WO2023036330A1 - Tricyclic compound as cbl-b inhibitor - Google Patents

Tricyclic compound as cbl-b inhibitor Download PDF

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Publication number
WO2023036330A1
WO2023036330A1 PCT/CN2022/118398 CN2022118398W WO2023036330A1 WO 2023036330 A1 WO2023036330 A1 WO 2023036330A1 CN 2022118398 W CN2022118398 W CN 2022118398W WO 2023036330 A1 WO2023036330 A1 WO 2023036330A1
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Prior art keywords
alkyl
membered
cycloalkyl
group
optionally substituted
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PCT/CN2022/118398
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French (fr)
Chinese (zh)
Inventor
麦万笋
刘晓武
祝伟
邹昊
李正涛
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先声再明医药有限公司
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Priority to CN202280061625.1A priority Critical patent/CN117940404A/en
Publication of WO2023036330A1 publication Critical patent/WO2023036330A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles

Definitions

  • Patent application No. 202111070011.3 submitted to the State Intellectual Property Office of China on September 13, 2021;
  • Patent application No. 202210103247.0 submitted to the State Intellectual Property Office of China on January 27, 2022;
  • Patent application No. 202210532103.7 filed with the State Intellectual Property Office of China on May 07, 2022;
  • Patent application No. 202210895442.1 submitted to the State Intellectual Property Office of China on July 26, 2022.
  • the present application relates to a tricyclic compound or its stereoisomer or its pharmaceutically acceptable salt as a Cbl-b inhibitor, its preparation method, and a pharmaceutical composition containing the compound or its stereoisomer or its pharmaceutically acceptable salt , and use of the compound or its stereoisomer or pharmaceutically acceptable salt thereof in the prevention or treatment of diseases or disorders mediated by Cbl-b.
  • Intracellular signal cascades are usually regulated by protein phosphorylation, and gene expression and regulation are affected by epigenetics, and the proteins that regulate these signals are themselves subject to the "production-degradation" balance of intracellular proteins regulation to maintain cellular homeostasis.
  • protein degradation mainly through two pathways: lysosomal degradation pathway and ubiquitin-mediated proteasomal degradation pathway.
  • the ubiquitin-mediated pathway is a specific protein degradation pathway subject to strict spatiotemporal regulation.
  • the ubiquitin system widely exists in eukaryotes and is a precise regulatory system for intracellular protein degradation.
  • Ubiquitin (Ub) is a highly conserved small protein present in most eukaryotic cells.
  • the ubiquitin system consists of ubiquitin, 26S proteasome, and various enzymes (E1, E2, E3, and deubiquitinase, etc.).
  • the ubiquitination of protein is through the E1-E2-E3 level involving ubiquitin activating enzyme E1 (ubactivating enzyme, E1), ubiquitin conjugating enzyme E2 (Ub conjugating enzyme, E2), ubiquitin ligase E3 (Ub ligase, E3)
  • E1 activating enzyme
  • E2 Ub conjugating enzyme
  • E3 ubiquitin ligase
  • the cascade reaction is completed, and then the ubiquitinated protein is degraded by the 26S proteasome (A patent review of the ubiquitin ligase system:2015-201 Expert Opin Ther Pat.2018,28(12):919–937).
  • the human genome encodes approximately 35 E2-conjugating enzymes and more than 500 E3 ligases.
  • Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is an E3 ligase that negatively regulates T cell activation.
  • Cbl-b belongs to the Cbl family, which includes c-Cbl, Cbl-b, and Cbl-3 (Cbl:many adaptations to regulate protein tyrosine kinases.Nat.Rev.Mol.Cell Biol.2:294–307).
  • Cbl protein mainly negatively regulates T cell activation, growth factors (such as epidermal growth factor receptor (EGFR), c-KIT, platelet-derived growth factor receptor (PDGFR) and non-receptor tyrosine kinase signaling (such as Src family kinases and Zap70) (Regulating the regulator: Negative regulation of Cbl ubiquitin ligases. Trends Biochem Sci 31:79–88; The Cbl family proteins: Ring leaders in regulation of cell signaling. J Cell Physiol.209:21–43). Functional inactivation of Cbl proteins is associated with human cancers (Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.
  • Cbl-b is important in establishing T cell activation thresholds and control of peripheral T cell tolerance, accumulating evidence suggests that Cbl-b also regulates innate immune responses and plays an important role in host defense against pathogens.
  • Cbl-b knockout mice show Severe autoimmune diseases (Negative regulation of lymphocyte activation and autoimmunity by the molecular adapter Cbl-b. Nature 403:211–216). Therefore, Cbl-b can be used as an important immunomodulatory therapeutic target.
  • the application relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof,
  • Z and Z are independently selected from CR a or N;
  • Z is selected from C, CH or N;
  • Y 1 , Y 2 , Y 3 and Y 4 are independently selected from CR b or N;
  • R b is selected from H, halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, NH 2 , NH(C 1 -C 6 alkyl ), N(C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHS(O) 2 (C 1 -C 6 alkyl), C 3 -C 6 cycloalkane group, C 3 -C 6 cycloalkyl-O-, C 3 -C 6 cycloalkyl-NH-, N(C 3 -C 6 cycloalkyl) 2 , NHC(O)-C 3 -C 6 ring Alkyl, NHS(O) 2 -C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, N(
  • R b and the C atoms connected to them jointly form a C 3 -C 6 cycloalkenyl group, a phenyl group, a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, and the C 3 -C 6 cycloalkenyl group , phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally substituted by R 2a ;
  • R a , R 4 , R 5 , R 7 , R 8 and R 9 are independently selected from H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, and the C 1 - C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted by R 4a ;
  • R 6a is selected from H, C 1 -C 6 alkyl, phenyl, 4-7 membered heterocyclic group or 5-6 membered heteroaryl, said C 1 -C 6 alkyl, phenyl, 4-7 membered Heterocyclyl or 5-6 membered heteroaryl is optionally further substituted by R 6b , or 2 R 6a on one N atom form a 4-7 membered heterocyclic group or 5-6 membered heteroaryl together with the N connected to it , the 4-7 membered heterocyclic group or 5-6 membered heteroaryl group is optionally further substituted by R 6b ;
  • Q is phenyl or 6-membered heteroaryl, and said phenyl or 6-membered heteroaryl is optionally substituted by R 10 ;
  • R 10 is selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclic group, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl are optionally substituted by R 10a ;
  • R c and R 11 and their respective connected atoms together form a 4-7 membered heterocyclic group, and the 4-7 membered heterocyclic group is optionally substituted by R 11c ;
  • R 1 and R 2 are independently selected from H, halogen, CN, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclic group, wherein said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 Cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R 1a ,
  • W is selected from (CR 12 R 13 ) k W 1 , said W 1 is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclic group, said 5-10 membered heteroaryl, 4-10 membered heterocyclic group
  • the ring group is optionally substituted by R 14 , R 12 and R 13 are independently selected from H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, R 14 is selected from halogen, OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl, wherein The C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R 14a ;
  • the group is optionally substituted by R 12a ;
  • R 8a and R 12a are independently selected from halogen, OH, CN, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, the C 1 -C 6 alkyl or C 1 -C 6 alkoxy
  • p and k are independently selected from 0 or 1.
  • R b is selected from H, halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , NH(C 1 -C 6 alkyl), N (C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHS(O) 2 (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-O-, C 3 -C 6 cycloalkyl-NH-, N(C 3 -C 6 cycloalkyl) 2 , NHC(O)-C 3 -C 6 cycloalkyl, NHS(O) 2 -C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, N(4-7 membered Heterocycl
  • Z1 and Z2 are independently selected from CH or N.
  • both Z1 and Z2 are CH.
  • Z 1 is CH and Z 2 is N.
  • Z1 is N and Z2 is CH.
  • Z is selected from C or CH.
  • Z is C.
  • Y 1 , Y 2 , Y 3 and Y 4 are all CR b .
  • Y1 , Y2 , Y3 , and Y4 are all CH.
  • Y 1 and Y 2 are independently selected from CR b or N, and Y 3 and Y 4 are both CR b .
  • Y 1 and Y 2 are independently selected from CH or N, Y 3 is CH, and Y 4 is CR b .
  • Y and Y are independently selected from CH or N, and both Y and Y are CH.
  • Y 1 and Y 2 are both N, and Y 3 and Y 4 are both CR b .
  • Y 1 and Y 2 are both N, Y 3 is CH, and Y 4 is CR b .
  • both Y1 and Y2 are N, and both Y3 and Y4 are CH.
  • Y 1 is N and Y 2 , Y 3 and Y 4 are all CR b .
  • Y 1 is N
  • Y 2 and Y 3 are both CH
  • Y 4 is CR b .
  • Y1 is N and Y2 , Y3 , and Y4 are all CH.
  • Y 4 is N and Y 1 , Y 2 and Y 3 are all CR b .
  • Y 4 is N and Y 1 , Y 2 and Y 3 are all CH.
  • R b is selected from H, halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-O-, C 3 -C 6 cycloalkyl- NH-, 4-7 membered heterocyclyl-O-, 4-7 membered heterocyclic group-NH- or 5-10 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 alkylthio, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted by R 2a .
  • R b is selected from H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl-O-, C 3 -C 6 cycloalkyl-NH-, 4-7 membered heterocyclyl-O-, 4-7 membered heterocycle Group -NH- or 5-10 membered heteroaryl, wherein said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclic Or 5-10 membered heteroaryl is optionally substituted by R 2a .
  • R b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH(C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl -O-, C 3 -C 6 cycloalkyl-NH-, 4-7 membered heterocyclyl-O-, 4-7 membered heterocyclyl-NH- or 5-6 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally substituted by R 2a .
  • R b is selected from H, halogen, or the following groups optionally substituted by R 2a : methyl, ethoxy, NHCH 3 , NHEt, NH(i-Pr), pyrazolyl, cyclopropyl -O-, cyclobutyl-NH- or oxetanyl-O-.
  • R 2a is selected from halogen, OH, or C 1 -C 3 alkyl.
  • R 2a is selected from F, OH or methyl.
