, 2, 3, or 4.
  • alkyl refers to a hydrocarbyl group having the general formula C n H 2n+1 .
  • the alkyl group may contain 1-20, 1-15, 1-12, 1-10, 1-8, 1-6 or 1-3 carbon atoms.
  • the alkyl group may be straight chain or branched.
  • C 1 -6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • the alkyl portion (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.
  • C 1 -3 alkyl refers to alkyl groups containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).
  • alkoxy refers to -O-alkyl
  • heteroalkyl refers to an alkyl structure containing heteroatoms. Unless otherwise indicated, the heteroalkyl group is generally an alkyl group containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Generally, where more than one heteroatom is present, the heteroatoms are not adjacent to each other. Exemplary heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, and the like.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond.
  • the alkenyl group may contain 2-20, 2-15, 2-12, 2-10, 2-8, 2-6 or 2-3 carbon atoms.
  • Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond.
  • the alkynyl group may contain 2-20, 2-15, 2-12, 2-10, 2-8, 2-6 or 2-3 carbon atoms.
  • Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH3), 2-propynyl (-CH2-C ⁇ CH), 1, 3-Butadiynyl (-C ⁇ C-C ⁇ CH), etc.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and may exist as a monocyclic, bicyclic bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is usually 4 to 20 membered, 4 to 15 membered, 4 to 10 membered, 4 to 8 membered, 3 to 12 membered, 3 to 10 membered, or 3 to 6 membered. ring.
  • Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring.
  • the carbocyclic ring is usually a 3- to 20-membered ring, a 3- to 15-membered ring, a 3- to 12-membered ring, a 3- to 10-membered ring (such as a 5- to 8-membered ring), a 3- to 6-membered ring, a 4- to 10-membered ring, 4- to 8-membered ring, 4- to 6-membered ring, 5- to 6-membered ring or 6-membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl Alkyl etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring.
  • the heterocyclic ring is generally a 3 to 20-membered ring, a 3- to 15-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. , 3 to 10 membered ring, 3 to 7 membered ring, 3 to 6 membered ring, 3 to 5 membered ring, 4 to 10 membered ring, 4 to 8 membered ring, 4 to 6 membered ring, 5 to 6 membered ring or 6 Yuan ring.
  • 3-membered heterocycloalkyl examples include, but are not limited to, oxirane, ethylene sulfide, and aziridyl.
  • 4-membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetane.
  • Examples of cyclyl, thibutylcyclyl, and 5-membered heterocycloalkyl include but are not limited to tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, and thiazolidine 1, 4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, examples of 7-membered heterocycloalkyl include But it is not limited to azepanyl, oxeptanyl, and thiopanyl. Preference is given to monocyclic heterocycloalkyl groups with 5 or 6 ring atoms.
  • heterocycloalkenyl includes those in which up to 3, in one embodiment up to 2, and in another embodiment 1 carbon atoms are each independently replaced by O, S(O), or N Cycloalkenyl, provided that at least one cycloalkenyl carbon-carbon double bond is retained.
  • the cyclic group can exist as a single ring, a bridged ring or a spiro ring, and can be a 3- to 20-membered ring, a 3- to 15-membered ring, a 3- to 12-membered ring, a 3- to 10-membered ring (for example, a 5- to 8-membered ring) , 3 to 6 membered rings.
  • heterocycloalkenyl include, but are not limited to, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepinyl, or azaspirocyclooctene.
  • heterocyclyl refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a monocyclic, bridged or spirocyclic ring.
  • the heterocyclic ring is generally a 3 to 20-membered ring, a 3- to 15-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. , 3 to 12 membered ring, 3 to 10 membered ring or 3 to 7 membered ring.
  • heterocyclyl include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, N-methyl Pyrrolidyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one (for example, 1, 2 or 3) ring atoms selected from N, O, S, and the remaining ring atoms are C, and has at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, a 5 to 10 membered ring, a 5 to 12 membered ring or contain 6 to 20, 6 to 15 or 6 to 14, especially It is multiple fused rings of 6 to 10 ring atoms, or a 5- or 6-membered monocyclic ring.
  • heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • the “Ring A” groups in this application are all divalent groups, so it should be understood that the options for “Ring A” are also divalent groups.
  • the "cycloalkyl” in ring A can be understood as “cycloalkylene”
  • the C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12-membered heterocycloalkenyl, C 6-12 aryl or 5-12-membered heteroaryl can be understood as C 3-12 cycloalkylene, 3-12-membered heterocycloalkylene, C 3-12 cycloalkylene Cycloalkenyl, 3-12 membered heterocycloalkenylene, C 6-12 arylene or 5-12 membered heteroarylene; C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl in ring A , C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10
  • C 3-10 cycloalkyl or 3-10-membered heterocycloalkyl in Cy can be understood as C 3-10 cycloalkylene or 3-10-membered heterocycloalkylene respectively;
  • C 3- in Cy 8 -cycloalkyl or 3-8-membered heterocycloalkyl can be understood as C 3-8 cycloalkylene or 3-8-membered heterocycloalkylene respectively;
  • the one-membered heterocycloalkyl group can be understood as C 5-6 cycloalkylene group or 5-6 membered heterocycloalkylene group;
  • the 3-6 membered heterocycloalkyl group in Cy can be understood as 3-6 membered heterocycloalkylene group.
  • the 6-membered heterocycloalkyl group in Cy can be understood as a 6-membered heterocycloalkylene group
  • the piperidinyl or piperazinyl group in Cy can be understood as a piperidinylene or piperazinylene group.
  • Groups or structural fragments in this application such as ring A, -Cy-L 3 -X 2 -, -Cy-, -L 1 -, -X 2 -, -Cy-L 1 - or -L 2 - and their Specific options, optionally, can be read from left to right, corresponding to the left-hand and right-hand groups of the group or fragment in the general formula, for example, when -Cy-L 1 -(i.e.
  • L selected from In reading order from left to right, -Cy-L 1 -the left side and the fragment corresponding to the left side in the general formula Join, right to right fragment Connect, forming fragments such as Optionally, a group or structural fragment in this application such as Ring A, -Cy-L 3 -X 2 -, -Cy-, -L 1 -, -X 2 -, -Cy-L 1 - or -L 2 - and its specific options can be read from right to left, corresponding to the left group and the right group of the group or fragment in the general formula, for example, when -Cy-L 1 - (i.e.
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevent means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such disease or condition is present in a mammal.
  • a mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treating or preventing a specified disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
  • the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. .
  • composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is the imidazole moiety, where the proton can migrate between two ring nitrogens.
  • Valence tautomers include tautomers by reorganization of some of the bonding electrons.
  • the present application also includes compounds of the present application that are the same as those described herein, but are isotopically labeled in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotopically labeled compounds of the present application can be used in compound and/or substrate tissue distribution analyses. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes and/or Examples below.
  • substitution with heavier isotopes such as deuterium (i.e. 2 H) may provide certain therapeutic advantages resulting from greater metabolic stability (e.g. such as increased half-life in vivo or reduced dosage requirements), and may therefore be preferred in certain circumstances, where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
  • Stereoisomers of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, dragees, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • dosages of 0.01 to 200 mg/kg body weight are administered per day, in single or divided doses.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred implementations include but are not limited to the embodiments of this application.
  • EDCI carbodiimide hydrochloride
  • DMAP 4-dimethylaminopyridine
  • Pd(PPh 3 ) 2 Cl 2 represents bistriphenylphosphine palladium dichloride
  • AcOH represents acetic acid
  • NaBH 3 CN represents cyanohydroboration Sodium
  • NaCl stands for sodium chloride.
  • Example 1 Referring to the preparation method of Example 1 in Step 9) of Example 1, the intermediate 1-10 therein was replaced by the intermediate 2-1 to obtain compound 2 (62 mg).
  • Example 1-10 was replaced by the intermediate 5-1 to obtain compound 5 (32 mg).
  • Example 1 Refer to the preparation method of Example 1 in step 9) of Example 1, replace intermediate 1-6 with intermediate 6-2, and replace intermediate 1-10 with intermediate 6-5 to obtain compound 6 (22 mg) .
  • Example 12-2 is replaced by the intermediate 18-2 to obtain compound 18.
  • Dissolve compound 19A (2.0g) in acetonitrile (40mL), add anhydrous potassium carbonate (1.17g), 1,6-dibromohexane (5.62g) in sequence, react at 60°C for 6 hours, and prepare the intermediate through liquid phase 19-1.
  • intermediate 13-2 is replaced by intermediate 33-2 to obtain compound 33.
  • Test Example 1 In vitro RS4;11 cell proliferation inhibitory effect
  • RS4;11 cells from Nanjing Kebai
  • RS4;11 cells from Nanjing Kebai
  • collect the cells into a centrifuge tube use a low-speed desktop centrifuge at 1000 rpm for 5 minutes, discard the supernatant, and add 3 mL of seed with a pipette.
  • Resuspend in plate culture medium RPMI basal medium + 5% fetal calf serum.
  • Use a cell counter to count, dilute with seed plate culture medium, adjust the cell density to 1 ⁇ 10 5 cells/mL, use a row gun to inoculate 100 ⁇ L/well on a 96-well plate, and place at 37°C in a saturated humidity containing 5% CO 2 cultured in a cell culture incubator.
  • the compounds of the present disclosure have RS4;11 cell proliferation inhibitory effects in vitro.
  • Test Example 2 Inhibitory effect on MOLT-4 cell proliferation in vitro
  • Inhibition rate (%) (average of negative control group - experimental group)/(negative control group) Average value - average value of blank group) ⁇ 100%, with the logarithm of compound concentration as the abscissa and the inhibition rate as the ordinate, four-parameter analysis, fitting the dose-effect curve, and calculating IC 50 . The results are shown in Table 2.
  • the compounds of the present disclosure have MOLT-4 cell proliferation inhibitory effects in vitro.
  • Test Example 3 Determination of BCL-XL protein degradation in MOLT-4 cells in vitro
  • Degradation rate (%) (average MFI of the negative control group - MFI of the compound group) / (average MFI of the negative control group - average MFI of the background group) ⁇ 100%, taking the logarithm of the compound concentration as the abscissa, and the degradation rate as the vertical axis Coordinates, four-parameter analysis, fitting dose-effect curve, and calculation of DC 50 (half degradation concentration). The results are shown in Table 3.
  • Compounds of the present disclosure have BCL-XL protein degradation effects on MOLT-4 cells in vitro.
  • dilution buffer in the kit (cisbio, 63ADK000CB04PEG) to dilute the Tag1-BCL-XL protein stock solution to 8nM, and at the same time dilute the Tag2-BAK protein stock solution to 20nM.
  • the compounds of the present disclosure possess BCL-XL/BAK binding inhibitory activity.
  • Test Example 5 Stability of liver microsomes in vitro
  • Liver microsome body temperature incubation samples (species: human, monkey, rat and mouse) were prepared as a mixture of PBS buffer (PH7.4), liver microsome solution (0.5mg/mL), test compound and NADPH+MgCl 2 The solution was incubated at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH7.4), liver microsome solution (0.5 mg/mL), and test compound. The sample was added to an acetonitrile solution containing an internal standard and subjected to protein precipitation to prepare a supernatant, which was diluted and used for LC/MS/MS measurement. The results are shown in Table 4.
  • ICR mice weighing 18 to 22 g, were randomly divided into groups of 9 mice after adapting for 3 to 5 days, and the test compound solution was injected intravenously at a dose of 1 mg/kg.
  • Blood collection time points are 5min, 15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 10h, and 24h. Blood is collected from the orbit to prepare plasma samples to be tested. Take 20 ⁇ L of the plasma sample to be tested and the standard sample, add acetonitrile solution containing the internal standard, undergo protein precipitation to obtain the supernatant, and dilute it for LC/MS/MS measurement.
  • Noncompartmental models were used to fit pharmacokinetic parameters.
  • the compounds of the present disclosure have good in vivo pharmacokinetic properties, such as excellent performance in AUC, C max , T 1/2 and T max and other parameters.
  • the detection reagent CCK-8 (manufacturer: Nippon Dojin Chemical, 10 ⁇ L/well) was added. After incubation in the cell culture incubator for 1.5 hours, the absorbance value was detected at 450 nm with the Envision microplate reader. Four-parameter analysis was performed to fit the dose-effect curve. Calculate IC 50 .
  • the detection reagent CCK-8 (manufacturer: Nippon Dojin Chemical, 10 ⁇ L/well) was added. After incubation in the cell culture incubator for 1.5 hours, the absorbance value was detected at 450 nm with the Envision microplate reader. Four-parameter analysis was performed to fit the dose-effect curve. Calculate IC 50 .
  • Compounds of the present disclosure have low platelet toxicity (canine or human platelets).

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Abstract

The present application provides a compound containing a trifluoromethyl group, and specifically relates to a compound as represented by formula I-0 or a pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof in treating tumor diseases.

Description

含有三氟甲基基团的化合物Compounds containing trifluoromethyl groups

相关申请的交叉引用Cross-references to related applications

本申请要求于2022年07月12日向中国国家知识产权局提交的第202210817391.0号中国专利申请、于2023年01月16日向中国国家知识产权局提交的第202310226014.4号中国专利申请以及于2023年07月04日向中国国家知识产权局提交的第202310815128.2号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。This application requires the Chinese Patent Application No. 202210817391.0 submitted to the State Intellectual Property Office of China on July 12, 2022, the Chinese Patent Application No. 202310226014.4 submitted to the State Intellectual Property Office of China on January 16, 2023, and the Chinese Patent Application No. 202310226014.4 submitted to the State Intellectual Property Office of China on July 16, 2023. The priority and rights of the Chinese patent application No. 202310815128.2 submitted to the State Intellectual Property Office of China on the 4th, and the disclosed content of the application is incorporated herein by reference in its entirety.

技术领域Technical field

本申请涉及含有三氟甲基基团的化合物、其制备方法、含有该化合物的药物组合物、以及其在治疗肿瘤疾病中的用途。The present application relates to compounds containing trifluoromethyl groups, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of tumor diseases.

背景技术Background technique

由促凋亡成员和抗凋亡成员组成的B细胞淋巴瘤2(Bcl-2)蛋白家族通过调节内在凋亡途径在确定细胞命运中起关键作用。抗凋亡Bcl-2家族蛋白(诸如Bcl-2、Bcl-xL、Bcl-W和Mcl-1)在许多癌症中被上调，并与肿瘤起始、进展和对化学疗法和靶向疗法的抗性相关。由于大部分实体瘤的生长不依赖于BCL-2蛋白，因此，单纯靶向BCL-2抑制剂在实体瘤治疗中无明显效果，BCL-XL蛋白在许多白血病细胞及实体瘤中表达显著升高，研究表明，肿瘤组织中BCL-XL表达和肿瘤耐药呈正相关，靶向BCL-XL是一潜在的理想的抗肿瘤分子靶点。The B-cell lymphoma 2 (Bcl-2) protein family, composed of pro-apoptotic and anti-apoptotic members, plays a key role in determining cell fate by regulating the intrinsic apoptotic pathway. Anti-apoptotic Bcl-2 family proteins (such as Bcl-2, Bcl-xL, Bcl-W, and Mcl-1) are upregulated in many cancers and are associated with tumor initiation, progression, and resistance to chemotherapy and targeted therapies. Sexually related. Since the growth of most solid tumors does not depend on BCL-2 protein, BCL-2 inhibitors alone have no obvious effect in the treatment of solid tumors. The expression of BCL-XL protein is significantly increased in many leukemia cells and solid tumors. , studies have shown that BCL-XL expression in tumor tissues is positively correlated with tumor drug resistance, and targeting BCL-XL is a potential ideal anti-tumor molecular target.

PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物，此类化合物能够诱导靶蛋白被细胞的蛋白酶体识别，引起靶向蛋白的降解，能够有效地降低靶向蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体，使PROTAC技术应用于各种疾病的治疗成为可能，该技术近年来同时得到了广泛的关注。PROTAC (proteolysis targeting chimera) molecules are a type of bifunctional compounds that can simultaneously bind targeting proteins and E3 ubiquitin ligases. Such compounds can induce the target protein to be recognized by the proteasome of the cell, causing the degradation of the targeted protein, and can effectively Reduce the content of target proteins in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases. This technology has also received widespread attention in recent years.

发明内容Contents of the invention

本申请涉及式I-0化合物或其药学上可接受的盐，
This application relates to compounds of formula I-0 or pharmaceutically acceptable salts thereof,

其中，in,

每一个R1分别独立地选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 1 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S( O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS (O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1 -6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6- 12 aryl or 5-12 membered heteroaryl;

n1选自1、2、3或4；n1 is selected from 1, 2, 3 or 4;

q选自0、1、2、3、4、5或6；q is selected from 0, 1, 2, 3, 4, 5 or 6;

每一个R2分别独立地选自卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基 NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 2 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1- 6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1 -6 alkylNHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O) NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered hetero Cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl;

m选自0、1、2、3、4、5或6；m is selected from 0, 1, 2, 3, 4, 5 or 6;

环A选自C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Ring A is selected from C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered hetero Aryl;

L为连接基团；L is the connecting group;

每一个R3分别独立地选自卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 3 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1- 6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1 -6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O) NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS (O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 Alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl base or 5-12 membered heteroaryl;

p选自0、1、2或3；p is selected from 0, 1, 2 or 3;

R4及R5分别独立地选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，R 4 and R 5 are independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O- , C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S (O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS (O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6 -12 aryl or 5-12 membered heteroaryl,

或者，R4及R5相互连接与相连的碳原子一起形成C3-6环烷基或3-6元杂环烷基；Alternatively, R 4 and R 5 are connected to each other and the connected carbon atoms together form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group;

X选自CRaRa’或C＝O；X is selected from CR a R a' or C=O;

X1选自CRb或N；X 1 is selected from CR b or N;

Ra和Ra’可以相同或不同，分别独立地选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；R a and R a ' may be the same or different, and are independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkylNHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered hetero Cycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl;

Rb选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；R b is selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio Base, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkyl Base NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5 -12-membered heteroaryl;

所述R1、R2、环A、R3、R4、R5、Ra、Ra’或Rb任选地被一个或多个取代基取代。The R 1 , R 2 , ring A, R 3 , R 4 , R 5 , R a , R a′ or R b are optionally substituted by one or more substituents.

在一些实施方案中，n1为1或2。在一些实施方案中，n1为1。In some embodiments, n1 is 1 or 2. In some embodiments, n1 is 1.

在一些实施方案中，每一个R1分别独立地选自氢、卤素、OH、NH2、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OCO-、C1-4烷基C(O)O-、C1-4烷基NHCO-、C1-4烷基CONH-、(C1-4烷基)2NCO-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-10环烷基、3-10元杂环烷基、C3-10环烯基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，所述R1任选地被一个或多个取代基取代。In some embodiments, each R 1 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- 4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO-, C 1-4 alkyl C (O)O-, C 1-4 alkylNHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS(O)-, C 1 -4 alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1-4 alkyl S(O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 cycloalkenyl, 3-10 membered heterocycle Alkenyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 1 is optionally substituted by one or more substituents.

在一些实施方案中，每一个R1分别独立地选自氢、卤素、OH、NH2、CN、C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基、C1-3烷硫基、C1-3烷基NH-、(C1-3烷基)2N-、C1-3烷基OCO-、C1-3烷基C(O)O-、C1-3烷基NHCO-、C1-3烷基CONH-、(C1-3烷基)2NCO-、C1-3烷基NHS(O)-、C1-3烷基S(O)NH-、(C1-3烷基)2NS(O)-、C1-3烷基NHS(O)2-、C1-3烷基S(O)2NH-、(C1-3烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6-10芳基或5-10元杂芳基，所述R1任选地被一个或多个取代基取代。In some embodiments, each R 1 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1- 3Alkoxy , C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO-, C 1-3 alkyl C (O)O-, C 1-3 alkylNHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS(O)-, C 1 -3 alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1-3 alkyl S(O) 2 NH-, (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycle Alkenyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 1 is optionally substituted by one or more substituents.

在一些实施方案中，每一个R1独立地选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6 炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-或(C1-6烷基)2NS(O)2-，所述R1任选地被一个或多个取代基取代。In some embodiments, each R 1 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl , C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS ( O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH- or (C 1-6 alkyl) 2 NS(O) 2 -, and R 1 is optionally substituted by one or more substituents.

在一些实施方案中，每一个R2分别独立地选自卤素、OH、NH2、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OCO-、C1-4烷基C(O)O-、C1-4烷基NHCO-、C1-4烷基CONH-、(C1-4烷基)2NCO-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-10环烷基、3-10元杂环烷基、C3-10环烯基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，所述R2任选地被一个或多个取代基取代。In some embodiments, each R 2 is independently selected from halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl Oxygen group, C 1-4 alkylthio group, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO-, C 1-4 alkyl C(O )O-, C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS(O)-, C 1-4 Alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1-4 alkyl S(O) 2 NH- , (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 cycloalkenyl, 3-10 membered heterocycloalkenyl , C 6-10 aryl or 5-10 membered heteroaryl, the R 2 is optionally substituted by one or more substituents.

在一些实施方案中，每一个R2分别独立地选自卤素、OH、NH2、CN、C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基、C1-3烷硫基、C1-3烷基NH-、(C1-3烷基)2N-、C1-3烷基OCO-、C1-3烷基C(O)O-、C1-3烷基NHCO-、C1-3烷基CONH-、(C1-3烷基)2NCO-、C1-3烷基NHS(O)-、C1-3烷基S(O)NH-、(C1-3烷基)2NS(O)-、C1-3烷基NHS(O)2-、C1-3烷基S(O)2NH-、(C1-3烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6-10芳基或5-10元杂芳基，所述R2任选地被一个或多个取代基取代。In some embodiments, each R 2 is independently selected from halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkyl Oxygen group, C 1-3 alkylthio group, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO-, C 1-3 alkyl C(O )O-, C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1-3 alkyl S(O) 2 NH- , (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl , C 6-10 aryl or 5-10 membered heteroaryl, the R 2 is optionally substituted by one or more substituents.

在一些实施方案中，每一个R2独立地选自卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-或(C1-6烷基)2NS(O)2-，所述R2任选地被一个或多个取代基取代。In some embodiments, each R 2 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy Base, C 1-6 alkylthio group, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O) O-, C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH- or (C 1-6 alkyl) 2 NS(O) 2 -, the R 2 is optionally substituted by one or more substituents.

在一些实施方案中，每一个R3分别独立地选自卤素、OH、NH2、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OCO-、C1-4烷基C(O)O-、C1-4烷基NHCO-、C1-4烷基CONH-、(C1-4烷基)2NCO-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-10环烷基、3-10元杂环烷基、C3-10环烯基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，所述R3任选地被一个或多个取代基取代。In some embodiments, each R 3 is independently selected from halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl Oxygen group, C 1-4 alkylthio group, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO-, C 1-4 alkyl C(O )O-, C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS(O)-, C 1-4 Alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1-4 alkyl S(O) 2 NH- , (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 cycloalkenyl, 3-10 membered heterocycloalkenyl , C 6-10 aryl or 5-10 membered heteroaryl, the R 3 is optionally substituted by one or more substituents.

在一些实施方案中，每一个R3分别独立地选自卤素、OH、NH2、CN、C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基、C1-3烷硫基、C1-3烷基NH-、(C1-3烷基)2N-、C1-3烷基OCO-、C1-3烷基C(O)O-、C1-3烷基NHCO-、C1-3烷基CONH-、(C1-3烷基)2NCO-、C1-3烷基NHS(O)-、C1-3烷基S(O)NH-、(C1-3烷基)2NS(O)-、C1-3烷基NHS(O)2-、C1-3烷基S(O)2NH-、(C1-3烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6-10芳基或5-10元杂芳基，所述R3任选地被一个或多个取代基取代。In some embodiments, each R 3 is independently selected from halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkyl Oxygen group, C 1-3 alkylthio group, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO-, C 1-3 alkyl C(O )O-, C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS(O)-, C 1-3 Alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1-3 alkyl S(O) 2 NH- , (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl , C 6-10 aryl or 5-10 membered heteroaryl, the R 3 is optionally substituted by one or more substituents.

在一些实施方案中，每一个R3独立地选自卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-或(C1-6烷基)2NS(O)2-，所述R3任选地被一个或多个取代基取代。In some embodiments, each R 3 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy Base, C 1-6 alkylthio group, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O) O-, C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH- or (C 1-6 alkyl) 2 NS(O) 2 -, the R 3 is optionally substituted by one or more substituents.

在一些实施方案中，每一个R4或R5分别独立地选自氢、卤素、OH、NH2、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OCO-、C1-4烷基C(O)O-、C1-4烷基NHCO-、C1-4烷基CONH-、(C1-4烷基)2NCO-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-10环烷基、3-10元杂环烷基、C3-10环烯基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，In some embodiments, each R 4 or R 5 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO-, C 1-4 Alkyl C(O)O-, C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS(O)- , C 1-4 alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1-4 alkyl S( O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 cycloalkenyl, 3-10 One-membered heterocyclic alkenyl, C 6-10 aryl or 5-10 membered heteroaryl,

或者，R4及R5相互连接与相连的碳原子一起形成C3-6环烷基或3-6元杂环烷基；所述R4或R5任选地被一个或多个取代基取代。Alternatively, R 4 and R 5 are connected to each other and the connected carbon atoms together form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group; the R 4 or R 5 is optionally substituted by one or more substituents replace.

在一些实施方案中，每一个R4或R5分别独立地选自氢、卤素、OH、NH2、CN、C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基、C1-3烷硫基、C1-3烷基NH-、(C1-3烷基)2N-、C1-3烷基OCO-、C1-3烷基 C(O)O-、C1-3烷基NHCO-、C1-3烷基CONH-、(C1-3烷基)2NCO-、C1-3烷基NHS(O)-、C1-3烷基S(O)NH-、(C1-3烷基)2NS(O)-、C1-3烷基NHS(O)2-、C1-3烷基S(O)2NH-、(C1-3烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6-10芳基或5-10元杂芳基，In some embodiments, each R 4 or R 5 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO-, C 1-3 alkyl C(O)O-, C 1-3 alkylNHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS(O)-, C 1-3 alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1-3 alkyl S(O) 2 NH-, (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered hetero Cycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl,

或者，R4及R5相互连接与相连的碳原子一起形成C3-6环烷基或3-6元杂环烷基；所述R4或R5任选地被一个或多个取代基取代。Alternatively, R 4 and R 5 are connected to each other and the connected carbon atoms together form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group; the R 4 or R 5 is optionally substituted by one or more substituents replace.

在一些实施方案中，R4及R5分别独立地选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-或(C1-6烷基)2NS(O)2-，所述R4或R5任选地被一个或多个取代基取代。In some embodiments, R 4 and R 5 are each independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkylNHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH- or (C 1-6 alkyl) 2 NS(O) 2 -, the R 4 or R 5 is optionally substituted by one or more substituents.

在一些实施方案中，R4及R5分别独立地选自C1-3烷基，或R4及R5相互连接与相连的碳原子一起形成C3-4环烷基或3-4元杂环烷基。在一些实施方案中，R4及R5分别独立地选自甲基，或R4及R5相互连接与相连的碳原子一起形成C3-4环烷基。在一些实施方案中，R4及R5分别独立地选自甲基。In some embodiments, R 4 and R 5 are each independently selected from C 1-3 alkyl, or R 4 and R 5 are connected to each other and the attached carbon atoms together to form a C 3-4 cycloalkyl or 3-4 membered Heterocycloalkyl. In some embodiments, R 4 and R 5 are each independently selected from methyl, or R 4 and R 5 are joined to each other and together with the attached carbon atom to form a C 3-4 cycloalkyl group. In some embodiments, R 4 and R 5 are each independently selected from methyl.

在一些实施方案中，Ra和Ra’可以相同或不同，分别独立地选自氢、卤素、OH、NH2、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OCO-、C1-4烷基C(O)O-、C1-4烷基NHCO-、C1-4烷基CONH-、(C1-4烷基)2NCO-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-10环烷基、3-10元杂环烷基、C3-10环烯基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，所述Ra或Ra’任选地被一个或多个取代基取代。In some embodiments, R a and R a' may be the same or different, and are each independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO- , C 1-4 alkyl C(O)O-, C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS (O)-, C 1-4 alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1-4 Alkyl S(O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 cycloalkenyl , 3-10 membered heterocyclic alkenyl, C 6-10 aryl or 5-10 membered heteroaryl, the R a or R a' is optionally substituted by one or more substituents.

在一些实施方案中，Ra和Ra’可以相同或不同，分别独立地选自氢、卤素、OH、NH2、CN、C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基、C1-3烷硫基、C1-3烷基NH-、(C1-3烷基)2N-、C1-3烷基OCO-、C1-3烷基C(O)O-、C1-3烷基NHCO-、C1-3烷基CONH-、(C1-3烷基)2NCO-、C1-3烷基NHS(O)-、C1-3烷基S(O)NH-、(C1-3烷基)2NS(O)-、C1-3烷基NHS(O)2-、C1-3烷基S(O)2NH-、(C1-3烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6-10芳基或5-10元杂芳基，所述Ra或Ra’任选地被一个或多个取代基取代。In some embodiments, R a and R a' may be the same or different, and are each independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2- 3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO- , C 1-3 alkyl C(O)O-, C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS (O)-, C 1-3 alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1-3 Alkyl S(O) 2 NH-, (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl , 3-6 membered heterocyclic alkenyl, C 6-10 aryl or 5-10 membered heteroaryl, the R a or R a' is optionally substituted by one or more substituents.

在一些实施方案中，Ra和Ra’可以相同或不同，分别独立地选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-或(C1-6烷基)2NS(O)2-，所述Ra和Ra’任选地被一个或多个取代基取代。In some embodiments, R a and R a ' may be the same or different, and are each independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO- , C 1-6 alkyl C(O)O-, C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS (O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 Alkyl S(O) 2 NH- or (C 1-6 alkyl) 2 NS(O) 2 -, the R a and R a ' are optionally substituted by one or more substituents.

在一些实施方案中，Ra和Ra’可以相同或不同，分别独立地选自氢或卤素。In some embodiments, R a and R a' may be the same or different, and are each independently selected from hydrogen or halogen.

在一些实施方案中，Ra和Ra’相同，分别独立地选自氢。In some embodiments, R a and R a' are the same and each is independently selected from hydrogen.

在一些实施方案中，Rb选自氢、卤素、OH、NH2、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OCO-、C1-4烷基C(O)O-、C1-4烷基NHCO-、C1-4烷基CONH-、(C1-4烷基)2NCO-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-10环烷基、3-10元杂环烷基、C3-10环烯基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，所述Rb任选地被一个或多个取代基取代。In some embodiments, R b is selected from hydrogen, halogen, OH, NH 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO-, C 1-4 alkyl C(O)O- , C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl NHS(O)-, C 1-4 alkyl S (O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS (O) 2 -, C 1-4 alkyl S(O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 cycloalkenyl, 3-10 membered heterocycloalkenyl, C 6 -10 aryl or 5-10 membered heteroaryl, the R b is optionally substituted by one or more substituents.

在一些实施方案中，Rb选自氢、卤素、OH、NH2、CN、C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基、C1-3烷硫基、C1-3烷基NH-、(C1-3烷基)2N-、C1-3烷基OCO-、C1-3烷基C(O)O-、C1-3烷基NHCO-、C1-3烷基CONH-、(C1-3烷基)2NCO-、C1-3烷基NHS(O)-、C1-3烷基S(O)NH-、(C1-3烷基)2NS(O)-、C1-3烷基NHS(O)2-、C1-3烷基S(O)2NH-、(C1-3烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6-10芳基或5-10元杂芳基，所述Rb任选地被一个或多个取代基取代。In some embodiments, R b is selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO-, C 1-3 alkyl C(O)O- , C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl NHS(O)-, C 1-3 alkyl S (O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS (O) 2 -, C 1-3 alkyl S(O) 2 NH-, (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 -10 aryl or 5-10 membered heteroaryl, the R b is optionally substituted by one or more substituents.

在一些实施方案中，Rb选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6 烷基NHS(O)2-、C1-6烷基S(O)2NH-或(C1-6烷基)2NS(O)2-，所述Rb任选地被一个或多个取代基取代。In some embodiments, R b is selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O- , C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S (O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 Alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH- or (C 1-6 alkyl) 2 NS(O) 2 -, the R b is optionally replaced by one or more substituted by substituents.

在一些实施方案中，Rb选自氢或卤素。In some embodiments, R b is selected from hydrogen or halogen.

在一些实施方案中，Rb选自氢。In some embodiments, R b is selected from hydrogen.

在一些实施方案中，环A选自C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6-10芳基或5-10元杂芳基，所述环A任选地被一个或多个取代基取代。在一些实施方案中，所述3-4元杂环烷基、3-6元杂环烷基、3-10元杂环烷基、3-12元杂环烷基、3-6元杂环烯基、3-10元杂环烯基、3-12元杂环烯基、5-10元杂芳基和5-12元杂芳基各自独立地含有1，2或3个独立地选自N、O和S的杂原子。In some embodiments, Ring A is selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10 aryl Or 5-10 membered heteroaryl, the ring A is optionally substituted by one or more substituents. In some embodiments, the 3-4 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 3-12 membered heterocycloalkyl, 3-6 membered heterocycle Alkenyl, 3-10 membered heterocyclic alkenyl, 3-12 membered heterocyclic alkenyl, 5-10 membered heteroaryl and 5-12 membered heteroaryl each independently contain 1, 2 or 3 independently selected from Heteroatoms of N, O and S.

在一些实施方案中，所述R1、R2、环A、R3、R4、R5、Ra、Ra’或Rb任选地被一个或多个选自以下的取代基取代：-OH、-SH、卤素、-NH2、硝基、亚硝基、-CN、叠氮基团、亚砜基团、砜基团、磺酰胺基团、羧基、羧醛基团、亚胺基团、烷基、卤代-烷基、环烷基、卤代-环烷基、烯基、卤代-烯基、环烯基、卤代-环烯基、炔基、卤代-炔基、环炔基、卤代-环炔基、杂烷基、卤代-杂烷基、烷氧基、烷硫基、芳基、芳基氧基、芳基硫基、芳烷基、芳基烷氧基、芳基烷硫基、杂芳基、杂芳基氧基、杂芳基硫基、杂芳烷基、杂芳基烷氧基、杂芳基烷硫基、杂环基、杂环基氧基、杂环基硫基、杂环基烷基、杂环基烷氧基、杂环基烷硫基、酰基、酰氧基、氨基甲酸酯基团、酰胺基团、脲基、环氧基团和酯基团等。In some embodiments, the R 1 , R 2 , Ring A, R 3 , R 4 , R 5 , R a , R a′ or R b are optionally substituted with one or more substituents selected from : -OH, -SH, halogen, -NH 2 , nitro group, nitroso group, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxyaldehyde group, sulfonate group Amine group, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo- Alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, Arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl , heterocyclyloxy group, heterocyclylthio group, heterocyclylalkyl group, heterocyclylalkoxy group, heterocyclylalkylthio group, acyl group, acyloxy group, carbamate group, amide group, Urea group, epoxy group and ester group, etc.

