WO2024012449A1 - Composé contenant un groupe trifluorométhyle - Google Patents

Composé contenant un groupe trifluorométhyle 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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alkyl
alkenyl
compound
optionally
membered
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PCT/CN2023/106784
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English (en)
Chinese (zh)
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王斌
丰巍伟
汪纪楠
姚绎焱
盛化策
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正大天晴药业集团股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—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

La présente invention concerne un composé contenant un groupe trifluorométhyle, et concerne spécifiquement un composé tel que représenté par la formule I-0 ou un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation, une composition pharmaceutique contenant le composé, et son utilisation dans le traitement de maladies tumorales.
PCT/CN2023/106784 2022-07-12 2023-07-11 Composé contenant un groupe trifluorométhyle WO2024012449A1 (fr)

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WO2021066873A1 (fr) * 2019-10-03 2021-04-08 Newave Pharmaceutical Inc. Hétérocycles condensés en tant qu'inhibiteurs de bcl-2
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CN115141198A (zh) * 2022-09-01 2022-10-04 上海睿跃生物科技有限公司 降解蛋白的化合物及其应用和药物
WO2022266491A1 (fr) * 2021-06-18 2022-12-22 University Of Maryland, Baltimore Chimères ciblant la protéolyse et agents polypharmacologiques ciblant bcl -2, et leurs procédés d'utilisation
CN116396288A (zh) * 2022-01-04 2023-07-07 上海科技大学 基于bcl-2家族蛋白配体化合物开发的蛋白降解剂及它们的应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017184995A1 (fr) * 2016-04-21 2017-10-26 Bioventures, Llc Composés induisant la dégradation de protéines anti-apoptotiques de la famille bcl-2 et utilisation de ces derniers
WO2020081880A1 (fr) * 2016-04-21 2020-04-23 Bioventures, Llc Compositions ciblant des cellules sénescentes et leurs utilisations
CN112105360A (zh) * 2018-01-22 2020-12-18 生物风险投资有限责任公司 用于癌症治疗的bcl-2蛋白降解剂
WO2020088442A1 (fr) * 2018-10-29 2020-05-07 正大天晴药业集团股份有限公司 Sulfonamide à substitution trifluorométhyle tenant lieu d'inhibiteur bcl-2-sélectif
WO2020238785A1 (fr) * 2019-05-24 2020-12-03 正大天晴药业集团股份有限公司 Inhibiteur de bcl-2 sélectif à base de sulfonamide disubstitué contenant du méthyle et du trifluorométhyle
WO2021066873A1 (fr) * 2019-10-03 2021-04-08 Newave Pharmaceutical Inc. Hétérocycles condensés en tant qu'inhibiteurs de bcl-2
CN112707900A (zh) * 2019-10-24 2021-04-27 上海科技大学 蛋白降解剂及其在疾病治疗中的应用
WO2022266491A1 (fr) * 2021-06-18 2022-12-22 University Of Maryland, Baltimore Chimères ciblant la protéolyse et agents polypharmacologiques ciblant bcl -2, et leurs procédés d'utilisation
CN116396288A (zh) * 2022-01-04 2023-07-07 上海科技大学 基于bcl-2家族蛋白配体化合物开发的蛋白降解剂及它们的应用
CN115141198A (zh) * 2022-09-01 2022-10-04 上海睿跃生物科技有限公司 降解蛋白的化合物及其应用和药物

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