  • Rb is selected from H, F, Cl, CN, CH3S- , methyl, CF3 , ethoxy, OCH2CHF2 , NHCH3 , NHEt, NH(i-Pr), NHCH 2 CH 2 OH, cyclopropyl,
  • Rb is selected from H, F, methyl, CF3 , ethoxy , OCH2CHF2 , NHCH3 , NHEt, NH(i-Pr), NHCH2CH2OH ,
  • R b is selected from H, F, CF 3 , ethoxy, OCH 2 CHF 2 , NHCH 3 , NHEt, NH(i-Pr), NHCH 2 CH 2 OH,
  • X is selected from
  • ring B is selected from the following groups optionally substituted by R : 5-10 membered nitrogen-containing heteroaryl, 4-7 membered monocyclic nitrogen-containing heterocyclyl, or 6-10 membered nitrogen-containing heterocyclyl Ring base.
  • ring B is selected from the following groups optionally substituted by R : pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, aza Cyclobutyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azepanyl,
  • Ring B is selected from the group consisting of pyrazolyl , azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, aza Cycloheptyl,
  • R 3a is selected from F, OH or methoxy.
  • R 4a is selected from halogen, OH, or C 1 -C 3 alkoxy.
  • R 4a is selected from F.
  • p is selected from 1.
  • p is selected from zero.
  • ring D is selected from the following groups optionally substituted by R 6 : C 3 -C 6 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered monocyclic heterocyclyl, or 6- 10-membered heterocyclic group, and the ring D is connected to L through a non-N atom.
  • ring D is selected from the following groups optionally substituted by R : cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, Pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl or isothiazolyl.
  • L is selected from a bond, -NR 7 -, -NR 7 CR 8 R 9 -, -O-, or -CR 8 R 9 -.
  • L is selected from a bond, -NR 7 -, -NR 7 CH 2 -, -O-, or -CR 8 R 9 -.
  • R 7 , R 8 and R 9 are independently selected from H, C 1 -C 3 alkyl, or OH.
  • R7 is selected from H or methyl.
  • R 8 , R 9 are selected from H or methyl.
  • R 8 , R 9 are selected from H.
  • L is selected from a bond, -NCH3- , -NHCH2- , -NHCH( CH3 )-, -O-, or -CH2- .
  • L is selected from a bond, -NCH3- , -NHCH2- , -O-, or -CH2- .
  • X is selected from the following groups:
  • X is selected from
  • Q is phenyl or 6-membered heteroaryl optionally substituted with R 10 .
  • Q is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, optionally substituted by R 10 .
  • Q is phenyl, pyridyl, pyridazinyl, or pyrimidinyl, optionally substituted by R 10 .
  • Q is phenyl optionally substituted with R 10 .
  • R 10 is selected from halogen, OH, CN, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, said C 1 -C 6 alkyl or C 1 -C 6 alkoxy The group is optionally substituted by R 10a .
  • R 10 is selected from halogen , C 1 -C 3 alkyl or C 1 -C 3 alkoxy, which is optionally replaced by R 10a is substituted.
  • R 10a is selected from halogen, OH, or C 1 -C 3 alkyl.
  • R 10a is selected from F or OH.
  • R 10 is selected from F, Cl, methyl, methoxy, CH 2 OH, or CF 3 .
  • Q is phenyl optionally substituted with halo.
  • Q is selected from wherein Z 4 and Z 5 are independently selected from CR c R d , NR 11 , O, S or SO 2 , represents a single or double bond, and when When it is a double bond, m is 1, when When it is a single bond, m is 1 or 2.
  • R c and R 11 and the atoms to which they are each attached together form a 4-7 membered heterocyclyl optionally substituted with R 11c .
  • both Rc and Rd together with the atoms to which they are attached, form cyclopropyl.
  • Q is selected from m is 1 or 2.
  • Q is selected from m is 1.
  • Q is selected from
  • Q is selected from phenyl, Wherein a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
  • Q is selected from phenyl, Wherein a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
  • Q is selected from phenyl
  • a represents the bond shared by Q and the 6-membered ring in the parent core
  • b represents the bond shared by Q and the 5-membered ring in the parent core
  • Q is selected from Wherein a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
  • Q is selected from Where a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
  • Q is selected from phenyl, Where a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
  • Q is selected from phenyl or Wherein a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
  • R 1 and R 2 together form a C 3 -C 8 cycloalkyl group or a 4-10 membered heterocyclic group, and the C 3 -C 8 cycloalkyl group or a 4-10 membered heterocyclic group Cyclic is optionally substituted by R 1b .
  • R 1 and R 2 together form a C 3 -C 6 cycloalkyl or a 4-7 membered heterocyclyl, and the C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl Cyclic is optionally substituted by R 1b .
  • R 1 , R 2 and the atoms to which they are attached together form a group optionally substituted by R 1b : cyclobutyl, spiro[2,3]hexyl, or oxetanyl.
  • R 1b is selected from halogen, CN, C 1 -C 3 alkyl or C 1 -C 3 alkoxy, and the C 1 -C 3 alkyl or C 1 -C 3 alkoxy is any is replaced by R 1c .
  • R 1c is selected from halogen, OH or CN.
  • R 1c is selected from CN.
  • R 1b is selected from F, CN, methyl, methoxy, or CH 2 CN.
  • R 1 and R 2 are independently selected from H, halogen, CN, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 4-7 membered heterocyclic group, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R 1a , and the C 3 -C 8 cycloalkyl or 4-7 membered heterocyclic group may be a spiro ring, bridged ring or in ring form.
  • R and R are independently selected from H, halogen, CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or C 3 -C 6 cycloalkyl, the C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 3 -C 6 cycloalkyl is optionally substituted by R 1a .
  • R 1 and R 2 are independently selected from H, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, said C 1 -C 3 alkyl or C 3 -C 6 cycloalkane The group is optionally substituted by R 1a .
  • R 1 and R 2 are independently selected from H, methyl, isopropyl, cyclopropyl or cyclobutyl, or R 1 , R 2 and the atoms to which they are attached together form the following group:
  • R 1 and R 2 are independently selected from H, methyl, isopropyl or cyclobutyl, or R 1 , R 2 and the atoms to which they are attached together form the following group:
  • R 1 and R 2 are independently selected from H, methyl or cyclobutyl, or R 1 , R 2 and the atoms to which they are attached together form the following group:
  • R 1 , R 2 and the atoms to which they are attached together form the following group:
  • R 1 , R 2 and the atoms to which they are attached together form the following group:
  • R 1 , R 2 and the atoms to which they are attached together form the following group:
  • R 1 , R 2 and the atoms to which they are attached together form the following group:
  • R and R are independently selected from H, methyl, isopropyl, or cyclobutyl.
  • R and R are independently selected from H, methyl, or cyclobutyl.
  • W is selected from -(CR 12 R 13 )W 1 .
  • R 12 , R 13 are independently selected from H, halogen, OH or methyl.
  • R 12 , R 13 are independently selected from H or F.
  • both R 12 and R 13 are H.
  • R 1 and R 12 together with the atoms and bonds to which they are attached form a C 3 -C 6 cycloalkyl optionally substituted with R 12a .
  • R 12a is selected from C 1 -C 3 alkyl.
  • R 12a is selected from methyl.
  • R and R together with the atoms and bonds to which they are attached form
  • W is selected from W 1 .
  • W is selected from 4-10 membered heterocyclyl optionally substituted by R.
  • W is selected from 5-10 membered heteroaryl optionally substituted by R.
  • W is selected from 5-membered heteroaryl optionally substituted with R.
  • W is selected from the following groups optionally substituted by R : pyrrole, thiophene, furan, pyrazole, imidazole, thiazole, isothiazole, thiadiazole, triazole, oxazole, isoxazole Azole, oxadiazole,
  • W 1 is selected from triazole, oxazole, isoxazole, or oxadiazole, optionally substituted by R 14 .
  • W is selected from the following groups optionally substituted by R :
  • R 14 is selected from halogen, OH, NH 2 , C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, said C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl Alkyl is optionally substituted by R 14a .
  • R 14 is selected from OH, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, the C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl optionally replaced by R 14a is substituted.
  • R 14 is selected from methyl or cyclopropyl optionally substituted with R 14a .
  • R 14a is selected from halogen, OH or CN.
  • R 14a is selected from F.
  • R 14 is selected from methyl, CHF 2 or cyclopropyl.
  • W is selected from the following groups:
  • W is selected from
  • W is selected from
  • Z 1 and Z 2 are independently selected from CH or N;
  • Z 3 is selected from C or CH;
  • Y 1 , Y 2 and Y 3 are all CH and Y 4 is CR b ; or
  • Y 1 is N, Both Y 2 and Y 3 are CH, and Y 4 is CR b ; or
  • Y 4 is N and Y 1 , Y 2 and Y 3 are all CH;
  • R b is selected from H, halogen, CN, C 1 -C 6 alkane Group, C 1 -C 6 alkylthio, NH (C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl;
  • X is selected from Q is selected from phenyl optionally substituted by R 10 or 6-membered nitrogen-containing heteroaryl optionally substituted by R 10 , or
  • Q is selected from
  • Wherein a represents the bond shared by Q and the 6-membered ring in the core, b represents the bond shared
  • Z 1 and Z 2 are both CH;
  • Z 3 is selected from C or CH;
  • Y 1 , Y 2 , Y 3 and Y 4 are all CH, Y 1 , Y 2 and Y 3 are all CH and Y 4 is CR b , or Y 1 is N, Y 2 and Y 3 are both CH, and Y 4 is CR b , or Y 4 is N and Y 1 , Y 2 and Y 3 are all CH;
  • R b is selected from H, halogen, CN or methyl;
  • X is Q from Or phenyl optionally substituted by halogen, wherein a represents the bond shared by Q and the 6-membered ring in the parent nucleus, and b represents the bond shared by Q and the 5-membered ring in the parent nucleus;
  • R 1 , R 2 are connected to the atom Together form cyclobutyl substituted by R 1b ,
  • R 1b is selected from halogen and C
  • the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof of the present application is selected from the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt:
  • j is selected from 0, 1, 2 or 3
  • Z 1 , Z 2 , Y 1 , Y 2 , Y 3 , Y 4 , X, W, R 1 , R 2 and R 10 are as shown in formula (I) definition.