在一些实施方案中，所述式I-0化合物或其药学上可接受的盐选自式I化合物或其药学上可接受的盐：
In some embodiments, the compound of Formula I-0 or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of Formula I or a pharmaceutically acceptable salt thereof:

其中：in:

R1选自氢、卤素或C1-3烷基；R 1 is selected from hydrogen, halogen or C 1-3 alkyl;

q选自0、1、2、3、4、5或6；q is selected from 0, 1, 2, 3, 4, 5 or 6;

每一个R2分别独立地选自OH、NH2、CN、卤素、C1-3烷基或C1-3烷氧基；Each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl or C 1-3 alkoxy;

m选自0、1、2或3；m is selected from 0, 1, 2 or 3;

环A选自C4-10环烷基或4-10元杂环烷基；Ring A is selected from C 4-10 cycloalkyl or 4-10 membered heterocycloalkyl;

L为连接基团；L is the connecting group;

每一个R3分别独立地选自OH、NH2、CN、卤素、C1-3烷基或C1-3烷氧基；Each R 3 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl or C 1-3 alkoxy;

p选自0、1、2或3；p is selected from 0, 1, 2 or 3;

X选自CH2或C＝O；X is selected from CH 2 or C=O;

X1选自CH或N；X 1 is selected from CH or N;

所述R1、R2、环A、R3、X或X1任选地被一个或多个取代基取代。The R 1 , R 2 , ring A, R 3 , X or X 1 are optionally substituted by one or more substituents.

所述式I-0化合物和所述式I化合物各自独立地包括以下实施方案。The compound of Formula I-0 and the compound of Formula I each independently include the following embodiments.

在一些实施方案中，In some embodiments,

R1选自氢、卤素或C1-3烷基；R 1 is selected from hydrogen, halogen or C 1-3 alkyl;

q选自0、1、2、3、4、5或6；q is selected from 0, 1, 2, 3, 4, 5 or 6;

每一个R2分别独立地选自OH、NH2、CN、卤素、C1-3烷基或C1-3烷氧基；Each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl or C 1-3 alkoxy;

m选自0、1、2或3；m is selected from 0, 1, 2 or 3;

环A选自C4-10环烷基或4-10元杂环烷基； Ring A is selected from C 4-10 cycloalkyl or 4-10 membered heterocycloalkyl;

L为连接基团；L is the connecting group;

每一个R3分别独立地选自OH、NH2、CN、卤素、C1-3烷基或C1-3烷氧基；Each R 3 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl or C 1-3 alkoxy;

p选自0、1、2或3；p is selected from 0, 1, 2 or 3;

X选自CH2或C＝O；X is selected from CH 2 or C=O;

X1选自CH或N。X 1 is selected from CH or N.

在一些实施方案中，每一个R1分别独立地选自氢、卤素或C1-3烷基，所述R1任选地被一个或多个取代基取代。In some embodiments, each R 1 is independently selected from hydrogen, halogen, or C 1-3 alkyl, and said R 1 is optionally substituted with one or more substituents.

在一些实施方案中，每一个R1分别独立地选自氢、卤素或C1-2烷基，所述R1任选地被一个或多个取代基取代。In some embodiments, each R 1 is independently selected from hydrogen, halogen, or C 1-2 alkyl, and said R 1 is optionally substituted with one or more substituents.

在一些实施方案中，每一个R1分别独立地选自氢、氟、氯、溴或甲基，所述R1任选地被一个或多个取代基取代。In some embodiments, each R 1 is independently selected from hydrogen, fluorine, chlorine, bromine, or methyl, and said R 1 is optionally substituted with one or more substituents.

在一些实施方案中，每一个R1分别独立地选自氢、氯或甲基，所述R1任选地被一个或多个取代基取代。In some embodiments, each R 1 is independently selected from hydrogen, chlorine, or methyl, and said R 1 is optionally substituted with one or more substituents.

在一些实施方案中，R1选自氢、卤素或C1-3烷基。In some embodiments, R 1 is selected from hydrogen, halogen, or C 1-3 alkyl.

在一些实施方案中，R1选自氢、卤素或C1-2烷基。In some embodiments, R 1 is selected from hydrogen, halogen, or C 1-2 alkyl.

在一些实施方案中，R1选自氢、氟、氯、溴或甲基。In some embodiments, R1 is selected from hydrogen, fluorine, chlorine, bromine, or methyl.

在一些实施方案中，R1选自氢、氯或甲基。In some embodiments, R1 is selected from hydrogen, chlorine, or methyl.

在一些实施方案中，R1为氢。In some embodiments, R1 is hydrogen.

在一些实施方案中，结构片段为 In some embodiments, structural fragments for

在一些实施方案中，结构片段选自 In some embodiments, structural fragments Selected from

在一些实施方案中，q选自0、1、2或3。在一些实施方案中，q选自0、1或2。在一些实施方案中，q为1。In some embodiments, q is selected from 0, 1, 2, or 3. In some embodiments, q is selected from 0, 1, or 2. In some embodiments, q is 1.

在一些实施方案中，每一个R2分别独立地选自OH、NH2、CN、卤素、C1-3烷基或C1-3烷氧基，所述R2任选地被一个或多个取代基取代。In some embodiments, each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl, or C 1-3 alkoxy, and the R 2 is optionally replaced by one or more substituted by substituents.

在一些实施方案中，每一个R2分别独立地选自CN、卤素或C1-3烷基，所述R2任选地被一个或多个取代基取代。In some embodiments, each R 2 is independently selected from CN, halogen, or C 1-3 alkyl, and the R 2 is optionally substituted with one or more substituents.

在一些实施方案中，每一个R2分别独立地选自OH、NH2、CN、卤素、C1-3烷基或C1-3烷氧基。In some embodiments, each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl, or C 1-3 alkoxy.

在一些实施方案中，每一个R2分别独立地选自OH、NH2、CN、卤素、C1-2烷基或C1-2烷氧基。In some embodiments, each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-2 alkyl, or C 1-2 alkoxy.

在一些实施方案中，每一个R2分别独立地选自CN、卤素或C1-3烷基。In some embodiments, each R is independently selected from CN, halogen, or C 1-3 alkyl.

在一些实施方案中，每一个R2分别独立地选自CN、卤素或C1-2烷基。In some embodiments, each R 2 is independently selected from CN, halogen, or C 1-2 alkyl.

在一些实施方案中，m选自0、1、2或3。In some embodiments, m is selected from 0, 1, 2, or 3.

在一些实施方案中，m选自0、1或2。在一些实施方案中，m选自0或1。在一些实施方案中，m为0。In some embodiments, m is selected from 0, 1, or 2. In some embodiments, m is selected from 0 or 1. In some embodiments, m is 0.

在一些实施方案中，环A选自C4-10环烷基或4-10元杂环烷基。In some embodiments, Ring A is selected from C 4-10 cycloalkyl or 4-10 membered heterocycloalkyl.

在一些实施方案中，环A选自C4-8环烷基或4-8元杂环烷基。In some embodiments, Ring A is selected from C 4-8 cycloalkyl or 4-8 membered heterocycloalkyl.

在一些实施方案中，环A选自C4-6环烷基或4-6元杂环烷基。In some embodiments, Ring A is selected from C 4-6 cycloalkyl or 4-6 membered heterocycloalkyl.

在一些实施方案中，环A选自C5-6环烷基或5-6元杂环烷基。In some embodiments, Ring A is selected from C 5-6 cycloalkyl or 5-6 membered heterocycloalkyl.

在一些实施方案中，环A选自C6环烷基或6元杂环烷基。In some embodiments, Ring A is selected from C 6 cycloalkyl or 6 membered heterocycloalkyl.

在一些实施方案中，环A选自C6环烷基或6元含N杂环烷基。In some embodiments, Ring A is selected from C 6 cycloalkyl or 6 membered N-containing heterocycloalkyl.

在一些实施方案中，环A选自环己基或哌啶基。 In some embodiments, Ring A is selected from cyclohexyl or piperidinyl.

在一些实施方案中，环A选自 In some embodiments, Ring A is selected from

在一些实施方案中，结构片段选自 In some embodiments, structural fragments Selected from

在一些实施方案中，L选自-Cy-L1-或-L2-；其中，Cy选自C3-10环烷基或3-10元杂环烷基，所述C3-10环烷基或3-10元杂环烷基任选地被一个或多个取代基取代；In some embodiments, L is selected from -Cy-L 1 - or -L 2 -; wherein Cy is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 cycloalkyl Alkyl or 3-10 membered heterocycloalkyl is optionally substituted by one or more substituents;

其中，-L1-或-L2-分别独立地选自1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-6烷基)-或-S-替换的-C1-20烷基-、1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-6烷基)-或-S-替换的-C2-20烯基-、或者1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-6烷基)-或-S-替换的-C2-20炔基-，所述-C1-20烷基-、-C2-20烯基-、或者-C2-20炔基-任选地被一个或多个取代基取代。Among them, -L 1 - or -L 2 - are each independently selected from 1 or more -CH 2 - optionally selected from -O-, phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 1-20 alkyl-, 1 or more -CH 2 - optionally selected from -O- , phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-20 alkenyl-, or 1 or more -CH 2 - optionally selected from -O -, phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 2-20 alkenyl -, or -C 2-20 alkynyl- optionally substituted by one or more substituents.

在一些实施方案中，所述取代基选自＝O、OH、NH2、卤素、CN、C1-6烷基或C1-6烷氧基。In some embodiments, the substituents are selected from =O, OH, NH2 , halogen, CN, C1-6 alkyl, or C1-6 alkoxy.

在一些实施方案中，所述取代基选自＝O、OH、NH2、卤素或CN。In some embodiments, the substituent is selected from =O, OH, NH2 , halogen, or CN.

在另外一些实施方案中，L选自-Cy-L1-或-L2-；其中，Cy选自C3-10环烷基或3-10元杂环烷基，所述C3-10环烷基或3-10元杂环烷基任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、卤素、CN、C1-6烷基或C1-6烷氧基；In other embodiments, L is selected from -Cy-L 1 - or -L 2 -; wherein Cy is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, and the C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more groups selected from: =O, OH, NH 2 , halogen, CN, C 1-6 alkyl or C 1- 6 alkoxy;

其中，-L1-或-L2-分别独立地选自1个或多个-CH2-任选地被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的-C1-20烷基-、1个或多个-CH2-任选地被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的-C2-20烯基-、或者1个或多个-CH2-任选地被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的-C2-20炔基-，所述-C1-20烷基-、-C2-20烯基-、或者-C2-20炔基-任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、卤素或CN。Among them, -L 1 - or -L 2 - are each independently selected from 1 or more -CH 2 - optionally selected from -O-, -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 1-20 alkyl-, 1 or more -CH 2 - optionally selected from -O-, -NH-, -N(C 1-6 alkyl)- or -S-substituted -C 2-20 alkenyl-, or 1 or more -CH 2 - optionally selected from -O-, -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 2-20 alkenyl-, or -C 2-20 alkynyl- is optionally replaced by one or more Substituted with a group selected from: =O, OH, NH 2 , halogen or CN.

在一些实施方案中，所述-L1-或-L2-分别独立地选自1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-6烷基)-或-S-替换的-C1-15烷基-、1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-6烷基)-或-S-替换的-C2-15烯基-、或者1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-6烷基)-或-S-替换的-C2-15炔基-，所述-C1-15烷基-、-C2-15烯基-、或者-C2-15炔基-任选地被一个或多个以下基团取代：＝O、OH、NH2、卤素或CN。In some embodiments, the -L 1 - or -L 2 - are each independently selected from 1 or more -CH 2 - optionally selected from -O-, phenyl (e.g. ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 1-15 alkyl-, 1 or more -CH 2 - optionally selected from -O- , phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-15 alkenyl-, or 1 or more -CH 2 - optionally selected from -O -, phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-15 alkynyl-, the -C 1-15 alkyl-, -C 2-15 alkenyl -, or -C 2-15 alkynyl - optionally substituted by one or more of: =O, OH, NH 2 , halogen or CN.

在另外一些实施方案中，所述-L1-或-L2-分别独立地选自1个或多个-CH2-任选地被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的-C1-15烷基-、1个或多个-CH2-任选地被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的-C2-15烯基-、或者1个或多个-CH2-任选地被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的-C2-15炔基-，所述-C1-15烷基-、-C2-15烯基-、或者-C2-15炔基-任选地被一个或多个以下基团取代：＝O、OH、NH2、卤素或CN。In other embodiments, -L 1 - or -L 2 - are each independently selected from 1 or more -CH 2 - optionally selected from -O-, -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 1-15 alkyl-, 1 or more -CH 2 - optionally selected from -O-, -NH-, -N(C 1 -6 alkyl)- or -S-substituted -C 2-15 alkenyl-, or 1 or more -CH 2 - optionally selected from -O-, -NH-, -N(C 1 -6 alkyl)-or -S-substituted -C 2-15 alkynyl-, said -C 1-15 alkyl-, -C 2-15 alkenyl-, or -C 2-15 alkynyl- Optionally substituted by one or more of: =O, OH, NH2 , halogen or CN.

在一些实施方案中，所述-L1-或-L2-分别独立地选自-1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-6烷基)-或-S-替换的-C1-12烷基-、1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-6烷基)-或-S-替换的-C2-12烯基-、或者1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-6烷基)-或-S-替换的-C2-12炔基-，所述-C1-12烷基-、-C2-12烯基-、或者-C2-12炔基-任选地被一个或多个以下基团取代：＝O、OH、NH2、卤素或CN。In some embodiments, -L 1 - or -L 2 - are each independently selected from -1 or more -CH 2 - optionally selected from -O-, phenyl (e.g. ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 1-12 alkyl-, 1 or more -CH 2 - optionally selected from -O- , phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-12 alkenyl-, or 1 or more -CH 2 - optionally selected from -O -, phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 2-12 alkynyl-, the -C 1-12 alkyl-, -C 2-12 alkenyl -, or -C 2-12 alkynyl - optionally substituted by one or more of: =O, OH, NH 2 , halogen or CN.

在另外一些实施方案中，所述-L1-或-L2-分别独立地选自-1个或多个-CH2-任选地被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的-C1-12烷基-、1个或多个-CH2-任选地被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的-C2-12烯基-、或者1个或多个-CH2-任选地被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的-C2-12炔基-，所述-C1-12烷基-、-C2-12烯基-、或者-C2-12炔基-任选地被一个或多个以下基团取代：＝O、OH、NH2、卤素或CN。 In other embodiments, -L 1 - or -L 2 - are each independently selected from -1 or more -CH 2 - optionally selected from -O-, -NH-, -N( C 1-6 alkyl)- or -S- substituted -C 1-12 alkyl-, 1 or more -CH 2 - optionally selected from -O-, -NH-, -N(C 1-6 alkyl)-or -S-substituted -C 2-12 alkenyl-, or 1 or more -CH 2 - optionally selected from -O-, -NH-, -N(C 1-6 alkyl)-or -S-substituted-C 2-12 alkynyl-, the -C 1-12 alkyl-, -C 2-12 alkenyl-, or -C 2-12 alkynyl - optionally substituted by one or more of the following groups: =O, OH, NH2 , halogen or CN.

在一些实施方案中，所述Cy选自C3-10环烷基或3-10元杂环烷基，所述C3-10环烷基或3-10元杂环烷基任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、卤素、CN、C1-6烷基或C1-6烷氧基。In some embodiments, the Cy is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, which is optionally replaced by Substitution with one or more groups selected from: =O, OH, NH 2 , halogen, CN, C 1-6 alkyl or C 1-6 alkoxy.

在一些实施方案中，所述Cy选自C3-8环烷基或3-8元杂环烷基，所述C3-8环烷基或3-8元杂环烷基任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、卤素、CN、C1-3烷基或C1-3烷氧基。In some embodiments, the Cy is selected from C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, which is optionally substituted by Substitution with one or more groups selected from: =O, OH, NH 2 , halogen, CN, C 1-3 alkyl or C 1-3 alkoxy.

在一些实施方案中，所述Cy选自C3-8环烷基或3-8元杂环烷基，所述C3-8环烷基或3-8元杂环烷基任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、氟、氯、溴、CN、C1-3烷基或C1-3烷氧基。In some embodiments, the Cy is selected from C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, which is optionally substituted by Substitution with one or more groups selected from: =O, OH, NH 2 , fluorine, chlorine, bromine, CN, C 1-3 alkyl or C 1-3 alkoxy.

在一些实施方案中，所述Cy选自C3-8环烷基或3-8元杂环烷基。In some embodiments, the Cy is selected from C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl.

在一些实施方案中，所述Cy选自C5-6环烷基或5-6元杂环烷基。In some embodiments, the Cy is selected from C 5-6 cycloalkyl or 5-6 membered heterocycloalkyl.

在一些实施方案中，所述Cy选自5-6元杂环烷基。In some embodiments, the Cy is selected from 5-6 membered heterocycloalkyl.

在一些实施方案中，所述Cy选自6元杂环烷基。In some embodiments, the Cy is selected from 6-membered heterocycloalkyl.

在一些实施方案中，所述Cy选自哌啶基或哌嗪基。In some embodiments, the Cy is selected from piperidinyl or piperazinyl.

在一些实施方案中，所述Cy选自在一些实施方案中，所述Cy选自 In some embodiments, the Cy is selected from In some embodiments, the Cy is selected from

在一些实施方案中，所述结构片段-Cy-L1-选自在一些实施方案中，所述结构片段-Cy-L1-为 In some embodiments, the structural fragment - Cy-L 1 - is selected from In some embodiments, the structural fragment -Cy- L1- is

一些实施方案中，所述-L1-选自1个或多个-CH2-任选地被选自苯基(如)、或-N(C1-6烷基)-替换的-C1-20烷基-、-C1-19烷基氧基-、-C1-19烷基硫基-、-C1-19烷基氨基-、-C2-20烯基-或-C2-20炔基-，所述-C1-20烷基-、-C1-19烷基氧基-、-C1-19烷基硫基-、-C1-19烷基氨基-、-C2-20烯基-或-C2-20炔基-任选地被一个或多个取代基取代。In some embodiments, the -L 1 - is selected from 1 or more -CH 2 - optionally selected from phenyl (e.g. ), or -N(C 1-6 alkyl)-substituted -C 1-20 alkyl-, -C 1-19 alkyloxy-, -C 1-19 alkylthio-, -C 1 -19 alkylamino-, -C 2-20 alkenyl- or -C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 1-19 alkyloxy-, -C 1 -19alkylthio- , -C1-19alkylamino- , -C2-20alkenyl- or -C2-20alkynyl- is optionally substituted by one or more substituents.

一些实施方案中，所述-L1-选自1个或多个-CH2-任选地被选自苯基(如)、或-N(C1-6烷基)-替换的-C1-15烷基-、-C1-14烷基氧基-、-C1-14烷基硫基-、-C1-14烷基氨基-、-C2-15烯基-或-C2-15炔基-，所述-C1-15烷基-、-C1-14烷基氧基-、-C1-14烷基硫基-、-C1-14烷基氨基-、-C2-15烯基-或-C2-15炔基-任选地被一个或多个取代基取代。In some embodiments, the -L 1 - is selected from 1 or more -CH 2 - optionally selected from phenyl (e.g. ), or -N(C 1-6 alkyl)-substituted -C 1-15 alkyl-, -C 1-14 alkyloxy-, -C 1-14 alkylthio-, -C 1 -14 alkylamino-, -C 2-15 alkenyl- or -C 2-15 alkynyl-, the -C 1-15 alkyl-, -C 1-14 alkyloxy-, -C 1 -14alkylthio- , -C1-14alkylamino- , -C2-15alkenyl- or -C2-15alkynyl- is optionally substituted by one or more substituents.

一些实施方案中，所述-L1-选自1个或多个-CH2-任选地被选自苯基(如)、或-N(C1-6烷基)-替换的-C1-12烷基-、-C1-11烷基氧基-、-C1-11烷基硫基-、-C1-11烷基氨基-、-C2-12烯基-或-C2-12炔基-，所述-C1-12烷基-、-C1-11烷基氧基-、-C1-11烷基硫基-、-C1-11烷基氨基-、-C2-12烯基-或-C2-12炔基-任选地被一个或多个取代基取代。In some embodiments, the -L 1 - is selected from 1 or more -CH 2 - optionally selected from phenyl (e.g. ), or -N(C 1-6 alkyl)-substituted -C 1-12 alkyl-, -C 1-11 alkyloxy-, -C 1-11 alkylthio-, -C 1 -11 alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkynyl-, the -C 1-12 alkyl-, -C 1-11 alkyloxy-, -C 1 -11 Alkylthio-, -C 1-11 alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkynyl- is optionally substituted by one or more substituents.

在一些实施方案中，所述取代基选自＝O、OH、NH2、卤素或CN。In some embodiments, the substituent is selected from =O, OH, NH2 , halogen, or CN.

另外一些实施方案中，所述-L1-选自-C1-20烷基-、-C1-19烷基氧基-、-C1-19烷基硫基-、-C1-19烷基氨基-、-C2-20烯基-或-C2-20炔基-，所述-C1-20烷基-、-C1-19烷基氧基-、-C1-19烷基硫基-、-C1-19烷基氨基-、-C2-20烯基-或-C2-20炔基-任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、卤素或CN。In other embodiments, the -L 1 - is selected from -C 1-20 alkyl-, -C 1-19 alkyloxy-, -C 1-19 alkylthio-, -C 1-19 Alkylamino-, -C 2-20 alkenyl- or -C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 1-19 alkyloxy-, -C 1-19 Alkylthio-, -C 1-19 alkylamino-, -C 2-20 alkenyl- or -C 2-20 alkynyl- optionally substituted by one or more groups selected from: = O, OH, NH 2 , halogen or CN.

另外一些实施方案中，所述-L1-选自-C1-15烷基-、-C1-14烷基氧基-、-C1-14烷基硫基-、-C1-14烷基氨基-、-C2-15烯基-或-C2-15炔基-，所述-C1-15烷基-、-C1-14烷基氧基-、-C1-14烷基硫基-、-C1-14烷基氨基-、 -C2-15烯基-或-C2-15炔基-任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、卤素或CN。In other embodiments, the -L 1 - is selected from -C 1-15 alkyl-, -C 1-14 alkyloxy-, -C 1-14 alkylthio-, -C 1-14 Alkylamino-, -C 2-15 alkenyl- or -C 2-15 alkynyl-, the -C 1-15 alkyl-, -C 1-14 alkyloxy-, -C 1-14 Alkylthio-, -C 1-14 alkylamino-, -C 2-15 alkenyl- or -C 2-15 alkynyl- is optionally substituted by one or more groups selected from: =O, OH, NH 2 , halogen or CN.

另外一些实施方案中，所述-L1-选自-C1-12烷基-、-C1-11烷基氧基-、-C1-11烷基硫基-、-C1-11烷基氨基-、-C2-12烯基-或-C2-12炔基-，所述-C1-12烷基-、-C1-11烷基氧基-、-C1-11烷基硫基-、-C1-11烷基氨基-、-C2-12烯基-或-C2-12炔基-任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、卤素或CN。In other embodiments, the -L 1 - is selected from -C 1-12 alkyl-, -C 1-11 alkyloxy-, -C 1-11 alkylthio-, -C 1-11 Alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkynyl-, the -C 1-12 alkyl-, -C 1-11 alkyloxy-, -C 1-11 Alkylthio-, -C 1-11 alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkynyl- is optionally substituted by one or more groups selected from: = O, OH, NH 2 , halogen or CN.

在一些实施方案中，所述-L1-或-L2-分别独立地选自-(CH2)nO-、-(CH2)nS-、-C(O)-(CH2)nO-、-C(O)-(CH2)nS-、-(CH2)nC≡C-、-C(O)-(CH2)nC≡C-、-(CH2)2N(CH3)-(CH2)nC≡C-、-(CH2)2N(CH3)-(CH2)nO-、-CH2N(CH3)-(CH2)nC≡C-、-CH2N(CH3)-(CH2)nO-、-(CH2)3N(CH3)-(CH2)nC≡C-或-(CH2)3N(CH3)-(CH2)nO-，其中n选自1-12。在一些实施方案中，所述-L1-或-L2-分别独立地选自-(CH2)nNH-或-CH2-苯基-(CH2)nO-，其中n选自1-12。在一些实施方案中，所述n选自1-10；或者n选自1、2、3、4、5、6、7、8、9或10，或者任意两者组成的整数范围。在一些实施方案中，n为3-5。在一些实施方案中，n为3-7。在一些实施方案中，n为3-9。在一些实施方案中，n为3-10。In some embodiments, -L 1 - or -L 2 - are each independently selected from -(CH 2 ) n O-, -(CH 2 ) n S-, -C(O)-(CH 2 ) n O-, -C(O)-(CH 2 ) n S-, -(CH 2 ) n C≡C-, -C(O)-(CH 2 ) n C≡C-, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n C≡C-, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n O-, -CH 2 N(CH 3 )-(CH 2 ) n C≡C-, -CH 2 N(CH 3 )-(CH 2 ) n O-, -(CH 2 ) 3 N(CH 3 )-(CH 2 ) n C≡C-or-(CH 2 ) 3 N(CH 3 )-(CH 2 ) n O-, where n is selected from 1-12. In some embodiments, -L 1 - or -L 2 - are each independently selected from -(CH 2 ) n NH- or -CH 2 -phenyl-(CH 2 ) n O-, where n is selected from 1-12. In some embodiments, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

在一些实施方案中，所述-L1-选自-(CH2)nO-、-(CH2)nS-、-C(O)-(CH2)nO-、-C(O)-(CH2)nS-、-(CH2)nC≡C-或-C(O)-(CH2)nC≡C-，其中n选自1-12。在一些实施方案中，所述-L1-选自-(CH2)nNH-、-(CH2)2N(CH3)-(CH2)nC≡C-、或-CH2-苯基-(CH2)nO-，其中n选自1-12。在一些实施方案中，所述-L1-选自-(CH2)nNH-、-(CH2)nO-、-(CH2)nS-、-(CH2)nC≡C-、-(CH2)3N(CH3)-(CH2)nC≡C-或-CH2-苯基-(CH2)nO-，其中n选自1-12。在一些实施方案中，所述-L1-选自-(CH2)nO-、-(CH2)nS-或-(CH2)nC≡C-，其中n选自1-12。在一些实施方案中，所述n选自1-10；或者n选自1、2、3、4、5、6、7、8、9或10，或者任意两者组成的整数范围。在一些实施方案中，所述n选自3-7。在一些实施方案中，n为3-5。在一些实施方案中，n为3-7。在一些实施方案中，n为3-9。在一些实施方案中，n为3-10。In some embodiments, -L 1 - is selected from -(CH 2 ) n O-, -(CH 2 ) n S-, -C(O)-(CH 2 ) n O-, -C(O )-(CH 2 ) n S-, -(CH 2 ) n C≡C- or -C(O)-(CH 2 ) n C≡C-, where n is selected from 1-12. In some embodiments, -L 1 - is selected from -(CH 2 ) n NH-, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n C≡C-, or -CH 2 - Phenyl-(CH 2 ) n O-, where n is selected from 1-12. In some embodiments, -L 1 - is selected from -(CH 2 ) n NH-, -(CH 2 ) n O-, -(CH 2 ) n S-, -(CH 2 ) n C≡C -, -(CH 2 ) 3 N(CH 3 )-(CH 2 ) n C≡C- or -CH 2 -phenyl-(CH 2 ) n O-, where n is selected from 1-12. In some embodiments, -L 1 - is selected from -(CH 2 ) n O-, -(CH 2 ) n S-, or -(CH 2 ) n C≡C-, where n is selected from 1-12 . In some embodiments, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two. In some embodiments, n is selected from 3-7. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

在一些实施方案中，所述-L2-选自-(CH2)2N(CH3)-(CH2)nC≡C-、-(CH2)2N(CH3)-(CH2)nO-、-CH2N(CH3)-(CH2)nC≡C-、-CH2N(CH3)-(CH2)nO-、-(CH2)3N(CH3)-(CH2)nC≡C-或-(CH2)3N(CH3)-(CH2)nO-，其中n选自1-12。在一些实施方案中，所述-L2-选自-(CH2)nO-、-(CH2)nS-、-(CH2)nNH-、-(CH2)nC≡C-、-(CH2)nN(CH3)(CH2)nC≡C-或-(CH2)n-苯基-(CH2)nO-，其中n选自1-12。在一些实施方案中，所述n选自1-10；或者n选自1、2、3、4、5、6、7、8、9或10，或者任意两者组成的整数范围。在一些实施方案中，n为3-5。在一些实施方案中，n为3-7。在一些实施方案中，n为3-9。在一些实施方案中，n为3-10。In some embodiments, -L 2 - is selected from -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n C≡C-, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n O-, -CH 2 N(CH 3 )-(CH 2 ) n C≡C-, -CH 2 N(CH 3 )-(CH 2 ) n O-, -(CH 2 ) 3 N( CH 3 )-(CH 2 ) n C≡C- or -(CH 2 ) 3 N(CH 3 )-(CH 2 ) n O-, where n is selected from 1-12. In some embodiments, the -L2- is selected from -( CH2 ) nO- , -( CH2 ) nS- , -( CH2 ) nNH- , -( CH2 ) nC≡C -, -(CH 2 ) n N(CH 3 )(CH 2 ) n C≡C- or -(CH 2 ) n -phenyl-(CH 2 ) n O-, where n is selected from 1-12. In some embodiments, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

在一些实施方案中，L选自-Cy-L3-X2-或-L2-，其中Cy及L2如前所述；L3选自1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-6烷基)-或-S-替换的-C1-20烷基-、-C2-20烯基-或-C2-20炔基-，所述-C1-20烷基-、-C2-20烯基-或-C2-20炔基-任选地被一个或多个以下基团取代：＝O、OH、NH2、卤素或CN；X2选自键、O、S或NH。In some embodiments, L is selected from -Cy-L 3 -X 2 - or -L 2 -, wherein Cy and L 2 are as described above; L 3 is selected from 1 or more -CH 2 - optionally Selected from -O-, phenyl (such as ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 1-20 alkyl-, -C 2-20 alkenyl- or -C 2-20 alkynyl-, The -C 1-20 alkyl-, -C 2-20 alkenyl- or -C 2-20 alkynyl- is optionally substituted by one or more of the following groups: =O, OH, NH 2 , halogen or CN; X 2 is selected from bond, O, S or NH.

在另外一些实施方案中，L选自-Cy-L3-X2-或-L2-，其中Cy及L2如前所述；L3选自-C1-20烷基-、-C2-20烯基-或-C2-20炔基-，所述-C1-20烷基-、-C2-20烯基-或-C2-20炔基-任选地被一个或多个以下基团取代：＝O、OH、NH2、卤素或CN；X2选自键、O或S。In other embodiments, L is selected from -Cy-L 3 -X 2 - or -L 2 -, wherein Cy and L 2 are as described above; L 3 is selected from -C 1-20 alkyl-, -C 2-20 alkenyl-or -C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 2-20 alkenyl- or -C 2-20 alkynyl- is optionally replaced by one or A plurality of the following groups are substituted: =O, OH, NH 2 , halogen or CN; X 2 is selected from bond, O or S.

在另外一些实施方案中，L选自-Cy-L3-X2-或-L2-，其中Cy及L2如前所述；L3选自1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-6烷基)-或-S-替换的-C1-20烷基-、-C2-20烯基-或-C2-20炔基-，所述-C1-20烷基-、-C2-20烯基-或-C2-20炔基-任选地被一个或多个取代基取代；任选地所述取代基选自以下基团：＝O、OH、NH2、卤素或CN；X2选自键、O或S。In other embodiments, L is selected from -Cy-L 3 -X 2 - or -L 2 -, wherein Cy and L 2 are as described above; L 3 is selected from 1 or more -CH 2 - optionally Ground is selected from -O-, phenyl (e.g. ), -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 1-20 alkyl-, -C 2-20 alkenyl- or -C 2-20 alkynyl-, The -C 1-20 alkyl-, -C 2-20 alkenyl- or -C 2-20 alkynyl- is optionally substituted by one or more substituents; optionally the substituents are selected from the following Group: =O, OH, NH 2 , halogen or CN; X 2 is selected from bond, O or S.

在一些实施方案中，L选自-Cy-L3-X2-或-L2-，其中Cy选自3-10元杂环烷基，L3选自1个或多个-CH2-任选地被选自-O-、苯基(如)、-NH-、-N(C1-4烷基)-或-S-替换的-C1-20烷基-或-C2-20炔基-，L2选自-C1-20烷基NH-；X2选自键、O、S或NH。In some embodiments, L is selected from -Cy-L 3 -X 2 - or -L 2 -, where Cy is selected from 3-10 membered heterocycloalkyl and L 3 is selected from 1 or more -CH 2 - Optionally selected from -O-, phenyl (e.g. ), -NH-, -N(C 1-4 alkyl)- or -S- substituted -C 1-20 alkyl- or -C 2-20 alkynyl-, L 2 is selected from -C 1-20 Alkyl NH-; X 2 is selected from bond, O, S or NH.

在一些实施方案中，L选自-Cy-L3-X2-或-L2-，其中Cy选自3-6元杂环烷基，L3选自1个或多个-CH2-任选地被选自苯基(如)或-N(C1-4烷基)-替换的-C3-15烷基-或-C3-15炔基-，L2选自-C3-15烷基NH-；X2选自键、O、S或NH。In some embodiments, L is selected from -Cy-L 3 -X 2 - or -L 2 -, where Cy is selected from 3-6 membered heterocycloalkyl and L 3 is selected from 1 or more -CH 2 - Optionally selected from phenyl (e.g. ) or -N(C 1-4 alkyl)-substituted -C 3-15 alkyl-or -C 3-15 alkynyl-, L 2 is selected from -C 3-15 alkyl NH-; X 2 is selected Self bond, O, S or NH.

在一些实施方案中，L选自-Cy-L3-X2-或-L2-，其中Cy选自6元杂环烷基，L3选自1个或多个-CH2- 任选地被选自苯基(如)或-N(C1-3烷基)-替换的-C3-10烷基-或-C5-11炔基-，L2选自-C3-10烷基NH-；X2选自键、O、S或NH。In some embodiments, L is selected from -Cy-L 3 -X 2 - or -L 2 -, where Cy is selected from 6-membered heterocycloalkyl and L 3 is selected from 1 or more -CH 2 - Optionally selected from phenyl (e.g. ) or -N(C 1-3 alkyl)-substituted -C 3-10 alkyl-or -C 5-11 alkynyl-, L 2 is selected from -C 3-10 alkyl NH-; X 2 is selected Self bond, O, S or NH.

在一些实施方案中，结构部分-Cy-L3-X2-选自-哌啶基-(CH2)3S-、-哌啶基-(CH2)4S-、-哌啶基-(CH2)5S-、-哌啶基-(CH2)6S-、-哌啶基-(CH2)7S-、-哌啶基-(CH2)8S-、-哌啶基-(CH2)9S-、-哌啶基-(CH2)3O-、-哌啶基-(CH2)4O-、-哌啶基-(CH2)5O-、-哌啶基-(CH2)6O-、-哌啶基-(CH2)7O-、-哌啶基-(CH2)8O-、-哌啶基-(CH2)10O-、-哌啶基-(CH2)9O-、-哌啶基-(CH2)3NH-、-哌啶基-(CH2)4NH-、-哌啶基-(CH2)5NH-、-哌啶基-(CH2)3C≡C-、-哌啶基-(CH2)4C≡C-、-哌啶基-(CH2)5C≡C-、-哌啶基-(CH2)6C≡C-、-哌啶基-(CH2)7C≡C-、-哌啶基-(CH2)8C≡C-、-哌啶基-(CH2)9C≡C-、-哌啶基-(CH2)2N(CH3)(CH2)3C≡C-或-哌啶基-CH2-苯基-CH2O–。在一些实施方案中，结构部分-L2-选自-(CH2)5NH-。In some embodiments, the moiety -Cy- L3 - X2- is selected from -piperidinyl-( CH2 ) 3S- , -piperidinyl-( CH2 ) 4S- , -piperidinyl- (CH 2 ) 5 S-, -piperidinyl-(CH 2 ) 6 S-, -piperidinyl-(CH 2 ) 7 S-, -piperidinyl-(CH 2 ) 8 S-, -piperidinyl Base-(CH 2 ) 9 S-, -piperidyl-(CH 2 ) 3 O-, -piperidyl-(CH 2 ) 4 O-, -piperidyl-(CH 2 ) 5 O-, - Piperidinyl-(CH 2 ) 6 O-, -piperidinyl-(CH 2 ) 7 O-, -piperidinyl-(CH 2 ) 8 O-, -piperidinyl-(CH 2 ) 10 O- , -piperidinyl-(CH 2 ) 9 O-, -piperidinyl-(CH 2 ) 3 NH-, -piperidinyl-(CH 2 ) 4 NH-, -piperidinyl-(CH 2 ) 5 NH-, -piperidinyl-(CH 2 ) 3 C≡C-, -piperidinyl-(CH 2 ) 4 C≡C-, -piperidinyl-(CH 2 ) 5 C≡C-, -piperidinyl Aldyl-(CH 2 ) 6 C≡C-, -piperidinyl-(CH 2 ) 7 C≡C-, -piperidinyl-(CH 2 ) 8 C≡C-, -piperidinyl-(CH 2 ) 9 C≡C-, -piperidinyl-(CH 2 ) 2 N(CH 3 )(CH 2 ) 3 C≡C- or -piperidinyl-CH 2 -phenyl-CH 2 O–. In some embodiments, moiety -L2- is selected from -( CH2 ) 5NH- .