  • the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof of the present application is selected from the compound of formula (III) or its stereoisomer or its pharmaceutically acceptable salt:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Y 1 , Y 2 , Y 3 , Y 4 , X, W, R 1 , R 2 and m are as defined in formula (I).
  • the compound of formula (I) of the present application or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or its pharmaceutically acceptable salt:
  • the application provides a pharmaceutical composition, which comprises the compound of formula (I), compound of formula (II), compound of formula (III) or its stereoisomer or pharmaceutically acceptable salt thereof and pharmaceutically Acceptable excipients.
  • the present application provides a method for treating a disease or condition mediated by Cbl-b in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I), formula (II) to a mammal in need of the treatment, preferably a human being ) compound, compound of formula (III) or its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present application provides a method for treating tumors or autoimmune diseases in mammals, comprising administering a therapeutically effective amount of a compound of formula (I), compound of formula (II), compound of formula (III) A compound or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present application provides compounds of formula (I), compounds of formula (II), compounds of formula (III) or their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of prevention or treatment of breastfeeding Use in medicine for diseases or conditions mediated by Cbl-b in animals, preferably humans.
  • the present application provides compounds of formula (I), compounds of formula (II), compounds of formula (III) or their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of prevention or treatment of breastfeeding Use in medicine for tumors or autoimmune diseases in animals, preferably humans.
  • the application provides compounds of formula (I), compounds of formula (II), compounds of formula (III) or their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the prevention or treatment of mammals , preferably human diseases or disorders mediated by Cbl-b.
  • the application provides compounds of formula (I), compounds of formula (II), compounds of formula (III) or their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the prevention or treatment of mammals , preferably for use in human tumors or autoimmune diseases.
  • the application provides a compound of formula (I), a compound of formula (II), a compound of formula (III) or its stereoisomer for preventing or treating mammals, preferably human, diseases or diseases mediated by Cbl-b. Constructs or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
  • the present application provides a compound of formula (I), a compound of formula (II), a compound of formula (III) or its stereoisomer or its A pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • the disease or condition mediated by Cbl-b is selected from tumors or autoimmune diseases.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. Compounds of the present application may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. This application encompasses all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present application may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present application may exist in specific geometric or stereoisomer forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof fall within the definition of the compounds of the present application.
  • asymmetric carbon atoms there may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included in Within the definition of the compounds of the present application.
  • the compounds containing asymmetric atoms of the present application can be isolated in optically pure form or racemic form, optically active form can be resolved from racemic mixture, or synthesized by using chiral raw materials or chiral reagents .
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • ethyl is “optionally” substituted with halogen , meaning that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted ( CH2CH2F , CH2CH2Cl , etc.), polysubstituted ( CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc. ) or fully substituted ( CF2CF3 , CF2CCl3 , CCl2CCl3 , etc.) . It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • any variable eg R 1a , R 2a
  • its definition is independent at each occurrence. For example, if a group is substituted by 2 R 1a , each R 1a has independent options.
  • linking group When the number of a linking group is 0, such as -(CR 12 R 13 ) 0 -, it means that the linking group is a bond.
  • linking group mentioned herein does not indicate its linking direction
  • its linking direction is arbitrary.
  • L in is selected from “-NR 7 CH 2 -”
  • L can be connected to ring D from left to right to form “ring D-NR 7 CH 2 -”
  • the direction of linking ring D constitutes "ring D-CH 2 NR 7 -”.
  • the substituent may be bonded to any atom on the ring.
  • the structural unit It means that R 10 can be substituted at any one of positions 1, 2, and 3 on the benzene ring.
  • Cm - Cn herein refers to having an integer number of carbon atoms in the range of mn.
  • C 1 -C 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.
  • alkyl refers to a hydrocarbon group having the general formula C n H 2n+1 , and the alkyl group may be straight or branched.
  • C 1 -C 6 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.
  • C 1 -C 3 alkyl is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms.
  • the "C 1 -C 6 alkyl group” may include “C 1 -C 3 alkyl group”.
  • alkoxy refers to a monovalent group produced by the loss of a hydrogen atom on a hydroxyl group of a straight-chain or branched alcohol, which can be understood as “alkyloxy” or “alkyl-O-”.
  • C 1 -C 6 alkoxy can be understood as “C 1 -C 6 alkyloxy” or “C 1 -C 6 alkyl-O-”; the term “C 1 -C 3 alkoxy” Can be understood as “C 1 -C 3 alkyloxy” or "C 1 -C 3 alkyl-O-”.
  • the "C 1 -C 6 alkoxy” may further include "C 1 -C 3 alkoxy”.
  • cycloalkyl refers to a fully saturated carbocyclic ring in the form of a monocyclic ring, a double ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monovalent monocyclic, fused, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbons atom.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2 .1] heptyl), bicyclo [2.2.2] octyl, adamantyl, spiro [4.5] decanyl, etc.
  • C 3 -C 10 cycloalkyl may include “C 3 -C 8 cycloalkyl", “C 3 -C 8 cycloalkyl” may include “C 3 -C 6 cycloalkyl”, “C 3 -C 6 cycloalkyl” may include “C 3 -C 4 cycloalkyl”.
  • C 3 -C 6 cycloalkyl can be understood as meaning a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms, specific examples include but are not limited to cyclopropyl, cyclo Butyl, cyclopentyl or cyclohexyl, etc.
  • cycloalkyloxy can be understood as “cycloalkyl-O-”.
  • cycloalkenyl refers to a non-aromatic monocyclic or polycyclic hydrocarbon group containing at least one carbon-carbon double bond.
  • C 3 -C 6 cycloalkenyl refers to a non-aromatic cyclic hydrocarbon having 3, 4, 5 or 6 carbon atoms as ring atoms and containing at least one carbon-carbon double bond.
  • Specific examples of C 3 -C 6 cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.
  • 4-10 membered heterocyclic group refers to a heterocyclic group with 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1, 2, 3, 4 or 5 independent selected from the heteroatoms or heteroatom groups described above.
  • the term "4-10 membered nitrogen-containing heterocyclic group” refers to a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic group containing at least one N atom in its ring atoms.
  • 4-7 membered monocyclic nitrogen-containing heterocyclic group refers to a 4, 5, 6 or 7-membered heterocyclic group in the form of a monocyclic ring containing at least one N atom.
  • “4-10 membered heterocyclic group” includes “6-10 membered heterocyclic group”, “6-10 membered heterocyclic group” further includes “6-7 membered heterocyclic group”, wherein, the specific Examples include, but are not limited to, azetidinyl, thietanyl, or oxetanyl; specific examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include, but are not limited to Tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridyl or
  • the heterocyclic group can also be a bicyclic group, wherein, specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; 5,6-membered bicyclic group Specific examples include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • the heterocyclic group may be a benzofused cyclic group of the above-mentioned 4-7 membered heterocyclic group, specific examples include but not limited to dihydroisoquinolyl and the like.
  • “4-10 membered heterocyclic group” may include “5-10 membered heterocyclic group”, “4-7 membered heterocyclic group”, “5-6 membered heterocyclic group”, “6-8 membered heterocyclic group” , “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered "Heterocycloalkyl” and other ranges, "4-7 membered heterocyclyl” may further include "4-6 membered heterocyclyl", “5-6 membered heterocyclyl”, “4-7 membered heterocyclyl” , “4-6 membered heterocycloalkyl", "5-6 membered
  • heterocyclyloxy can be understood as “heterocyclyl-O-”.
  • 4-10 membered heterocycloalkyl refers to a heterocycloalkyl group with 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1, 2, 3, 4 or 5 independently selected from the heteroatoms or heteroatom groups described above.
  • 4-membered heterocycloalkyl includes “4-7 membered heterocycloalkyl", wherein specific examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl or thibutanyl; Specific examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, or tetrahydrofuranyl.
  • 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thiaxanyl , 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, or 1,4-dithianyl; specific examples of 7-membered heterocycloalkyl include, but are not limited to, aza Cycloheptyl, oxepanyl or thiepanyl.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • Aryl groups can have 6-14 carbon atoms or 6-10 carbon atoms.
  • C 6 -C 10 aryl is understood as a monovalent aromatic monocyclic or bicyclic group having 6 to 10 carbon atoms.
  • rings having 6 carbon atoms such as phenyl; or rings having 10 carbon atoms (“C 10 aryl”), such as naphthyl.
  • aryloxy is understood to mean “aryl-O-”.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S.
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazole Linyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
  • cinnolinyl phthalazinyl, quinazolinyl, quinoxalinyl, naphthalene Pyridyl, pteridyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, etc.
  • the term "5-10 membered nitrogen-containing heteroaryl” refers to a 5, 6, 7, 8, 9 or 10 membered heteroaryl group containing at least one N atom in its ring atoms.
  • 5-6 membered heteroaryl refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1, 2 or 3, preferably 1 or 2, heteroatoms independently selected from N, O and S .
  • 6-membered heteroaryl refers to an aromatic ring system having 6 ring atoms and which contains 1, 2 or 3, preferably 1 or 2 N as heteroatoms.
  • 5-10 membered heteroaryl includes “5-6 membered heteroaryl”.
  • heteroaryloxy is understood to mean “heteroaryl-O-”.
  • halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • hydroxyl refers to a -OH group.
  • cyano refers to a -CN group.
  • mercapto refers to a -SH group.
  • amino refers to a -NH2 group.
  • nitro refers to a -NO2 group.
  • terapéuticaally effective amount means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying the The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder.
  • 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 a person skilled in the art according to its own knowledge and 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 tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of pharmaceutically acceptable acids or bases, including salts formed between compounds and inorganic or organic acids, and salts formed between compounds and inorganic or organic bases.
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the invention to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will 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 and the like.
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally 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 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.
  • Certain isotopically labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (ie3H ) and carbon-14 (ie14C ) isotopes are especially preferred for 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 following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administering a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, emulsifying methods, freeze-drying methods and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
  • the daily dosage is 0.01 mg/kg to 200 mg/kg body weight, preferably 0.05 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 30 mg /kg body weight, 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, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art In an equivalent alternative, preferred implementations include but are not limited to the examples of the present application.