在一些实施方案中，结构部分-L3-X2-或-L2-选自-(CH2)3NH-、-(CH2)4NH-、-(CH2)5NH-、-(CH2)3O-、-(CH2)4O-、-(CH2)5O-、-(CH2)6O-、-(CH2)7O-、-(CH2)8O-、-(CH2)9O-、-(CH2)10O-、-(CH2)3S-、-(CH2)4S-、-(CH2)5S-、-(CH2)6S-、-(CH2)7S-、-(CH2)8S-、-(CH2)9S-、-(CH2)3C≡C-、-(CH2)4C≡C-、-(CH2)5C≡C-、-(CH2)6C≡C-、-(CH2)7C≡C-、-(CH2)8C≡C-、-(CH2)9C≡C-、-(CH2)2N(CH3)(CH2)3C≡C-或-CH2-苯基-CH2O-。在一些实施方案中，结构部分-L3-X2-或-L2-选自-(CH2)3O-、-(CH2)4O-、-(CH2)5O-、-(CH2)6O-、-(CH2)7O-、-(CH2)8O-、-(CH2)9O-、-(CH2)10O-、-(CH2)3S-、-(CH2)4S-、-(CH2)5S-、-(CH2)6S-、-(CH2)7S-、-(CH2)8S-、-(CH2)9S-、-(CH2)3C≡C-、-(CH2)4C≡C-、-(CH2)5C≡C-、-(CH2)6C≡C-、-(CH2)7C≡C-、-(CH2)8C≡C-或-(CH2)9C≡C-。In some embodiments, moiety -L3 - X2- or -L2- is selected from -( CH2 ) 3NH- , -( CH2 ) 4NH- , -( CH2 ) 5NH- , - (CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 6 O-, -(CH 2 ) 7 O-, -(CH 2 ) 8 O-, -(CH 2 ) 9 O-, -(CH 2 ) 10 O-, -(CH 2 ) 3 S-, -(CH 2 ) 4 S-, -(CH 2 ) 5 S-, -( CH 2 ) 6 S-, -(CH 2 ) 7 S-, -(CH 2 ) 8 S-, -(CH 2 ) 9 S-, -( CH 2 ) 3 C≡C-, -(CH 2 ) 4 C≡C-, -(CH 2 ) 5 C≡C-, -(CH 2 ) 6 C≡C-, -(CH 2 ) 7 C≡C-, -(CH 2 ) 8 C≡C-, -(CH 2 ) 9 C≡C-, -(CH 2 ) 2 N(CH 3 )(CH 2 ) 3 C≡C- or -CH 2 -phenyl-CH 2 O-. In some embodiments, moiety -L3 - X2- or -L2- is selected from -( CH2 ) 3O- , -( CH2 ) 4O- , -( CH2 ) 5O- , - (CH 2 ) 6 O-, -(CH 2 ) 7 O-, -(CH 2 ) 8 O-, -(CH 2 ) 9 O-, -(CH 2 ) 10 O-, -(CH 2 ) 3 S-, -(CH 2 ) 4 S-, -(CH 2 ) 5 S-, -(CH 2 ) 6 S-, -(CH 2 ) 7 S-, -(CH 2 ) 8 S-, -( CH 2 ) 9 S-, -(CH 2 ) 3 C≡C-, -(CH 2 ) 4 C≡C-, -(CH 2 ) 5 C≡C-, -(CH 2 ) 6 C≡C- , -(CH 2 ) 7 C≡C-, -(CH 2 ) 8 C≡C- or -(CH 2 ) 9 C≡C-.

在一些实施方案中，L选自 In some embodiments, L is selected from

在一些实施方案中，L3选自-C1-15烷基-、-C2-15烯基-或-C2-15炔基-，所述-C1-15烷基-、-C2-15烯基-或-C2-15炔基-任选地被一个或多个＝O取代。在一些方案中，L3选自-C1-12烷基-、-C2-12烯基-或-C2-12炔基-，所述-C1-12烷基-、-C2-12烯基-或-C2-12炔基-任选地被一个或多个＝O取代。在一些方案中，L3选自-C3-12烷基-或-C3-12炔基-，所述-C3-12烷基-或-C3-12炔基-任选地被一个或多个＝O取代。在一些方案中，L3选自-C3-10烷基-或-C3-10炔基-，所述-C3-10烷基-或-C3-10炔基-任选地被一个或多个＝O取代。在一些方案中，L3选自-C3-7烷基-或-C3-7炔基-，所述-C3-7烷基-或-C3-7炔基-任选地被一个或多个＝O取代。In some embodiments, L 3 is selected from -C 1-15 alkyl-, -C 2-15 alkenyl-, or -C 2-15 alkynyl-, -C 1-15 alkyl-, -C 2-15 Alkenyl - or - C 2-15 Alkynyl - optionally substituted with one or more =O. In some embodiments, L 3 is selected from -C 1-12 alkyl-, -C 2-12 alkenyl-, or -C 2-12 alkynyl-, -C 1-12 alkyl-, -C 2 -12Alkenyl- or -C2-12Alkynyl- is optionally substituted with one or more =O. In some embodiments, L 3 is selected from -C 3-12 alkyl- or -C 3-12 alkynyl-, which -C 3-12 alkyl- or -C 3-12 alkynyl- is optionally replaced by One or more =O substitutions. In some embodiments, L 3 is selected from -C 3-10 alkyl- or -C 3-10 alkynyl-, which is optionally replaced by -C 3-10 alkyl- or -C 3-10 alkynyl- One or more =O substitutions. In some embodiments, L 3 is selected from -C 3-7 alkyl- or -C 3-7 alkynyl-, which -C 3-7 alkyl- or -C 3-7 alkynyl- is optionally replaced by One or more =O substitutions.

在一些实施方案中，L选自 n的定义如前所述。在一些实施方案中，n为3-5。在一些实施方案中，n为3-7。在一些实施方案中，n为3-9。在一些实施方案中，n为3-10。在一些实施方案中，L选自 n的定义如前所述。在一些实施方案中，L选自n的定义如前所述。在一些实施方案中，n为3-5。在一些实施方案中，n为3-7。在一些实施方案中，n为3-9。在一些实施方案中，n为3-10。In some embodiments, L is selected from The definition of n is as mentioned above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10. In some embodiments, L is selected from The definition of n is as mentioned above. In some embodiments, L is selected from The definition of n is as mentioned above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

在一些实施方案中，L选自 n的定义如前所述。在一些实施方案中，n为3-5。在一些实施方案中，n为3-7。在一些实施方案中，n为3-9。在一些实施方案中，n为3-10。In some embodiments, L is selected from The definition of n is as mentioned above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

在一些实施方案中，L选自 -(CH2)n-NH-或n的定义如前所述。在一些实施方案中，n为3-5。在一些实施方案中，n为3-7。在一些实施方案中，n为3-9。在一些实施方案中，n为3-10。In some embodiments, L is selected from -(CH 2 ) n -NH-or The definition of n is as mentioned above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

在另外一些实施方案中，L选自 n的定义如前所述。在一些实施方案中，n为3-5。在一些实施方案中，n为3-7。在一些实施方案中，n为3-9。在一些实施方案中，n为3-10。In other embodiments, L is selected from The definition of n is as mentioned above. In some embodiments, n is 3-5. In some embodiments, n is 3-7. In some embodiments, n is 3-9. In some embodiments, n is 3-10.

在一些实施方案中，每一个R3分别独立地选自OH、NH2、CN、卤素、C1-3烷基或C1-3烷氧基。In some embodiments, each R 3 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl, or C 1-3 alkoxy.

在一些实施方案中，每一个R3分别独立地选自OH、NH2、CN、卤素、C1-2烷基或C1-2烷氧基。在一些实施方案中，每一个R3分别独立地选自OH、NH2、氟、氯或甲基。在一些实施方案中，每一个R3分别独立地选自氟。In some embodiments, each R 3 is independently selected from OH, NH 2 , CN, halogen, C 1-2 alkyl, or C 1-2 alkoxy. In some embodiments, each R 3 is independently selected from OH, NH 2 , fluorine, chlorine, or methyl. In some embodiments, each R 3 is independently selected from fluorine.

在一些实施方案中，p选自0、1或2。在一些实施方案中，p选自0或1。在一些实施方案中，p选自0。In some embodiments, p is selected from 0, 1, or 2. In some embodiments, p is selected from 0 or 1. In some embodiments, p is selected from 0.

在一些实施方案中，X选自CH2或C＝O。In some embodiments, X is selected from CH2 or C=O.

在一些实施方案中，X选自CH2。在一些实施方案中，X选自C＝O。In some embodiments, X is selected from CH2 . In some embodiments, X is selected from C=O.

在一些实施方案中，X1选自CH或N。In some embodiments, X1 is selected from CH or N.

在一些实施方案中，X1选自CH。在一些实施方案中，X1选自N。In some embodiments, X1 is selected from CH. In some embodiments, X1 is selected from N.

在一些实施方案中，结构片段选自 In some embodiments, structural fragments Selected from

在一些实施方案中，R1为氢；结构片段为m为0；L选自 -(CH2)n-NH-或 n为3-5或3-9或3-10；q为1或2；且结构片段选自 In some embodiments, R1 is hydrogen; structural fragment for m is 0; L is selected from -(CH 2 ) n -NH-or n is 3-5 or 3-9 or 3-10; q is 1 or 2; and the structural fragment Selected from

在一些实施方案中，R1为氢；结构片段为m为0；L选自 q为1或2；且结构片段选自 In some embodiments, R1 is hydrogen; structural fragment for m is 0; L is selected from q is 1 or 2; and the structure fragment Selected from

本申请式I化合物或其药学上可接受的盐选自式II、II-A或II-B化合物或其药学上可接受的盐， The compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from the compounds of formula II, II-A or II-B or a pharmaceutically acceptable salt thereof,

其中，R1、R2、m、L、R3、p或X的定义如本申请所述；Wherein, R 1 , R 2 , m, L, R 3 , p or X are defined as described in this application;

X3及X4分别独立地选自N、NH、CH或CH2；X 3 and X 4 are independently selected from N, NH, CH or CH 2 ;

任选地，所述R1、R2、R3、X、X3及X4任选地被一个或多个取代基取代。Optionally, the R 1 , R 2 , R 3 , X, X 3 and X 4 are optionally substituted with one or more substituents.

在一些实施方案中，所述式I、II、II-A或II-B化合物或其药学上可接受的盐，其中，R1、R2、m、L、R3、p或X的定义如本申请所述，X3及X4分别独立地选自N、NH、CH或CH2。In some embodiments, the compound of Formula I, II, II-A or II-B, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , m, L, R 3 , p or X is defined As described herein, X 3 and X 4 are each independently selected from N, NH, CH or CH 2 .

在一些实施方案中，X3及X4分别独立地选自NH或CH2。In some embodiments, X 3 and X 4 are each independently selected from NH or CH 2 .

另一方面，本申请涉及式III化合物或其药学上可接受的盐，
In another aspect, the present application relates to a compound of formula III or a pharmaceutically acceptable salt thereof,

其中，q、R2、R4、R5、m、环A、R3、p、X、X1的定义如本申请所述；Among them, the definitions of q, R 2 , R 4 , R 5 , m, ring A, R 3 , p, X, and X 1 are as described in this application;

每一个R11分别独立地选自氢、卤素、OH、NH2、CN、C1-6烷基、卤代C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6 烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述R11任选地被一个或多个取代基取代；Each R 11 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH- , (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl ) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the R 11 is optionally substituted by one or more substituents;

k选自0、1、2或3；k is selected from 0, 1, 2 or 3;

L选自-Cy-L1-；其中，Cy选自C3-10环烷基或3-10元杂环烷基，所述C3-10环烷基或3-10元杂环烷基任选地被一个或多个取代基取代；L is selected from -Cy-L 1 -; wherein, Cy is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, said C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl optionally substituted with one or more substituents;

-L1-选自1个或多个-CH2-被C6-10芳基或5-10元杂芳基(如苯基、)替换、且任选地1个或多个-CH2-被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的以下基团：-C1-20烷基-、-C2-20烯基-或-C2-20炔基-，所述-C1-20烷基-、-C2-20烯基-、或者-C2-20炔基-任选地被一个或多个取代基取代。-L 1 -selected from 1 or more -CH 2 -C 6-10 aryl or 5-10 membered heteroaryl (such as phenyl, ), and optionally 1 or more -CH 2 - are replaced by the following groups selected from -O-, -NH-, -N(C 1-6 alkyl)- or -S-: -C 1-20 alkyl-, -C 2-20 alkenyl- or -C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 2-20 alkenyl-, or -C 2- 20 Alkynyl - optionally substituted with one or more substituents.

在一些实施方案中，每一个R11分别独立地选自氢、卤素、OH、NH2、CN、C1-4烷基、卤代C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OCO-、C1-4烷基C(O)O-、C1-4烷基NHCO-、C1-4烷基CONH-、(C1-4烷基)2NCO-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-10环烷基、3-10元杂环烷基、C3-10环烯基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，所述R11任选地被一个或多个取代基取代。In some embodiments, each R 11 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-4 alkyl, haloC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OCO -, C 1-4 alkyl C(O)O-, C 1-4 alkyl NHCO-, C 1-4 alkyl CONH-, (C 1-4 alkyl) 2 NCO-, C 1-4 alkyl Base NHS(O)-, C 1-4 alkyl S(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl NHS(O) 2 -, C 1 -4 alkyl S(O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 ring Alkenyl, 3-10 membered heterocyclic alkenyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 11 is optionally substituted by one or more substituents.

在一些实施方案中，每一个R11分别独立地选自氢、卤素、OH、NH2、CN、C1-3烷基、卤代C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基、C1-3烷硫基、C1-3烷基NH-、(C1-3烷基)2N-、C1-3烷基OCO-、C1-3烷基C(O)O-、C1-3烷基NHCO-、C1-3烷基CONH-、(C1-3烷基)2NCO-、C1-3烷基NHS(O)-、C1-3烷基S(O)NH-、(C1-3烷基)2NS(O)-、C1-3烷基NHS(O)2-、C1-3烷基S(O)2NH-、(C1-3烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6-10芳基或5-10元杂芳基，所述R11任选地被一个或多个取代基取代。In some embodiments, each R 11 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, haloC 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO -, C 1-3 alkyl C(O)O-, C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl Base NHS(O)-, C 1-3 alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1 -3 alkyl S(O) 2 NH-, (C 1-3 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 ring Alkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 aryl or 5-10 membered heteroaryl, the R 11 is optionally substituted by one or more substituents.

在一些实施方案中，每一个R11分别独立地选自氢、卤素、OH、NH2、CN、C1-3烷基、卤代C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基、C1-3烷硫基、C1-3烷基NH-、(C1-3烷基)2N-、C1-3烷基OCO-、C1-3烷基C(O)O-、C1-3烷基NHCO-、C1-3烷基CONH-、(C1-3烷基)2NCO-、C1-3烷基NHS(O)-、C1-3烷基S(O)NH-、(C1-3烷基)2NS(O)-、C1-3烷基NHS(O)2-、C1-3烷基S(O)2NH-或(C1-3烷基)2NS(O)2-，所述R11任选地被一个或多个取代基取代。在一些实施方案中，每一个R11分别独立地选自卤素或C1-3烷基，所述C1-3烷基任选地被一个或多个取代基取代。在一些实施方案中，每一个R11分别独立地选自卤素或C1-3烷基，所述C1-3烷基任选地被一个或多个卤素取代。In some embodiments, each R 11 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-3 alkyl, haloC 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 1-3 alkyl OCO -, C 1-3 alkyl C(O)O-, C 1-3 alkyl NHCO-, C 1-3 alkyl CONH-, (C 1-3 alkyl) 2 NCO-, C 1-3 alkyl Base NHS(O)-, C 1-3 alkyl S(O)NH-, (C 1-3 alkyl) 2 NS(O)-, C 1-3 alkyl NHS(O) 2 -, C 1 -3 alkyl S(O) 2 NH- or (C 1-3 alkyl) 2 NS(O) 2 -, the R 11 is optionally substituted by one or more substituents. In some embodiments, each R 11 is independently selected from halogen or C 1-3 alkyl, which is optionally substituted with one or more substituents. In some embodiments, each R 11 is independently selected from halogen or C 1-3 alkyl, which is optionally substituted with one or more halogens.

在一些实施方案中，每一个R11分别独立地选自氟、氯或甲基，所述甲基任选地被一个或多个卤素取代。In some embodiments, each R 11 is independently selected from fluorine, chlorine, or methyl, with the methyl optionally substituted by one or more halogens.

在一些实施方案中，每一个R11分别独立地选自氯或甲基，所述甲基任选地被一个或多个氟或氯取代。在一些实施方案中，R11选自氯、甲基或三氟甲基。In some embodiments, each R 11 is independently selected from chlorine or methyl, optionally substituted with one or more fluorine or chlorine. In some embodiments, R 11 is selected from chloro, methyl, or trifluoromethyl.

在一些实施方案中，R4及R5分别独立地选自C1-3烷基，或R4及R5相互连接与相连的碳原子一起形成C3-6环烷基或3-6元杂环烷基，所述C1-3烷基、C3-6环烷基或3-6元杂环烷基任选地被一个或多个取代基取代。In some embodiments, R 4 and R 5 are each independently selected from C 1-3 alkyl, or R 4 and R 5 are connected to each other and the attached carbon atoms together to form a C 3-6 cycloalkyl or 3-6 membered Heterocycloalkyl, the C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more substituents.

在一些实施方案中，R4及R5分别独立地选自C1-3烷基，或R4及R5相互连接与相连的碳原子一起形成C3-4环烷基或3-4元杂环烷基。在一些实施方案中，R4及R5分别独立地选自甲基，或R4及R5相互连接与相连的碳原子一起形成C3-4环烷基。在一些实施方案中，R4及R5分别独立地选自甲基。In some embodiments, R 4 and R 5 are each independently selected from C 1-3 alkyl, or R 4 and R 5 are connected to each other and the attached carbon atoms together to form a C 3-4 cycloalkyl or 3-4 membered Heterocycloalkyl. In some embodiments, R 4 and R 5 are each independently selected from methyl, or R 4 and R 5 are joined to each other and together with the attached carbon atom to form a C 3-4 cycloalkyl group. In some embodiments, R 4 and R 5 are each independently selected from methyl.

在一些实施方案中，k选自0、1或2。在一些实施方案中，k选自1。In some embodiments, k is selected from 0, 1, or 2. In some embodiments, k is selected from 1.

在一些实施方案中，所述-L1-选自1个或多个-CH2-被C6芳基或5-6元杂芳基(如苯基、)替换、且任选地1个或多个-CH2-被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的以下基团：-C1-15烷基-、-C2-15烯基-、或者-C2-15炔基-，所述-C1-15烷基-、-C2-15烯基-、或者-C2-15炔基-任选地被一个或多个以下基团取代：＝O、OH、NH2、卤素或CN。In some embodiments, the -L 1 - is selected from 1 or more -CH 2 - by C 6 aryl or 5-6 membered heteroaryl (such as phenyl, ), and optionally 1 or more -CH 2 - are replaced by the following groups selected from -O-, -NH-, -N(C 1-6 alkyl)- or -S-: -C 1-15 alkyl-, -C 2-15 alkenyl-, or -C 2-15 alkynyl-, the -C 1-15 alkyl-, -C 2-15 alkenyl-, or -C 2 -15 Alkynyl - optionally substituted by one or more of: =O, OH, NH2 , halogen or CN.

在一些实施方案中，所述Cy的定义如本申请所述。 In some embodiments, the Cy is as defined herein.

在一些实施方案中，所述结构片段-Cy-L1-选自 In some embodiments, the structural fragment - Cy-L 1 - is selected from

在一些实施方案中，所述-L1-如本申请所定义。In some embodiments, -L1- is as defined herein.

在一些实施方案中，所述-L1-选自1个或多个-CH2-被苯基(如)替换、且任选地1个或多个-CH2-被-N(C1-6烷基)-替换的以下基团：-C1-20烷基-、-C1-19烷基氧基-、-C1-19烷基硫基-、-C1-19烷基氨基-、-C2-20烯基-或-C2-20炔基-，所述-C1-20烷基-、-C1-19烷基氧基-、-C1-19烷基硫基-、-C1-19烷基氨基-、-C2-20烯基-或-C2-20炔基-任选地被一个或多个取代基取代。In some embodiments, the -L 1 - is selected from 1 or more -CH 2 -phenyl groups (e.g. ), and optionally one or more -CH 2 -are replaced by -N(C 1-6 alkyl)-: -C 1-20 alkyl-, -C 1-19 alkyl Oxy-, -C 1-19 alkylthio-, -C 1-19 alkylamino-, -C 2-20 alkenyl- or -C 2-20 alkynyl-, the -C 1-20 Alkyl-, -C 1-19 alkyloxy-, -C 1-19 alkylthio-, -C 1-19 alkylamino-, -C 2-20 alkenyl- or -C 2-20 Alkynyl - optionally substituted with one or more substituents.

在一些实施方案中，所述-L1-选自1个或多个-CH2-被苯基(如)替换、且任选地1个或多个-CH2-被-N(C1-6烷基)-替换的以下基团：-C1-15烷基-、-C1-14烷基氧基-、-C1-14烷基硫基-、-C1-14烷基氨基-、-C2-15烯基-或-C2-15炔基-，所述-C1-15烷基-、-C1-14烷基氧基-、-C1-14烷基硫基-、-C1-14烷基氨基-、-C2-15烯基-或-C2-15炔基-任选地被一个或多个取代基取代。In some embodiments, the -L 1 - is selected from 1 or more -CH 2 -phenyl groups (e.g. ), and optionally one or more -CH 2 -are replaced by -N(C 1-6 alkyl)-: -C 1-15 alkyl-, -C 1-14 alkyl Oxy-, -C 1-14 alkylthio-, -C 1-14 alkylamino-, -C 2-15 alkenyl- or -C 2-15 alkynyl-, the -C 1-15 Alkyl-, -C 1-14 alkyloxy-, -C 1-14 alkylthio-, -C 1-14 alkylamino-, -C 2-15 alkenyl- or -C 2-15 Alkynyl - optionally substituted with one or more substituents.

在一些实施方案中，所述-L1-选自1个或多个-CH2-被苯基替换、且任选地1个或多个-CH2-被-N(C1-6烷基)-替换的以下基团：-C1-12烷基-、-C1-11烷基氧基-、-C1-11烷基硫基-、-C1-11烷基氨基-、-C2-12烯基-或-C2-12炔基-，所述-C1-12烷基-、-C1-11烷基氧基-、-C1-11烷基硫基-、-C1-11烷基氨基-、-C2-12烯基-或-C2-12炔基-任选地被一个或多个取代基取代。In some embodiments, the -L 1 - is selected from 1 or more -CH 2 -phenyl The following groups are replaced, and optionally 1 or more -CH 2 - are replaced by -N(C 1-6 alkyl)-: -C 1-12 alkyl-, -C 1-11 alkyloxy Base-, -C 1-11 alkylthio-, -C 1-11 alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkynyl-, the -C 1-12 alkyl Base-, -C 1-11 alkyloxy-, -C 1-11 alkylthio-, -C 1-11 alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkyne Group - optionally substituted by one or more substituents.

在一些实施方案中，所述取代基选自＝O、OH、NH2、卤素或CN。In some embodiments, the substituent is selected from =O, OH, NH2 , halogen, or CN.

在一些实施方案中，所述-L1-选自-CH2-苯基-(CH2)nO-，其中n选自1-12。在一些实施方案中，所述n选自1-10；或者n选自1、2、3、4、5、6、7、8、9或10，或者任意两者组成的整数范围。在一些实施方案中，所述n选自1-8。In some embodiments, -L 1 - is selected from -CH 2 -phenyl-(CH 2 ) n O-, where n is selected from 1-12. In some embodiments, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two. In some embodiments, n is selected from 1-8.

在一些实施方案中，L选自-Cy-L3-X2-，其中Cy如前所述；L3选自1个或多个-CH2-被C6-10芳基或5-10元杂芳基替换、且任选地1个或多个-CH2-被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的以下基团：-C1-20烷基-、-C2-20烯基-或-C2-20炔基-，所述-C1-20烷基-、-C2-20烯基-或-C2-20炔基-任选地被一个或多个以下基团取代：＝O、OH、NH2、卤素或CN；X2选自键、O、S或NH。In some embodiments, L is selected from -Cy-L 3 -X 2 -, wherein Cy is as described above; L 3 is selected from 1 or more -CH 2 - by C 6-10 aryl or 5-10 The following groups are substituted by heteroaryl groups and optionally 1 or more -CH 2 -selected from -O-, -NH-, -N(C 1-6 alkyl)- or -S- : -C 1-20 alkyl-, -C 2-20 alkenyl- or -C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 2-20 alkenyl- or -C 2-20 Alkynyl - optionally substituted by one or more of: =O, OH, NH2 , halogen or CN; X2 is selected from bond, O, S or NH.

在一些实施方案中，L选自-Cy-L3-X2-，其中Cy选自3-10元杂环烷基，L3选自1个或多个-CH2-被C6芳基或5-6元杂芳基替换、且任选地1个或多个-CH2-被选自-O-、-NH-、-N(C1-4烷基)-或-S-替换的以下基团：-C1-20烷基-或-C2-20炔基-；X2选自键、O、S或NH。In some embodiments, L is selected from -Cy-L 3 -X 2 -, where Cy is selected from 3-10 membered heterocycloalkyl and L 3 is selected from 1 or more -CH 2 -C 6 aryl or 5-6 membered heteroaryl substituted, and optionally 1 or more -CH 2 -selected from -O-, -NH-, -N(C 1-4 alkyl)- or -S- The following groups: -C 1-20 alkyl- or -C 2-20 alkynyl-; X 2 is selected from bond, O, S or NH.

在一些实施方案中，L选自-Cy-L3-X2-，其中Cy选自3-6元杂环烷基，L3选自1个或多个-CH2-被C6芳基或6元杂芳基替换、且任选地1个或多个-CH2-被选自-N(C1-4烷基)-替换的以下基团：-C3-15烷基-或-C3-15炔基-；X2选自键、O、S或NH。In some embodiments, L is selected from -Cy-L 3 -X 2 -, where Cy is selected from 3-6 membered heterocycloalkyl and L 3 is selected from 1 or more -CH 2 - by C 6 aryl or 6-membered heteroaryl substituted, and optionally 1 or more -CH 2 -selected from -N(C 1-4 alkyl)-substituted with the following groups: -C 3-15 alkyl- or -C 3-15 alkynyl-; X 2 is selected from bond, O, S or NH.

在一些实施方案中，L选自-Cy-L3-X2-，其中Cy选自6元杂环烷基，L3选自1个或多个-CH2-被苯基替换、且任选地1个或多个-CH2-被选自-N(C1-3烷基)-替换的以下基团：-C3-10烷基-；X2选自键、O、S或NH。In some embodiments, L is selected from -Cy-L 3 -X 2 -, where Cy is selected from 6-membered heterocycloalkyl, L 3 is selected from 1 or more -CH 2 - replaced by phenyl, and any Optionally 1 or more -CH 2 - are selected from -N(C 1-3 alkyl)- replaced by the following groups: -C 3-10 alkyl-; X 2 is selected from bond, O, S or NH.

在一些实施方案中，结构部分-Cy-L3-X2-选自-哌啶基-CH2-苯基-(CH2)nO-，n的定义如本申请所述。在一些实施方案中，结构部分-Cy-L3-X2-选自-哌啶基-CH2-苯基-CH2O-。In some embodiments, the moiety -Cy- L3 - X2- is selected from -piperidinyl- CH2 -phenyl-( CH2 ) nO- , n is as defined herein. In some embodiments, the moiety -Cy- L3 - X2- is selected from -piperidinyl- CH2 -phenyl- CH2O- .

在一些实施方案中，结构部分-L3-X2-选自-CH2-苯基-CH2O-。在一些实施方案中，L选自 In some embodiments, moiety -L3 - X2- is selected from -CH2 -phenyl- CH2O- . In some embodiments, L is selected from

在一些实施方案中，L选自n的定义如前所述。In some embodiments, L is selected from The definition of n is as mentioned above.

本申请涉及以下化合物或其药学上可接受的盐，
This application relates to the following compounds or pharmaceutically acceptable salts thereof,

其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;

其中，n为1、2、3、4、5、6、7、8、9、10或11；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

其中，n为1、2、3、4、5、6、7、8、9、10或11；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

其中，n为1、2、3、4、5、6、7、8、9、10或11；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

其中，n为1、2、3、4、5、6、7或8。Where n is 1, 2, 3, 4, 5, 6, 7 or 8.

本申请涉及以下化合物或其药学上可接受的盐，


This application relates to the following compounds or pharmaceutically acceptable salts thereof,


另一方面，本申请涉及式I-0化合物或其药学上可接受的盐，其中R1、n、q、R2、m、环A、L、R3、p、R4、R5、X、X1、Ra、Ra’或Rb的定义如本申请所述，并且式I-0化合物所示结构中的结构片段 任选地被一个或多个取代基取代。In another aspect, the present application relates to a compound of formula I-0, or a pharmaceutically acceptable salt thereof, wherein R 1 , n, q, R 2 , m, ring A, L, R 3 , p, R 4 , R 5 , The definitions of X , Optionally substituted by one or more substituents.

在一些实施方案中，所述式I-0化合物所示结构中的结构片段中的哌嗪基或亚甲基任选地被一个或多个取代基取代。In some embodiments, the structural fragments in the structure shown in the compound of formula I-0 The piperazinyl or methylene group in is optionally substituted by one or more substituents.

在一些实施方案中，所述式I-0化合物所示结构中的结构片段中的苯基或-NH-连接片段任选地被一个或多个取代基取代。In some embodiments, the structural fragments in the structure shown in the compound of formula I-0 The phenyl or -NH-linked moiety in is optionally substituted with one or more substituents.

另一方面，本申请涉及一种药物组合物，所述药物组合物含有本申请上述的化合物或其药学上可接受的盐，本申请的药物组合物还包括药学上可接受的辅料。On the other hand, the present application relates to a pharmaceutical composition, which contains the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present application also includes pharmaceutically acceptable excipients.

另一方面，本申请涉及上述化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗通过降解与靶向配体结合的靶蛋白而治疗的病症的药物中的用途。In another aspect, the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a condition treated by degrading a target protein bound to a targeting ligand.

另一方面，本申请涉及上述化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗通过体内与小脑蛋白质结合而治疗的病症的药物中的用途。On the other hand, the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a condition treated by binding to a cerebellar protein in vivo.

另一方面，本申请涉及上述化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗与BCL-XL相关疾病的药物中的用途。On the other hand, the present application relates to the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for preventing or treating diseases related to BCL-XL.

本申请涉及治疗或预防哺乳动物通过降解与靶向配体结合的靶蛋白而治疗的病症的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的本申请的上述化合物或其药学上可接受的盐、或其药物组合物。The present application relates to a method for treating or preventing a condition in a mammal treated by degrading a target protein bound to a targeting ligand, which includes administering a therapeutically effective amount of the above compound of the present application or its application to a mammal in need of such treatment, preferably a human. Pharmaceutically acceptable salts, or pharmaceutical compositions thereof.

本申请涉及治疗或预防通过体内与小脑蛋白质结合而治疗的病症的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的本申请的上述化合物或其药学上可接受的盐、或其药物组合物。The present application relates to methods for treating or preventing diseases treated by binding to cerebellar proteins in vivo, which include administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof to a mammal, preferably a human, in need of such treatment. or pharmaceutical compositions thereof.

另一方面，本申请涉及治疗哺乳动物与BCL-XL相关疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的本申请的上述化合物或其药学上可接受的盐、或其药物组合物。On the other hand, the present application relates to a method for treating mammals and BCL-XL-related diseases, which includes administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment, preferably a human. or pharmaceutical compositions thereof.

另一方面，本申请涉及预防或者治疗通过降解与靶向配体结合的靶蛋白而治疗的病症的上述化合物或其药学上可接受的盐、或其药物组合物。On the other hand, the present application relates to the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a condition treated by degrading a target protein bound to a targeting ligand.

另一方面，本申请涉及预防或者治疗通过体内与小脑蛋白质结合而治疗的病症的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。On the other hand, the present application relates to the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating a disorder treated by binding to cerebellar protein in vivo.

另一方面，本申请涉及预防或者治疗与BCL-XL相关疾病的上述化合物或其药学上可接受的盐、或其药物组合物。On the other hand, the present application relates to the above compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating diseases related to BCL-XL.

另一方面，本申请涉及上述化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗通过降解与靶向配体结合的靶蛋白而治疗的病症中的用途。 In another aspect, the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disorder treated by degrading a target protein bound to a targeting ligand.

另一方面，本申请涉及上述化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗通过体内与小脑蛋白质结合而治疗的病症中的用途。In another aspect, the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disorder treated by binding to cerebellar proteins in vivo.

另一方面，本申请涉及上述化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗与BCL-XL相关疾病中的用途。On the other hand, the present application relates to the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in preventing or treating diseases related to BCL-XL.

另一方面，本申请涉及上述化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗癌症的药物中的用途。On the other hand, the present application relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating cancer.

另一方面，本申请涉及上述化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗癌症中的用途。On the other hand, the present application relates to the use of the above-mentioned compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in preventing or treating cancer.

另一方面，本申请涉及预防或者治疗癌症的上述化合物或其药学上可接受的盐、或其药物组合物。On the other hand, the present application relates to the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating cancer.

另一方面，本申请涉及治疗或预防哺乳动物癌症的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的本申请的上述化合物或其药学上可接受的盐、或其药物组合物。On the other hand, the present application relates to a method for treating or preventing mammalian cancer, which includes administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a medicament thereof to a mammal in need of such treatment, preferably a human. combination.

在一些具体实施方案中，上述BCL-XL相关疾病选自通过降解和/或抑制与BCL-XL靶蛋白配体结合的蛋白而治疗的病症；在一些具体实施方案中，上述BCL-XL相关疾病选自通过在体内与小脑蛋白结合而治疗的病症；在一些实施方案中，上述疾病或病症选自癌症。In some specific embodiments, the above-mentioned BCL-XL-related diseases are selected from conditions treated by degrading and/or inhibiting proteins that bind to BCL-XL target protein ligands; in some specific embodiments, the above-mentioned BCL-XL-related diseases Selected from conditions treated by binding to cerebellar protein in vivo; in some embodiments, the disease or condition is selected from cancer.

在一些具体实施方案中，上述通过在体内与小脑蛋白质结合而治疗的病症选自与BCL-XL相关疾病；在一些具体实施方案中，上述BCL-XL相关疾病选自癌症。在一些实施方案中，所述癌症选自白血病；在一些实施方案中，所述癌症选自淋巴性白血病。In some embodiments, the conditions treated by binding to cerebellar proteins in vivo are selected from BCL-XL-related diseases; in some embodiments, the BCL-XL-related diseases are selected from cancer. In some embodiments, the cancer is selected from leukemia; in some embodiments, the cancer is selected from lymphoid leukemia.