  • some compounds of the general formula (II) of the present application can be prepared by those skilled in the field of organic synthesis through the following synthetic route 1:
  • X' is halogen
  • R is C 1 -C 3 alkyl
  • Ring B Z 1 , Z 2 , Y 1 , Y 2 , Y 3 , Y 4 , W, R 1 , R 2 , R 10 and j as defined in formula (II).
  • some compounds of the general formula (III) of the present application can be prepared by those skilled in the field of organic synthesis through the following synthetic route 2:
  • X' is halogen
  • R is C 1 -C 3 alkyl
  • Ring B, Z 1 , Z 2 , Z 4 , Z 5 , Y 1 , Y 2 , Y 3 , Y 4 , W, R 1 and R 2 is as defined in formula (III).
  • some compounds of the general formula (II) of the present application can be prepared by those skilled in the field of organic synthesis through the following synthetic route 3:
  • X' is halogen
  • ring B, Z 1 , Z 2 , Y 1 , Y 2 , Y 3 , Y 4 , W, R 1 , R 2 , R 10 and j are as defined in formula (II).
  • ratios indicated for mixed solvents are volume mixing ratios. Unless otherwise stated, % means wt%.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • EtOH ethanol
  • MeCN acetonitrile
  • TsCl p-toluenesulfonyl chloride
  • TEA triethylamine
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIEA or DIPEA N,N-diisopropylethyl Amine
  • DMF N,N-dimethylformamide
  • PivOH trimethylacetic acid
  • DEAD diethyl azodicarboxylate
  • TFE trifluoroethanol
  • Brettphos Pd G3 methanesulfonic acid (2-dicyclohexyl Phosphine)-3,6-dimethoxy-2',4',6'-triiso
  • the following eluents can be mixed eluents formed by two or more solvents, and the ratio is the volume ratio of each solvent.
  • “0-10% methanol/dichloromethane” means that in the gradient elution process, mixed eluents
  • the volume ratio of methanol and dichloromethane in the mixture is 0:100 ⁇ 10:100.
  • Step 1 Preparation of methyl 1-(3-bromophenyl)-3-methylcyclobutyl-1-carboxylate (1B)
  • the reaction mixture was poured into 160 mL of water to precipitate a solid, filtered, and the solid was first washed with 200 mL of saturated aqueous sodium bicarbonate solution, then washed with 200 mL of water, filtered and dried to obtain an intermediate.
  • 52mL of 1.4mol/L sodium hydroxide aqueous solution Raise the temperature to 100°C and react for 3 hours, then spin dry the ethanol.
  • Add 3 mL of concentrated hydrochloric acid to the reaction solution, and a solid precipitates out.
  • the filter cake is washed with water and dried to obtain a yellow solid.
  • 300 mL of ethyl acetate was added, stirred overnight at room temperature, filtered, and the filtrate was concentrated to obtain the title compound 1J (1.6 g) as a white solid.
  • Step 12 (S)-1-(3-(3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)- Preparation of 4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (Compound 1)
  • the reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was spin-dried.
  • 6-bromo-1,2,3,4-tetrahydronaphthalene-1-amine (2A, 0.8g, 3.5mmol) was dissolved in N,N-dimethylformamide (10mL), followed by Add 2-pyridinecarboxylic acid (522.7mg, 4.3mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.0g, 5.3 mmol) and N,N-diisopropylethylamine (1.4g, 10.6mmol), add ethyl acetate (50ml) after reacting for 1 hour, and wash with water (30mlx3), the organic phase is dried with anhydrous sodium sulfate, filtered , the filtrate was concentrated.
  • 2-pyridinecarboxylic acid 522.7mg, 4.3mmol
  • Step 5 4-(((S)-3-Methylpiperidin-1-yl)methyl)-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one Preparation of (2F)
  • Step 6 1-(3-(3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-((( Preparation of S)-3-methylpiperidin-1-yl)methyl)-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (Compound 2)
  • reaction solution was cooled to room temperature, 100 mL of acetone was added, filtered, the solid was washed with acetone, and the filtrate was evaporated to dryness to obtain 420 mg of the crude product of the title compound in the form of light yellow gum, which was directly used in the next reaction.
  • Step 4 (S)-6-Fluoro-1-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)benzene base)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 3)
  • Step 2 Preparation of 1-((1-(2-chloropyridin-4-yl)-3-methylcyclobutylcarbonyl)amino)-3-methylthiourea (54C)
  • Step 3 5-(1-(2-Chloropyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (54D ) preparation
  • Step 4 Preparation of 2-chloro-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (54E)
  • Step 5 (S)-6-Fluoro-1-(4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl) Preparation of pyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 54)
  • Step 1 Preparation of methyl 1-(5-bromopyridin-3-yl)-3-methylcyclobutyl-1-carboxylate (55A)
  • Step 3 Preparation of 2-(1-(5-bromopyridin-3-yl)-3-methylcyclobutyl-1-carbonyl)-N-methylhydrazino-1-carbothioamide (55C)
  • Step 5 Preparation of 3-bromo-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (55E)
  • Step 6 (S)-6-Fluoro-1-(5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl) Preparation of pyridin-3-yl)-4-((3-methylpiperidin-1-yl)methyl)benzindol-2(1H)-one (compound 55)
  • Mobile phase A CO 2
  • mobile phase B EtOH (containing 0.05% DEA);
  • ABSPR Automatic Back Pressure Regulator
  • Step 1 Preparation of ethyl 2-(2-chloropyridin-4-yl)-3-methylbutyrate
  • Step 2 Preparation of ethyl 2-(2-chloropyridin-4-yl)-2,3-dimethylbutyrate
  • step 2 of Example 4 the difference is that 54B in step 2 is replaced by 2-(2-chloropyridin-4-yl)-2,3-dimethylbutanoic acid (550mg, 2.2mmol), The title compound (691 mg, 2.2 mmol) was obtained in the same manner.
  • step 4 With reference to the synthetic method of Example 4 step 4, the difference is that 54D in step 4 is replaced by 5-(2-(2-chloropyridin-4-yl)-3-methylbutan-2-yl)-4 -Methyl-4H-1,2,4-triazole-3-thiol (580mg, 1.62mmol), the title compound (220mg, 0.83mmol) was obtained by the same method.
  • Step 7 6-Fluoro-1-(4-(3-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)butan-2-yl)pyridine- Preparation of 2-yl)-4-(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 56)
  • step 4 is replaced by 2-chloro-4-(3-methyl-2-(4-methyl-4H-1,2,4-tri (Azol-3-yl)butan-2-yl)pyridine (9 mg), and the title compound (2.7 mg) was obtained in the same manner.
  • step 2 With reference to the synthetic method of Example 4 step 2, the difference is that 54B in step 2 is replaced by 1-(2-chloro-6-methylpyridin-4-yl)-3-methylcyclobutylcarboxylic acid (2.9g , 12.1mmol), the title compound (2.81g, 8.60mmol) was obtained by the same method.
  • Step 4 5-(1-(2-Chloro-6-methylpyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3 - Preparation of thiols
  • Step 5 Preparation of 2-chloro-6-methyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine
  • step 4 the difference is that 54D in step 4 is replaced by 5-(1-(2-chloro-6-methylpyridin-4-yl)-3-methylcyclobutyl) -4-Methyl-4H-1,2,4-triazole-3-thiol (500mg, 1.62mmol), the title compound (200mg, 0.72mmol) was obtained by the same method.
  • Step 6 (S)-6-Fluoro-1-(6-methyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) Preparation of cyclobutyl)pyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 57)
  • Step 1 Preparation of cis-1-(3-bromophenyl)-3-hydroxycyclobutanecarboxylic acid
  • Step 2 Preparation of cis-2-(1-(3-bromophenyl)-3-hydroxycyclobutylcarbonyl)-N-methylhydrazinemethylthioamide
  • step 2 of Example 4 Referring to the synthesis method in step 2 of Example 4, the difference is that 54B in step 2 is replaced by cis-1-(3-bromophenyl)-3-hydroxycyclobutanecarboxylic acid (294mg, 1.08mmol), the same method The title compound (171 mg, 0.48 mmol) was obtained.
  • Step 3 Preparation of cis-3-(3-bromophenyl)-3-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanol
  • step 3 of Example 4 the difference is that 54C in step 3 is replaced by cis-2-(1-(3-bromophenyl)-3-hydroxycyclobutylcarbonyl)-N-methyl Hydrazinemethylthioamide (161mg, 0.45mmol), the title compound (122mg, 0.36mmol) was obtained by the same method.
  • Step 4 Preparation of cis-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanol
  • step 4 of Example 4 the difference is that 54D in step 4 is replaced by cis-3-(3-bromophenyl)-3-(5-mercapto-4-methyl-4H-1, 2,4-Triazol-3-yl)cyclobutanol (1.1g, 3.23mmol), and the title compound (328mg, 1.06mmol) was obtained by the same method.
  • Step 6 Preparation of 3-(3-bromophenyl)-1-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanol
  • Step 7 Preparation of 3-(1-(3-bromophenyl)-3-fluoro-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole
  • Step 8 (S)-6-Fluoro-1-(3-(3-fluoro-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) ring Preparation of butyl)phenyl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 58)
  • step 5 of Example 4 the difference is that 54E in step 5 is replaced by 3-(1-(3-bromophenyl)-3-fluoro-3-methylcyclobutyl)-4-methanol -4H-1,2,4-triazole (11mg), and the title compound (4.7mg) was obtained by the same method.
  • Step 3 to Step 6 3-(1-(3-Bromo-5-chlorophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (59G) preparation of
  • Step 7 (S)-1-(3-chloro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)benzene base)-6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 59)
  • Step 1 Preparation of 3-chloro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)benzonitrile (60A)
  • Step 2 (S)-3-(6-fluoro-4-((3-methylpiperidin-1-yl)methyl)-2-carbonylbenzo[cd]indol-1(2H)-yl
  • Step 2 (S)-3-(6-fluoro-4-((3-methylpiperidin-1-yl)methyl)-2-carbonylbenzo[cd]indol-1(2H)-yl
  • Step 1 cis-3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (1F-P1) preparation
  • Step 2 to Step 3 Preparation of 6-fluoro-4-(((1-methylcyclobutyl)amino)methyl)benzo[cd]indol-2(1H)-one (61B)
  • Step 4 cis-6-fluoro-1-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) Preparation of cyclobutyl)phenyl)-4-(((1-methylcyclobutyl)amino)methyl)benzo[cd]indol-2(1H)-one (compound 61)
  • Example 12 1-(3-((S)-cyclopropyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-6-fluoro-4 -(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one and 1-(3-((R)-cyclopropyl( 4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-6-fluoro-4-(((S)-3-methylpiperidin-1-yl) Preparation of methyl)benzo[cd]indol-2(1H)-one (compound 62, compound 63)
  • Step 4 Preparation of 1-[(2-(3-bromophenyl)-2-cyclopropylacetyl)amino]-3-methylthiourea (62D)
  • Step 5 Preparation of 5-[(3-bromophenyl)cyclopropylmethyl]-4-methyl-4H-1,2,4-triazole-3-thiol (62E)
  • Step 7 (R)-((3-bromophenyl)cyclopropylmethyl)-4-methyl-4H-1,2,4-triazole and (S)-((3-bromophenyl) Preparation of cyclopropylmethyl)-4-methyl-4H-1,2,4-triazole
  • Chromatographic column Chiralpak IC-3 column length 100mm, inner diameter 4.6mm, particle size 3 ⁇ m; mobile phase: A: CO 2 B: methanol (containing 0.05% DEA); gradient: mobile phase B from 5% to 40% takes 4 minutes , and maintain 40% elution for 0.5 minutes, then elution with 5% mobile phase B for 1.5 minutes; flow rate: 2.8mL/min; column temperature: 35 ° C; ABPR: 1500psi
  • Step 8 1-(3-((S)-Cyclopropyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-6-fluoro-4- (((S)-3-Methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one and 1-(3-((R)-cyclopropyl(4 -Methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-6-fluoro-4-(((S)-3-methylpiperidin-1-yl)methyl base) benzo[cd]indol-2(1H)-one (compound 62, compound 63) preparation
  • Example 13 trans-6-fluoro-1-(3-((1R,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl) Preparation of cyclobutyl)phenyl)-4-(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 64)
  • Step 1 Preparation of trans-3-(1-(3-bromophenyl)-3-fluorocyclobutyl)-4-methyl-4H-1,2,4-triazole (64A)
  • Step 2 trans-6-fluoro-1-(3-(trans-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl) Preparation of phenyl)-4-(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 64)
  • Step 1 Preparation of 3-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole (65A)
  • triethylamine hydrogen fluoride (663.0mg, 3.92mmol) was added into dichloromethane (5.0mL), replaced by argon gas protection for 4 times, and then added to the solution successively under the purging of argon flow (two Ethylamino) difluorosulfonium tetrafluoroborate (897.5mg, 3.92mmol) and 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazole-3 -yl)cyclobutan-1-one (400.0 mg, 1.31 mmol). Then the reaction solution was slowly warmed to room temperature and stirred for 2.0 hours.
  • reaction solution was cooled to 0° C., quenched by adding saturated ammonium chloride aqueous solution (60 mL), and extracted with dichloromethane (50 mL ⁇ 3).
  • the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain the crude product.
  • Step 2 (S)-1-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl) - Preparation of 6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 65)
  • Step 1 Preparation of methyl 2-(2-bromoethoxy)-2-(3-bromophenyl)acetate (66A)
  • Dissolve 66B (695.0 mg, 2.56 mmol) in acetonitrile (10.0 mL) at room temperature, add aqueous sodium hydroxide solution (10.0 mL, 3.0 M), and react at 65°C for 1.0 hour. After the reaction, the temperature was lowered to 0° C., a saturated aqueous solution of citric acid was added to adjust the pH to 3, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the title crude product 66C (594.0 mg), which was directly used in the next reaction without further purification.
  • 66C (594.0mg, 2.31mmol), 4-methylthiosemicarbazide (292.0mg, 2.77mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (1.05g, 2.77mmol), potassium phosphate (1.05g, 2.77mmol) and DIPEA (896.0mg, 6.93mmol, 1.21mL) were added to DMF (6.0mL) and reacted at room temperature for 1.0 hour . After the reaction was completed, water (60.0 mL) was added and extracted with dichloromethane (6.0 mL ⁇ 3). The extracted organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the title product 66D (720.0m), which was directly used in the next reaction without further purification.
  • Step 5 5-(2-(3-Bromophenyl)oxetan-2-yl)-4-methyl-4H-1,2,4-triazole-3-thiol (66E) preparation
  • 66D (720.0 mg, 2.09 mmol) was added into an aqueous solution of sodium hydroxide (10.0 mL, 3.0 M), and the reaction was carried out at 80° C. for 1.0 hour. After the reaction was completed, the temperature of the reaction was lowered to 0° C., a saturated aqueous solution of citric acid was added to adjust the pH to acidic, and the mixture was extracted three times with dichloromethane. The extracted organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the title product 66E (614.0 mg), which was directly used in the next reaction without further purification.
  • Step 6 Preparation of 3-(2-(3-bromophenyl)oxetan-2-yl)-4-methyl-4H-1,2,4-triazole (66F)
  • Step 7 6-Fluoro-1-(3-(2-(4-methyl-4H-1,2,4-triazol-3-yl)oxetan-2-yl)phenyl)- Preparation of 4-(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (Compound 66)
  • Eu-Ubquitin (Cisbio) was incubated with UbcH5B (ENZO), E1 (ENZO) at 37°C for 4 hours to prepare Eu-Ubquitin-UbcH5B. Store Eu-Ubquitin-UbcH5B at -80°C. Cbl-b activity assays were performed in 384-well plates (Perkin Elmer).
  • Test example 2 Jurkat T activation experiment

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Abstract

Disclosed in the present application are a compound of formula (I) as a Cbl-b inhibitor or a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition containing the compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, and the use of the compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof in the prevention or treatment of diseases or conditions mediated by Cbl-b, such as tumors or autoimmune diseases.

Description

作为Cbl-b抑制剂的三环类化合物Tricyclic compounds as Cbl-b inhibitors
相关申请的交叉引用Cross References to Related Applications
本申请要求以下4件中国发明专利申请的权益和优先权，在此将它们的全部内容以援引的方式整体并入本文中：This application claims the benefit and priority of the following 4 Chinese invention patent applications, the entire contents of which are hereby incorporated by reference in their entirety:
2021年9月13日向中国国家知识产权局提交的第202111070011.3号专利申请；Patent application No. 202111070011.3 submitted to the State Intellectual Property Office of China on September 13, 2021;
2022年01月27日向中国国家知识产权局提交的第202210103247.0号专利申请；Patent application No. 202210103247.0 submitted to the State Intellectual Property Office of China on January 27, 2022;
2022年05月07日向中国国家知识产权局提交的第202210532103.7号专利申请；以及Patent application No. 202210532103.7 filed with the State Intellectual Property Office of China on May 07, 2022; and
2022年7月26日向中国国家知识产权局提交的第202210895442.1号专利申请。Patent application No. 202210895442.1 submitted to the State Intellectual Property Office of China on July 26, 2022.
技术领域technical field
本申请涉及作为Cbl-b抑制剂的三环类化合物或其立体异构体或其可药用盐、其制备方法、含有该化合物或其立体异构体或其可药用盐的药物组合物、以及所述化合物或其立体异构体或其可药用盐在预防或治疗由Cbl-b介导的疾病或病症中的用途。The present application relates to a tricyclic compound or its stereoisomer or its pharmaceutically acceptable salt as a Cbl-b inhibitor, its preparation method, and a pharmaceutical composition containing the compound or its stereoisomer or its pharmaceutically acceptable salt , and use of the compound or its stereoisomer or pharmaceutically acceptable salt thereof in the prevention or treatment of diseases or disorders mediated by Cbl-b.
背景技术Background technique
细胞内的信号级联传导通常由蛋白磷酸化进行调控，基因的表达和调控则受到表观遗传学的影响，而调控这些信号的蛋白质，其本身也受到细胞内蛋白质的“生成-降解”平衡的调控，以维持细胞的自稳态。目前所知蛋白质降解主要通过两种途径：溶酶体降解途径和泛素介导的蛋白酶体降解途径。其中泛素介导的途径是一个受到严格的时空调控的特异性蛋白质降解途径。泛素系统广泛存在于真核生物中，是精确的胞内蛋白质降解调控系统。泛素(ubiquitin，Ub)是一种存在于大多数真核细胞中的高度保守的小蛋白质。它的主要功能是标记需要分解掉的蛋白质，使其水解。泛素系统由泛素、26S蛋白酶体、多种酶(E1、E2、E3及去泛素酶等)组成。蛋白的泛素化通过泛素激活酶E1(ubactivating enzyme，E1)、泛素结合酶E2(Ub conjugating enzyme，E2)、泛素连接酶E3(Ub ligase，E3)参与的E1-E2-E3级联反应完成，随后泛素化的蛋白被26S蛋白酶体降解(A patent review of the ubiquitin ligase system:2015-201 Expert Opin Ther Pat.2018,28(12):919–937)。Intracellular signal cascades are usually regulated by protein phosphorylation, and gene expression and regulation are affected by epigenetics, and the proteins that regulate these signals are themselves subject to the "production-degradation" balance of intracellular proteins regulation to maintain cellular homeostasis. Currently known protein degradation mainly through two pathways: lysosomal degradation pathway and ubiquitin-mediated proteasomal degradation pathway. Among them, the ubiquitin-mediated pathway is a specific protein degradation pathway subject to strict spatiotemporal regulation. The ubiquitin system widely exists in eukaryotes and is a precise regulatory system for intracellular protein degradation. Ubiquitin (Ub) is a highly conserved small protein present in most eukaryotic cells. Its main function is to mark proteins that need to be broken down so that they can be hydrolyzed. The ubiquitin system consists of ubiquitin, 26S proteasome, and various enzymes (E1, E2, E3, and deubiquitinase, etc.). The ubiquitination of protein is through the E1-E2-E3 level involving ubiquitin activating enzyme E1 (ubactivating enzyme, E1), ubiquitin conjugating enzyme E2 (Ub conjugating enzyme, E2), ubiquitin ligase E3 (Ub ligase, E3) The cascade reaction is completed, and then the ubiquitinated protein is degraded by the 26S proteasome (A patent review of the ubiquitin ligase system:2015-201 Expert Opin Ther Pat.2018,28(12):919–937).