在一些实施方案中，所述“一个或多个”选自一个、两个、三个、四个、五个或六个。在一些实施方案中，所述“一个或多个”选自一个、两个、或三个。在一些实施方案中，所述“一个或多个”选自一个、或两个。In some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

在一些实施方案中，所述“任选地被一个或多个取代基取代”中的取代基选自羟基、巯基、卤素、氨基、硝基、亚硝基、氰基、羧基、醛基、C1-12烷基、卤代-C1-12烷基、3-12元环烷基、卤代-3-12元环烷基、C2-12烯基、卤代-C2-12烯基、3-12元环烯基、卤代-3-12元环烯基、C2-12炔基、卤代-C2-12炔基、8-12元环炔基、卤代-8-12元环炔基、C1-12杂烷基、卤代-C1-12杂烷基、C1-12烷氧基、C1-12烷硫基、6-10元芳基、5-10元杂芳基、3-12元杂环基、C1-12酰基、C1-12酰氧基或C1-12酰胺基。In some embodiments, the substituent in "optionally substituted by one or more substituents" is selected from hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, carboxyl, aldehyde, C 1-12 alkyl, halo-C 1-12 alkyl, 3-12-membered cycloalkyl, halo-3-12-membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 Alkenyl, 3-12-membered cycloalkenyl, halogenated-3-12-membered cycloalkenyl, C 2-12 alkynyl, halogenated-C 2-12 alkynyl, 8-12-membered cycloalkynyl, halogenated- 8-12 membered ring alkynyl, C 1-12 heteroalkyl, halo-C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10 membered aryl, 5-10 membered heteroaryl group, 3-12 membered heterocyclyl group, C 1-12 acyl group, C 1-12 acyloxy group or C 1-12 amide group.

在一些实施方案中，本申请包含上述定义的变量及其实施方案，以及它们的任意组合。In some embodiments, this application encompasses the variables defined above and embodiments thereof, as well as any combinations thereof.

技术效果Technical effect

本申请化合物针对RS4；11细胞及MOLT-4细胞具有增殖抑制作用；可以降解BCL-XL蛋白，例如MOLT-4细胞中BCL-XL蛋白；对于BCL-XL/BAK具有结合抑制活性；体外(如人、猴、犬、大鼠或小鼠肝微粒体)代谢稳定；以及具有良好的体内(小鼠、大鼠或犬)药代动学性质，以及体内药效数据；血小板毒性低(犬或人血小板)，毒副作用低。The compound of the present application has a proliferation inhibitory effect on RS4;11 cells and MOLT-4 cells; it can degrade BCL-XL protein, such as BCL-XL protein in MOLT-4 cells; it has binding inhibitory activity on BCL-XL/BAK; in vitro (such as Human, monkey, dog, rat or mouse liver microsomes) metabolically stable; and has good in vivo (mouse, rat or dog) pharmacokinetic properties, as well as in vivo pharmacodynamic data; low platelet toxicity (canine or human platelets), with low toxic and side effects.

定义definition

除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms used in this application have the following meanings. A particular term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in accordance with its ordinary meaning in the art. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (i.e. =O), it means that two hydrogen atoms are replaced, and oxo does not occur on aromatic groups.

术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and absence of the stated event or circumstance. For example, the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), or poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.

本文所述的“取代基”包括本文上下文中所提及的所有取代基，包括但不限于下文提及的术语“烷基”、“烷氧基”、“杂烷基”、“烯基”、“炔基”、“环烯基”、“环烷基”、“杂环烷基”、"杂环烯基"、“杂环基”、 “杂芳基”等，及相应的非限制性或示例性基团，其中所述“取代基”一些非限制性实例包括氘、氚、-OH、-SH、卤素、-NH2、硝基、亚硝基、-CN、叠氮基团、亚砜基团、砜基团、磺酰胺基团、羧基、羧醛基团、亚胺基团、烷基、卤代-烷基、环烷基、卤代-环烷基、烯基、卤代-烯基、环烯基、卤代-环烯基、炔基、卤代-炔基、环炔基、卤代-环炔基、杂烷基、卤代-杂烷基、烷氧基、烷硫基、芳基、芳基氧基、芳基硫基、芳烷基、芳基烷氧基、芳基烷硫基、杂芳基、杂芳基氧基、杂芳基硫基、杂芳烷基、杂芳基烷氧基、杂芳基烷硫基、杂环基、杂环基氧基、杂环基硫基、杂环基烷基、杂环基烷氧基、杂环基烷硫基、酰基、酰氧基、氨基甲酸酯基团、酰胺基团、脲基、环氧基团和酯基团等，所述基团任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH2、-C(O)NH-烷基、-C(O)N(烷基)2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O)2-烷基、-S(O)2NH2、-S(O)2NH-烷基、-S(O)2N(烷基)2、环烷基、环烷基烷基、环烷基氧基、杂环基、杂环基烷基、杂环基氧基、杂环烷基、杂环烷基烷基、杂环烷基氧基、杂芳基、杂芳基烷基、杂芳基氧基、芳基、芳基烷基或芳基氧基。"Substituent" as used herein includes all substituents mentioned in the context of this article, including but not limited to the terms "alkyl", "alkoxy", "heteroalkyl", "alkenyl" mentioned below , "alkynyl", "cycloalkenyl", "cycloalkyl", "heterocycloalkyl", "heterocycloalkenyl", "heterocyclyl", "Heteroaryl" and the like, and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include deuterium, tritium, -OH, -SH, halogen, -NH 2 , nitro , nitroso group, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxyaldehyde group, imine group, alkyl group, halogenated-alkyl group, cycloalkane base, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, hetero Alkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl , heteroaryloxy, heteroarylthio, heteroarylalkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocycle alkyl group, heterocyclyl alkoxy group, heterocyclyl alkylthio group, acyl group, acyloxy group, carbamate group, amide group, urea group, epoxy group and ester group, etc., the The group is optionally substituted with one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2 , - C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S (O) 2 -alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkylalkyl , cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroarylalkyl radical, heteroaryloxy, aryl, arylalkyl or aryloxy.

本文中的Cm-n，是该部分具有给定范围中的整数个碳原子。例如“C1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。例如C1-3是指该基团可具有1个碳原子、2个碳原子、3个碳原子。C mn as used herein means that the part has an integer number of carbon atoms in the given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example, C 1-3 means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

在本文的部分实施方案中，所述取代基选自羟基、巯基、卤素、氨基、硝基、亚硝基、氰基、叠氮基团、亚砜基团、砜基团、磺酰胺基团、羧基、醛基、亚胺基团、C1-12烷基、卤代-C1-12烷基、3-12元环烷基、卤代-3-12元环烷基、C2-12烯基、卤代-C2-12烯基、3-12元环烯基、卤代-3-12元环烯基、C2-12炔基、卤代-C2-12炔基、8-12元环炔基、卤代-8-12元环炔基、C1-12杂烷基、卤代-C1-12杂烷基、C1-12烷氧基、C1-12烷硫基、6-10元芳基、6-10元芳基氧基、6-10元芳基硫基、6-10元芳基C1-12亚烷基、6-10元芳基C1-12烷氧基、6-10元芳基C1-12烷硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、5-10元杂芳基亚烷基、5-10元杂芳基烷氧基、5-10元杂芳基烷硫基、3-12元杂环基、3-12元杂环基氧基、3-12元杂环基硫基、3-12元杂环基C1-12亚烷基、3-12元杂环基C1-12烷氧基、3-12元杂环基C1-12烷硫基、C1-12酰基、C1-12酰氧基、氨基甲酸酯基团、C1-12酰胺基、脲基、环氧基团、C2-12酯基团和氧代，所述取代基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、C1-12烷基、C2-12烯基、C2-12炔基、C1-12烷氧基、卤代C1-12烷氧基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、羧基、-C(O)O-C1-12烷基、-OC(O)-C1-12烷基、-C(O)NH2、-C(O)NH-C1-12烷基、-C(O)N(C1-12烷基)2、-NHC(O)-C1-12烷基、-C(O)-C1-12烷基、-S(O)-C1-12烷基、-S(O)2-C1-12烷基、-S(O)2NH2、-S(O)2NH-C1-12烷基、-S(O)2N(C1-12烷基)2、3-12元环烷基、3-12元环烷基C1-12亚烷基、3-12元环烷基氧基、3-12元杂环基、3-12元杂环基C1-12亚烷基、3-12元杂环基氧基、3-12元杂环烷基、3-12元杂环烷基C1-12亚烷基、3-12元杂环烷基氧基、5-10元杂芳基、5-10元杂芳基C1-12亚烷基、5-10元杂芳基氧基、6-10元芳基、6-10元芳基C1-12亚烷基或6-10元芳基氧基。In some embodiments herein, the substituent is selected from the group consisting of hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azide group, sulfoxide group, sulfone group, and sulfonamide group , carboxyl group, aldehyde group, imine group, C 1-12 alkyl group, halogenated-C 1-12 alkyl group, 3-12-membered cycloalkyl group, halogenated-3-12-membered cycloalkyl group, C 2- 12- alkenyl, halo-C 2-12 alkenyl, 3-12-membered cycloalkenyl, halogen-3-12-membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8-12-membered cycloalkynyl, halogenated-8-12-membered cycloalkynyl, C 1-12 heteroalkyl, halogenated-C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 Alkylthio group, 6-10-membered aryl group, 6-10-membered aryloxy group, 6-10-membered arylthio group, 6-10-membered aryl C 1-12 alkylene group, 6-10-membered aryl C 1-12 alkoxy group, 6-10 membered aryl C 1-12 alkylthio group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, 5-10 membered heteroarylthio group, 5 -10-membered heteroaryl alkylene, 5-10-membered heteroarylalkoxy, 5-10-membered heteroarylalkylthio, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, 3-12-membered heterocyclylthio group, 3-12-membered heterocyclyl C 1-12 alkylene group, 3-12-membered heterocyclyl C 1-12 alkoxy group, 3-12-membered heterocyclyl C 1- 12 alkylthio group, C 1-12 acyl group, C 1-12 acyloxy group, carbamate group, C 1-12 amide group, urea group, epoxy group, C 2-12 ester group and oxygen Generation, the substituent is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl , C 2-12 alkynyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl amino group, halogenated di-C 1-12 alkylamino group, carboxyl group, -C(O)OC 1-12 alkyl group, -OC(O)-C 1-12 alkyl group, -C(O)NH 2 , - C(O)NH-C 1-12 alkyl, -C(O)N(C 1-12 alkyl) 2 , -NHC(O)-C 1-12 alkyl, -C(O)-C 1 -12 alkyl, -S(O)-C 1-12 alkyl, -S(O) 2 -C 1-12 alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-C 1-12 alkyl, -S(O) 2 N(C 1-12 alkyl) 2 , 3-12-membered cycloalkyl, 3-12-membered cycloalkyl C 1-12 alkylene, 3-12-membered Cycloalkyloxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyl C 1-12 alkylene, 3-12-membered heterocyclyloxy, 3-12-membered heterocycloalkyl, 3- 12-membered heterocycloalkyl C 1-12 alkylene, 3-12-membered heterocycloalkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl C 1-12 alkylene, 5- 10-membered heteroaryloxy group, 6-10-membered aryl group, 6-10-membered aryl C 1-12 alkylene group or 6-10-membered aryloxy group.

本文中的“一个或多个”指一个至十个以内的整数。例如“一个或多个”指一个、两个、三个、四个、五个、六个、七个、八个、九个或十个；或者，“一个或多个”指一个、两个、三个、四个、五个或六个；或者，“一个或多个”指一个、两个或三个。“One or more” in this article refers to an integer ranging from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine or ten; or "one or more" refers to one, two , three, four, five or six; alternatively, "one or more" means one, two or three.

当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团含2个R，则每个R都有独立的选项。When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. For example, if a group contains 2 R's, there will be separate options for each R.

当一个键交叉连接到一个环(包括单环、并环或螺环)的两个原子时，这种键可以与环(包括单环、并环或螺环)上的任意原子相键合。例如，上述环A表示两边的键可与环A上的任意两个不同的原子发生连接；When a bond is cross-connected to two atoms of a ring (including a single ring, a parallel ring, or a spiro ring), such a bond can be bonded to any atom on the ring (including a single ring, a parallel ring, or a spiro ring). For example, the above-mentioned ring A means that the bonds on both sides can be connected to any two different atoms on ring A;

术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.

术语“羟基”指-OH基团。The term "hydroxy" refers to the -OH group.

术语“氨基”指-NH2基团。The term "amino" refers to the -NH 2 group.

术语“氰基”指-CN基团。The term "cyano" refers to the -CN group.

术语“巯基”指-SH基团。The term "mercapto" refers to the -SH group.

术语“硝基”指-NO2基团。The term "nitro" refers to the -NO group.

术语“杂原子”包括除碳或氢外的任何元素的原子。优选的杂原子是硼、氮、氧、硫、硅和磷。在 一个实施方案中，杂原子选自N、O和S。在一些实施方案中，杂原子的数量为1个、2个、3个或4个。The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, sulfur, silicon and phosphorus. exist In one embodiment, the heteroatoms are selected from N, O, and S. In some embodiments, the number of heteroatoms is 1, 2, 3, or 4.

术语“烷基”是指通式为CnH2n+1的烃基。该烷基可以含有1-20、1-15、1-12、1-10、1-8、1-6或1-3个碳原子。该烷基可以是直链或支链的。例如，术语“C1-6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。又例如，术语“C1-3烷基”指含有1至3个碳原子的烷基(例如甲基、乙基、丙基和异丙基)。The term "alkyl" refers to a hydrocarbyl group having the general formula C n H 2n+1 . The alkyl group may contain 1-20, 1-15, 1-12, 1-10, 1-8, 1-6 or 1-3 carbon atoms. The alkyl group may be straight chain or branched. For example, the term "C 1 -6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above. As another example, the term "C 1 -3 alkyl" refers to alkyl groups containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).

术语“烷氧基”指-O-烷基。The term "alkoxy" refers to -O-alkyl.

术语“杂烷基”指含有杂原子的烷基结构。除非另有指示，该杂烷基通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的烷基。通常，在存在超过一个杂原子的情况下，所述杂原子彼此不相邻。示例性杂烷基包括烷氧基、烷氧基烷基、烷基氨基、烷基氨基烷基、二烷基氨基、二烷基氨基烷基等。The term "heteroalkyl" refers to an alkyl structure containing heteroatoms. Unless otherwise indicated, the heteroalkyl group is generally an alkyl group containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Generally, where more than one heteroatom is present, the heteroatoms are not adjacent to each other. Exemplary heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, and the like.

术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。该烯基可以含有2-20、2-15、2-12、2-10、2-8、2-6或2-3个碳原子。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2-20, 2-15, 2-12, 2-10, 2-8, 2-6 or 2-3 carbon atoms. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。该炔基可以含有2-20、2-15、2-12、2-10、2-8、2-6或2-3个碳原子。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH3)、2-丙炔基(-CH2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。The term "alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2-20, 2-15, 2-12, 2-10, 2-8, 2-6 or 2-3 carbon atoms. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1, 3-Butadiynyl (-C≡C-C≡CH), etc.

术语“环烯基”是指不完全饱和的并且可以以呈单环、双环桥环或螺环存在的非芳族碳环。除非另有指示，该碳环通常为4至20元环、4至15元环、4至10元环、4至8元环、3至12元环、3至10元环或3至6元环。环烯基的非限制性实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基等。The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and may exist as a monocyclic, bicyclic bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is usually 4 to 20 membered, 4 to 15 membered, 4 to 10 membered, 4 to 8 membered, 3 to 12 membered, 3 to 10 membered, or 3 to 6 membered. ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至20元环、3至15元环、3至12元环、3至10元环(例如5至8元环)、3至6元环、4至10元环、4至8元环、4至6元环、5至6元环或6元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is usually a 3- to 20-membered ring, a 3- to 15-membered ring, a 3- to 12-membered ring, a 3- to 10-membered ring (such as a 5- to 8-membered ring), a 3- to 6-membered ring, a 4- to 10-membered ring, 4- to 8-membered ring, 4- to 6-membered ring, 5- to 6-membered ring or 6-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl Alkyl etc.

术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至20元环、3至15元环、3至10元环、3至7元环、3至6元环、3至5元环、4至10元环、4至8元环、4至6元环、5至6元环或6元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is generally a 3 to 20-membered ring, a 3- to 15-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. , 3 to 10 membered ring, 3 to 7 membered ring, 3 to 6 membered ring, 3 to 5 membered ring, 4 to 10 membered ring, 4 to 8 membered ring, 4 to 6 membered ring, 5 to 6 membered ring or 6 Yuan ring. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxirane, ethylene sulfide, and aziridyl. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetane. Examples of cyclyl, thibutylcyclyl, and 5-membered heterocycloalkyl include but are not limited to tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, and thiazolidine 1, 4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, examples of 7-membered heterocycloalkyl include But it is not limited to azepanyl, oxeptanyl, and thiopanyl. Preference is given to monocyclic heterocycloalkyl groups with 5 or 6 ring atoms.

术语"杂环烯基"包括其中至多3个碳原子、在一个实施方案中至多2个碳原子、在另一个实施方案中1个碳原子各自独立地被O、S(O)或N代替的环烯基，条件是保留至少一个环烯基碳-碳双键。可以以单环、桥环或螺环存在的环状基团，可以是3至20元环、3至15元环、3至12元环、3至10元环(例如5至8元环)、3至6元环。杂环烯基的实例包括但不限于二氢吡咯基、四氢吡啶基、四氢氮杂卓基或氮杂螺环辛烯。The term "heterocycloalkenyl" includes those in which up to 3, in one embodiment up to 2, and in another embodiment 1 carbon atoms are each independently replaced by O, S(O), or N Cycloalkenyl, provided that at least one cycloalkenyl carbon-carbon double bond is retained. The cyclic group can exist as a single ring, a bridged ring or a spiro ring, and can be a 3- to 20-membered ring, a 3- to 15-membered ring, a 3- to 12-membered ring, a 3- to 10-membered ring (for example, a 5- to 8-membered ring) , 3 to 6 membered rings. Examples of heterocycloalkenyl include, but are not limited to, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepinyl, or azaspirocyclooctene.

术语“杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、桥环或螺环存在的非芳族环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至20元环、3至15元环、3至12元环、3至10元环或3至7元环。杂环基的非限制性实例包括但不限于环氧乙烷基、四氢呋喃基、二氢呋喃基、吡咯烷基、N-甲基 吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基等。The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is generally a 3 to 20-membered ring, a 3- to 15-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. , 3 to 12 membered ring, 3 to 10 membered ring or 3 to 7 membered ring. Non-limiting examples of heterocyclyl include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, N-methyl Pyrrolidyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc.

术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子、6-12个碳原子或6-10个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、和蒽基等。The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.

术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个(例如，1个、2个或3个)选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个4至8元环，尤其是5至8元环，5至10元环、5至12元环或包含6至20个、6至15个或6至14个，尤其是6至10个环原子的多个稠合环，或者5元或6元单环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one (for example, 1, 2 or 3) ring atoms selected from N, O, S, and the remaining ring atoms are C, and has at least one aromatic ring. Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, a 5 to 10 membered ring, a 5 to 12 membered ring or contain 6 to 20, 6 to 15 or 6 to 14, especially It is multiple fused rings of 6 to 10 ring atoms, or a 5- or 6-membered monocyclic ring. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

本申请中的“环A”基团均为二价基团，因而应当理解，“环A”的选项也均为二价基团。例如，环A中的“环烷基”可以理解为“亚环烷基”，环A中的C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基可以理解为C3-12亚环烷基、3-12元杂亚环烷基、C3-12亚环烯基、3-12元杂亚环烯基、C6-12亚芳基或5-12元杂亚芳基；环A中C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6-10芳基或5-10元杂芳基可以理解为C3-6亚环烷基、3-6元杂亚环烷基、C3-6亚环烯基、3-6元杂亚环烯基、C6-10亚芳基或5-10元杂亚芳基；环A中的C4-10环烷基或4-10元杂环烷基可以理解为C4-10亚环烷基或4-10元杂亚环烷基；环A中的C4-6环烷基或4-6元杂环烷基可以理解为C4-6亚环烷基或4-6元杂亚环烷基；环A中的C5-6环烷基或5-6元杂环烷基可以理解为C5-6亚环烷基或5-6元杂亚环烷基；环A中的C6环烷基或6元杂环烷基可以理解为C6亚环烷基或6元杂亚环烷基；环A中的C6环烷基或6元含N杂环烷基可以理解为C6亚环烷基或6元含N杂亚环烷基；环A中的环己基或哌啶基可以理解为亚环己基或亚哌啶基。The "Ring A" groups in this application are all divalent groups, so it should be understood that the options for "Ring A" are also divalent groups. For example, the "cycloalkyl" in ring A can be understood as "cycloalkylene", and the C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12-membered heterocycloalkenyl, C 6-12 aryl or 5-12-membered heteroaryl can be understood as C 3-12 cycloalkylene, 3-12-membered heterocycloalkylene, C 3-12 cycloalkylene Cycloalkenyl, 3-12 membered heterocycloalkenylene, C 6-12 arylene or 5-12 membered heteroarylene; C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl in ring A , C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl can be understood as C 3-6 cycloalkylene, 3-6 membered heteroarylene Cycloalkyl, C 3-6 cycloalkenylene, 3-6 membered heterocycloalkenylene, C 6-10 arylene or 5-10 membered heteroarylene; C 4-10 cycloalkane in ring A group or 4-10 membered heterocycloalkyl group can be understood as C 4-10 cycloalkylene group or 4-10 membered heterocycloalkylene group; C 4-6 cycloalkyl group or 4-6 membered heterocycle in ring A Alkyl can be understood as C 4-6 cycloalkylene or 4-6 membered heterocycloalkylene; C 5-6 cycloalkyl or 5-6 membered heterocycloalkyl in ring A can be understood as C 5- 6 -membered cycloalkylene or 5-6-membered heterocycloalkylene; C 6- membered cycloalkylene or 6-membered heterocycloalkylene in ring A can be understood as C 6 -membered cycloalkylene or 6-membered heterocycloalkylene; The C 6 cycloalkyl or 6-membered N-containing heterocycloalkylene in ring A can be understood as C 6 cycloalkylene or 6-membered N-containing heterocycloalkylene; the cyclohexyl or piperidinyl in ring A can be understood It is cyclohexylene or piperidinylene.

本申请中的“Cy”基团均为二价基团，因而应当理解，“Cy”基团的选项也均为二价基团。例如，Cy中的C3-10环烷基或3-10元杂环烷基分别可以理解为C3-10亚环烷基或3-10元杂亚环烷基；Cy中的C3-8环烷基或3-8元杂环烷基可以分别理解为C3-8亚环烷基或3-8元杂亚环烷基；Cy中的C5-6环烷基或5-6元杂环烷基可以分别理解为C5-6亚环烷基或5-6元杂亚环烷基；Cy中的3-6元杂环烷基可以理解为3-6元杂亚环烷基；Cy中的6元杂环烷基可以理解为6元杂亚环烷基；Cy中的哌啶基或哌嗪基可以理解为亚哌啶基或亚哌嗪基。The “Cy” groups in this application are all divalent groups, so it should be understood that the options for the “Cy” group are also divalent groups. For example, C 3-10 cycloalkyl or 3-10-membered heterocycloalkyl in Cy can be understood as C 3-10 cycloalkylene or 3-10-membered heterocycloalkylene respectively; C 3- in Cy 8 -cycloalkyl or 3-8-membered heterocycloalkyl can be understood as C 3-8 cycloalkylene or 3-8-membered heterocycloalkylene respectively; C 5-6 cycloalkyl or 5-6 in Cy The one-membered heterocycloalkyl group can be understood as C 5-6 cycloalkylene group or 5-6 membered heterocycloalkylene group; the 3-6 membered heterocycloalkyl group in Cy can be understood as 3-6 membered heterocycloalkylene group. group; the 6-membered heterocycloalkyl group in Cy can be understood as a 6-membered heterocycloalkylene group; the piperidinyl or piperazinyl group in Cy can be understood as a piperidinylene or piperazinylene group.

本申请中的基团或结构片段如环A、-Cy-L3-X2-、-Cy-、-L1-、-X2-、-Cy-L1-或-L2-及其具体选项，任选地可以采用从左至右的阅读顺序，对应的分别与通式中该基团或者片段左侧基团及右侧基团连接，例如当-Cy-L1-(即L)选自按照从左至右的阅读顺序，-Cy-L1-左侧与通式中对应左侧的片段连接，右侧与右侧片段连接，形成的片段如任选地，本申请中的基团或结构片段如环A、-Cy-L3-X2-、-Cy-、-L1-、-X2-、-Cy-L1-或-L2-及其具体选项，可以采用从右至左的阅读顺序，对应的分别与通式中该基团或者片段左侧基团及右侧基团连接，例如当-Cy-L1-(即L)选自按照从右至左的阅读顺序，-Cy-L1- 右侧与通式中对应左侧的片段连接，左侧与通式中对应右侧的片段连接形成的片段如其他基团同上所述。Groups or structural fragments in this application such as ring A, -Cy-L 3 -X 2 -, -Cy-, -L 1 -, -X 2 -, -Cy-L 1 - or -L 2 - and their Specific options, optionally, can be read from left to right, corresponding to the left-hand and right-hand groups of the group or fragment in the general formula, for example, when -Cy-L 1 -(i.e. L ) selected from In reading order from left to right, -Cy-L 1 -the left side and the fragment corresponding to the left side in the general formula Join, right to right fragment Connect, forming fragments such as Optionally, a group or structural fragment in this application such as Ring A, -Cy-L 3 -X 2 -, -Cy-, -L 1 -, -X 2 -, -Cy-L 1 - or -L 2 - and its specific options can be read from right to left, corresponding to the left group and the right group of the group or fragment in the general formula, for example, when -Cy-L 1 - (i.e. L) selected from In reading order from right to left, -Cy-L 1 - The right side corresponds to the fragment on the left side in the general formula Connect, the left side and the fragment corresponding to the right side in the general formula Connected fragments such as Other groups are as described above.

术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "treating" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i)抑制疾病或疾病状态，即遏制其发展；(i) To inhibit a disease or disease state, that is, to arrest its progression;

(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(ii) Alleviation of a disease or condition, i.e. resolution of the disease or condition.

术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。The term "prevent" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such disease or condition is present in a mammal. A mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically effective amount" means (i) treating or preventing a specified disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.

术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。Examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. .

术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.

术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。The words "comprise" or "comprise" and their English variants such as compris or comprising should be understood in an open, non-exclusive sense, that is, "including but not limited to."

本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, where the proton can migrate between two ring nitrogens. Valence tautomers include tautomers by reorganization of some of the bonding electrons.

本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。The present application also includes compounds of the present application that are the same as those described herein, but are isotopically labeled in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature. Examples of isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

某些同位素标记的本申请化合物(例如用3H及14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。Certain isotopically labeled compounds of the present application (eg, those labeled with 3 H and 14 C) can be used in compound and/or substrate tissue distribution analyses. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes and/or Examples below.

此外，用较重同位素(诸如氘(即2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例 如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。Additionally, substitution with heavier isotopes such as deuterium (i.e. 2 H) may provide certain therapeutic advantages resulting from greater metabolic stability (e.g. such as increased half-life in vivo or reduced dosage requirements), and may therefore be preferred in certain circumstances, where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。Compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.

本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, dragees, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.

可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

本文所述的通式Ⅰ化合物的所有施用方法中，每天给药的剂量为0.01到200mg/kg体重，以单独或分开剂量的形式。In all methods of administration of the compounds of general formula I described herein, dosages of 0.01 to 200 mg/kg body weight are administered per day, in single or divided doses.

本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred implementations include but are not limited to the embodiments of this application.

本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present application are completed in a suitable solvent. The solvent must be suitable for the chemical changes of the present application and the required reagents and materials. In order to obtain the compounds of the present application, those skilled in the art sometimes need to modify or select the synthesis steps or reaction procedures based on the existing embodiments.

本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.
An important consideration in planning synthetic routes in this field is the selection of appropriate protecting groups for reactive functional groups (such as amino groups in this application). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

其中，q、R2、m、环A、R1、L、R3、p、X、X1的定义如前所述，Z选自反应位点基团，包括但不限于F、Cl、Br、I或-CHO等。Among them, q, R 2 , m, ring A, R 1 , L, R 3 , p , Br, I or -CHO, etc.

本申请采用下述缩略词：This application uses the following abbreviations:

EDCI代表碳二亚胺盐酸盐；DMAP代表4-二甲氨基吡啶；Pd(PPh3)2Cl2代表双三苯基膦二氯化钯；AcOH代表醋酸；NaBH3CN代表氰基硼氢化钠；NaCl代表氯化钠。EDCI represents carbodiimide hydrochloride; DMAP represents 4-dimethylaminopyridine; Pd(PPh 3 ) 2 Cl 2 represents bistriphenylphosphine palladium dichloride; AcOH represents acetic acid; NaBH 3 CN represents cyanohydroboration Sodium; NaCl stands for sodium chloride.

为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。For the sake of clarity, examples are further used to illustrate the invention, but the examples do not limit the scope of the application. All reagents used in this application are commercially available and used without further purification.

具体实施方式Detailed ways

实施例1：化合物1的制备
Example 1: Preparation of Compound 1

1)中间体1-1的制备1) Preparation of intermediate 1-1

将4-氟-3-硝基苯磺酰胺(10g)于四氢呋喃(20mL)中，依次加入1-叔丁氧羰基-4-氨甲基哌啶(9.7g)和三乙胺(6.8g)，室温下搅拌反应12h，反应完全。减压蒸除溶剂得到中间体1-1(14g)。Dissolve 4-fluoro-3-nitrobenzenesulfonamide (10g) in tetrahydrofuran (20mL), add 1-tert-butoxycarbonyl-4-aminomethylpiperidine (9.7g) and triethylamine (6.8g) in sequence , the reaction was stirred for 12 hours at room temperature, and the reaction was complete. The solvent was evaporated under reduced pressure to obtain intermediate 1-1 (14 g).

2)中间体1-2的制备2) Preparation of intermediate 1-2

将化合物中间体1-1(5.0g)溶于二氯甲烷(50mL)中，加入三氟乙酸(5mL)室温下搅拌反应3h，反应完全。减压蒸除溶剂和三氟乙酸。加入水(50mL)和乙腈(10mL)，溶清，滴加饱和NaHCO3水溶液，调节pH值至8～9，析出固体，过滤得到中间体1-2(4.9g)。Compound intermediate 1-1 (5.0 g) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (5 mL) was added, and the reaction was stirred at room temperature for 3 h until the reaction was complete. The solvent and trifluoroacetic acid were evaporated under reduced pressure. Add water (50 mL) and acetonitrile (10 mL), dissolve, add saturated NaHCO 3 aqueous solution dropwise, adjust the pH value to 8-9, precipitate a solid, and filter to obtain intermediate 1-2 (4.9 g).

3)中间体1-3的制备3) Preparation of intermediate 1-3

将中间体1-2(1.0g)溶于甲醇(50mL)中，加入N-叔丁氧羰基-4-哌啶酮(0.95g)，室温下搅拌30min，加入AcOH(1mL)，室温下搅拌30min，加入NaBH3CN(0.60g)，室温下搅拌反应12h。加入饱和碳酸氢钠淬灭反应，水相用二氯甲烷(100mL×3)萃取，合并有机相，减压蒸除溶剂、并通过柱层析(展开剂：二氯甲烷:甲醇＝10:1)得到中间体1-3(0.5g)。Dissolve intermediate 1-2 (1.0g) in methanol (50mL), add N-tert-butoxycarbonyl-4-piperidone (0.95g), stir at room temperature for 30 min, add AcOH (1mL), and stir at room temperature 30min, add NaBH 3 CN (0.60g), and stir the reaction at room temperature for 12h. Add saturated sodium bicarbonate to quench the reaction, extract the aqueous phase with dichloromethane (100 mL ) to obtain intermediate 1-3 (0.5g).

4)中间体1-5的制备4) Preparation of intermediates 1-5

将中间体1-3(1.2g)和化合物1-4(1.46g)于二氯甲烷中(20mL)，加入EDCI(0.64g)和DMAP(0.58g)，室温下搅拌反应12h，反应完全。加入二氯甲烷(30mL)，并用饱和NaCl水溶液洗涤，减压蒸除溶剂、并通过柱层析(展开剂：二氯甲烷:甲醇＝30:1)得中间体1-5(1.2g)。Intermediate 1-3 (1.2g) and compound 1-4 (1.46g) were added to dichloromethane (20 mL), EDCI (0.64g) and DMAP (0.58g) were added, and the reaction was stirred for 12 hours at room temperature until the reaction was complete. Dichloromethane (30 mL) was added, washed with saturated NaCl aqueous solution, the solvent was evaporated under reduced pressure, and intermediate 1-5 (1.2 g) was obtained by column chromatography (developing solvent: dichloromethane:methanol=30:1).

5)中间体1-6的制备5) Preparation of intermediates 1-6

将得到的中间体1-5(1.0g)溶于二氯甲烷(10mL)中，加入三氟乙酸(1mL)，室温下搅拌反应2h，减压蒸除溶剂和三氟乙酸，得到中间体1-6(800mg)。The obtained Intermediate 1-5 (1.0g) was dissolved in dichloromethane (10mL), trifluoroacetic acid (1mL) was added, and the reaction was stirred at room temperature for 2h. The solvent and trifluoroacetic acid were evaporated under reduced pressure to obtain Intermediate 1 -6(800mg).

6)中间体1-8的制备6) Preparation of intermediates 1-8

将五水硫代硫酸钠(53.7g)，氯化苄(27.4g)，五水硫酸铜(77.4mg)及联吡啶(0.72g)于甲醇(120mL)和水(120mL)中，缓慢升温至80℃，搅拌2h。反应液降至室温，加入化合物1-7(8.0g)，缓慢滴加亚硝酸叔丁酯(4.78g)，滴毕，升温至80℃，搅拌8h。反应完全，反应液降至室温，加入水(200mL)，水相用乙酸乙酯萃取(200mL×2)，合并有机相，水洗、饱和NaCl水溶液洗涤，无水硫酸钠干燥，减压蒸除溶剂、并通过柱层析(展开剂：石油醚:乙酸乙酯＝1:2)得中间体1-8(6.8g)。Dissolve sodium thiosulfate pentahydrate (53.7g), benzyl chloride (27.4g), copper sulfate pentahydrate (77.4mg) and bipyridine (0.72g) in methanol (120mL) and water (120mL), and slowly heat to 80℃, stir for 2h. The reaction solution was cooled to room temperature, compound 1-7 (8.0g) was added, tert-butyl nitrite (4.78g) was slowly added dropwise, and after the dropwise completion, the temperature was raised to 80°C and stirred for 8 hours. The reaction is complete, the reaction solution is brought to room temperature, water (200mL) is added, the aqueous phase is extracted with ethyl acetate (200mL×2), the organic phases are combined, washed with water and saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. , and obtained intermediate 1-8 (6.8g) through column chromatography (developing solvent: petroleum ether: ethyl acetate = 1:2).

LC-MS:m/z＝367.11[M+H]+.LC-MS: m/z=367.11[M+H] + .