人类基因组大约编码35个E2结合酶以及超过500个E3连接酶。Casitas B谱系淋巴瘤原癌基因-b(Casitas B-lineage lymphoma proto-oncogene-b,Cbl-b)是一个负反馈调节T细胞激活的E3连接酶。Cbl-b属于Cbl家族，该家族包括c-Cbl,Cbl-b,以及Cbl-3(Cbl:many adaptations to regulate protein tyrosine kinases.Nat.Rev.Mol.Cell Biol.2:294–307)。Cbl蛋白主要负调控T细胞活化、生长因子(例如表皮生长因子受体(EGFR)、c-KIT、血小板衍生生长因子受体(PDGFR)和非受体型酪氨酸激酶信号(如Src家族激酶和Zap70)(Regulating the regulator:Negative regulation of Cbl ubiquitin ligases.Trends Biochem Sci 31:79–88；The Cbl family proteins:Ring leaders in regulation of cell signaling.J Cell Physiol.209:21–43)。研究发现Cbl蛋白的功能性失活与人类癌症有关(Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.Nat Genet 42:794–800)。在三种Cbl蛋白中，Cbl-b在建立T细胞激活阈值和控制外周T细胞耐受性方面起着关键作用，越来越多的证据表明Cbl-b还调节先天免疫反应，并在宿主防御病原体中起重要作用。Cbl-b基因敲除小鼠显示出严重的自身免疫性疾病(Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b.Nature 403:211–216)。因此，Cbl-b可以作为一个重要的免疫调节治疗靶点。The human genome encodes approximately 35 E2-conjugating enzymes and more than 500 E3 ligases. Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is an E3 ligase that negatively regulates T cell activation. Cbl-b belongs to the Cbl family, which includes c-Cbl, Cbl-b, and Cbl-3 (Cbl:many adaptations to regulate protein tyrosine kinases.Nat.Rev.Mol.Cell Biol.2:294–307). Cbl protein mainly negatively regulates T cell activation, growth factors (such as epidermal growth factor receptor (EGFR), c-KIT, platelet-derived growth factor receptor (PDGFR) and non-receptor tyrosine kinase signaling (such as Src family kinases and Zap70) (Regulating the regulator: Negative regulation of Cbl ubiquitin ligases. Trends Biochem Sci 31:79–88; The Cbl family proteins: Ring leaders in regulation of cell signaling. J Cell Physiol.209:21–43). Functional inactivation of Cbl proteins is associated with human cancers (Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42:794–800). Of the three Cbl proteins, Cbl-b is important in establishing T cell activation thresholds and control of peripheral T cell tolerance, accumulating evidence suggests that Cbl-b also regulates innate immune responses and plays an important role in host defense against pathogens. Cbl-b knockout mice show Severe autoimmune diseases (Negative regulation of lymphocyte activation and autoimmunity by the molecular adapter Cbl-b. Nature 403:211–216). Therefore, Cbl-b can be used as an important immunomodulatory therapeutic target.
发明内容Contents of the invention
本申请涉及式(I)化合物或其立体异构体或其药学上可接受的盐，The application relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022118398-appb-000001
Figure PCTCN2022118398-appb-000001
其中，in,
Z 1和Z 2独立选自CR a或N； Z and Z are independently selected from CR a or N;
Z 3选自C、CH或N； Z is selected from C, CH or N;
Y 1、Y 2、Y 3和Y 4独立选自CR b或N； Y 1 , Y 2 , Y 3 and Y 4 are independently selected from CR b or N;
X选自卤素、CN、OH、COOH、CONH 2、C 1-C 6烷基、C 1-C 6烷氧基、
Figure PCTCN2022118398-appb-000002
Figure PCTCN2022118398-appb-000003
其中C 1-C 6烷基或C 1-C 6烷氧基任选被R e取代，环B选自任选被R 3取代的以下基团：4-10元含氮杂环基或5-10元含氮杂芳基，环D选自任选被R 6取代的以下基团：C 3-C 10环烷基、4-10元杂环基、苯基或5-10元杂芳基，并且环D以非N原子与L相连，L选自键、-NR 7-、-NR 7CR 8R 9-、-O-、-C(＝O)-、-C(＝O)NH-或-CR 8R 9-； X is selected from halogen, CN, OH, COOH, CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy,
Figure PCTCN2022118398-appb-000002
Figure PCTCN2022118398-appb-000003
wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted by R e , ring B is selected from the following groups optionally substituted by R 3 : 4-10 membered nitrogen-containing heterocyclic group or 5 -10-membered nitrogen-containing heteroaryl, ring D is selected from the following groups optionally substituted by R 6 : C 3 -C 10 cycloalkyl, 4-10-membered heterocyclic group, phenyl or 5-10-membered heteroaryl group, and the ring D is connected to L by a non-N atom, and L is selected from a bond, -NR 7 -, -NR 7 CR 8 R 9 -, -O-, -C(=O)-, -C(=O) NH-or-CR 8 R 9 -;
R b选自H、卤素、OH、CN、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、NHC(O)(C 1-C 6烷基)、NHS(O) 2(C 1-C 6烷基)、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 3-C 6环烷基-NH-、N(C 3-C 6环烷基) 2、NHC(O)-C 3-C 6环烷基、NHS(O) 2-C 3-C 6环烷基、4-7元杂环基、4-7元杂环基氧基、4-7元杂环基-NH-、N(4-7元杂环基) 2、NHC(O)-4-7元杂环基、NHS(O) 2-4-7元杂环基、C 6-C 10芳基、C 6-C 10芳基氧基、C 6-C 10芳基-NH-、N(C 6-C 10芳基) 2、NHC(O)-C 6-C 10芳基、NHS(O) 2-C 6-C 10芳基、5-10元杂芳基、5-10元杂芳基氧基或5-10元杂芳基-NH-、N(5-10元杂芳基) 2、NHC(O)-5-10元杂芳基、NHS(O) 2-5-10元杂芳基，其中所述的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 3-C 6环烷基、4-7元杂环基、C 6-C 10芳基或5-10元杂芳基任选被R 2a取代； R b is selected from H, halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, NH 2 , NH(C 1 -C 6 alkyl ), N(C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHS(O) 2 (C 1 -C 6 alkyl), C 3 -C 6 cycloalkane group, C 3 -C 6 cycloalkyl-O-, C 3 -C 6 cycloalkyl-NH-, N(C 3 -C 6 cycloalkyl) 2 , NHC(O)-C 3 -C 6 ring Alkyl, NHS(O) 2 -C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, N(4 -7-membered heterocyclyl) 2 , NHC(O)-4-7-membered heterocyclyl, NHS(O) 2 -4-7-membered heterocyclyl, C 6 -C 10 aryl, C 6 -C 10 aryl Oxygen, C 6 -C 10 aryl-NH-, N(C 6 -C 10 aryl) 2 , NHC(O)-C 6 -C 10 aryl, NHS(O) 2 -C 6 -C 10- aryl, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy or 5-10-membered heteroaryl-NH-, N(5-10-membered heteroaryl) 2 , NHC(O)- 5-10 membered heteroaryl, NHS(O) 2 -5-10 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio Base, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by R 2a ;
或者两个R b与其相连的C原子共同形成C 3-C 6环烯基、苯基、4-7元杂环基或5-6元杂芳基，所述C 3-C 6环烯基、苯基、4-7元杂环基或5-6元杂芳基任选被R 2a取代； Or two R b and the C atoms connected to them jointly form a C 3 -C 6 cycloalkenyl group, a phenyl group, a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, and the C 3 -C 6 cycloalkenyl group , phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally substituted by R 2a ;
R a、R 4、R 5、R 7、R 8和R 9彼此独立地选自H、卤素、OH、C 1-C 6烷基或C 1-C 6烷氧基，所述C 1-C 6烷基或C 1-C 6烷氧基任选被R 4a取代； R a , R 4 , R 5 , R 7 , R 8 and R 9 are independently selected from H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, and the C 1 - C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted by R 4a ;
或者R 8、R 9及其相连的原子一起形成C 3-C 6环烷基或4-7元杂环基，或者R 4、R 5及其相连的原子一起形成C 3-C 6环烷基或4-7元杂环基，所述C 3-C 6环烷基或4-7元杂环基任选进一步被R 8a取代，或者R 4、R 5一起形成＝O； Or R 8 , R 9 and their connected atoms together form a C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group, or R 4 , R 5 and their connected atoms together form a C 3 -C 6 cycloalkane A group or a 4-7 membered heterocyclic group, the C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group is optionally further substituted by R 8a , or R 4 and R 5 together form =O;
R 3和R 6独立地选自卤素、CN、＝O、NO 2、C 1-C 6烷基、OR 6a、SR 6a、N(R 6a) 2、S(O) 2R 6a、S(O) 2N(R 6a) 2、S(O)R 6a、S(O)N(R 6a) 2、C(O)R 6a、C(O)OR 6a、C(O)N(R 6a) 2、C(O)N(R 6a)OR 6a、OC(O)R 6a、OC(O)N(R 6a) 2、N(R 6a)C(O)OR 6a、N(R 6a)C(O)R 6a、N(R 6a)C(O)N(R 6a) 2、N(R 6a)C(NR 6a)N(R 6a) 2、N(R 6a)S(O) 2N(R 6a) 2、N(R 6a)S(O) 2R 6a、C 3-C 10环烷基、4-7元杂环基、6-10元芳基或5-10元杂芳基，其中C 1-C 6烷基、C 3-C 10环烷基、4-7元杂环基、6-10元芳基或5-10元杂芳基任选进一步被R 3a取代； R 3 and R 6 are independently selected from halogen, CN, =O, NO 2 , C 1 -C 6 alkyl, OR 6a , SR 6a , N(R 6a ) 2 , S(O) 2 R 6a , S( O) 2 N(R 6a ) 2 , S(O)R 6a , S(O)N(R 6a ) 2 , C(O)R 6a , C(O)OR 6a , C(O)N(R 6a ) 2 , C(O)N(R 6a )OR 6a , OC(O)R 6a , OC(O)N(R 6a ) 2 , N(R 6a )C(O)OR 6a , N(R 6a ) C(O)R 6a , N(R 6a )C(O)N(R 6a ) 2 , N(R 6a )C(NR 6a )N(R 6a ) 2 , N(R 6a )S(O) 2 N(R 6a ) 2 , N(R 6a )S(O) 2 R 6a , C 3 -C 10 cycloalkyl, 4-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl A group, wherein C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally further substituted by R 3a ;
R 6a选自H、C 1-C 6烷基、苯基、4-7元杂环基或5-6元杂芳基，所述C 1-C 6烷基、苯基、4-7元杂环基或5-6元杂芳基任选进一步被R 6b取代，或者一个N原子上的2个R 6a与其相连 的N一起形成4-7元杂环基或5-6元杂芳基，所述4-7元杂环基或5-6元杂芳基任选进一步被R 6b取代； R 6a is selected from H, C 1 -C 6 alkyl, phenyl, 4-7 membered heterocyclic group or 5-6 membered heteroaryl, said C 1 -C 6 alkyl, phenyl, 4-7 membered Heterocyclyl or 5-6 membered heteroaryl is optionally further substituted by R 6b , or 2 R 6a on one N atom form a 4-7 membered heterocyclic group or 5-6 membered heteroaryl together with the N connected to it , the 4-7 membered heterocyclic group or 5-6 membered heteroaryl group is optionally further substituted by R 6b ;
R 3a、R 4a、R 6b和R e独立选自卤素、OH、CN、＝O、NH 2、COOH或C 1-C 6烷氧基； R 3a , R 4a , R 6b and Re are independently selected from halogen, OH, CN, =O, NH 2 , COOH or C 1 -C 6 alkoxy;
Q为苯基或6元杂芳基，所述苯基或6元杂芳基任选被R 10取代； Q is phenyl or 6-membered heteroaryl, and said phenyl or 6-membered heteroaryl is optionally substituted by R 10 ;
或者Q为如下所示基团：
Figure PCTCN2022118398-appb-000004
其中Z 4和Z 5独立选自CR cR d、NR 11、O、S、或S(＝O) 2，
Figure PCTCN2022118398-appb-000005
代表单键或双键，并且当
Figure PCTCN2022118398-appb-000006
为双键时，m为1，当
Figure PCTCN2022118398-appb-000007
为单键时m为1或2； Or Q is a group as shown below:
Figure PCTCN2022118398-appb-000004
wherein Z 4 and Z 5 are independently selected from CR c R d , NR 11 , O, S, or S(=O) 2 ,
Figure PCTCN2022118398-appb-000005
represents a single or double bond, and when
Figure PCTCN2022118398-appb-000006
When it is a double bond, m is 1, when
Figure PCTCN2022118398-appb-000007
When it is a single bond, m is 1 or 2;
R 10选自卤素、OH、NH 2、CN、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基或4-7元杂环基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基或4-7元杂环基任选被R 10a取代； R 10 is selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclic group, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl are optionally substituted by R 10a ;
R 2a和R 10a独立选自卤素、OH、CN、＝O、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 2a and R 10a are independently selected from halogen, OH, CN, =O, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl , halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy;
R c、R d和R 11独立选自H、卤素、OH、CN、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 1-C 6烷基或C 1-C 6烷氧基，其中所述的C 1-C 6烷基或C 1-C 6烷氧基任选被R 11a取代，或者R c、R d共同形成＝O，或者R c、R d与其相连的原子共同形成C 3-C 10环烷基或4-7元杂环基，所述C 3-C 10环烷基或4-7元杂环基任选被R 11b取代； R c , R d and R 11 are independently selected from H, halogen, OH, CN, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Alkyl or C 1 -C 6 alkoxy, wherein said C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted by R 11a , or R c and R d jointly form =O, Or R c , R d and the atoms connected to them jointly form a C 3 -C 10 cycloalkyl group or a 4-7 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or a 4-7 membered heterocyclic group is optionally replaced by R 11b is substituted;
或者R c与R 11及其各自相连的原子共同形成4-7元杂环基，所述4-7元杂环基任选被R 11c取代； Or R c and R 11 and their respective connected atoms together form a 4-7 membered heterocyclic group, and the 4-7 membered heterocyclic group is optionally substituted by R 11c ;
R 11a、R 11b和R 11c独立地选自卤素、OH、＝O、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2或C 1-C 6烷基； R 11a , R 11b and R 11c are independently selected from halogen, OH, =O, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 or C 1 -C 6 alkyl;
R 1和R 2独立选自H、卤素、CN、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基或4-10元杂环基，其中所述的C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基或4-10元杂环基任选被R 1a取代， R 1 and R 2 are independently selected from H, halogen, CN, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclic group, wherein said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 Cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R 1a ,
或者R 1、R 2与其连接的原子共同形成C 3-C 10环烷基或4-10元杂环基，所述C 3-C 10环烷基或4-10元杂环基任选被R 1b取代； Or R 1 , R 2 and the atoms they connect together form a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group is optionally replaced by R 1b replaces;
R 1a和R 1b独立选自卤素、OH、CN、＝O、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 1-C 6烷基或C 1-C 6烷氧基，所述C 1-C 6烷基或C 1-C 6烷氧基任选进一步被R 1c取代； R 1a and R 1b are independently selected from halogen, OH, CN, =O, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl or C 1 -C 6 alkoxy, the C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally further substituted by R 1c ;
R 1c选自卤素、OH、CN、＝O、NH 2或COOH； R 1c is selected from halogen, OH, CN, =O, NH 2 or COOH;
W选自(CR 12R 13) kW 1，所述W 1选自5-10元杂芳基或4-10元杂环基，所述5-10元杂芳基、4-10元杂环基任选被R 14取代，R 12、R 13独立选自H、卤素、OH、C 1-C 6烷基或C 1-C 6烷氧基，R 14选自卤素、OH、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基，其中所述的C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基任选被R 14a取代； W is selected from (CR 12 R 13 ) k W 1 , said W 1 is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclic group, said 5-10 membered heteroaryl, 4-10 membered heterocyclic group The ring group is optionally substituted by R 14 , R 12 and R 13 are independently selected from H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, R 14 is selected from halogen, OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl, wherein The C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R 14a ;
或者R 1与R 12及其各自相连的原子和键共同形成C 3-C 6环烷基或4-7元杂环基，所述C 3-C 6环烷基或4-7元杂环基任选被R 12a取代； Or R 1 and R 12 and their respective connected atoms and bonds together form a C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group, the C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group The group is optionally substituted by R 12a ;
R 8a和R 12a独立地选自卤素、OH、CN、C 1-C 6烷基或C 1-C 6烷氧基，所述C 1-C 6烷基或C 1-C 6烷氧基任选进一步被卤素取代，R 14a选自卤素、＝O、OH、CN或C 1-C 6烷基； R 8a and R 12a are independently selected from halogen, OH, CN, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, the C 1 -C 6 alkyl or C 1 -C 6 alkoxy Optionally further substituted by halogen, R 14a is selected from halogen, =O, OH, CN or C 1 -C 6 alkyl;
p和k独立地选自0或1。p and k are independently selected from 0 or 1.
在一些实施方案中，X选自卤素、CN、OH、COOH、CONH 2、C 1-C 6烷基、C 1-C 6烷氧基、
Figure PCTCN2022118398-appb-000008
其中C 1-C 6烷基或C 1-C 6烷氧基任选被R e取代，环B选自任选被R 3取代的以下基团：4-10元含氮杂环基或5-10元含氮杂芳基，环D选自任选被R 6取代的以下基团：C 3-C 10环烷基、4-10元杂环基、苯基或5-10元杂芳基，并且环D以非N原子 与L相连，L选自键、-NR 7-、-NR 7CH 2-、-O-、-C(＝O)-、-C(＝O)NH-或-CR 8R 9-。 In some embodiments, X is selected from halogen, CN, OH, COOH, CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy,
Figure PCTCN2022118398-appb-000008
wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted by R e , ring B is selected from the following groups optionally substituted by R 3 : 4-10 membered nitrogen-containing heterocyclic group or 5 -10-membered nitrogen-containing heteroaryl, ring D is selected from the following groups optionally substituted by R 6 : C 3 -C 10 cycloalkyl, 4-10-membered heterocyclic group, phenyl or 5-10-membered heteroaryl group, and the ring D is connected to L by a non-N atom, and L is selected from a bond, -NR 7 -, -NR 7 CH 2 -, -O-, -C(=O)-, -C(=O)NH- or -CR 8 R 9 -.