7)中间体1-9的制备 7) Preparation of intermediates 1-9

将无水三氯化铝(2.61g)溶于无水甲苯(70mL)中，搅拌下缓慢加入中间体1-8(1.8g)，加毕，35℃下搅拌反应7h。反应完毕，搅拌下缓慢加入20％柠檬酸水溶液至不再析出固体，抽滤，滤饼分别用水和乙酸乙酯淋洗，干燥得中间体1-9(1.15g)。Dissolve anhydrous aluminum trichloride (2.61g) in anhydrous toluene (70 mL), slowly add intermediate 1-8 (1.8g) while stirring, complete the addition, and stir for 7 hours at 35°C. After the reaction is completed, slowly add 20% citric acid aqueous solution with stirring until no more solid precipitates, filter with suction, rinse the filter cake with water and ethyl acetate, and dry to obtain intermediate 1-9 (1.15g).

LC-MS:m/z＝277.06[M+H]+.LC-MS: m/z=277.06[M+H] + .

8)中间体1-10的制备8) Preparation of intermediates 1-10

将化合物中间体1-9(1.0g)及无水碳酸钾(1.0g)于无水N,N-二甲基甲酰胺(10mL)中，搅拌下缓慢加入1,3-二溴丙烷(0.87g)，室温下搅拌反应1h。反应完毕，加入水淬灭反应，水相用乙酸乙酯(50mL×3)萃取，合并有机相，减压蒸除溶剂得中间体1-10(150mg)。Add compound intermediate 1-9 (1.0g) and anhydrous potassium carbonate (1.0g) to anhydrous N,N-dimethylformamide (10mL), and slowly add 1,3-dibromopropane (0.87 g), stir the reaction at room temperature for 1 h. After the reaction was completed, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the solvent was evaporated under reduced pressure to obtain intermediate 1-10 (150 mg).

LC-MS:m/z＝397.02[M+H]+.LC-MS: m/z＝397.02[M+H] + .

9)化合物1的制备9) Preparation of compound 1

将中间体1-6(0.15g)于N,N-二甲基甲酰胺(10mL)中，依次加入碳酸钾(0.14g)、碘化钠(0.15g)和中间体1-10(0.12g)，50℃下搅拌反应8h，反应液经制备液相得到化合物1(13mg)。Intermediate 1-6 (0.15g) was added to N,N-dimethylformamide (10 mL), potassium carbonate (0.14g), sodium iodide (0.15g) and intermediate 1-10 (0.12g) were added successively ), the reaction was stirred at 50°C for 8 hours, and the reaction solution was prepared into a liquid phase to obtain compound 1 (13 mg).

LC-MS:m/z＝651.2[M+2H]2+.LC-MS: m/z＝651.2[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.86(d,1H),8.56(s,1H),8.44(s,1H),8.15(d,1H),8.05(d,1H),7.94(d,1H),7.65(d,1H),7.43(dd,3H),7.09(d,2H),7.03(d,1H),7.00(d,1H),6.55(dd,2H),6.02(s,1H),5.24(dd,1H),4.44(d,1H),4.31(d,1H),4.07–4.01(m,2H),3.20(m,2H),3.06(m,4H),2.93–2.83(m,5H),2.73–2.22(m,15H),1.98–1.79(m,12H),1.52–1.26(m,10H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.86(d,1H),8.56(s,1H),8.44(s,1H),8.15(d,1H),8.05(d,1H),7.94(d, 1H),7.65(d,1H),7.43(dd,3H),7.09(d,2H),7.03(d,1H),7.00(d,1H),6.55(dd,2H),6.02(s,1H ),5.24(dd,1H),4.44(d,1H),4.31(d,1H),4.07–4.01(m,2H),3.20(m,2H),3.06(m,4H),2.93–2.83( m,5H),2.73–2.22(m,15H),1.98–1.79(m,12H),1.52–1.26(m,10H),0.95(s,6H).

实施例2：化合物2的制备Example 2: Preparation of Compound 2

1)中间体2-1的制备
1) Preparation of intermediate 2-1

参考实施例1步骤8)中中间体1-10的制备方法，将1,3-二溴丙烷替换为1,4-二溴丁烷，得到中间体2-1(166mg)。Referring to the preparation method of intermediate 1-10 in step 8) of Example 1, 1,3-dibromopropane was replaced with 1,4-dibromobutane to obtain intermediate 2-1 (166 mg).

LC-MS:m/z＝411.0[M+H]+.LC-MS: m/z＝411.0[M+H] + .

2)化合物2的制备
2) Preparation of compound 2

参考实施例1步骤9)中实施例1的制备方法，将其中的中间体1-10换成中间体2-1，得到化合物2(62mg)。Referring to the preparation method of Example 1 in Step 9) of Example 1, the intermediate 1-10 therein was replaced by the intermediate 2-1 to obtain compound 2 (62 mg).

LC-MS:m/z＝657.6[M+2H]2+.LC-MS: m/z＝657.6[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.87(d,1H),8.57(s,1H),8.45(s,1H),8.15(d,1H),8.07(d,1H),7.95(d,1H),7.65(d,1H),7.44(dd,3H),7.10(d,2H),7.03(d,1H),7.00(d,1H),6.56(dd,2H),6.03(s,1H),5.25(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21(m,2H),3.06(m,4H),2.93–2.83(m,6H),2.73–2.22(m,14H),1.98–1.79(m,14H),1.52–1.26(m,10H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.87(d,1H),8.57(s,1H),8.45(s,1H),8.15(d,1H),8.07(d,1H),7.95(d, 1H),7.65(d,1H),7.44(dd,3H),7.10(d,2H),7.03(d,1H),7.00(d,1H),6.56(dd,2H),6.03(s,1H ),5.25(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21(m,2H),3.06(m,4H),2.93–2.83( m,6H),2.73–2.22(m,14H),1.98–1.79(m,14H),1.52–1.26(m,10H),0.95(s,6H).

实施例3：化合物3的制备Example 3: Preparation of Compound 3

1)中间体3-1的制备
1) Preparation of intermediate 3-1

参考实施例1步骤8)中中间体1-10的制备方法，将1,3-二溴丙烷替换为1,5-二溴戊烷，得到中间体3-1(210mg)。Referring to the preparation method of intermediate 1-10 in step 8) of Example 1, 1,3-dibromopropane was replaced with 1,5-dibromopentane to obtain intermediate 3-1 (210 mg).

LC-MS:m/z＝425.0[M+H]+.LC-MS: m/z＝425.0[M+H] + .

2)化合物3的制备
2) Preparation of compound 3

参考实施例1步骤9)中实施例1的制备方法，将其中的中间体1-10换成中间体3-1，得到化合物3(21mg)。Referring to the preparation method of Example 1 in step 9) of Example 1, the intermediate 1-10 was replaced by the intermediate 3-1 to obtain compound 3 (21 mg).

LC-MS:m/z＝664.7[M+2H]2+.LC-MS: m/z＝664.7[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.86(d,1H),8.57(s,1H),8.43(s,1H),8.14(d,1H),8.07(d,1H),7.93(d,1H),7.66(d,1H),7.45(dd,3H),7.10(d,2H),7.02(d,1H),7.00(d,1H),6.56(dd,2H),6.02(s,1H),5.24(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21(m,2H),3.06(m,4H),2.93–2.83(m,8H),2.73–2.22(m,12H),1.98–1.79(m,15H),1.52–1.26(m,11H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.86(d,1H),8.57(s,1H),8.43(s,1H),8.14(d,1H),8.07(d,1H),7.93(d, 1H),7.66(d,1H),7.45(dd,3H),7.10(d,2H),7.02(d,1H),7.00(d,1H),6.56(dd,2H),6.02(s,1H ),5.24(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21(m,2H),3.06(m,4H),2.93–2.83( m,8H),2.73–2.22(m,12H),1.98–1.79(m,15H),1.52–1.26(m,11H),0.95(s,6H).

实施例4：化合物4的制备Example 4: Preparation of Compound 4

1)中间体4-2的制备
1) Preparation of intermediate 4-2

将化合物4-1(1.0g)、1,4-二溴丁烷(2.49g)及碳酸钾(0.58g)于乙腈(20mL)中，80℃下搅拌反应9h，过滤，滤饼用二氯甲烷淋洗，滤液减压蒸除溶剂、并通过柱层析(展开剂：二氯甲烷:甲醇＝150:1～100:1)得中间体4-2(670mg)。Add compound 4-1 (1.0g), 1,4-dibromobutane (2.49g) and potassium carbonate (0.58g) in acetonitrile (20mL), stir and react at 80°C for 9 hours, filter, and filter the filter cake with dichloromethane. Elute with methane, evaporate the solvent from the filtrate under reduced pressure, and pass through column chromatography (developing solvent: methylene chloride: methanol = 150:1 to 100:1) to obtain intermediate 4-2 (670 mg).

LC-MS:m/z＝396.9[M+H]+.LC-MS: m/z=396.9[M+H] + .

1H NMR(500MHz,CDCl3)δ8.86(d,1H),8.54(s,1H),8.43(s,1H),8.13(d,1H),8.07(d,1H),7.96(d,1H),7.64(d,1H),7.43(dd,3H),7.08(d,2H),7.03(d,1H),7.00(d,1H),6.55(dd,2H),6.04(s,1H),5.25(dd,1H),4.43(d,1H),4.31(d,1H),4.07–4.02(m,2H),3.22(m,2H),3.06(m,4H),2.93–2.83(m,6H),2.73–2.22(m,14H),1.98–1.79(m,14H),1.52–1.26(m,10H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.86(d,1H),8.54(s,1H),8.43(s,1H),8.13(d,1H),8.07(d,1H),7.96(d, 1H),7.64(d,1H),7.43(dd,3H),7.08(d,2H),7.03(d,1H),7.00(d,1H),6.55(dd,2H),6.04(s,1H ),5.25(dd,1H),4.43(d,1H),4.31(d,1H),4.07–4.02(m,2H),3.22(m,2H),3.06(m,4H),2.93–2.83( m,6H),2.73–2.22(m,14H),1.98–1.79(m,14H),1.52–1.26(m,10H),0.95(s,6H).

2)化合物4的制备
2) Preparation of compound 4

参考实施例1步骤9)中实施例1的制备方法，将其中的中间体1-10换成中间体4-2，得到化合物4(88mg)。Referring to the preparation method of Example 1 in step 9) of Example 1, the intermediate 1-10 was replaced by the intermediate 4-2 to obtain compound 4 (88 mg).

LC-MS:m/z＝649.8[M+2H]2+.LC-MS: m/z＝649.8[M+2H] 2+ .

实施例5：化合物5的制备Example 5: Preparation of Compound 5

1)中间体5-1的制备
1) Preparation of intermediate 5-1

参考实施例4步骤1)中中间体4-2的制备方法，将1,4-二溴丁烷替换为1,5-二溴戊烷，得到中间体5-1(980mg)。Referring to the preparation method of intermediate 4-2 in step 1) of Example 4, 1,4-dibromobutane was replaced with 1,5-dibromopentane to obtain intermediate 5-1 (980 mg).

LC-MS:m/z＝411.0[M+H]+.LC-MS: m/z＝411.0[M+H] + .

2)化合物5的制备
2) Preparation of compound 5

参考实施例1步骤9)中实施例1的制备方法，将其中的中间体1-10换成中间体5-1，得到化合物5(32mg)。Referring to the preparation method of Example 1 in Step 9) of Example 1, the intermediate 1-10 was replaced by the intermediate 5-1 to obtain compound 5 (32 mg).

LC-MS:m/z＝656.8[M+2H]2+ LC-MS: m/z＝656.8[M+2H] 2+

1H NMR(500MHz,CDCl3)δ8.87(d,1H),8.55(s,1H),8.43(s,1H),8.13(d,1H),8.07(d,1H),7.95(d,1H),7.66(d,1H),7.44(dd,3H),7.10(d,2H),7.02(d,1H),7.00(d,1H),6.55(dd,2H),6.03(s,1H),5.24(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21–3.06(m,7H),2.93–2.83(m,8H),2.73–2.22(m,13H),1.98–1.79(m,14H),1.52–1.26(m,10H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.87(d,1H),8.55(s,1H),8.43(s,1H),8.13(d,1H),8.07(d,1H),7.95(d, 1H),7.66(d,1H),7.44(dd,3H),7.10(d,2H),7.02(d,1H),7.00(d,1H),6.55(dd,2H),6.03(s,1H ),5.24(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21–3.06(m,7H),2.93–2.83(m,8H), 2.73–2.22(m,13H),1.98–1.79(m,14H),1.52–1.26(m,10H),0.95(s,6H).

实施例6：化合物6的制备Example 6: Preparation of Compound 6

1)中间体6-2的制备
1) Preparation of intermediate 6-2

参考实施例1步骤5)中中间体1-6的制备方法，将其中的中间体1-5换成中间体6-1，得到中间体6-2(850mg)。Referring to the preparation method of Intermediate 1-6 in Step 5) of Example 1, Intermediate 1-5 was replaced by Intermediate 6-1 to obtain Intermediate 6-2 (850 mg).

LC-MS:m/z＝958.4[M+H]+.LC-MS: m/z=958.4[M+H] + .

2)中间体6-4的制备
2) Preparation of intermediate 6-4

将化合物6-3(0.50g)溶于N,N-二甲基甲酰胺(5mL)中，依次加入4-戊炔-1-醇(0.21g)、Pd(PPh3)2Cl2(0.10g)及CuI(57mg)。室温下搅拌5min，加入三乙胺(2.5mL)，N2保护下80℃搅拌反应16h。自然冷却到室温，加入水(50mL)淬灭反应，水相用乙酸乙酯(50mL×3)萃取，合并有机相，水洗(30mL×2)，饱和NaCl水溶液(50mL×3)洗涤，无水硫酸钠干燥，减压蒸除溶剂、并通过柱层析(展开剂：二氯甲烷:甲醇＝5:1)得中间体6-4(350mg)。Compound 6-3 (0.50g) was dissolved in N,N-dimethylformamide (5mL), and 4-pentyn-1-ol (0.21g) and Pd(PPh 3 ) 2 Cl 2 (0.10 g) and CuI (57 mg). Stir at room temperature for 5 min, add triethylamine (2.5 mL), stir and react at 80°C for 16 h under N2 protection. Cool to room temperature naturally, add water (50mL) to quench the reaction, extract the aqueous phase with ethyl acetate (50mL×3), combine the organic phases, wash with water (30mL×2), wash with saturated NaCl aqueous solution (50mL×3), and anhydrous Dry over sodium sulfate, evaporate the solvent under reduced pressure, and obtain intermediate 6-4 (350 mg) through column chromatography (developing solvent: dichloromethane:methanol=5:1).

LC-MS:m/z＝327.13[M+H]+.LC-MS: m/z=327.13[M+H] + .

3)中间体6-5的制备
3) Preparation of intermediate 6-5

将中间体6-4(50mg)及三溴化磷(42mg)于N-甲基吡咯烷酮(2mL)中，70℃下搅拌反应12h。自然冷却到室温，加入水(50mL)淬灭反应，水相用乙酸乙酯(50mL×3)萃取，合并有机相，水洗、饱和NaCl水溶液洗涤，无水硫酸钠干燥，减压蒸除溶剂、并通过柱层析(展开剂：二氯甲烷:甲醇＝100:1)得中间体6-5(120mg)。Intermediate 6-4 (50 mg) and phosphorus tribromide (42 mg) were added to N-methylpyrrolidone (2 mL), and the reaction was stirred at 70°C for 12 h. Cool to room temperature naturally, add water (50 mL) to quench the reaction, extract the aqueous phase with ethyl acetate (50 mL × 3), combine the organic phases, wash with water and saturated NaCl aqueous solution, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. And through column chromatography (developing solvent: dichloromethane: methanol = 100:1), intermediate 6-5 (120 mg) was obtained.

LC-MS:m/z＝389.2[M+H]+.LC-MS: m/z＝389.2[M+H] + .

4)化合物6的制备
4) Preparation of compound 6

参考实施例1步骤9)中实施例1的制备方法，将其中的中间体1-6换成中间体6-2，中间体1-10换成中间体6-5，得到化合物6(22mg)。Refer to the preparation method of Example 1 in step 9) of Example 1, replace intermediate 1-6 with intermediate 6-2, and replace intermediate 1-10 with intermediate 6-5 to obtain compound 6 (22 mg) .

LC-MS:m/z＝634.0[M+2H]2+.LC-MS: m/z＝634.0[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ10.74(s,1H),8.80(d,1H),8.41(s,1H),8.07(d,1H),7.98(d,1H),7.88(d,1H),7.77(d,1H),7.68(d,1H),7.53(t,2H),7.43(m,3H),7.10(d,2H),6.78(d,1H),6.53(dd,1H),6.50(d,1H),5.97(s,1H),5.23(dd,1H),4.50(d,1H),4.38(d,1H),3.22–3.10(m,10H),2.97–2.78(m,7H),2.57–2.43(m,12H),2.00–1.83(m,8H),1.63–1.26(m,9H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ10.74(s,1H),8.80(d,1H),8.41(s,1H),8.07(d,1H),7.98(d,1H),7.88(d, 1H),7.77(d,1H),7.68(d,1H),7.53(t,2H),7.43(m,3H),7.10(d,2H),6.78(d,1H),6.53(dd,1H ),6.50(d,1H),5.97(s,1H),5.23(dd,1H),4.50(d,1H),4.38(d,1H),3.22–3.10(m,10H),2.97–2.78( m,7H),2.57–2.43(m,12H),2.00–1.83(m,8H),1.63–1.26(m,9H),0.95(s,6H).

实施例7：化合物7的制备
Example 7: Preparation of Compound 7

1)中间体7-2的制备1) Preparation of intermediate 7-2

将化合物7-1(1.0g)溶于无水N,N-二甲基甲酰胺(10mL)，依次加入无水碳酸钾(1.1g)，碘化钠(1.1g)室温搅拌下缓慢加入1，3-二溴丙烷(0.87g,4.34mmol)，60℃加热6h,液相制备，得到中间体7-2。Dissolve compound 7-1 (1.0g) in anhydrous N,N-dimethylformamide (10mL), add anhydrous potassium carbonate (1.1g) and sodium iodide (1.1g) slowly at room temperature while stirring. , 3-dibromopropane (0.87g, 4.34mmol), heated at 60°C for 6 hours, prepared in liquid phase, and obtained intermediate 7-2.

LC-MS:m/z＝393.9[M+H]+ LC-MS: m/z＝393.9[M+H] +

2)化合物7的制备2) Preparation of compound 7

将中间体1-6(0.50g)溶于10mL DMF中，依次加入碳酸钾(0.14g)、碘化钠(0.15g)和中间体7-2(0.33g)，50℃加热8h，液相制备，化合物7(88mg)。Dissolve intermediate 1-6 (0.50g) in 10mL DMF, add potassium carbonate (0.14g), sodium iodide (0.15g) and intermediate 7-2 (0.33g) in sequence, heat at 50°C for 8h, liquid phase Preparation, compound 7 (88 mg).

LC-MS:m/z＝1297.54[M+H]+ LC-MS: m/z＝1297.54[M+H] +

实施例8：化合物8的制备
Example 8: Preparation of Compound 8

1)中间体8-1的制备1) Preparation of intermediate 8-1

参考实施例7步骤1)中中间体7-2的制备方法，将1,3-二溴丙烷替换为1,4-二溴丁烷，得到中间体8-1(166mg)。Referring to the preparation method of intermediate 7-2 in step 1) of Example 7, 1,3-dibromopropane was replaced with 1,4-dibromobutane to obtain intermediate 8-1 (166 mg).

LC-MS:m/z＝408.2[M+H]+.LC-MS: m/z＝408.2[M+H] + .

2)化合物8的制备2) Preparation of compound 8

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体8-1，得到化合物8(62mg)。Referring to the preparation method of compound 7 in step 2) of Example 7, intermediate 7-2 was replaced by intermediate 8-1 to obtain compound 8 (62 mg).

LC-MS:m/z＝656.3[M+2H]2+.LC-MS: m/z＝656.3[M+2H] 2+ .

实施例9：化合物9的制备
Example 9: Preparation of Compound 9

1)中间体9-1的制备1) Preparation of intermediate 9-1

参考实施例7步骤1)中中间体7-2的制备方法，将1,3-二溴丙烷替换为1,5-二溴戊烷，得到中间体9-1(180mg)。Referring to the preparation method of intermediate 7-2 in step 1) of Example 7, 1,3-dibromopropane was replaced with 1,5-dibromopentane to obtain intermediate 9-1 (180 mg).

LC-MS:m/z＝422.1[M+H]+.LC-MS: m/z=422.1[M+H] + .

2)化合物9的制备2) Preparation of compound 9

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体9-1，得到化合物9(80mg)。Referring to the preparation method of compound 7 in step 2) of Example 7, intermediate 7-2 was replaced by intermediate 9-1 to obtain compound 9 (80 mg).

LC-MS:m/z＝663.3[M+2H]2+.LC-MS: m/z＝663.3[M+2H] 2+ .

实施例10：化合物10的制备
Example 10: Preparation of Compound 10

1)中间体10-1的制备1) Preparation of intermediate 10-1

参考实施例1步骤4)中中间体1-5的制备方法，将其中的中间体1-3换成中间体1-1，得到中间体10-1(800mg)。Referring to the preparation method of Intermediate 1-5 in Step 4) of Example 1, Intermediate 1-3 was replaced by Intermediate 1-1 to obtain Intermediate 10-1 (800 mg).

2)中间体10-2的制备2) Preparation of intermediate 10-2

参考实施例1步骤5)中中间体1-6的制备方法，将其中的中间体1-5换成中间体10-1，得到中间体10-2(600mg)。Referring to the preparation method of Intermediate 1-6 in Step 5) of Example 1, Intermediate 1-5 was replaced by Intermediate 10-1 to obtain Intermediate 10-2 (600 mg).

3)化合物10的制备3) Preparation of compound 10

参考实施例9步骤2)中化合物9的制备方法，将其中的中间体1-6换成中间体10-2，得到化合物10(120mg)。Referring to the preparation method of compound 9 in step 2) of Example 9, intermediate 1-6 was replaced by intermediate 10-2 to obtain compound 10 (120 mg).

LC-MS:m/z＝621.8[M+2H]2+.LC-MS: m/z＝621.8[M+2H] 2+ .

实施例11:化合物11的制备
Example 11: Preparation of Compound 11

1)中间体11-1的制备1) Preparation of intermediate 11-1

参考实施例8步骤1)中中间体8-1的制备方法，将化合物7-1替换为来那度胺，得到中间体11-1(180mg)。Referring to the preparation method of intermediate 8-1 in step 1) of Example 8, compound 7-1 was replaced with lenalidomide to obtain intermediate 11-1 (180 mg).

LC-MS:m/z＝394.1[M+H]+.LC-MS: m/z=394.1[M+H] + .

2)化合物11的制备2) Preparation of compound 11

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体11-1，得到化合物11(45mg)。Referring to the preparation method of compound 7 in step 2) of Example 7, intermediate 7-2 was replaced by intermediate 11-1 to obtain compound 11 (45 mg).

LC-MS:m/z＝649.3[M+2H]2+.LC-MS: m/z＝649.3[M+2H] 2+ .

实施例12：化合物12的制备
Example 12: Preparation of Compound 12

1)中间体12-1的制备1) Preparation of intermediate 12-1

称取1g化合物12A、871mg双三苯基磷二氯化钯、118mg碘化亚铜，加入20mL N,N-二甲基甲酰胺溶解，室温搅拌，随后加入783mg 7-辛炔-1-醇和1.539mL N,N-二异丙基乙胺，氮气保护，移至70℃搅拌5小时。向反应液中加入40mL水，用50mL乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液38℃浓缩，所得粗品通过硅胶柱层析(二氯甲烷：甲醇)得到795mg中间体12-1。Weigh 1g of compound 12A, 871mg of palladium bistriphenylphosphonium dichloride, and 118mg of copper iodide, add 20mL of N,N-dimethylformamide to dissolve, stir at room temperature, and then add 783mg of 7-octyn-1-ol and 1.539mL N,N-diisopropylethylamine, protected by nitrogen, moved to 70°C and stirred for 5 hours. Add 40 mL of water to the reaction solution, extract with 50 mL of ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate at 38°C. The crude product is passed through silica gel column chromatography (dichloromethane). : methanol) to obtain 795 mg of intermediate 12-1.

ESI-MS:m/z＝369.1[M+H]+ ESI-MS:m/z＝369.1[M+H] +

2)中间体12-2的制备2) Preparation of intermediate 12-2

将200mg中间体12-1分散于5mL二氯甲烷中，加入345mg戴斯马丁试剂，氮气保护，40℃搅拌3小时。冷却至室温，向反应液中加入45mL二氯甲烷、25mL饱和碳酸氢钠溶液和25mL饱和硫代硫酸钠溶液，室温搅拌10分钟后分液，水相用50mL二氯甲烷萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液38℃浓缩，得到246mg中间体12-2。Disperse 200 mg of intermediate 12-1 in 5 mL of methylene chloride, add 345 mg of Desmartin's reagent, and stir under nitrogen protection at 40°C for 3 hours. Cool to room temperature, add 45 mL dichloromethane, 25 mL saturated sodium bicarbonate solution and 25 mL saturated sodium thiosulfate solution to the reaction solution. Stir at room temperature for 10 minutes and then separate the liquids. Extract the aqueous phase with 50 mL dichloromethane and combine the organic phases. Wash with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate at 38°C to obtain 246 mg of intermediate 12-2.

ESI-MS:m/z＝367.33[M+H]+ ESI-MS:m/z＝367.33[M+H] +

3)化合物12的制备3) Preparation of compound 12

将156mg中间体12-2和419mg中间体1-6分散于8mL二氯甲烷中，加入0.037mL冰乙酸，室温搅拌30分钟，再加入37mg氰基硼氢化钠，室温搅拌3小时。向反应液中加入25mL二氯甲烷、25mL饱和氯化铵溶液、25mL饱和食盐水和25mL水，室温搅拌5分钟后分液，水相用二氯甲烷：甲醇＝3：2(v:v)萃取，合并有机相，38℃浓缩，粗品经制备液相得到85mg化合物12。Disperse 156 mg of intermediate 12-2 and 419 mg of intermediate 1-6 in 8 mL of methylene chloride, add 0.037 mL of glacial acetic acid, stir at room temperature for 30 minutes, then add 37 mg of sodium cyanoborohydride, and stir at room temperature for 3 hours. Add 25 mL dichloromethane, 25 mL saturated ammonium chloride solution, 25 mL saturated saline solution and 25 mL water to the reaction solution. Stir at room temperature for 5 minutes and then separate the liquids. Use dichloromethane: methanol = 3: 2 (v: v) for the water phase. Extract, combine the organic phases, and concentrate at 38°C. The crude product is prepared into a liquid phase to obtain 85 mg of compound 12.

ESI-MS:m/z＝667.8[M+2H]2+ ESI-MS: m/z＝667.8[M+2H] 2+

1H NMR(500MHz,DMSO)δ11.53(d,J＝2.4Hz,1H),11.03–10.99(m,1H),8.40(d,J＝2.2Hz,2H),8.15(s,2H),7.93(d,J＝2.6Hz,1H),7.71(dd,J＝7.6,1.0Hz,1H),7.69–7.64(m,3H),7.62(dd,J＝7.6,1.0Hz,1H),7.58(d,J＝8.8Hz,1H),7.52(t,J＝7.6Hz,1H),7.42(t,J＝3.0Hz,1H),7.30(d,J＝2.6Hz,1H),7.26(d,J＝7.9Hz,2H),6.87(d,J＝9.3Hz,1H),6.62(dd,J＝8.9,2.4Hz,1H),6.30(dd,J＝3.4,1.9Hz,1H),6.23(d,J＝2.3Hz,1H),5.15(dd,J＝13.4,5.2Hz,1H),4.44(d,J＝17.6Hz,1H),4.30(d,J＝17.5Hz,1H),3.28(d,J＝12.7Hz,5H),3.10(d,J＝11.1Hz,5H),3.03–2.97(m,4H),2.92(ddd,J＝17.2,13.7,5.4Hz,2H),2.72(s,2H),2.59(ddd,J＝17.4,4.5,2.3Hz,2H),2.47(d,J＝7.0Hz,2H),2.25–2.15(m,8H),1.98(s,2H),1.84(d,J＝12.3Hz,2H),1.78(d,J＝13.1Hz,2H),1.57(p,J＝6.7Hz,4H),1.53–1.46(m,2H),1.44(d,J＝7.9Hz,2H),1.41(t,J＝6.5Hz,3H),1.30(p,J＝8.5,7.8Hz,4H),0.94(s,6H). 1 H NMR (500MHz, DMSO) δ11.53(d,J＝2.4Hz,1H),11.03–10.99(m,1H),8.40(d,J＝2.2Hz,2H),8.15(s,2H), 7.93(d,J＝2.6Hz,1H),7.71(dd,J＝7.6,1.0Hz,1H),7.69–7.64(m,3H),7.62(dd,J＝7.6,1.0Hz,1H),7.58 (d,J＝8.8Hz,1H),7.52(t,J＝7.6Hz,1H),7.42(t,J＝3.0Hz,1H),7.30(d,J＝2.6Hz,1H),7.26(d ,J＝7.9Hz,2H),6.87(d,J＝9.3Hz,1H),6.62(dd,J＝8.9,2.4Hz,1H),6.30(dd,J＝3.4,1.9Hz,1H),6.23 (d,J＝2.3Hz,1H),5.15(dd,J＝13.4,5.2Hz,1H),4.44(d,J＝17.6Hz,1H),4.30(d,J＝17.5Hz,1H),3.28 (d,J＝12.7Hz,5H),3.10(d,J＝11.1Hz,5H),3.03–2.97(m,4H),2.92(ddd,J＝17.2,13.7,5.4Hz,2H),2.72( s,2H),2.59(ddd,J＝17.4,4.5,2.3Hz,2H),2.47(d,J＝7.0Hz,2H),2.25–2.15(m,8H),1.98(s,2H),1.84 (d,J＝12.3Hz,2H),1.78(d,J＝13.1Hz,2H),1.57(p,J＝6.7Hz,4H),1.53–1.46(m,2H),1.44(d,J＝ 7.9Hz, 2H), 1.41 (t, J = 6.5Hz, 3H), 1.30 (p, J = 8.5, 7.8Hz, 4H), 0.94 (s, 6H).

实施例13：化合物13的制备
Example 13: Preparation of Compound 13

1)中间体13-1的制备1) Preparation of intermediate 13-1

参考实施例12步骤1)中中间体12-1的制备方法，将其中的7-辛炔-1-醇换成4-戊炔-1-醇，得到中间体13-1。Referring to the preparation method of intermediate 12-1 in step 1) of Example 12, 7-octyn-1-ol is replaced with 4-pentyn-1-ol to obtain intermediate 13-1.

ESI-MS:m/z＝327.1[M+H]+ ESI-MS:m/z＝327.1[M+H] +

2)中间体13-2的制备2) Preparation of intermediate 13-2

参考实施例12步骤2)中中间体12-2的制备方法，将其中的中间体12-1换成中间体13-1，得到中间体13-2。Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 13-1 to obtain intermediate 13-2.

ESI-MS:m/z＝325.1[M+H]+ ESI-MS:m/z＝325.1[M+H] +

3)化合物13的制备3) Preparation of compound 13

参考实施例12步骤3)中化合物12的制备方法，将其中的中间体12-2换成中间体13-2，得到化合物13。Referring to the preparation method of compound 12 in step 3) of Example 12, intermediate 12-2 is replaced by intermediate 13-2 to obtain compound 13.

LC-MS:m/z＝646.8[M+2H]2+.LC-MS: m/z＝646.8[M+2H] 2+ .

1H NMR(500MHz,DMSO)δ11.55(d,J＝2.4Hz,1H),11.01(s,1H),8.49–8.41(m,2H),8.15(s,3H),7.95(d,J＝2.6Hz,1H),7.75–7.60(m,5H),7.59–7.49(m,2H),7.44(m,1H),7.34(m,1H),7.26(d,J＝8.0Hz,2H),6.93(d,J＝9.2Hz,1H),6.63(m,1H),6.32(m,1H),6.22(d,J＝2.3Hz,1H),5.16(m,1H),4.46(d,J＝17.6Hz,2H),4.30(d,J＝17.5Hz,2H),3.31(m,3H),3.24(m,3H),3.05(m,3H),3.00(m,3H),2.72(s,2H),2.70–2.61(m,3H),2.41(m,1H),2.18(m,5H),2.12–2.00(m,3H),1.98(s,2H),1.92–1.81(m,5H),1.76(m,2H),1.59(m,2H),1.39(m,4H),0.94(s,6H). 1 H NMR (500MHz, DMSO) δ11.55(d,J＝2.4Hz,1H),11.01(s,1H),8.49–8.41(m,2H),8.15(s,3H),7.95(d,J ＝2.6Hz,1H),7.75–7.60(m,5H),7.59–7.49(m,2H),7.44(m,1H),7.34(m,1H),7.26(d,J＝8.0Hz,2H) ,6.93(d,J＝9.2Hz,1H),6.63(m,1H),6.32(m,1H),6.22(d,J＝2.3Hz,1H),5.16(m,1H),4.46(d, J＝17.6Hz,2H),4.30(d,J＝17.5Hz,2H),3.31(m,3H),3.24(m,3H),3.05(m,3H),3.00(m,3H),2.72( s,2H),2.70–2.61(m,3H),2.41(m,1H),2.18(m,5H),2.12–2.00(m,3H),1.98(s,2H),1.92–1.81(m, 5H),1.76(m,2H),1.59(m,2H),1.39(m,4H),0.94(s,6H).

实施例14:化合物14的制备
Example 14: Preparation of Compound 14

1)中间体14-1的制备1) Preparation of intermediate 14-1

参考实施例12步骤1)中中间体12-1的制备方法，将其中的7-辛炔-1-醇换成6-庚炔-1-醇，得到中间体14-1。Referring to the preparation method of intermediate 12-1 in step 1) of Example 12, 7-octyn-1-ol is replaced with 6-heptyyn-1-ol to obtain intermediate 14-1.

ESI-MS:m/z＝355.2[M+H]+ ESI-MS:m/z＝355.2[M+H] +

2)中间体14-2的制备2) Preparation of intermediate 14-2

参考实施例12步骤2)中中间体12-2的制备方法，将其中的中间体12-1换成中间体14-1，得到中间体14-2。Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 14-1 to obtain intermediate 14-2.

ESI-MS:m/z＝353.1[M+H]+ ESI-MS:m/z＝353.1[M+H] +

3)化合物14的制备3) Preparation of compound 14

参考实施例12步骤3)中化合物12的制备方法，将其中的中间体12-2换成中间体14-2，得到化合物14。Referring to the preparation method of compound 12 in step 3) of Example 12, intermediate 12-2 is replaced by intermediate 14-2 to obtain compound 14.

LC-MS:m/z＝660.8[M+2H]2+.LC-MS: m/z＝660.8[M+2H] 2+ .

1H NMR(500MHz,DMSO)δ11.50(s,1H),11.02(s,1H),8.41–8.36(m,1H),7.91(d,J＝2.6Hz,1H),7.71(dd,J＝7.5,1.0Hz,1H),7.65(s,1H),7.66–7.59(m,3H),7.57(d,J＝8.8Hz,1H),7.51(t,J＝7.6Hz,1H),7.41(t,J＝3.0Hz,1H),7.30–7.23(m,3H),6.82(d,J＝9.2Hz,1H),6.60(dd,J＝8.9,2.4Hz,1H),6.30(dd,J＝3.3,1.9Hz,1H),6.24(d,J＝2.4Hz,1H),5.13(dd,J＝13.3,5.2Hz,1H),4.43(d,J＝17.6Hz,1H),4.29(d,J＝17.6Hz,1H),3.06(s,2H),3.03–2.97(m,4H),2.91(ddd,J＝17.1,13.7,5.5Hz,1H),2.72(s,2H),2.59(ddd,J＝17.3,4.4,2.3Hz,2H),2.54(s,4H),2.47(d,J＝7.0Hz,2H),2.42(dd,J＝13.2,4.6Hz,2H),2.22–2.15(m,6H),1.97(s,2H),1.90(s,8H),1.79(dd,J＝25.1,12.6Hz,4H),1.57(p,J＝7.1Hz,4H),1.45–1.37(m,4H),1.30–1.20(m,5H),0.94(s,6H). 1 H NMR (500MHz, DMSO) δ11.50 (s, 1H), 11.02 (s, 1H), 8.41–8.36 (m, 1H), 7.91 (d, J = 2.6Hz, 1H), 7.71 (dd, J ＝7.5,1.0Hz,1H),7.65(s,1H),7.66–7.59(m,3H),7.57(d,J＝8.8Hz,1H),7.51(t,J＝7.6Hz,1H),7.41 (t,J＝3.0Hz,1H),7.30–7.23(m,3H),6.82(d,J＝9.2Hz,1H),6.60(dd,J＝8.9,2.4Hz,1H),6.30(dd, J＝3.3,1.9Hz,1H),6.24(d,J＝2.4Hz,1H),5.13(dd,J＝13.3,5.2Hz,1H),4.43(d,J＝17.6Hz,1H),4.29( d,J＝17.6Hz,1H),3.06(s,2H),3.03–2.97(m,4H),2.91(ddd,J＝17.1,13.7,5.5Hz,1H),2.72(s,2H),2.59 (ddd,J＝17.3,4.4,2.3Hz,2H),2.54(s,4H),2.47(d,J＝7.0Hz,2H),2.42(dd,J＝13.2,4.6Hz,2H),2.22– 2.15(m,6H),1.97(s,2H),1.90(s,8H),1.79(dd,J＝25.1,12.6Hz,4H),1.57(p,J＝7.1Hz,4H),1.45–1.37 (m,4H),1.30–1.20(m,5H),0.94(s,6H).

实施例15：化合物15的制备
Example 15: Preparation of Compound 15

1)中间体15-1的制备1) Preparation of intermediate 15-1

参考实施例12步骤1)中中间体12-1的制备方法，将其中的7-辛炔-1-醇换成8-壬炔-1-醇，得到中间体15-1。Referring to the preparation method of intermediate 12-1 in step 1) of Example 12, 7-octyn-1-ol is replaced with 8-nonynyn-1-ol to obtain intermediate 15-1.

ESI-MS:m/z＝383.2[M+H]+ ESI-MS:m/z＝383.2[M+H] +

2)中间体15-2的制备2) Preparation of intermediate 15-2

参考实施例12步骤2)中中间体12-2的制备方法，将其中的中间体12-1换成中间体15-1，得到中间体15-2。Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 15-1 to obtain intermediate 15-2.

ESI-MS:m/z＝381.1[M+H]+ ESI-MS:m/z＝381.1[M+H] +

3)化合物15的制备3) Preparation of compound 15

参考实施例12步骤3)中化合物12的制备方法，将其中的中间体12-2换成中间体15-2，得到化合物15。Referring to the preparation method of compound 12 in step 3) of Example 12, intermediate 12-2 is replaced by intermediate 15-2 to obtain compound 15.

LC-MS:m/z＝674.3[M+2H]2+.LC-MS: m/z＝674.3[M+2H] 2+ .

1H NMR(500MHz,DMSO)δ11.52(s,1H),11.03(s,1H),8.39(dd,J＝7.5,4.1Hz,2H),8.15(s,3H),7.92(d,J＝2.6Hz,1H),7.73–7.68(m,1H),7.65(t,J＝6.8Hz,3H),7.63–7.60(m,1H),7.58(d,J＝8.8Hz,1H),7.52(t,J＝7.6Hz,1H),7.41(t,J＝3.0Hz,1H),7.31–7.23(m,3H),6.85(d,J＝9.2Hz,1H),6.61(dd,J＝8.9,2.4Hz,1H),6.30(dd,J＝3.4,1.9Hz,1H),6.24(d,J＝2.3Hz,1H),5.15(dd,J＝13.3,5.2Hz,1H),4.44(d,J＝17.6Hz,1H),4.30(d,J＝17.6Hz,1H),3.27(t,J＝6.3Hz,5H),3.08(d,J＝10.9Hz,5H),3.03– 2.97(m,4H),2.92(ddd,J＝17.2,13.7,5.4Hz,2H),2.72(s,2H),2.60(ddd,J＝17.3,4.5,2.3Hz,2H),2.43(dd,J＝13.0,4.6Hz,2H),2.19(q,J＝8.4,6.6Hz,8H),2.06–1.97(m,3H),1.80(s,1H),1.77(d,J＝13.1Hz,2H),1.72(s,1H),1.57(p,J＝6.9Hz,4H),1.43(dt,J＝22.9,6.6Hz,6H),1.30(s,1H),1.30–1.22(m,4H),0.94(s,6H). 1 H NMR (500MHz, DMSO) δ11.52 (s, 1H), 11.03 (s, 1H), 8.39 (dd, J = 7.5, 4.1Hz, 2H), 8.15 (s, 3H), 7.92 (d, J ＝2.6Hz,1H),7.73–7.68(m,1H),7.65(t,J＝6.8Hz,3H),7.63–7.60(m,1H),7.58(d,J＝8.8Hz,1H),7.52 (t,J＝7.6Hz,1H),7.41(t,J＝3.0Hz,1H),7.31–7.23(m,3H),6.85(d,J＝9.2Hz,1H),6.61(dd,J＝ 8.9,2.4Hz,1H),6.30(dd,J＝3.4,1.9Hz,1H),6.24(d,J＝2.3Hz,1H),5.15(dd,J＝13.3,5.2Hz,1H),4.44( d,J＝17.6Hz,1H),4.30(d,J＝17.6Hz,1H),3.27(t,J＝6.3Hz,5H),3.08(d,J＝10.9Hz,5H),3.03– 2.97(m,4H),2.92(ddd,J＝17.2,13.7,5.4Hz,2H),2.72(s,2H),2.60(ddd,J＝17.3,4.5,2.3Hz,2H),2.43(dd, J＝13.0,4.6Hz,2H),2.19(q,J＝8.4,6.6Hz,8H),2.06–1.97(m,3H),1.80(s,1H),1.77(d,J＝13.1Hz,2H ),1.72(s,1H),1.57(p,J＝6.9Hz,4H),1.43(dt,J＝22.9,6.6Hz,6H),1.30(s,1H),1.30–1.22(m,4H) ,0.94(s,6H).

实施例16：化合物16的制备
Example 16: Preparation of Compound 16

1)中间体16-1的制备1) Preparation of intermediate 16-1

参考实施例12步骤1)中中间体12-1的制备方法，将其中的7-辛炔-1-醇换成9-癸炔-1-醇，得到中间体16-1。Referring to the preparation method of intermediate 12-1 in step 1) of Example 12, 7-octyn-1-ol is replaced with 9-decyn-1-ol to obtain intermediate 16-1.

ESI-MS:m/z＝397.2[M+H]+ ESI-MS:m/z＝397.2[M+H] +

2)中间体16-2的制备2) Preparation of intermediate 16-2

参考实施例12步骤2)中中间体12-2的制备方法，将其中的中间体12-1换成中间体16-1，得到中间体16-2。Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 16-1 to obtain intermediate 16-2.

ESI-MS:m/z＝395.1[M+H]+ ESI-MS:m/z＝395.1[M+H] +

3)化合物16的制备3) Preparation of compound 16

参考实施例12步骤3)中化合物12的制备方法，将其中的中间体12-2换成中间体16-2，得到化合物16。Referring to the preparation method of compound 12 in step 3) of Example 12, intermediate 12-2 is replaced by intermediate 16-2 to obtain compound 16.

LC-MS:m/z＝681.8[M+2H]2+.LC-MS: m/z＝681.8[M+2H] 2+ .

1H NMR(500MHz,DMSO)δ11.53(t,J＝2.4Hz,1H),11.02(s,1H),8.43–8.38(m,2H),8.15(s,3H),7.93(d,J＝2.6Hz,1H),7.71(dd,J＝7.6,1.0Hz,1H),7.67(d,J＝2.2Hz,1H),7.64(ddd,J＝17.2,6.3,1.7Hz,3H),7.58(d,J＝8.7Hz,1H),7.52(t,J＝7.6Hz,1H),7.42(t,J＝3.0Hz,1H),7.31(d,J＝2.6Hz,1H),7.26(d,J＝7.9Hz,2H),6.88(d,J＝9.2Hz,1H),6.62(dd,J＝8.9,2.4Hz,1H),6.31(dd,J＝3.4,1.9Hz,1H),6.23(d,J＝2.4Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.44(d,J＝17.6Hz,1H),4.30(d,J＝17.6Hz,1H),3.28(t,J＝6.3Hz,3H),3.11(d,J＝12.1Hz,4H),3.00(t,J＝4.8Hz,4H),2.92(ddd,J＝17.2,13.6,5.4Hz,2H),2.72(s,2H),2.60(ddd,J＝17.3,4.4,2.3Hz,2H),2.47(d,J＝7.0Hz,2H),2.43(dd,J＝13.1,4.6Hz,1H),2.18(q,J＝7.8,6.3Hz,8H),2.02(ddt,J＝9.9,5.4,2.2Hz,1H),1.98(s,2H),1.87–1.81(m,2H),1.78(d,J＝13.3Hz,2H),1.72(d,J＝10.6Hz,1H),1.57(p,J＝7.1Hz,4H),1.45(d,J＝7.6Hz,2H),1.41(q,J＝7.3,6.6Hz,4H),1.32–1.22(m,8H),0.94(s,6H). 1 H NMR (500MHz, DMSO) δ11.53(t,J＝2.4Hz,1H),11.02(s,1H),8.43–8.38(m,2H),8.15(s,3H),7.93(d,J ＝2.6Hz,1H),7.71(dd,J＝7.6,1.0Hz,1H),7.67(d,J＝2.2Hz,1H),7.64(ddd,J＝17.2,6.3,1.7Hz,3H),7.58 (d,J＝8.7Hz,1H),7.52(t,J＝7.6Hz,1H),7.42(t,J＝3.0Hz,1H),7.31(d,J＝2.6Hz,1H),7.26(d ,J＝7.9Hz,2H),6.88(d,J＝9.2Hz,1H),6.62(dd,J＝8.9,2.4Hz,1H),6.31(dd,J＝3.4,1.9Hz,1H),6.23 (d,J＝2.4Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.44(d,J＝17.6Hz,1H),4.30(d,J＝17.6Hz,1H),3.28 (t,J＝6.3Hz,3H),3.11(d,J＝12.1Hz,4H),3.00(t,J＝4.8Hz,4H),2.92(ddd,J＝17.2,13.6,5.4Hz,2H) ,2.72(s,2H),2.60(ddd,J＝17.3,4.4,2.3Hz,2H),2.47(d,J＝7.0Hz,2H),2.43(dd,J＝13.1,4.6Hz,1H), 2.18(q,J＝7.8,6.3Hz,8H),2.02(ddt,J＝9.9,5.4,2.2Hz,1H),1.98(s,2H),1.87–1.81(m,2H),1.78(d, J＝13.3Hz,2H),1.72(d,J＝10.6Hz,1H),1.57(p,J＝7.1Hz,4H),1.45(d,J＝7.6Hz,2H),1.41(q,J＝ 7.3,6.6Hz,4H),1.32–1.22(m,8H),0.94(s,6H).

实施例17：化合物17的制备
Example 17: Preparation of Compound 17

1)中间体17-1的制备1) Preparation of intermediate 17-1

参考实施例12步骤1)中中间体12-1的制备方法，将其中的7-辛炔-1-醇换成10-十一炔-1-醇，得到中间体17-1。Referring to the preparation method of intermediate 12-1 in step 1) of Example 12, 7-octyn-1-ol is replaced with 10-undecyn-1-ol to obtain intermediate 17-1.

ESI-MS:m/z＝411.2[M+H]+ ESI-MS:m/z＝411.2[M+H] +

2)中间体17-2的制备2) Preparation of intermediate 17-2

参考实施例12步骤2)中中间体12-2的制备方法，将其中的中间体12-1换成中间体17-1，得到中间体17-2。Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 17-1 to obtain intermediate 17-2.

ESI-MS:m/z＝409.2[M+H]+ ESI-MS:m/z＝409.2[M+H] +

3)化合物17的制备3) Preparation of compound 17

参考实施例12步骤3)中化合物12的制备方法，将其中的中间体12-2换成中间体17-2，得到化合物17。Referring to the preparation method of compound 12 in step 3) of Example 12, intermediate 12-2 is replaced by intermediate 17-2 to obtain compound 17.

LC-MS:m/z＝688.8[M+2H]2+.LC-MS: m/z＝688.8[M+2H] 2+ .

1H NMR(500MHz,DMSO)δ11.51(s,1H),11.03(s,1H),8.41–8.37(m,1H),7.92(d,J＝2.6Hz,1H),7.71(dd,J＝7.5,1.0Hz,1H),7.66(s,1H),7.66–7.60(m,3H),7.58(d,J＝8.8Hz,1H),7.51(t,J＝7.6Hz,1H),7.41(t,J＝3.0Hz,1H),7.30–7.23(m,3H),6.84(d,J＝9.2Hz,1H),6.61(dd,J＝8.9,2.4Hz,1H),6.30(dd,J＝3.3,1.9Hz,1H),6.24(d,J＝2.4Hz,1H),5.15(dd,J＝13.3,5.2Hz,1H),4.44(d,J＝17.6Hz,1H),4.29(d,J＝17.6Hz,1H),3.07(s,2H),3.03–2.97(m,4H),2.92(ddd,J＝17.1,13.7,5.5Hz,1H),2.72(s,2H),2.59(ddd,J＝17.3,4.4,2.3Hz,2H),2.54(s,4H),2.47(d,J＝7.0Hz,2H),2.42(dd,J＝13.2,4.6Hz,2H),2.22–2.16(m,6H),1.98(s,2H),1.91(s,10H),1.79(dd,J＝25.1,12.6Hz,4H),1.57(p,J＝7.1Hz,4H),1.45–1.37(m,6H),1.30–1.20(m,9H),0.94(s,6H). 1 H NMR (500MHz, DMSO) δ11.51(s,1H),11.03(s,1H),8.41–8.37(m,1H),7.92(d,J＝2.6Hz,1H),7.71(dd,J ＝7.5,1.0Hz,1H),7.66(s,1H),7.66–7.60(m,3H),7.58(d,J＝8.8Hz,1H),7.51(t,J＝7.6Hz,1H),7.41 (t,J＝3.0Hz,1H),7.30–7.23(m,3H),6.84(d,J＝9.2Hz,1H),6.61(dd,J＝8.9,2.4Hz,1H),6.30(dd, J＝3.3,1.9Hz,1H),6.24(d,J＝2.4Hz,1H),5.15(dd,J＝13.3,5.2Hz,1H),4.44(d,J＝17.6Hz,1H),4.29( d,J＝17.6Hz,1H),3.07(s,2H),3.03–2.97(m,4H),2.92(ddd,J＝17.1,13.7,5.5Hz,1H),2.72(s,2H),2.59 (ddd,J＝17.3,4.4,2.3Hz,2H),2.54(s,4H),2.47(d,J＝7.0Hz,2H),2.42(dd,J＝13.2,4.6Hz,2H),2.22– 2.16(m,6H),1.98(s,2H),1.91(s,10H),1.79(dd,J＝25.1,12.6Hz,4H),1.57(p,J＝7.1Hz,4H),1.45–1.37 (m,6H),1.30–1.20(m,9H),0.94(s,6H).

实施例18：化合物18的制备
Example 18: Preparation of Compound 18

1)中间体18-1的制备1) Preparation of intermediate 18-1

参考实施例12步骤1)中中间体12-1的制备方法，将其中的7-辛炔-1-醇换成5-己炔-1-醇，得到中间体18-1。 Referring to the preparation method of intermediate 12-1 in step 1) of Example 12, 7-octyn-1-ol is replaced with 5-hexyn-1-ol to obtain intermediate 18-1.

ESI-MS:m/z＝341.1[M+H]+ ESI-MS:m/z＝341.1[M+H] +

2)中间体18-2的制备2) Preparation of intermediate 18-2

参考实施例12步骤2)中中间体12-2的制备方法，将其中的中间体12-1换成中间体18-1，得到中间体18-2。Refer to the preparation method of intermediate 12-2 in step 2) of Example 12, and replace intermediate 12-1 with intermediate 18-1 to obtain intermediate 18-2.

ESI-MS:m/z＝339.1[M+H]+ ESI-MS:m/z＝339.1[M+H] +

3)化合物18的制备3) Preparation of compound 18

参考实施例12步骤3)中实施例12的制备方法，将其中的中间体12-2换成中间体18-2，得到化合物18。Referring to the preparation method of Example 12 in Step 3) of Example 12, the intermediate 12-2 is replaced by the intermediate 18-2 to obtain compound 18.

LC-MS:m/z＝653.8[M+2H]2+.LC-MS: m/z＝653.8[M+2H] 2+ .

1H NMR(500MHz,DMSO)δ11.53(s,1H),11.00(s,1H),8.44–8.39(m,2H),8.14(s,4H),7.93(d,J＝2.6Hz,1H),7.74–7.60(m,5H),7.57(d,J＝8.8Hz,1H),7.52(t,J＝7.6Hz,1H),7.42(t,J＝3.0Hz,1H),7.32(d,J＝2.6Hz,1H),7.26(d,J＝7.9Hz,2H),6.89(d,J＝9.2Hz,1H),6.62(dd,J＝8.9,2.4Hz,1H),6.31(dd,J＝3.4,1.9Hz,1H),6.23(d,J＝2.3Hz,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.45(d,J＝17.6Hz,1H),4.30(d,J＝17.6Hz,1H),3.29(d,J＝6.9Hz,3H),3.16(d,J＝10.9Hz,3H),3.09(d,J＝11.1Hz,3H),3.00(t,J＝5.1Hz,4H),2.93(ddd,J＝17.0,13.5,5.2Hz,2H),2.74(d,J＝16.8Hz,3H),2.61(d,J＝3.5Hz,1H),2.54(s,3H),2.46–2.37(m,1H),2.19(d,J＝5.8Hz,6H),2.02(dq,J＝7.3,2.9,2.4Hz,1H),1.99(s,2H),1.89–1.78(m,4H),1.65–1.55(m,5H),1.41(t,J＝6.5Hz,2H),1.34(d,J＝12.5Hz,1H),1.24(s,1H),0.94(s,6H). 1 H NMR (500MHz, DMSO) δ11.53 (s, 1H), 11.00 (s, 1H), 8.44–8.39 (m, 2H), 8.14 (s, 4H), 7.93 (d, J＝2.6Hz, 1H ),7.74–7.60(m,5H),7.57(d,J＝8.8Hz,1H),7.52(t,J＝7.6Hz,1H),7.42(t,J＝3.0Hz,1H),7.32(d ,J＝2.6Hz,1H),7.26(d,J＝7.9Hz,2H),6.89(d,J＝9.2Hz,1H),6.62(dd,J＝8.9,2.4Hz,1H),6.31(dd ,J＝3.4,1.9Hz,1H),6.23(d,J＝2.3Hz,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.45(d,J＝17.6Hz,1H),4.30 (d,J＝17.6Hz,1H),3.29(d,J＝6.9Hz,3H),3.16(d,J＝10.9Hz,3H),3.09(d,J＝11.1Hz,3H),3.00(t ,J＝5.1Hz,4H),2.93(ddd,J＝17.0,13.5,5.2Hz,2H),2.74(d,J＝16.8Hz,3H),2.61(d,J＝3.5Hz,1H),2.54 (s,3H),2.46–2.37(m,1H),2.19(d,J＝5.8Hz,6H),2.02(dq,J＝7.3,2.9,2.4Hz,1H),1.99(s,2H), 1.89–1.78(m,4H),1.65–1.55(m,5H),1.41(t,J＝6.5Hz,2H),1.34(d,J＝12.5Hz,1H),1.24(s,1H),0.94 (s,6H).

实施例19：化合物19的制备
Example 19: Preparation of Compound 19

1)中间体19-1的制备1) Preparation of intermediate 19-1

将化合物19A(2.0g)溶于乙腈(40mL)，依次加入无水碳酸钾(1.17g)，1,6-二溴己烷(5.62g)，60℃反应6h，经液相制备得到中间体19-1。Dissolve compound 19A (2.0g) in acetonitrile (40mL), add anhydrous potassium carbonate (1.17g), 1,6-dibromohexane (5.62g) in sequence, react at 60°C for 6 hours, and prepare the intermediate through liquid phase 19-1.

ESI-MS:m/z＝423.1[M+H]+ ESI-MS:m/z＝423.1[M+H] +

2)化合物19的制备2) Preparation of compound 19

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体19-1，得到化合物19。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 19-1 to obtain compound 19.

LC-MS:m/z＝663.8[M+2H]2+.LC-MS: m/z＝663.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.86(d,1H),8.56(s,1H),8.44(s,1H),8.15(d,1H),8.05(d,1H),7.94(d,1H),7.65(d,1H),7.43(dd,3H),7.09(d,2H),7.03(d,1H),7.00(d,1H),6.55(dd,2H),6.02(s,1H),5.24(dd,1H),4.44(d,1H),4.31(d,1H),4.07–4.01(m,2H),3.20(m,2H),3.06(m,4H),2.93–2.83(m,4H),2.73(m,2H),2.42(m,4H),2.22(dd,9H),1.98–1.79(m,15H),1.52–1.26(m,14H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.86(d,1H),8.56(s,1H),8.44(s,1H),8.15(d,1H),8.05(d,1H),7.94(d, 1H),7.65(d,1H),7.43(dd,3H),7.09(d,2H),7.03(d,1H),7.00(d,1H),6.55(dd,2H),6.02(s,1H ),5.24(dd,1H),4.44(d,1H),4.31(d,1H),4.07–4.01(m,2H),3.20(m,2H),3.06(m,4H),2.93–2.83( m,4H),2.73(m,2H),2.42(m,4H),2.22(dd,9H),1.98–1.79(m,15H),1.52–1.26(m,14H),0.95(s,6H) .

实施例20：化合物20的制备
Example 20: Preparation of Compound 20

1)中间体20-1的制备1) Preparation of intermediate 20-1

参考实施例19步骤1)中中间体19-1的制备方法，将其中的1,6-二溴己烷换成1,7-二溴庚烷，得到中间体20-1。Referring to the preparation method of intermediate 19-1 in step 1) of Example 19, 1,6-dibromohexane was replaced with 1,7-dibromoheptane to obtain intermediate 20-1.

ESI-MS:m/z＝437.1[M+H]+ ESI-MS:m/z＝437.1[M+H] +

2)化合物20的制备2) Preparation of compound 20

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体20-1，得到化合物20。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 20-1 to obtain compound 20.

LC-MS:m/z＝670.8[M+2H]2+.LC-MS: m/z＝670.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.81(d,1H),8.41(s,1H),8.11(d,1H),7.97(d,1H),7.91(d,1H),7.62(d,1H),7.52(t,2H),7.43(dd,3H),7.10(d,2H),7.00(d,1H),6.75(d,1H),6.55(dd,1H),6.47(d,1H),6.04(s,1H),5.24(dd,1H),4.43(d,1H),4.30(d,1H),4.07–4.02(m,3H),3.19(m,2H),3.07(m,4H),2.93–2.83(m,3H),2.73(m,2H),2.42–2.22(m,14H),1.98–1.79(m,15H),1.52–1.26(m,14H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.81(d,1H),8.41(s,1H),8.11(d,1H),7.97(d,1H),7.91(d,1H),7.62(d, 1H),7.52(t,2H),7.43(dd,3H),7.10(d,2H),7.00(d,1H),6.75(d,1H),6.55(dd,1H),6.47(d,1H ),6.04(s,1H),5.24(dd,1H),4.43(d,1H),4.30(d,1H),4.07–4.02(m,3H),3.19(m,2H),3.07(m, 4H),2.93–2.83(m,3H),2.73(m,2H),2.42–2.22(m,14H),1.98–1.79(m,15H),1.52–1.26(m,14H),0.95(s, 6H).

实施例21：化合物21的制备
Example 21: Preparation of Compound 21

1)中间体21-1的制备1) Preparation of intermediate 21-1

参考实施例19步骤1)中中间体19-1的制备方法，将其中的1,6-二溴己烷换成1,8-二溴辛烷，得到中间体21-1。Referring to the preparation method of intermediate 19-1 in step 1) of Example 19, 1,6-dibromohexane was replaced with 1,8-dibromooctane to obtain intermediate 21-1.

ESI-MS:m/z＝451.1[M+H]+ ESI-MS:m/z＝451.1[M+H] +

2)化合物21的制备2) Preparation of compound 21

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体21-1，得到化合物21。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 21-1 to obtain compound 21.

LC-MS:m/z＝677.8[M+2H]2+.LC-MS: m/z＝677.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.79(d,1H),8.38(s,1H),8.11(d,1H),7.97(d,1H),7.91(d,1H),7.59(d,1H),7.51(t,2H),7.43(dd,3H),7.10(d,2H),7.01(d,1H),6.72(d,1H),6.54(dd,1H),6.45(d,1H),6.06(s, 1H),5.24(dd,1H),4.43(d,1H),4.30(d,1H),4.08–4.00(m,4H),3.16(m,2H),3.07(m,6H),2.93–2.83(m,2H),2.74(m,2H),2.40–2.22(m,13H),1.98–1.77(m,13H),1.52–1.26(m,17H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.79(d,1H),8.38(s,1H),8.11(d,1H),7.97(d,1H),7.91(d,1H),7.59(d, 1H),7.51(t,2H),7.43(dd,3H),7.10(d,2H),7.01(d,1H),6.72(d,1H),6.54(dd,1H),6.45(d,1H ),6.06(s, 1H),5.24(dd,1H),4.43(d,1H),4.30(d,1H),4.08–4.00(m,4H),3.16(m,2H),3.07(m,6H),2.93–2.83 (m,2H),2.74(m,2H),2.40–2.22(m,13H),1.98–1.77(m,13H),1.52–1.26(m,17H),0.95(s,6H).

实施例22：化合物22的制备
Example 22: Preparation of Compound 22

1)中间体22-1的制备1) Preparation of intermediate 22-1

参考实施例19步骤1)中中间体19-1的制备方法，将其中的1,6-二溴己烷换成1,9-二溴壬烷，得到中间体22-1。Referring to the preparation method of intermediate 19-1 in step 1) of Example 19, 1,6-dibromohexane was replaced with 1,9-dibromononane to obtain intermediate 22-1.

ESI-MS:m/z＝465.1[M+H]+ ESI-MS:m/z＝465.1[M+H] +

2)化合物22的制备2) Preparation of compound 22

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体22-1，得到化合物22。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 22-1 to obtain compound 22.

LC-MS:m/z＝684.8[M+2H]2+.LC-MS: m/z＝684.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.81(d,1H),8.40(s,1H),8.11(d,1H),7.99(d,1H),7.91(d,1H),7.62(d,1H),7.51(t,2H),7.43(dd,3H),7.10(d,2H),7.01(d,1H),6.75(d,1H),6.55(dd,1H),6.46(d,1H),6.04(s,1H),5.24(dd,1H),4.43(d,1H),4.30(d,1H),4.09–4.01(m,4H),3.18(m,2H),3.07(m,6H),2.91–2.83(m,2H),2.74(m,2H),2.38–2.20(m,13H),1.98–1.76(m,13H),1.56–1.28(m,19H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.81(d,1H),8.40(s,1H),8.11(d,1H),7.99(d,1H),7.91(d,1H),7.62(d, 1H),7.51(t,2H),7.43(dd,3H),7.10(d,2H),7.01(d,1H),6.75(d,1H),6.55(dd,1H),6.46(d,1H ),6.04(s,1H),5.24(dd,1H),4.43(d,1H),4.30(d,1H),4.09–4.01(m,4H),3.18(m,2H),3.07(m, 6H),2.91–2.83(m,2H),2.74(m,2H),2.38–2.20(m,13H),1.98–1.76(m,13H),1.56–1.28(m,19H),0.95(s, 6H).

实施例23：化合物23的制备
Example 23: Preparation of Compound 23

1)中间体23-1的制备1) Preparation of intermediate 23-1

参考实施例19步骤1)中中间体19-1的制备方法，将其中的1,6-二溴己烷换成1,10-二溴癸烷，得到中间体23-1。Referring to the preparation method of intermediate 19-1 in step 1) of Example 19, 1,6-dibromohexane was replaced with 1,10-dibromodecane to obtain intermediate 23-1.

ESI-MS:m/z＝479.1[M+H]+ ESI-MS:m/z＝479.1[M+H] +

2)化合物23的制备2) Preparation of compound 23

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体23-1，得到化合物23。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 23-1 to obtain compound 23.

LC-MS:m/z＝691.8[M+2H]2+. LC-MS: m/z＝691.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.73(d,1H),8.44(s,1H),8.07(d,1H),7.84(m,2H),7.55(d,1H),7.50(t,2H),7.40(dd,3H),7.10(d,2H),6.98(d,1H),6.74(d,1H),6.52(dd,1H),6.40(d,1H),6.03(s,1H),5.20(dd,1H),4.43(d,1H),4.30(d,1H),4.02(m,2H),3.60–3.07(m,10H),2.96–2.77(m,2H),2.74(m,2H),2.38–2.20(m,13H),1.98–1.76(m,13H),1.56–1.28(m,21H),0.94(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.73(d,1H),8.44(s,1H),8.07(d,1H),7.84(m,2H),7.55(d,1H),7.50(t, 2H),7.40(dd,3H),7.10(d,2H),6.98(d,1H),6.74(d,1H),6.52(dd,1H),6.40(d,1H),6.03(s,1H ),5.20(dd,1H),4.43(d,1H),4.30(d,1H),4.02(m,2H),3.60–3.07(m,10H),2.96–2.77(m,2H),2.74( m,2H),2.38–2.20(m,13H),1.98–1.76(m,13H),1.56–1.28(m,21H),0.94(s,6H).

实施例24：化合物24的制备
Example 24: Preparation of Compound 24

1)中间体24-1的制备1) Preparation of intermediate 24-1

参考实施例19步骤1)中中间体19-1的制备方法，将其中的化合物19A替换为化合物24A，1,6-二溴己烷换成1,3-二溴丙烷，得到中间体24-1。Refer to the preparation method of intermediate 19-1 in step 1) of Example 19, replace compound 19A with compound 24A, and replace 1,6-dibromohexane with 1,3-dibromopropane to obtain intermediate 24- 1.

ESI-MS:m/z＝395.1[M+H]+ ESI-MS:m/z＝395.1[M+H] +

2)化合物24的制备2) Preparation of compound 24

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体24-1，得到化合物24。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 24-1 to obtain compound 24.

LC-MS:m/z＝649.8[M+2H]2+.LC-MS: m/z＝649.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ9.92(s,1H),8.87(d,J＝2.3Hz,1H),8.48(t,J＝5.5Hz,1H),8.11(d,J＝2.6Hz,1H),8.03(dd,J＝9.2,2.3Hz,1H),7.93(d,J＝9.2Hz,1H),7.78–7.61(m,2H),7.51(d,J＝7.9Hz,2H),7.48–7.38(m,2H),7.23(d,J＝8.5Hz,1H),7.10(d,J＝7.9Hz,2H),6.82(d,J＝9.3Hz,1H),6.62–6.45(m,2H),5.99(d,J＝2.4Hz,1H),4.94(dd,J＝12.2,5.4Hz,1H),4.25(t,J＝5.9Hz,2H),3.35–3.11(m,7H),3.07(t,J＝5.1Hz,4H),2.90(d,J＝3.6Hz,1H),2.87(t,J＝3.1Hz,1H),2.82(d,J＝4.4Hz,1H),2.79(d,J＝3.7Hz,1H),2.74(s,2H),2.72(d,J＝3.9Hz,1H),2.71–2.64(m,3H),2.35(q,J＝12.4Hz,4H),2.22(t,J＝5.1Hz,3H),2.18(d,J＝7.7Hz,2H),2.12(d,J＝12.4Hz,2H),2.06(s,3H),1.98(s,3H),1.86(s,4H),1.64–1.51(m,2H),1.43(t,J＝6.4Hz,2H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ9.92 (s, 1H), 8.87 (d, J = 2.3Hz, 1H), 8.48 (t, J = 5.5Hz, 1H), 8.11 (d, J = 2.6Hz ,1H),8.03(dd,J＝9.2,2.3Hz,1H),7.93(d,J＝9.2Hz,1H),7.78–7.61(m,2H),7.51(d,J＝7.9Hz,2H) ,7.48–7.38(m,2H),7.23(d,J＝8.5Hz,1H),7.10(d,J＝7.9Hz,2H),6.82(d,J＝9.3Hz,1H),6.62–6.45( m,2H),5.99(d,J＝2.4Hz,1H),4.94(dd,J＝12.2,5.4Hz,1H),4.25(t,J＝5.9Hz,2H),3.35–3.11(m,7H ),3.07(t,J＝5.1Hz,4H),2.90(d,J＝3.6Hz,1H),2.87(t,J＝3.1Hz,1H),2.82(d,J＝4.4Hz,1H), 2.79(d,J＝3.7Hz,1H),2.74(s,2H),2.72(d,J＝3.9Hz,1H),2.71–2.64(m,3H),2.35(q,J＝12.4Hz,4H ),2.22(t,J＝5.1Hz,3H),2.18(d,J＝7.7Hz,2H),2.12(d,J＝12.4Hz,2H),2.06(s,3H),1.98(s,3H ),1.86(s,4H),1.64–1.51(m,2H),1.43(t,J=6.4Hz,2H),0.95(s,6H).

实施例25：化合物25的制备
Example 25: Preparation of Compound 25

1)中间体25-1的制备1) Preparation of intermediate 25-1

参考实施例24步骤1)中中间体24-1的制备方法，将其中的1,3-二溴丙烷换成1,4-二溴丁烷，得 到中间体25-1。Referring to the preparation method of intermediate 24-1 in step 1) of Example 24, replacing 1,3-dibromopropane with 1,4-dibromobutane to obtain to intermediate 25-1.

ESI-MS:m/z＝409.0[M+H]+ ESI-MS:m/z＝409.0[M+H] +

2)化合物25的制备2) Preparation of compound 25

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体25-1，得到化合物25。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 25-1 to obtain compound 25.

LC-MS:m/z＝656.8[M+2H]2+.LC-MS: m/z＝656.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.85(s,1H),8.44(s,1H),8.10(d,J＝2.6Hz,1H),7.98(d,J＝9.2Hz,1H),7.94(d,J＝9.1Hz,1H),7.70–7.62(m,2H),7.52(d,J＝7.9Hz,3H),7.48–7.38(m,3H),7.21(d,J＝8.5Hz,2H),7.10(d,J＝8.0Hz,2H),6.75(s,1H),6.58–6.53(m,1H),6.50(s,1H),6.04(s,1H),4.94(dd,J＝12.1,5.4Hz,1H),4.23(d,J＝6.1Hz,1H),4.16(d,J＝6.9Hz,1H),3.20(s,5H),3.06(d,J＝5.6Hz,5H),2.75(d,J＝7.5Hz,4H),2.62(s,1H),2.30(d,J＝11.2Hz,3H),2.21(d,J＝17.4Hz,12H),2.05(s,6H),1.51(m,4H),1.43(t,J＝6.4Hz,2H),1.25(m,4H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.85 (s, 1H), 8.44 (s, 1H), 8.10 (d, J = 2.6Hz, 1H), 7.98 (d, J = 9.2Hz, 1H), 7.94 (d,J＝9.1Hz,1H),7.70–7.62(m,2H),7.52(d,J＝7.9Hz,3H),7.48–7.38(m,3H),7.21(d,J＝8.5Hz, 2H),7.10(d,J＝8.0Hz,2H),6.75(s,1H),6.58–6.53(m,1H),6.50(s,1H),6.04(s,1H),4.94(dd,J ＝12.1,5.4Hz,1H),4.23(d,J＝6.1Hz,1H),4.16(d,J＝6.9Hz,1H),3.20(s,5H),3.06(d,J＝5.6Hz,5H ),2.75(d,J＝7.5Hz,4H),2.62(s,1H),2.30(d,J＝11.2Hz,3H),2.21(d,J＝17.4Hz,12H),2.05(s,6H ),1.51(m,4H),1.43(t,J＝6.4Hz,2H),1.25(m,4H),0.95(s,6H).

实施例26：化合物26的制备
Example 26: Preparation of Compound 26

1)中间体26-1的制备1) Preparation of intermediate 26-1

参考实施例24步骤1)中中间体24-1的制备方法，将其中的1,3-二溴丙烷换成1,6-二溴己烷，得到中间体26-1。Referring to the preparation method of intermediate 24-1 in step 1) of Example 24, 1,3-dibromopropane was replaced with 1,6-dibromohexane to obtain intermediate 26-1.

ESI-MS:m/z＝437.1[M+H]+ ESI-MS:m/z＝437.1[M+H] +

2)化合物26的制备2) Preparation of compound 26

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体26-1，得到化合物26。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 26-1 to obtain compound 26.

LC-MS:m/z＝670.8[M+2H]2+.LC-MS: m/z＝670.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.82(s,1H),8.39(s,1H),8.13(d,J＝2.6Hz,1H),7.96(s,1H),7.67(t,J＝7.9Hz,1H),7.60(s,1H),7.52(d,J＝7.9Hz,3H),7.46–7.40(m,3H),7.37(s,1H),7.22(d,J＝8.5Hz,1H),7.11(d,J＝7.9Hz,2H),6.70(s,1H),6.57(d,J＝9.2Hz,1H),6.49(d,J＝3.5Hz,1H),6.07(s,1H),5.35(d,J＝4.7Hz,3H),4.17(d,J＝6.5Hz,3H),3.62(s,4H),3.34(s,1H),3.12–3.04(m,6H),2.81(d,J＝1.4Hz,2H),2.75(s,4H),2.45(s,4H),2.39(s,3H),2.04–1.97(m,13H),1.44–1.04(m,11H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.82 (s, 1H), 8.39 (s, 1H), 8.13 (d, J = 2.6Hz, 1H), 7.96 (s, 1H), 7.67 (t, J = 7.9Hz,1H),7.60(s,1H),7.52(d,J＝7.9Hz,3H),7.46–7.40(m,3H),7.37(s,1H),7.22(d,J＝8.5Hz, 1H),7.11(d,J＝7.9Hz,2H),6.70(s,1H),6.57(d,J＝9.2Hz,1H),6.49(d,J＝3.5Hz,1H),6.07(s, 1H),5.35(d,J＝4.7Hz,3H),4.17(d,J＝6.5Hz,3H),3.62(s,4H),3.34(s,1H),3.12–3.04(m,6H), 2.81(d,J＝1.4Hz,2H),2.75(s,4H),2.45(s,4H),2.39(s,3H),2.04–1.97(m,13H),1.44–1.04(m,11H) ,0.95(s,6H).

实施例27：化合物27的制备
Example 27: Preparation of Compound 27

1)中间体27-1的制备1) Preparation of intermediate 27-1

参考实施例24步骤1)中中间体24-1的制备方法，将其中的1,3-二溴丙烷换成1,7-二溴庚烷，得到中间体27-1。Referring to the preparation method of intermediate 24-1 in step 1) of Example 24, 1,3-dibromopropane was replaced with 1,7-dibromoheptane to obtain intermediate 27-1.

ESI-MS:m/z＝451.1[M+H]+ ESI-MS:m/z＝451.1[M+H] +

2)化合物27的制备2) Preparation of compound 27

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体27-1，得到化合物27。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 27-1 to obtain compound 27.

LC-MS:m/z＝677.8[M+2H]2+.LC-MS: m/z＝677.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.84(d,J＝2.2Hz,1H),8.41(s,1H),8.14(d,J＝2.6Hz,1H),8.01(d,J＝9.3Hz,1H),7.95(d,J＝9.1Hz,1H),7.70–7.63(m,2H),7.52(d,J＝7.9Hz,2H),7.47–7.43(m,2H),7.21(d,J＝8.5Hz,1H),7.10(d,J＝7.9Hz,3H),6.72(s,1H),6.56(dd,J＝9.1,2.4Hz,1H),6.54–6.50(m,1H),6.04(s,1H),4.94(dd,J＝12.1,5.4Hz,1H),4.23–4.12(m,2H),3.19(d,J＝17.8Hz,4H),3.08(t,J＝5.0Hz,5H),2.74(s,3H),2.53(s,4H),2.23(d,J＝5.3Hz,8H),2.19(s,4H),2.06(s,4H),1.99(s,3H),1.81(s,5H),1.53(dd,J＝14.7,7.5Hz,4H),1.43–1.26(m,10H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.84(d,J＝2.2Hz,1H),8.41(s,1H),8.14(d,J＝2.6Hz,1H),8.01(d,J＝9.3Hz ,1H),7.95(d,J＝9.1Hz,1H),7.70–7.63(m,2H),7.52(d,J＝7.9Hz,2H),7.47–7.43(m,2H),7.21(d, J＝8.5Hz,1H),7.10(d,J＝7.9Hz,3H),6.72(s,1H),6.56(dd,J＝9.1,2.4Hz,1H),6.54–6.50(m,1H), 6.04(s,1H),4.94(dd,J＝12.1,5.4Hz,1H),4.23–4.12(m,2H),3.19(d,J＝17.8Hz,4H),3.08(t,J＝5.0Hz ,5H),2.74(s,3H),2.53(s,4H),2.23(d,J＝5.3Hz,8H),2.19(s,4H),2.06(s,4H),1.99(s,3H) ,1.81(s,5H),1.53(dd,J＝14.7,7.5Hz,4H),1.43–1.26(m,10H),0.95(s,6H).

实施例28：化合物28的制备
Example 28: Preparation of Compound 28

1)中间体28-1的制备1) Preparation of intermediate 28-1

参考实施例24步骤1)中中间体24-1的制备方法，将其中的1,3-二溴丙烷换成1,5-二溴戊烷，得到中间体28-1。Referring to the preparation method of intermediate 24-1 in step 1) of Example 24, 1,3-dibromopropane was replaced with 1,5-dibromopentane to obtain intermediate 28-1.

ESI-MS:m/z＝423.1[M+H]+ ESI-MS:m/z＝423.1[M+H] +

2)化合物28的制备2) Preparation of compound 28

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体28-1，得到化合物28。 Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 28-1 to obtain compound 28.

LC-MS:m/z＝663.8[M+2H]2+.LC-MS: m/z＝663.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ9.60(s,1H),8.87(d,J＝2.3Hz,1H),8.55–8.42(m,2H),8.10(d,J＝2.6Hz,1H),7.98–7.88(m,2H),7.73–7.61(m,2H),7.52(d,J＝8.0Hz,2H),7.49–7.42(m,2H),7.20(d,J＝8.4Hz,1H),7.10(d,J＝7.9Hz,2H),6.76(d,J＝9.3Hz,1H),6.60–6.48(m,2H),6.02(d,J＝2.4Hz,1H),4.93(dd,J＝12.2,5.6Hz,1H),4.29–4.10(m,3H),3.27(d,J＝15.4Hz,5H),3.08(t,J＝5.1Hz,4H),2.90–2.80(m,3H),2.73(d,J＝12.7Hz,5H),2.48(s,4H),1.99(s,8H),1.94–1.83(m,6H),1.77–1.60(m,9H),1.43(t,J＝6.5Hz,3H),1.28(d,J＝21.4Hz,1H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ9.60 (s, 1H), 8.87 (d, J = 2.3Hz, 1H), 8.55–8.42 (m, 2H), 8.10 (d, J = 2.6Hz, 1H) ,7.98–7.88(m,2H),7.73–7.61(m,2H),7.52(d,J＝8.0Hz,2H),7.49–7.42(m,2H),7.20(d,J＝8.4Hz,1H ),7.10(d,J＝7.9Hz,2H),6.76(d,J＝9.3Hz,1H),6.60–6.48(m,2H),6.02(d,J＝2.4Hz,1H),4.93(dd ,J＝12.2,5.6Hz,1H),4.29–4.10(m,3H),3.27(d,J＝15.4Hz,5H),3.08(t,J＝5.1Hz,4H),2.90–2.80(m, 3H),2.73(d,J＝12.7Hz,5H),2.48(s,4H),1.99(s,8H),1.94–1.83(m,6H),1.77–1.60(m,9H),1.43(t ,J＝6.5Hz,3H),1.28(d,J＝21.4Hz,1H),0.95(s,6H).

实施例29：化合物29的制备
Example 29: Preparation of Compound 29

1)中间体29-1的制备1) Preparation of intermediate 29-1

将五水硫代硫酸钠(53.7g)，氯化苄(27.4g)，五水硫酸铜(77.4mg)及联吡啶(0.72g)加入装有甲醇(120mL)和水(120mL)的反应瓶中，随后缓慢升温至80℃并搅拌2h。随后将反应液降至室温，加入化合物29A(8.0g)，最后缓慢滴加亚硝酸叔丁酯(4.78g)，滴毕，再次升温至80℃并搅拌8h。反应结束后，将反应液降至室温，加水(200mL)，乙酸乙酯萃取，合并有机相，水洗，饱和食盐水洗，无水硫酸钠干燥，减压蒸去溶剂，粗品经柱层析(石油醚/乙酸乙酯＝1:2)经液相制备得中间体29-1(6.8g)。Add sodium thiosulfate pentahydrate (53.7g), benzyl chloride (27.4g), copper sulfate pentahydrate (77.4mg) and bipyridine (0.72g) into a reaction bottle containing methanol (120mL) and water (120mL). medium, then slowly raised the temperature to 80°C and stirred for 2 h. Then the reaction solution was lowered to room temperature, compound 29A (8.0g) was added, and finally tert-butyl nitrite (4.78g) was slowly added dropwise. After the dropwise completion, the temperature was raised to 80°C again and stirred for 8 hours. After the reaction, the reaction solution was lowered to room temperature, water (200 mL) was added, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was subjected to column chromatography (petroleum). Intermediate 29-1 (6.8g) was prepared through liquid phase (ether/ethyl acetate = 1:2).

ESI-MS:m/z＝367.11[M+H]+ ESI-MS:m/z＝367.11[M+H] +

2)中间体29-2的制备2) Preparation of intermediate 29-2

将无水三氯化铝(2.61g)及无水甲苯(70mL)加到250mL的蛋形瓶中，搅拌下缓慢加入中间体29-1(1.8g)，加毕，35℃下反应7h。反应结束后，在搅拌下将20％的柠檬酸水溶液缓慢加入，随后抽滤，滤饼分别用水和乙酸乙酯洗涤，滤饼干燥得中间体29-2(1.15g)。Add anhydrous aluminum trichloride (2.61g) and anhydrous toluene (70mL) to a 250mL egg-shaped bottle, slowly add intermediate 29-1 (1.8g) under stirring, complete the addition, and react at 35°C for 7 hours. After the reaction, 20% citric acid aqueous solution was slowly added under stirring, followed by suction filtration. The filter cake was washed with water and ethyl acetate respectively, and the filter cake was dried to obtain intermediate 29-2 (1.15g).

ESI-MS:m/z＝277.06[M+H]+ ESI-MS:m/z＝277.06[M+H] +

3)中间体29-3的制备3) Preparation of intermediate 29-3

参考实施例19步骤1)中中间体19-1的制备方法，将其中的化合物19A换成中间体29-2，得到中间体29-3。Referring to the preparation method of intermediate 19-1 in step 1) of Example 19, compound 19A is replaced with intermediate 29-2 to obtain intermediate 29-3.

ESI-MS:m/z＝439.02[M+H]+ ESI-MS:m/z＝439.02[M+H] +

4)化合物29的制备4) Preparation of compound 29

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体29-3，得到化合物29。Referring to the preparation method of compound 7 in step 2) of Example 7, intermediate 7-2 was replaced by intermediate 29-3 to obtain compound 29.

LC-MS:m/z＝671.8[M+2H]2+.LC-MS: m/z＝671.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.86(d,1H),8.57(s,1H),8.43(s,1H),8.14(d,1H),8.07(d,1H),7.93(d,1H),7.66(d,1H),7.45(dd,3H),7.10(d,2H),7.02(d,1H),7.00(d,1H),6.56(dd,2H),6.02(s,1H),5.24(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21(m,3H),3.06(m,4H),2.93–2.83(m,9H),2.73–2.22(m,12H),1.98–1.79(m,14H),1.52–1.26(m,12H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.86(d,1H),8.57(s,1H),8.43(s,1H),8.14(d,1H),8.07(d,1H),7.93(d, 1H),7.66(d,1H),7.45(dd,3H),7.10(d,2H),7.02(d,1H),7.00(d,1H),6.56(dd,2H),6.02(s,1H ),5.24(dd,1H),4.44(d,1H),4.30(d,1H),4.07–4.00(m,2H),3.21(m,3H),3.06(m,4H),2.93–2.83( m,9H),2.73–2.22(m,12H),1.98–1.79(m,14H),1.52–1.26(m,12H),0.95(s,6H).

实施例30：化合物30的制备
Example 30: Preparation of Compound 30

1)中间体30-1的制备1) Preparation of intermediate 30-1

参考实施例29步骤3)中中间体29-3的制备方法，将其中的1,6-二溴己烷换成1,7-二溴庚烷，得到中间体30-1。Referring to the preparation method of intermediate 29-3 in step 3) of Example 29, 1,6-dibromohexane was replaced with 1,7-dibromoheptane to obtain intermediate 30-1.

ESI-MS:m/z＝453.1[M+H]+ ESI-MS:m/z＝453.1[M+H] +

2)实施例30的制备2) Preparation of Example 30

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体30-1，得到实施例30。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 30-1 to obtain Example 30.

LC-MS:m/z＝678.8[M+2H]2+.LC-MS: m/z＝678.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.87(d,1H),8.58(s,1H),8.43(s,1H),8.16(d,1H),8.07(d,1H),7.95(d,1H),7.67(d,1H),7.44(dd,3H),7.10(d,2H),7.03(d,1H),7.01(d,1H),6.55(dd,2H),6.03(s,1H),5.25(dd,1H),4.44(d,1H),4.31(d,1H),4.09–4.02(m,2H),3.23(m,3H),3.08(m,4H),2.98–2.79(m,9H),2.76–2.20(m,13H),1.98–1.78(m,15H),1.53–1.22(m,12H),0.94(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.87(d,1H),8.58(s,1H),8.43(s,1H),8.16(d,1H),8.07(d,1H),7.95(d, 1H),7.67(d,1H),7.44(dd,3H),7.10(d,2H),7.03(d,1H),7.01(d,1H),6.55(dd,2H),6.03(s,1H ),5.25(dd,1H),4.44(d,1H),4.31(d,1H),4.09–4.02(m,2H),3.23(m,3H),3.08(m,4H),2.98–2.79( m,9H),2.76–2.20(m,13H),1.98–1.78(m,15H),1.53–1.22(m,12H),0.94(s,6H).

实施例31：化合物31的制备
Example 31: Preparation of Compound 31

1)中间体31-1的制备 1) Preparation of intermediate 31-1

参考实施例29步骤3)中中间体29-3的制备方法，将其中的1,6-二溴己烷换成1,8-二溴辛烷，得到中间体31-1。Referring to the preparation method of intermediate 29-3 in step 3) of Example 29, 1,6-dibromohexane was replaced with 1,8-dibromooctane to obtain intermediate 31-1.

ESI-MS:m/z＝467.1[M+H]+ ESI-MS:m/z＝467.1[M+H] +

2)化合物31的制备2) Preparation of compound 31

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体31-1，得到化合物31。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 31-1 to obtain compound 31.

LC-MS:m/z＝685.8[M+2H]2+.LC-MS: m/z＝685.8[M+2H] 2+ .

1H NMR(500MHz,DMSO)δ11.50(d,J＝2.7Hz,1H),10.99(s,1H),8.39–8.31(m,2H),7.91(d,J＝2.6Hz,1H),7.72–7.49(m,8H),7.40(m,1H),7.29–7.24(m,4H),6.81(d,J＝9.2Hz,1H),6.61(m,1H),6.31–6.21(m,2H),5.13(m,1H),4.35(m,1H),4.21(m,1H),3.25(m,2H),3.07(m,3H),3.00(m,6H),2.72(s,3H),2.59–2.51(m,4H),2.39(s,1H),2.19(m,6H),1.99(s,3H),1.91(s,6H),1.74(m,3H),1.59(m,2H),1.41(m,6H),1.24(s,10H),0.94(s,6H).1H NMR(500MHz,DMSO)δ11.50(d,J＝2.7Hz,1H),10.99(s,1H),8.39–8.31(m,2H),7.91(d,J＝2.6Hz,1H),7.72 –7.49(m,8H),7.40(m,1H),7.29–7.24(m,4H),6.81(d,J＝9.2Hz,1H),6.61(m,1H),6.31–6.21(m,2H ),5.13(m,1H),4.35(m,1H),4.21(m,1H),3.25(m,2H),3.07(m,3H),3.00(m,6H),2.72(s,3H) ,2.59–2.51(m,4H),2.39(s,1H),2.19(m,6H),1.99(s,3H),1.91(s,6H),1.74(m,3H),1.59(m,2H ),1.41(m,6H),1.24(s,10H),0.94(s,6H).

实施例32：化合物32的制备
Example 32: Preparation of Compound 32

1)中间体32-1的制备1) Preparation of intermediate 32-1

参考实施例29步骤3)中中间体29-3的制备方法，将其中的1,6-二溴己烷换成1,9-二溴壬烷，得到中间体32-1。Referring to the preparation method of intermediate 29-3 in step 3) of Example 29, 1,6-dibromohexane was replaced with 1,9-dibromononane to obtain intermediate 32-1.

ESI-MS:m/z＝481.1[M+H]+ ESI-MS:m/z＝481.1[M+H] +

2)化合物32的制备2) Preparation of compound 32

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体32-1，得到化合物32。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 32-1 to obtain compound 32.

LC-MS:m/z＝692.8[M+2H]2+.LC-MS: m/z＝692.8[M+2H] 2+ .

1H NMR(500MHz,DMSO)δ11.55(s,1H),10.99(s,1H),8.43(s,2H),8.16(s,3H),7.95(s,1H),7.78–7.48(m,7H),7.46–7.19(m,4H),6.90(s,1H),6.63(s,1H),6.27(d,J＝42.8Hz,2H),5.13(s,1H),4.43–4.12(m,4H),3.28(s,2H),3.04(m,12H),2.72(s,3H),2.32(s,3H),2.19(s,6H),1.98(s,3H),1.82(m,5H),1.59(s,4H),1.40(s,6H),1.23(s,10H),0.94(s,6H). 1 H NMR (500MHz, DMSO) δ11.55(s,1H),10.99(s,1H),8.43(s,2H),8.16(s,3H),7.95(s,1H),7.78–7.48(m ,7H),7.46–7.19(m,4H),6.90(s,1H),6.63(s,1H),6.27(d,J＝42.8Hz,2H),5.13(s,1H),4.43–4.12( m,4H),3.28(s,2H),3.04(m,12H),2.72(s,3H),2.32(s,3H),2.19(s,6H),1.98(s,3H),1.82(m ,5H),1.59(s,4H),1.40(s,6H),1.23(s,10H),0.94(s,6H).

实施例33：化合物33的制备
Example 33: Preparation of Compound 33

1)中间体33-1的制备1) Preparation of intermediate 33-1

参考实施例13步骤1)中中间体13-1的制备方法，将其中的化合物12A换成化合物33A，得到中间体33-1。Referring to the preparation method of intermediate 13-1 in step 1) of Example 13, compound 12A is replaced with compound 33A to obtain intermediate 33-1.

ESI-MS:m/z＝341.1[M+H]+.ESI-MS: m/z＝341.1[M+H] + .

2)中间体33-2的制备2) Preparation of intermediate 33-2

参考实施例13步骤2)中中间体13-2的制备方法，将其中的中间体13-1换成中间体33-1，得到中间体33-2。Refer to the preparation method of intermediate 13-2 in step 2) of Example 13, and replace intermediate 13-1 with intermediate 33-1 to obtain intermediate 33-2.

ESI-MS:m/z＝338.1[M+H]+ ESI-MS:m/z＝338.1[M+H] +

3)化合物33的制备3) Preparation of compound 33

参考实施例13步骤3)中化合物13的制备方法，将其中的中间体13-2换成中间体33-2，得到化合物33。Referring to the preparation method of compound 13 in step 3) of Example 13, intermediate 13-2 is replaced by intermediate 33-2 to obtain compound 33.

LC-MS:m/z＝653.8[M+2H]2+.LC-MS: m/z＝653.8[M+2H] 2+ .

实施例34：化合物34的制备
Example 34: Preparation of Compound 34

1)中间体34-1的制备1) Preparation of intermediate 34-1

参考实施例19步骤1)中中间体19-1的制备方法，将其中的1,6-二溴己烷换成1,4-二(溴甲基)苯，得到中间体34-1。Referring to the preparation method of intermediate 19-1 in step 1) of Example 19, 1,6-dibromohexane was replaced with 1,4-di(bromomethyl)benzene to obtain intermediate 34-1.

ESI-MS:m/z＝443.1[M+H]+ ESI-MS:m/z＝443.1[M+H] +

2)化合物34的制备 2) Preparation of compound 34

参考实施例7步骤2)中化合物7的制备方法，将其中的中间体7-2换成中间体34-1，得到化合物34。Refer to the preparation method of compound 7 in step 2) of Example 7, and replace intermediate 7-2 with intermediate 34-1 to obtain compound 34.

LC-MS:m/z＝673.8[M+2H]2+.LC-MS: m/z＝673.8[M+2H] 2+ .

1H NMR(500MHz,CDCl3)δ8.81(d,1H),8.46(s,1H),8.42(s,1H),8.09(d,1H),7.95(d,1H),7.93(d,1H),7.90(d,1H),7.67(d,1H),7.50(t,2H),7.43(dd,4H),7.10(d,3H),6.78(d,1H),6.55(dd,1H),6.51(d,1H),6.01(s,1H),5.23(dd,1H),5.13(s,2H),4.43(d,1H),4.30(d,1H),3.63(m,2H),3.38–3.01(m,4H),2.98–2.75(m,9H),2.60(m,2H),2.37–2.15(m,11H),1.98–1.82(m,12H),1.42–1.24(m,6H),0.95(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ8.81(d,1H),8.46(s,1H),8.42(s,1H),8.09(d,1H),7.95(d,1H),7.93(d, 1H),7.90(d,1H),7.67(d,1H),7.50(t,2H),7.43(dd,4H),7.10(d,3H),6.78(d,1H),6.55(dd,1H ),6.51(d,1H),6.01(s,1H),5.23(dd,1H),5.13(s,2H),4.43(d,1H),4.30(d,1H),3.63(m,2H) ,3.38–3.01(m,4H),2.98–2.75(m,9H),2.60(m,2H),2.37–2.15(m,11H),1.98–1.82(m,12H),1.42–1.24(m, 6H),0.95(s,6H).

试验例1：体外RS4；11细胞增殖抑制作用Test Example 1: In vitro RS4;11 cell proliferation inhibitory effect

取处于指数生长期状态良好的RS4；11细胞(来源于南京科佰)，收集细胞至离心管，低速台式离心机，1000转/min，离心5min，弃上清，用移液器加入3mL种板培养基(RPMI基础培养基+5％胎牛血清)重悬。使用细胞计数仪计数，用种板培养基稀释，调整细胞密度至1×105个/mL，使用排枪接种于96孔板上，100μL/孔，置于37℃、含5％CO2饱和湿度的细胞培养箱中培养。培养24h后，使用纳升加样仪进行化合物加样，使化合物终浓度为2000nM-0.91nM，2个复孔，同时设置对照。细胞培养箱中继续培养72小时后，加入检测试剂CCK-8(厂家:日本同仁化学)，10μL/孔，细胞培养箱中孵育4小时后，Envision酶标仪450nm处检测其吸光值，计算抑制率，抑制率(％)＝(阴性对照组平均值-实验组平均值)/(阴性对照组平均值-空白组平均值)*100％，以化合物浓度对数为横坐标，抑制率为纵坐标，四参数分析，拟合量效曲线，计算IC50。结果见表1。Take RS4;11 cells (from Nanjing Kebai) that are in good exponential growth phase, collect the cells into a centrifuge tube, use a low-speed desktop centrifuge at 1000 rpm for 5 minutes, discard the supernatant, and add 3 mL of seed with a pipette. Resuspend in plate culture medium (RPMI basal medium + 5% fetal calf serum). Use a cell counter to count, dilute with seed plate culture medium, adjust the cell density to 1×10 5 cells/mL, use a row gun to inoculate 100 μL/well on a 96-well plate, and place at 37°C in a saturated humidity containing 5% CO 2 cultured in a cell culture incubator. After culturing for 24 hours, use a nanoliter sampler to add compounds to a final concentration of 2000 nM-0.91 nM in 2 duplicate wells, and set controls at the same time. After continuing to culture in the cell culture incubator for 72 hours, add detection reagent CCK-8 (Manufacturer: Nippon Dojin Chemical), 10 μL/well, and after incubating in the cell culture incubator for 4 hours, detect the absorbance value at 450 nm with the Envision microplate reader, and calculate the inhibition Rate, inhibition rate (%) = (average of the negative control group - average of the experimental group) / (average of the negative control group - average of the blank group) * 100%, taking the logarithm of the compound concentration as the abscissa, and the inhibition rate as the vertical axis coordinates, four-parameter analysis, fitting dose-response curve, and calculating IC 50 . The results are shown in Table 1.

表1.体外RS4；11细胞化合物抑制活性测试结果
Table 1. In vitro RS4;11 cell compound inhibitory activity test results

本公开的化合物在体外具有RS4；11细胞增殖抑制作用。The compounds of the present disclosure have RS4;11 cell proliferation inhibitory effects in vitro.

试验例2：体外MOLT-4细胞增殖抑制作用Test Example 2: Inhibitory effect on MOLT-4 cell proliferation in vitro

取处于指数生长期状态良好的MOLT-4细胞皿，收集细胞至离心管，低速台式离心机，1500转/min，离心3min，弃上清，用移液器加入5mL完全培养基(RPMI基础培养基+10％FBS)进行细胞重悬。使用细胞计数仪计数，完全培养基进行稀释，调整细胞密度至1.6*105个/mL，再加入等量的RPMI基础培养基调整血清浓度为5％，细胞密度为8*104个/mL种板。使用排枪接种于96孔板上，100μL/孔，置于37℃、含5％CO2饱和湿度的细胞培养箱中培养。培养24h后，使用纳升加样仪进行化合物加样，使化合物终浓度为1000nM-0.46nM，每一浓度设置2个复孔，以不加化合物的细胞作为阴性对照，72小时后加CCK-8(日本同仁化学)，10μL/孔，3.5小时后Envision酶标仪450nm处检测其吸光值，计算抑制率，抑制率(％)＝(阴性对照组平均值—实验组)/(阴性对照组平均值—空白组平均值)×100％，以化合物浓度对数为横坐标，抑制率为纵坐标，四参数分析，拟合量效曲线，计算IC50。结果如表2。 Take the MOLT-4 cell dish that is in good condition in the exponential growth phase, collect the cells into a centrifuge tube, and centrifuge in a low-speed desktop centrifuge at 1500 rpm for 3 minutes. Discard the supernatant and add 5 mL of complete culture medium (RPMI basic culture) with a pipette. base + 10% FBS) to resuspend the cells. Use a cell counter to count, dilute the complete culture medium, adjust the cell density to 1.6*10 5 cells/mL, then add an equal amount of RPMI basal medium to adjust the serum concentration to 5%, and the cell density to 8*10 4 cells/mL Seed board. Use a row gun to inoculate 100 μL/well on a 96-well plate, and place it in a cell culture incubator containing 5% CO2 at 37°C and saturated humidity. After 24 hours of culture, use a nanoliter sampler to add compounds to a final concentration of 1000 nM-0.46 nM. Set up 2 duplicate wells for each concentration. Use cells without compound as a negative control. Add CCK- after 72 hours. 8 (Japan Dojin Chemical), 10 μL/well, after 3.5 hours, detect the absorbance value at 450nm with an Envision microplate reader, and calculate the inhibition rate. Inhibition rate (%) = (average of negative control group - experimental group)/(negative control group) Average value - average value of blank group) × 100%, with the logarithm of compound concentration as the abscissa and the inhibition rate as the ordinate, four-parameter analysis, fitting the dose-effect curve, and calculating IC 50 . The results are shown in Table 2.

表2.化合物抑制活性测试结果
Table 2. Compound inhibitory activity test results

本公开的化合物在体外具有MOLT-4细胞增殖抑制作用。The compounds of the present disclosure have MOLT-4 cell proliferation inhibitory effects in vitro.

试验例3：体外MOLT-4细胞中BCL-XL蛋白降解测定Test Example 3: Determination of BCL-XL protein degradation in MOLT-4 cells in vitro

取处于指数生长期状态良好的MOLT-4细胞皿，收集细胞至离心管，低速台式离心机，1500转/min，离心3min，弃上清，用移液器加入5mL完全培养基(RPMI基础培养基+10％FBS)进行细胞重悬。使用细胞计数仪计数，完全培养基进行稀释，调整细胞密度至1*107个/mL，使用排枪接种于96孔板上，100μL/孔。使用纳升加样仪进行化合物加样，使化合物终浓度为1000nM-1nM，每一浓度设置2个复孔，置于37℃、含5％CO2饱和湿度的细胞培养箱中培养。Take the MOLT-4 cell dish that is in good condition in the exponential growth phase, collect the cells into a centrifuge tube, and centrifuge in a low-speed desktop centrifuge at 1500 rpm for 3 minutes. Discard the supernatant and add 5 mL of complete culture medium (RPMI basic culture) with a pipette. base + 10% FBS) to resuspend the cells. Use a cell counter to count, dilute the complete culture medium, adjust the cell density to 1*10 7 cells/mL, and use a row gun to inoculate onto a 96-well plate, 100 μL/well. Use a nanoliter sampler to add compounds to a final concentration of 1000 nM-1 nM. Set up 2 duplicate wells for each concentration and place them in a cell culture incubator at 37°C with 5% CO2 saturated humidity.

培养24h后，收集细胞进行流式检测。细胞用含有2％BSA的PBS清洗后，细胞首先用80％甲醇固定，然后用含0.1％Tween20的PBS破膜，后续用含有10％BSA的PBS封闭，最后进行抗体标记。分别用BCL-XL(54H6)Rabbit mAb(CST，2764S)一抗室温孵育0.5h，细胞用含有2％BSA的PBS清洗后，用Anti-rabbit IgG(H+L),F(ab')2Fragment(Alexa488Conjugate)(CST，4412S)室温孵育0.5h，孵育结束后用含有2％BSA的PBS清洗重悬细胞，使用IQue3(Sartorius)上机检测。After 24 h of culture, cells were collected for flow cytometric detection. After the cells were washed with PBS containing 2% BSA, the cells were first fixed with 80% methanol, then ruptured with PBS containing 0.1% Tween20, and subsequently blocked with PBS containing 10% BSA, and finally labeled with antibodies. The cells were incubated with BCL-XL (54H6) Rabbit mAb (CST, 2764S) primary antibody for 0.5h at room temperature respectively. After the cells were washed with PBS containing 2% BSA, they were washed with Anti-rabbit IgG (H+L), F(ab')2Fragment. (Alexa 488 Conjugate) (CST, 4412S) was incubated at room temperature for 0.5 h. After the incubation, the cells were washed and resuspended in PBS containing 2% BSA, and IQue3 (Sartorius) was used for detection.

将只用二抗标记的组作为背景组，以不加化合物的细胞作为阴性对照组，用平均荧光强度MFI指标衡量BCL-XL蛋白表达，计算抑制率。降解率(％)＝(阴性对照组MFI平均值—化合物组MFI)/(阴性对照组MFI平均值—背景组MFI平均值)×100％，以化合物浓度对数为横坐标，降解率为纵坐标，四参数分析，拟合量效曲线，计算DC50(半数降解浓度)。结果如表3。The group labeled only with the secondary antibody was used as the background group, and the cells without compound were used as the negative control group. The average fluorescence intensity MFI index was used to measure the expression of BCL-XL protein and calculate the inhibition rate. Degradation rate (%) = (average MFI of the negative control group - MFI of the compound group) / (average MFI of the negative control group - average MFI of the background group) × 100%, taking the logarithm of the compound concentration as the abscissa, and the degradation rate as the vertical axis Coordinates, four-parameter analysis, fitting dose-effect curve, and calculation of DC 50 (half degradation concentration). The results are shown in Table 3.

表3.化合物降解活性测试结果
Table 3. Compound degradation activity test results

本公开的化合物在体外针对MOLT-4细胞具有BCL-XL蛋白降解作用。Compounds of the present disclosure have BCL-XL protein degradation effects on MOLT-4 cells in vitro.

试验例4：BCL-XL/BAK结合抑制活性评价Test Example 4: Evaluation of BCL-XL/BAK Binding Inhibitory Activity

用试剂盒(cisbio，63ADK000CB04PEG)中的稀释缓冲液将Tag1-BCL-XL蛋白母液稀释成8nM，同时将Tag2-BAK蛋白母液稀释成20nM，加入5μL/孔的Tag1-BCL-XL蛋白稀释液到384孔板内，使用纳升加样仪进行化合物加样，使化合物终浓度为1000nM-0.24nM，2个复孔，同时设置对照，加入5μL/孔的Tag2-BAK蛋白稀释液，离心混匀，室温孵育15分钟。用试剂盒(cisbio，63ADK000CB04PEG)中的检测缓冲液将Anti-Tag1-Eu3+抗体和Anti-Tag2-XL665抗体稀释成1X浓度，将Anti-Tag1-Eu3+和Anti-Tag2-XL665抗体稀释液按1：1体积混匀，加入10μL/孔的抗体混合液，离心混匀，室温孵育2h。Envision酶标仪665nm/620nm处检测其荧光值，四参数分析，拟合量效曲线，计算IC50。 Use the dilution buffer in the kit (cisbio, 63ADK000CB04PEG) to dilute the Tag1-BCL-XL protein stock solution to 8nM, and at the same time dilute the Tag2-BAK protein stock solution to 20nM. Add 5 μL/well of Tag1-BCL-XL protein diluent to In the 384-well plate, use a nanoliter sampler to add the compound to a final concentration of 1000nM-0.24nM, 2 duplicate wells, and set controls at the same time. Add 5 μL/well of Tag2-BAK protein diluent, and centrifuge to mix. , incubate at room temperature for 15 minutes. Dilute Anti-Tag1-Eu 3+ and Anti-Tag2-XL665 antibodies to 1X concentration using the detection buffer in the kit (cisbio, 63ADK000CB04PEG) . Mix the solution at a volume of 1:1, add 10 μL/well of the antibody mixture, centrifuge to mix, and incubate at room temperature for 2 hours. Envision microplate reader detects its fluorescence value at 665nm/620nm, performs four-parameter analysis, fits the dose-effect curve, and calculates IC 50 .

本公开的化合物具备BCL-XL/BAK结合抑制活性。The compounds of the present disclosure possess BCL-XL/BAK binding inhibitory activity.

试验例5：体外肝微粒体稳定性Test Example 5: Stability of liver microsomes in vitro

肝微粒体温孵样本(种属：人、猴、大鼠及小鼠)制备为混合PBS缓冲液(PH7.4)，肝微粒体溶液(0.5mg/mL)，受试化合物及NADPH+MgCl2溶液于37℃及300rpm孵育1小时。0小时样本制备为混合PBS缓冲液(pH7.4)，肝微粒体溶液(0.5mg/mL)，受试化合物。样本加入含内标的乙腈溶液经蛋白沉淀制备上清液，稀释后用于LC/MS/MS测定。结果如表4。Liver microsome body temperature incubation samples (species: human, monkey, rat and mouse) were prepared as a mixture of PBS buffer (PH7.4), liver microsome solution (0.5mg/mL), test compound and NADPH+MgCl 2 The solution was incubated at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH7.4), liver microsome solution (0.5 mg/mL), and test compound. The sample was added to an acetonitrile solution containing an internal standard and subjected to protein precipitation to prepare a supernatant, which was diluted and used for LC/MS/MS measurement. The results are shown in Table 4.

表4.体外肝微粒体代谢稳定性结果
Table 4. In vitro liver microsomal metabolic stability results

本公开的化合物体外肝微粒体代谢稳定。Compounds of the present disclosure are stable to hepatic microsomal metabolism in vitro.

试验例6：小鼠体内药代动力学Test Example 6: Pharmacokinetics in mice

ICR小鼠，体重18～22g，适应3～5天后，随机分组，每组9只，按1mg/kg剂量静注受试化合物溶液。采血时间点5min、15min、30min、1h、2h、3h、4h、6h、8h、10h、24h，于眼眶取血制备待测血浆样品。吸取20μL待测血浆样品和标曲样品，加入含内标的乙腈溶液经蛋白沉淀得到上清液，稀释后用于LC/MS/MS测定。采用非房室模型拟合药代参数。ICR mice, weighing 18 to 22 g, were randomly divided into groups of 9 mice after adapting for 3 to 5 days, and the test compound solution was injected intravenously at a dose of 1 mg/kg. Blood collection time points are 5min, 15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 10h, and 24h. Blood is collected from the orbit to prepare plasma samples to be tested. Take 20 μL of the plasma sample to be tested and the standard sample, add acetonitrile solution containing the internal standard, undergo protein precipitation to obtain the supernatant, and dilute it for LC/MS/MS measurement. Noncompartmental models were used to fit pharmacokinetic parameters.

本公开的化合物具有良好的体内药代动力学性质，比如AUC、Cmax、T1/2及Tmax等参数表现优异。The compounds of the present disclosure have good in vivo pharmacokinetic properties, such as excellent performance in AUC, C max , T 1/2 and T max and other parameters.

试验例7Test example 7

7.1犬血小板增殖抑制活性测定7.1 Determination of canine platelet proliferation inhibitory activity

采集犬全血，分离犬血小板，acid citrate buffer工作液重悬并计数，Tyrode's Solution工作液调整血小板密度至108个/ml，接种于96孔U底板(厂家：Costar)中，每孔90μl，铺板后所有孔加入10μl FBS。使用纳升加样仪进行化合物加样，使化合物终浓度为5000nM-13nM，2个复孔，同时设置对照。然后，封板膜封板后置于微孔板恒温振荡器上，20℃、300rpm振荡孵育72h。最后，加入检测试剂CCK-8(厂家：日本同仁化学，10μL/孔)，细胞培养箱中孵育1.5小时后，Envision酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC50。Collect canine whole blood, separate canine platelets, resuspend and count in acid citrate buffer working solution, adjust platelet density to 108 /ml in Tyrode's Solution working solution, inoculate into 96-well U bottom plate (manufacturer: Costar), 90 μl per well, After plating, add 10 μl FBS to all wells. Use a nanoliter sampler to add the compound to a final concentration of 5000nM-13nM, into 2 duplicate wells, and set controls at the same time. Then, the plate was sealed with a sealing film and placed on a microplate constant-temperature oscillator, and incubated with shaking at 20°C and 300 rpm for 72 h. Finally, the detection reagent CCK-8 (manufacturer: Nippon Dojin Chemical, 10 μL/well) was added. After incubation in the cell culture incubator for 1.5 hours, the absorbance value was detected at 450 nm with the Envision microplate reader. Four-parameter analysis was performed to fit the dose-effect curve. Calculate IC 50 .

7.2人血小板增殖抑制活性测定7.2 Determination of human platelet proliferation inhibitory activity

采集人全血，分离人血小板，acid citrate buffer工作液重悬并计数，Tyrode's Solution工作液调整血小板密度至108个/ml，接种于96孔U底板(厂家：Costar)中，每孔90μl，铺板后所有孔加入10μl FBS。使用纳升加样仪进行化合物加样，使化合物终浓度为5000nM-13nM，2个复孔，同时设置对照。然后，封板膜封板后置于微孔板恒温振荡器上，20℃、300rpm振荡孵育72h。最后，加入检测试剂CCK-8(厂家：日本同仁化学，10μL/孔)，细胞培养箱中孵育1.5小时后，Envision酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC50。Collect human whole blood, separate human platelets, resuspend and count in acid citrate buffer working solution, adjust platelet density to 108 /ml in Tyrode's Solution working solution, inoculate into 96-well U bottom plate (manufacturer: Costar), 90 μl per well, After plating, add 10 μl FBS to all wells. Use a nanoliter sampler to add the compound to a final concentration of 5000nM-13nM, into 2 duplicate wells, and set controls at the same time. Then, the plate was sealed with a sealing film and placed on a microplate constant-temperature oscillator, and incubated with shaking at 20°C and 300 rpm for 72 h. Finally, the detection reagent CCK-8 (manufacturer: Nippon Dojin Chemical, 10 μL/well) was added. After incubation in the cell culture incubator for 1.5 hours, the absorbance value was detected at 450 nm with the Envision microplate reader. Four-parameter analysis was performed to fit the dose-effect curve. Calculate IC 50 .

本公开的化合物血小板毒性低(犬或人血小板)。 Compounds of the present disclosure have low platelet toxicity (canine or human platelets).

Claims (22)

式I-0化合物或其药学上可接受的盐，
A compound of formula I-0 or a pharmaceutically acceptable salt thereof,
其中，in, 每一个R1分别独立地选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 1 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S( O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS (O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1 -6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6- 12 aryl or 5-12 membered heteroaryl; n1选自1、2、3或4；n1 is selected from 1, 2, 3 or 4; q选自0、1、2、3、4、5或6；q is selected from 0, 1, 2, 3, 4, 5 or 6; 每一个R2分别独立地选自卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 2 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1- 6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1 -6 alkylNHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O) NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 Alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl base or 5-12 membered heteroaryl; m选自0、1、2、3、4、5或6；m is selected from 0, 1, 2, 3, 4, 5 or 6; 环A选自C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Ring A is selected from C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered hetero Aryl; L为连接基团；L is the connecting group; 每一个R3分别独立地选自卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 3 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1- 6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1 -6 alkylNHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O) NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 Alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl base or 5-12 membered heteroaryl; p选自0、1、2或3；p is selected from 0, 1, 2 or 3; R4及R5分别独立地选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，R 4 and R 5 are independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O- , C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S (O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS (O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6 -12 aryl or 5-12 membered heteroaryl, 或者，R4及R5相互连接与相连的碳原子一起形成C3-6环烷基或3-6元杂环烷基；Alternatively, R 4 and R 5 are connected to each other and the connected carbon atoms together form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group; X选自CRaRa’或C＝O；X is selected from CR a R a' or C=O; X1选自CRb或N；X 1 is selected from CR b or N; Ra和Ra’相同或不同，分别独立地选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6 烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；R a and R a ' are the same or different, and are independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C (O)O-、C 1-6 Alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH- , (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl ) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; Rb选自氢、卤素、OH、NH2、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；R b is selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio Base, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 alkyl C(O)O-, C 1-6 alkyl Base NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)-, C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5 -12-membered heteroaryl; 所述R1、R2、环A、R3、R4、R5、Ra、Ra’或Rb任选地被一个或多个取代基取代。The R 1 , R 2 , ring A, R 3 , R 4 , R 5 , R a , R a′ or R b are optionally substituted by one or more substituents. 如权利要1所述的化合物或其药学上可接受的盐，其选自式I化合物或其药学上可接受的盐，
The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of compounds of formula I or a pharmaceutically acceptable salt thereof,
其中，in, R1选自氢、卤素或C1-3烷基；R 1 is selected from hydrogen, halogen or C 1-3 alkyl; q选自0、1、2、3、4、5或6；q is selected from 0, 1, 2, 3, 4, 5 or 6; 每一个R2分别独立地选自OH、NH2、CN、卤素、C1-3烷基或C1-3烷氧基；Each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl or C 1-3 alkoxy; m选自0、1、2或3；m is selected from 0, 1, 2 or 3; 环A选自C4-10环烷基或4-10元杂环烷基；Ring A is selected from C 4-10 cycloalkyl or 4-10 membered heterocycloalkyl; L为连接基团；L is the connecting group; 每一个R3分别独立地选自OH、NH2、CN、卤素、C1-3烷基或C1-3烷氧基；Each R 3 is independently selected from OH, NH 2 , CN, halogen, C 1-3 alkyl or C 1-3 alkoxy; p选自0、1、2或3；p is selected from 0, 1, 2 or 3; X选自CH2或C＝O；X is selected from CH 2 or C=O; X1选自CH或N；X 1 is selected from CH or N; 所述R1、R2、环A、R3、X、X1或X2任选地被一个或多个取代基取代。The R 1 , R 2 , Ring A, R 3 , X, X 1 or X 2 are optionally substituted by one or more substituents. 如权利要求1或2所述的化合物或其药学上可接受的盐，其中R1选自氢、卤素或C1-2烷基；The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, halogen or C 1-2 alkyl; 或者，R1选自氢、氟、氯、溴或甲基；Alternatively, R 1 is selected from hydrogen, fluorine, chlorine, bromine or methyl; 或者，R1选自氢、氯或甲基；Alternatively, R 1 is selected from hydrogen, chlorine or methyl; 或者，结构片段为 Or, structure fragment for 或者，结构片段选自 Or, structure fragment Selected from 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中q选自0、1、2或3；The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein q is selected from 0, 1, 2 or 3; 或者，q选自0、1或2；Alternatively, q is selected from 0, 1 or 2; 或者，q为1。Or, q is 1. 如权利要求1-4任一项所述的化合物或其药学上可接受的盐，其中每一个R2分别独立地选自OH、NH2、CN、卤素、C1-2烷基或C1-2烷氧基； The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from OH, NH 2 , CN, halogen, C 1-2 alkyl or C 1 -2 alkoxy; 或者，每一个R2分别独立地选自CN、卤素或C1-3烷基。Alternatively, each R 2 is independently selected from CN, halogen, or C 1-3 alkyl. 如权利要求1-5任一项所述的化合物或其药学上可接受的盐，其中m选自0、1或2；The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1 or 2; 或者，m选自0或1；Alternatively, m is selected from 0 or 1; 或者，m为0。Or, m is 0. 如权利要求1-6任一项所述的化合物或其药学上可接受的盐，其中环A选自C4-8环烷基或4-8元杂环烷基；The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from C 4-8 cycloalkyl or 4-8 membered heterocycloalkyl; 或者，环A选自C4-6环烷基或4-6元杂环烷基；Alternatively, Ring A is selected from C 4-6 cycloalkyl or 4-6 membered heterocycloalkyl; 或者，环A选自C5-6环烷基或5-6元杂环烷基；Alternatively, ring A is selected from C 5-6 cycloalkyl or 5-6 membered heterocycloalkyl; 或者，环A选自C6环烷基或6元杂环烷基；Alternatively, Ring A is selected from C 6 cycloalkyl or 6-membered heterocycloalkyl; 或者，环A选自C6环烷基或6元含N杂环烷基；Alternatively, Ring A is selected from C 6 cycloalkyl or 6-membered N-containing heterocycloalkyl; 或者，环A选自环己基或哌啶基；Alternatively, Ring A is selected from cyclohexyl or piperidinyl; 或者，环A选自 Alternatively, Ring A is selected from 或者，结构片段选自 Or, structure fragment Selected from 如权利要求1-7任一项所述的化合物或其药学上可接受的盐，其中L选自-Cy-L1-或-L2-；其中，-Cy-L1-或-L2-；其中，Cy选自C3-10环烷基或3-10元杂环烷基，所述C3-10环烷基或3-10元杂环烷基任选地被一个或多个取代基取代；其中，-L1-或-L2-分别独立地选自1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C1-20烷基-、1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C2-20烯基-、或者1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C2-20炔基-，所述-C1-20烷基-、-C2-20烯基-、或者-C2-20炔基-任选地被一个或多个取代基取代；The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein L is selected from -Cy-L 1 - or -L 2 -; wherein, -Cy-L 1 - or -L 2 -; wherein, Cy is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, and the C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl is optionally replaced by one or more Substituent substitution; wherein, -L 1 - or -L 2 - are independently selected from 1 or more -CH 2 - optionally selected from -O-, phenyl, -NH-, -N(C 1-6 alkyl)- or -S- substituted -C 1-20 alkyl-, 1 or more -CH 2 - optionally selected from -O-, phenyl, -NH-, -N (C 1-6 alkyl)- or -S- substituted -C 2-20 alkenyl-, or 1 or more -CH 2 - optionally selected from -O-, phenyl, -NH- , -N(C 1-6 alkyl)- or -S-substituted-C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 2-20 alkenyl-, or -C 2-20 Alkynyl-optionally substituted by one or more substituents; Cy选自C3-10环烷基或3-10元杂环烷基，所述C3-10环烷基或3-10元杂环烷基任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、卤素、CN、C1-6烷基或C1-6烷氧基；Cy is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, and the C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl is optionally replaced by one or more selected from the following Group substitution: =O, OH, NH 2 , halogen, CN, C 1-6 alkyl or C 1-6 alkoxy; 其中，L1或L2分别独立地选自1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C1-20烷基-、1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C2-20烯基-、或者1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C2-20炔基-，所述-C1-20烷基-、-C2-20烯基-、或者-C2-20炔基-任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、卤素或CN；Wherein, L 1 or L 2 are independently selected from 1 or more -CH 2 - optionally selected from -O-, phenyl, -NH-, -N(C 1-6 alkyl)- or -S-substituted -C 1-20 alkyl-, 1 or more -CH 2 - optionally selected from -O-, phenyl, -NH-, -N(C 1-6 alkyl) - or -S-substituted -C 2-20 alkenyl-, or 1 or more -CH 2 - optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)-or -S-substituted-C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 2-20 alkenyl-, or -C 2-20 alkynyl-optional is substituted by one or more groups selected from: =O, OH, NH 2 , halogen or CN; 或者，所述L1或L2分别独立地选自1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C1-15烷基-、1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C2-15烯基-、或者1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C2-15炔基-，所述-C1-15烷基-、-C2-15烯基-、或者-C2-15炔基-任选地被一个或多个以下基团取代：＝O、OH、NH2、卤素或CN；Alternatively, the L 1 or L 2 are each independently selected from 1 or more -CH 2 - optionally selected from -O-, phenyl, -NH-, -N(C 1-6 alkyl) - or -S- substituted -C 1-15 alkyl-, 1 or more -CH 2 - optionally selected from -O-, phenyl, -NH-, -N(C 1-6 alkyl base)-or -S-substituted -C 2-15 alkenyl-, or 1 or more -CH 2 - optionally selected from -O-, phenyl, -NH-, -N(C 1 -6 alkyl)-or -S-substituted -C 2-15 alkynyl-, said -C 1-15 alkyl-, -C 2-15 alkenyl-, or -C 2-15 alkynyl- Optionally substituted by one or more of the following groups: =O, OH, NH 2 , halogen or CN; 或者，所述L1或L2分别独立地选自-1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C1-12烷基-、1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C2-12烯基-、或者1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C2-12炔基-，所述-C1-12烷基-、-C2-12烯基-、或者-C2-12炔基-任选地被一个或多个以下基团取代：＝O、OH、NH2、卤素或CN；Alternatively, the L 1 or L 2 are each independently selected from -1 or more -CH 2 - optionally selected from -O-, phenyl, -NH-, -N(C 1-6 alkyl )- or -S-substituted -C 1-12 alkyl-, 1 or more -CH 2 - optionally selected from -O-, phenyl, -NH-, -N(C 1-6 Alkyl)-or -S-substituted -C 2-12 alkenyl-, or 1 or more -CH 2 - optionally selected from -O-, phenyl, -NH-, -N(C 1-6 alkyl)-or -S-substituted-C 2-12 alkynyl-, the -C 1-12 alkyl-, -C 2-12 alkenyl-, or -C 2-12 alkynyl - optionally substituted by one or more of the following groups: =O, OH, NH 2 , halogen or CN; 任选地，所述Cy选自C3-10环烷基或3-10元杂环烷基，所述C3-10环烷基或3-10元杂环烷基任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、卤素、CN、C1-6烷基或C1-6烷氧基；Optionally, the Cy is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, and the C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl is optionally replaced by one or Substituted with multiple groups selected from the following: =O, OH, NH 2 , halogen, CN, C 1-6 alkyl or C 1-6 alkoxy; 或者，所述Cy选自C3-8环烷基或3-8元杂环烷基，所述C3-8环烷基或3-8元杂环烷基任选地被一 个或多个选自以下的基团取代：＝O、OH、NH2、卤素、CN、C1-3烷基或C1-3烷氧基；Alternatively, the Cy is selected from C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, and the C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally replaced by a One or more groups selected from the following groups are substituted: =O, OH, NH 2 , halogen, CN, C 1-3 alkyl or C 1-3 alkoxy; 或者，所述Cy选自C3-8环烷基或3-8元杂环烷基，所述C3-8环烷基或3-8元杂环烷基任选地被一个或多个选自以下的基团取代：＝O、OH、NH2、氟、氯、溴、CN、C1-3烷基或C1-3烷氧基；Alternatively, the Cy is selected from C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, and the C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally replaced by one or more Substituted with a group selected from: =O, OH, NH 2 , fluorine, chlorine, bromine, CN, C 1-3 alkyl or C 1-3 alkoxy; 或者，所述Cy选自C3-8环烷基或3-8元杂环烷基；Alternatively, the Cy is selected from C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl; 或者，所述Cy选自C5-6环烷基或5-6元杂环烷基；Alternatively, the Cy is selected from C 5-6 cycloalkyl or 5-6 membered heterocycloalkyl; 或者，所述Cy选自5-6元杂环烷基；Alternatively, the Cy is selected from 5-6 membered heterocycloalkyl; 或者，所述Cy选自6元杂环烷基；Alternatively, the Cy is selected from 6-membered heterocycloalkyl; 或者，所述Cy选自哌啶基或哌嗪基；Alternatively, the Cy is selected from piperidinyl or piperazinyl; 或者，所述Cy选自 Alternatively, the Cy is selected from 或者，所述结构片段-Cy-L1-选自 Alternatively, the structural fragment -Cy-L 1 -is selected from 任选地，所述L1选自1个或多个-CH2-任选地被选自苯基或-N(C1-6烷基)-替换的-C1-20烷基-、-C1-19烷基氧基-、-C1-19烷基硫基-、-C1-19烷基氨基-、-C2-20烯基-或-C2-20炔基-，所述-C1-20烷基-、-C1-19烷基氧基-、-C1-19烷基硫基-、-C1-19烷基氨基-、-C2-20烯基-或-C2-20炔基-任选地被一个或多个取代基取代；Optionally, the L 1 is selected from 1 or more -CH 2 - optionally selected from phenyl or -N(C 1-6 alkyl)-replaced -C 1-20 alkyl-, -C 1-19 alkyloxy-, -C 1-19 alkylthio-, -C 1-19 alkylamino-, -C 2-20 alkenyl- or -C 2-20 alkynyl-, The -C 1-20 alkyl-, -C 1-19 alkyloxy-, -C 1-19 alkylthio-, -C 1-19 alkylamino-, -C 2-20 alkenyl - or - C 2-20 alkynyl - optionally substituted by one or more substituents; 或者，所述L1选自1个或多个-CH2-任选地被选自苯基或-N(C1-6烷基)-替换的--C1-15烷基-、-C1-14烷基氧基-、-C1-14烷基硫基-、-C1-14烷基氨基-、-C2-15烯基-或-C2-15炔基-，所述-C1-15烷基-、-C1-14烷基氧基-、-C1-14烷基硫基-、-C1-14烷基氨基-、-C2-15烯基-或-C2-15炔基-任选地被一个或多个取代基取代；Alternatively, the L 1 is selected from 1 or more -CH 2 - optionally selected from phenyl or -N(C 1-6 alkyl)-replaced -C 1-15 alkyl-, - C 1-14 alkyloxy-, -C 1-14 alkylthio-, -C 1-14 alkylamino-, -C 2-15 alkenyl- or -C 2-15 alkynyl-, so -C 1-15 alkyl-, -C 1-14 alkyloxy-, -C 1-14 alkylthio-, -C 1-14 alkylamino-, -C 2-15 alkenyl- or -C 2-15 alkynyl - optionally substituted by one or more substituents; 或者，所述L1选自1个或多个-CH2-任选地被选自苯基或-N(C1-6烷基)-替换的--C1-12烷基-、-C1-11烷基氧基-、-C1-11烷基硫基-、-C1-11烷基氨基-、-C2-12烯基-或-C2-12炔基-，所述-C1-12烷基-、-C1-11烷基氧基-、-C1-11烷基硫基-、-C1-11烷基氨基-、-C2-12烯基-或-C2-12炔基-任选地被一个或多个取代基取代；Alternatively, the L 1 is selected from 1 or more -CH 2 - optionally selected from phenyl or -N(C 1-6 alkyl)-replaced -C 1-12 alkyl-, - C 1-11 alkyloxy-, -C 1-11 alkylthio-, -C 1-11 alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkynyl-, so -C 1-12 alkyl-, -C 1-11 alkyloxy-, -C 1-11 alkylthio-, -C 1-11 alkylamino-, -C 2-12 alkenyl- or -C 2-12 alkynyl - optionally substituted by one or more substituents; 任选地，所述取代基选自＝O、OH、NH2、卤素或CN；Optionally, the substituent is selected from =O, OH, NH 2 , halogen or CN; 或者，所述L1或L2分别独立地选自-(CH2)nO-、-(CH2)nS-、-C(O)-(CH2)nO-、-C(O)-(CH2)nS-、-(CH2)nC≡C-、-C(O)-(CH2)nC≡C-、-(CH2)2N(CH3)-(CH2)nC≡C-、-(CH2)2N(CH3)-(CH2)nO-、-CH2N(CH3)-(CH2)nC≡C-、-CH2N(CH3)-(CH2)nO-、-(CH2)3N(CH3)-(CH2)nC≡C-、-(CH2)3N(CH3)-(CH2)nO-、-(CH2)nNH-或-CH2-苯基-(CH2)nO-，其中n选自1-12；或者，所述n选自1-10；或者n选自1、2、3、4、5、6、7、8、9或10，或者任意两者组成的整数范围；Alternatively, the L 1 or L 2 are independently selected from -(CH 2 ) n O-, -(CH 2 ) n S-, -C(O)-(CH 2 ) n O-, -C(O )-(CH 2 ) n S-, -(CH 2 ) n C≡C-, -C(O)-(CH 2 ) n C≡C-, -(CH 2 ) 2 N(CH 3 )-( CH 2 ) n C≡C-, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n O-, -CH 2 N(CH 3 )-(CH 2 ) n C≡C-, -CH 2 N(CH 3 )-(CH 2 ) n O-, -(CH 2 ) 3 N(CH 3 )-(CH 2 ) n C≡C-, -(CH 2 ) 3 N(CH 3 )-( CH 2 ) n O-, -(CH 2 ) n NH- or -CH 2 -phenyl-(CH 2 ) n O-, where n is selected from 1-12; or, n is selected from 1-10; Or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or an integer range consisting of any two; 或者，所述L1选自-(CH2)nO-、-(CH2)nS-、-C(O)-(CH2)nO-、-C(O)-(CH2)nS-、-(CH2)nC≡C-、-C(O)-(CH2)nC≡C-、-(CH2)nNH-、-(CH2)2N(CH3)-(CH2)nC≡C-、或-CH2-苯基-(CH2)nO-，其中n选自1-12；或者，所述n选自1-10；或者n选自1、2、3、4、5、6、7、8、9或10，或者任意两者组成的整数范围；Alternatively, the L 1 is selected from -(CH 2 ) n O-, -(CH 2 ) n S-, -C(O)-(CH 2 ) n O-, -C(O)-(CH 2 ) n S-, -(CH 2 ) n C≡C-, -C(O)-(CH 2 ) n C≡C-, -(CH 2 ) n NH-, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n C≡C-, or -CH 2 -phenyl-(CH 2 ) n O-, where n is selected from 1-12; or, n is selected from 1-10; or n is selected from An integer range from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or any two; 或者，所述L2选自-(CH2)2N(CH3)-(CH2)nC≡C-、-(CH2)2N(CH3)-(CH2)nO-、-CH2N(CH3)-(CH2)nC≡C-、-CH2N(CH3)-(CH2)nO-、-(CH2)3N(CH3)-(CH2)nC≡C-、-(CH2)3N(CH3)-(CH2)nO-、-(CH2)nO-、-(CH2)nS-、-(CH2)nNH-、-(CH2)nC≡C-、-(CH2)nN(CH3)(CH2)nC≡C-或-(CH2)n-苯基-(CH2)nO-，其中n选自1-12；或者，所述n选自1-10；或者n选自1、2、3、4、5、6、7、8、9或10，或者任意两者组成的整数范围。Or, the L 2 is selected from -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n C≡C-, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) n O-, -CH 2 N(CH 3 )-(CH 2 ) n C≡C-, -CH 2 N(CH 3 )-(CH 2 ) n O-, -(CH 2 ) 3 N(CH 3 )-(CH 2 ) n C≡C-, -(CH 2 ) 3 N(CH 3 )-(CH 2 ) n O-, -(CH 2 ) n O-, -(CH 2 ) n S-, -(CH 2 ) n NH-, -(CH 2 ) n C≡C-, -(CH 2 ) n N(CH 3 )(CH 2 ) n C≡C- or -(CH 2 ) n -phenyl-(CH 2 ) n O-, where n is selected from 1-12; or, n is selected from 1-10; or n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or any The range of integers composed of the two. 如权利要求1-8任一项所述的化合物或其药学上可接受的盐，其中L选自-Cy-L3-X2-或-L2-，其中Cy及L2如权利要求7所述；The compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein L is selected from -Cy-L 3 -X 2 - or -L 2 -, wherein Cy and L 2 are as claimed in claim 7 described; L3选自1个或多个-CH2-任选地被选自-O-、苯基、-NH-、-N(C1-6烷基)-或-S-替换的-C1-20烷基-、-C2-20烯基-或-C2-20炔基-，所述-C1-20烷基-、-C2-20烯基-或-C2-20炔基-任选地被一个或多个取代基取代；任选的所述取代基选自以下基团：＝O、OH、NH2、卤素或CN；X2选自键、O或S；L 3 is selected from 1 or more -CH 2 -C 1 optionally selected from -O-, phenyl, -NH-, -N(C 1-6 alkyl)- or -S- -20 alkyl-, -C 2-20 alkenyl- or -C 2-20 alkynyl-, the -C 1-20 alkyl-, -C 2-20 alkenyl- or -C 2-20 alkyne Group - optionally substituted by one or more substituents; optionally the substituents are selected from the following groups: =O, OH, NH 2 , halogen or CN; X 2 is selected from bond, O or S; 或者，L3选自-C1-15烷基-、-C2-15烯基-或-C2-15炔基-，所述-C1-15烷基-、-C2-15烯基-或-C2-15炔基-任 选地被一个或多个＝O取代；Alternatively, L 3 is selected from -C 1-15 alkyl-, -C 2-15 alkenyl- or -C 2-15 alkynyl-, which is -C 1-15 alkyl-, -C 2-15 alkenyl Base-or-C 2-15 alkynyl-any optionally replaced by one or more =O; 任选地，L3选自-C1-12烷基-、-C2-12烯基-或-C2-12炔基-，所述-C1-12烷基-、-C2-12烯基-或-C2-12炔基-任选地被一个或多个＝O取代；Optionally, L 3 is selected from -C 1-12 alkyl-, -C 2-12 alkenyl- or -C 2-12 alkynyl-, -C 1-12 alkyl-, -C 2- 12Alkenyl -or-C 2-12Alkynyl -optionally substituted by one or more =O; 任选地L选自 Optionally L is selected from 任选地，结构部分-L3-X2-或-L2-选自-(CH2)3NH-、-(CH2)4NH-、-(CH2)5NH-、-(CH2)3O-、-(CH2)4O-、-(CH2)5O-、-(CH2)6O-、-(CH2)7O-、-(CH2)8O-、-(CH2)9O-、-(CH2)10O-、-(CH2)3S-、-(CH2)4S-、-(CH2)5S-、-(CH2)6S-、-(CH2)7S-、-(CH2)8S-、-(CH2)9S-、-(CH2)3C≡C-、-(CH2)4C≡C-、-(CH2)5C≡C-、-(CH2)6C≡C-、-(CH2)7C≡C-、-(CH2)8C≡C-、-(CH2)9C≡C-、-(CH2)2N(CH3)(CH2)3C≡C-或-CH2-苯基-CH2O-。Optionally, the moiety -L3 - X2- or -L2- is selected from -( CH2 ) 3NH- , -( CH2 ) 4NH- , -( CH2 ) 5NH- , -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 6 O-, -(CH 2 ) 7 O-, -(CH 2 ) 8 O- , -(CH 2 ) 9 O-, -(CH 2 ) 10 O-, -(CH 2 ) 3 S-, -(CH 2 ) 4 S-, -(CH 2 ) 5 S-, -(CH 2 ) 6 S-, -(CH 2 ) 7 S-, -(CH 2 ) 8 S-, -(CH 2 ) 9 S-, -(CH 2 ) 3 C≡C-, -(CH 2 ) 4 C ≡C-, -(CH 2 ) 5 C≡C-, -(CH 2 ) 6 C≡C-, -(CH 2 ) 7 C≡C-, -(CH 2 ) 8 C≡C-, -( CH 2 ) 9 C≡C-, -(CH 2 ) 2 N(CH 3 )(CH 2 ) 3 C≡C- or -CH 2 -phenyl-CH 2 O-. 如权利要求1-9任一项所述的化合物或其药学上可接受的盐，其中每一个R3分别独立地选自OH、The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from OH, NH2、CN、卤素、C1-2烷基或C1-2烷氧基；NH 2 , CN, halogen, C 1-2 alkyl or C 1-2 alkoxy; 或者，每一个R3分别独立地选自OH、NH2、氟、氯或甲基。Alternatively, each R 3 is independently selected from OH, NH 2 , fluorine, chlorine or methyl. 如权利要求1-10任一项所述的化合物或其药学上可接受的盐，其中p选自0、1或2；The compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof, wherein p is selected from 0, 1 or 2; 或者，p选自0或1；Alternatively, p is selected from 0 or 1; 或者，p选自0。Alternatively, p is selected from 0. 如权利要求1-11任一项所述的化合物或其药学上可接受的盐，其中X选自CH2；或者X选自C＝O。The compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein X is selected from CH2 ; or X is selected from C=O. 如权利要求1-12任一项所述的化合物或其药学上可接受的盐，其中X1选自CH；或者X1选自N。The compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof, wherein X1 is selected from CH; or X1 is selected from N. 如权利要求1-13任一项所述的化合物或其药学上可接受的盐，其中结构片段选自 The compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein the structural fragment Selected from 如权利要求1-14任一项所述的化合物或其药学上可接受的盐，其选自式II、II-A或II-B化合物或其药学上可接受的盐，

The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, which is selected from the group consisting of compounds of formula II, II-A or II-B or a pharmaceutically acceptable salt thereof,

X3及X4分别独立地选自N、NH、CH或CH2。X 3 and X 4 are each independently selected from N, NH, CH or CH 2 . 式III化合物或其药学上可接受的盐，
A compound of formula III or a pharmaceutically acceptable salt thereof,
其中，q、R2、R4、R5、m、环A、R3、p、X、X1的定义如权利要求1-15任一项所述；Wherein, q, R 2 , R 4 , R 5 , m, ring A, R 3 , p, X, X 1 are as defined in any one of claims 1 to 15; 每一个R11分别独立地选自氢、卤素、OH、NH2、CN、C1-6烷基、卤代C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述R11任选地被一个或多个取代基取代；Each R 11 is independently selected from hydrogen, halogen, OH, NH 2 , CN, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 1-6 alkyl OCO-, C 1-6 Alkyl C(O)O-, C 1-6 alkyl NHCO-, C 1-6 alkyl CONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkyl NHS(O)- , C 1-6 alkyl S(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S( O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 One-membered heterocyclic alkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the R 11 is optionally substituted by one or more substituents; k选自0、1、2或3；k is selected from 0, 1, 2 or 3; L选自-Cy-L1-；其中，Cy选自C3-10环烷基或3-10元杂环烷基，所述C3-10环烷基或3-10元杂环烷基任选地被一个或多个取代基取代；L is selected from -Cy-L 1 -; wherein, Cy is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, said C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl optionally substituted with one or more substituents; -L1-选自1个或多个-CH2-被C6-10芳基或5-10元杂芳基替换、且任选地1个或多个-CH2-被选自-O-、-NH-、-N(C1-6烷基)-或-S-替换的以下基团：-C1-20烷基-、-C2-20烯基-或-C2-20炔基-，所述-C1-20烷基-、-C2-20烯基-、或者-C2-20炔基-任选地被一个或多个取代基取代。-L 1 - is selected from 1 or more -CH 2 - replaced by C 6-10 aryl or 5-10 membered heteroaryl, and optionally 1 or more -CH 2 - is selected from -O The following groups replaced by -, -NH-, -N(C 1-6 alkyl)- or -S-: -C 1-20 alkyl-, -C 2-20 alkenyl- or -C 2-20 Alkynyl-, the -C 1-20 alkyl-, -C 2-20 alkenyl-, or -C 2-20 alkynyl- is optionally substituted by one or more substituents. 以下化合物或其药学上可接受的盐，
The following compounds or pharmaceutically acceptable salts thereof,
其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7、8、9或10；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
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其中，n为1、2、3、4、5、6、7或8；
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其中，n为1、2、3、4、5、6、7或8；
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其中，n为1、2、3、4、5、6、7或8；
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其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
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其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7或8；
Where, n is 1, 2, 3, 4, 5, 6, 7 or 8;
其中，n为1、2、3、4、5、6、7、8、9、10或11；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
其中，n为1、2、3、4、5、6、7、8、9、10或11；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
其中，n为1、2、3、4、5、6、7、8、9、10或11；
Where, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
其中，n为1、2、3、4、5、6、7或8。Where n is 1, 2, 3, 4, 5, 6, 7 or 8. 以下化合物或其药学上可接受的盐，



The following compounds or pharmaceutically acceptable salts thereof,



一种药物组合物，所述药物组合物含有权利要求1-18任一项所述的化合物或其药学上可接受的盐。A pharmaceutical composition containing the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof. 权利要求1-18任一项所述的化合物或其药学上可接受的盐、或权利要求19所述的药物组合物在制备预防或者治疗通过降解与靶向配体结合的靶蛋白而治疗的病症的药物中的用途。The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 is used in the preparation of a method for preventing or treating a disease treated by degrading a target protein bound to a targeting ligand. Use in medicines for medical conditions. 权利要求1-18任一项所述的化合物或其药学上可接受的盐、或权利要求19所述的药物组合物在制备预防或者治疗通过体内与小脑蛋白质结合而治疗的病症的药物中的用途。The compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19 in the preparation of medicaments for preventing or treating diseases treated by binding to cerebellar proteins in vivo use. 权利要求1-18任一项所述的化合物或其药学上可接受的盐、或权利要求19所述的药物组合物在制备预防或者治疗肿瘤的药物中的用途。 The use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for preventing or treating tumors.
PCT/CN2023/106784 2022-07-12 2023-07-11 Compound containing trifluoromethyl group WO2024012449A1 (en)

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