在一些实施方案中，R b选自H、卤素、OH、CN、C 1-C 6烷基、C 1-C 6烷氧基、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、NHC(O)(C 1-C 6烷基)、NHS(O) 2(C 1-C 6烷基)、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 3-C 6环烷基-NH-、N(C 3-C 6环烷基) 2、NHC(O)-C 3-C 6环烷基、NHS(O) 2-C 3-C 6环烷基、4-7元杂环基、4-7元杂环基氧基、4-7元杂环基-NH-、N(4-7元杂环基) 2、NHC(O)-4-7元杂环基、NHS(O) 2-4-7元杂环基、C 6-C 10芳基、C 6-C 10芳基氧基、C 6-C 10芳基-NH-、N(C 6-C 10芳基) 2、NHC(O)-C 6-C 10芳基、NHS(O) 2-C 6-C 10芳基、5-10元杂芳基、5-10元杂芳基氧基或5-10元杂芳基-NH-、N(5-10元杂芳基) 2、NHC(O)-5-10元杂芳基、NHS(O) 2-5-10元杂芳基，其中所述的C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、4-7元杂环基、C 6-C 10芳基或5-10元杂芳基任选被R 2a取代；或者两个R b与其相连的C原子共同形成C 3-C 6环烯基、苯基、4-7元杂环基或5-6元杂芳基，所述C 3-C 6环烯基、苯基、4-7元杂环基或5-6元杂芳基任选被R 2a取代。 In some embodiments, R b is selected from H, halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , NH(C 1 -C 6 alkyl), N (C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHS(O) 2 (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-O-, C 3 -C 6 cycloalkyl-NH-, N(C 3 -C 6 cycloalkyl) 2 , NHC(O)-C 3 -C 6 cycloalkyl, NHS(O) 2 -C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, N(4-7 membered Heterocyclyl) 2 , NHC(O)-4-7 membered heterocyclyl, NHS(O) 2 -4-7 membered heterocyclyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy , C 6 -C 10 aryl-NH-, N(C 6 -C 10 aryl) 2 , NHC(O)-C 6 -C 10 aryl, NHS(O) 2 -C 6 -C 10 aryl , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or 5-10 membered heteroaryl-NH-, N(5-10 membered heteroaryl) 2 , NHC(O)-5-10 Member heteroaryl, NHS(O) 2 -5-10 member heteroaryl, wherein said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4 -7-membered heterocyclic group, C 6 -C 10 aryl group or 5-10 membered heteroaryl group is optionally substituted by R 2a ; or two R b and the C atoms connected to it together form a C 3 -C 6 cycloalkenyl group, Phenyl, 4-7 membered heterocyclic group or 5-6 membered heteroaryl group, the C 3 -C 6 cycloalkenyl, phenyl, 4-7 membered heterocyclic group or 5-6 membered heteroaryl group are optionally Replaced by R 2a .
在一些实施方案中，Z 1和Z 2独立选自CH或N。 In some embodiments, Z1 and Z2 are independently selected from CH or N.
在一些实施方案中，Z 1和Z 2均为CH。 In some embodiments, both Z1 and Z2 are CH.
在一些实施方案中，Z 1为CH，Z 2为N。 In some embodiments, Z 1 is CH and Z 2 is N.
在一些实施方案中，Z 1为N，Z 2为CH。 In some embodiments, Z1 is N and Z2 is CH.
在一些实施方案中，Z 3选自C或CH。 In some embodiments, Z is selected from C or CH.
在一些实施方案中，Z 3为C。 In some embodiments, Z is C.
在一些实施方案中，Y 1、Y 2、Y 3和Y 4均为CR b。 In some embodiments, Y 1 , Y 2 , Y 3 and Y 4 are all CR b .
在一些实施方案中，Y 1、Y 2、Y 3和Y 4均为CH。 In some embodiments, Y1 , Y2 , Y3 , and Y4 are all CH.
在一些实施方案中，Y 1和Y 2独立选自CR b或N，Y 3和Y 4均为CR b。 In some embodiments, Y 1 and Y 2 are independently selected from CR b or N, and Y 3 and Y 4 are both CR b .
在一些实施方案中，Y 1和Y 2独立选自CH或N，Y 3为CH，以及Y 4为CR b。 In some embodiments, Y 1 and Y 2 are independently selected from CH or N, Y 3 is CH, and Y 4 is CR b .
在一些实施方案中，Y 1和Y 2独立选自CH或N，以及Y 3和Y 4均为CH。 In some embodiments, Y and Y are independently selected from CH or N, and both Y and Y are CH.
在一些实施方案中，Y 1和Y 2均为N，Y 3和Y 4均为CR b。 In some embodiments, Y 1 and Y 2 are both N, and Y 3 and Y 4 are both CR b .
在一些实施方案中，Y 1和Y 2均为N，Y 3为CH，以及Y 4为CR b。 In some embodiments, Y 1 and Y 2 are both N, Y 3 is CH, and Y 4 is CR b .
在一些实施方案中，Y 1和Y 2均为N，以及Y 3和Y 4均为CH。 In some embodiments, both Y1 and Y2 are N, and both Y3 and Y4 are CH.
在一些实施方案中，Y 1为N，Y 2、Y 3和Y 4均为CR b。 In some embodiments, Y 1 is N and Y 2 , Y 3 and Y 4 are all CR b .
在一些实施方案中，Y 1为N，Y 2和Y 3均为CH，以及Y 4为CR b。 In some embodiments, Y 1 is N, Y 2 and Y 3 are both CH, and Y 4 is CR b .
在一些实施方案中，Y 1为N，Y 2、Y 3和Y 4均为CH。 In some embodiments, Y1 is N and Y2 , Y3 , and Y4 are all CH.
在一些实施方案中，Y 4为N，Y 1、Y 2和Y 3均为CR b。 In some embodiments, Y 4 is N and Y 1 , Y 2 and Y 3 are all CR b .
在一些实施方案中，Y 4为N，Y 1、Y 2和Y 3均为CH。 In some embodiments, Y 4 is N and Y 1 , Y 2 and Y 3 are all CH.
在一些实施方案中，R b选自H、卤素、OH、CN、C 1-C 6烷基、C 1-C 6烷硫基、C 1-C 6烷氧基、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 3-C 6环烷基-NH-、4-7元杂环基-O-、4-7元杂环基-NH-或5-10元杂芳基，其中所述的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 3-C 6环烷基、4-7元杂环基或5-10元杂芳基任选被R 2a取代。 In some embodiments, R b is selected from H, halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-O-, C 3 -C 6 cycloalkyl- NH-, 4-7 membered heterocyclyl-O-, 4-7 membered heterocyclic group-NH- or 5-10 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 alkylthio, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted by R 2a .
在一些实施方案中，R b选自H、卤素、OH、C 1-C 6烷基、C 1-C 6烷氧基、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 3-C 6环烷基-O-、C 3-C 6环烷基-NH-、4-7元杂环基-O-、4-7元杂环基-NH-或5-10元杂芳基，其中所述的C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、4-7元杂环基或5-10元杂芳基任选被R 2a取代。 In some embodiments, R b is selected from H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl-O-, C 3 -C 6 cycloalkyl-NH-, 4-7 membered heterocyclyl-O-, 4-7 membered heterocycle Group -NH- or 5-10 membered heteroaryl, wherein said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclic Or 5-10 membered heteroaryl is optionally substituted by R 2a .
在一些实施方案中，R b选自H、卤素、C 1-C 6烷基、C 1-C 6烷氧基、NH(C 1-C 6烷基)、C 3-C 6环烷基-O-、C 3-C 6环烷基-NH-、4-7元杂环基-O-、4-7元杂环基-NH-或5-6元杂芳基，其中所述的C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、4-7元杂环基或5-6元杂芳基任选被R 2a取代。 In some embodiments, R b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH(C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl -O-, C 3 -C 6 cycloalkyl-NH-, 4-7 membered heterocyclyl-O-, 4-7 membered heterocyclyl-NH- or 5-6 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally substituted by R 2a .
在一些实施方案中，R b选自H、卤素或任选被R 2a取代的以下基团：甲基、乙氧基、NHCH 3、NHEt、NH(i-Pr)、吡唑基、环丙基-O-、环丁基-NH-或氧杂环丁基-O-。 In some embodiments, R b is selected from H, halogen, or the following groups optionally substituted by R 2a : methyl, ethoxy, NHCH 3 , NHEt, NH(i-Pr), pyrazolyl, cyclopropyl -O-, cyclobutyl-NH- or oxetanyl-O-.
在一些实施方案中，R 2a选自卤素、OH、＝O、C 1-C 3烷基或C 1-C 3烷氧基。 In some embodiments, R 2a is selected from halogen, OH, =0, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.
在一些实施方案中，R 2a选自卤素、OH或C 1-C 3烷基。 In some embodiments, R 2a is selected from halogen, OH, or C 1 -C 3 alkyl.
在一些实施方案中，R 2a选自F、OH或甲基。 In some embodiments, R 2a is selected from F, OH or methyl.
在一些实施方案中，R b选自H、F、Cl、CN、CH 3S-、甲基、CF 3、乙氧基、OCH 2CHF 2、NHCH 3、NHEt、NH(i-Pr)、NHCH 2CH 2OH、环丙基、
Figure PCTCN2022118398-appb-000009
In some embodiments, Rb is selected from H, F, Cl, CN, CH3S- , methyl, CF3 , ethoxy, OCH2CHF2 , NHCH3 , NHEt, NH(i-Pr), NHCH 2 CH 2 OH, cyclopropyl,
Figure PCTCN2022118398-appb-000009
在一些实施方案中，R b选自H、F、甲基、CF 3、乙氧基、OCH 2CHF 2、NHCH 3、NHEt、NH(i-Pr)、NHCH 2CH 2OH、
Figure PCTCN2022118398-appb-000010
In some embodiments, Rb is selected from H, F, methyl, CF3 , ethoxy , OCH2CHF2 , NHCH3 , NHEt, NH(i-Pr), NHCH2CH2OH ,
Figure PCTCN2022118398-appb-000010
在一些实施方案中，R b选自H、F、CF 3、乙氧基、OCH 2CHF 2、NHCH 3、NHEt、NH(i-Pr)、NHCH 2CH 2OH、
Figure PCTCN2022118398-appb-000011
In some embodiments, R b is selected from H, F, CF 3 , ethoxy, OCH 2 CHF 2 , NHCH 3 , NHEt, NH(i-Pr), NHCH 2 CH 2 OH,
Figure PCTCN2022118398-appb-000011
在一些实施方案中，
Figure PCTCN2022118398-appb-000012
选自
Figure PCTCN2022118398-appb-000013
Figure PCTCN2022118398-appb-000014
In some embodiments,
Figure PCTCN2022118398-appb-000012
selected from
Figure PCTCN2022118398-appb-000013
Figure PCTCN2022118398-appb-000014
在一些实施方案中，
Figure PCTCN2022118398-appb-000015
选自
Figure PCTCN2022118398-appb-000016
Figure PCTCN2022118398-appb-000017
In some embodiments,
Figure PCTCN2022118398-appb-000015
selected from
Figure PCTCN2022118398-appb-000016
Figure PCTCN2022118398-appb-000017
在一些实施方案中，
Figure PCTCN2022118398-appb-000018
选自
Figure PCTCN2022118398-appb-000019
Figure PCTCN2022118398-appb-000020
In some embodiments,
Figure PCTCN2022118398-appb-000018
selected from
Figure PCTCN2022118398-appb-000019
Figure PCTCN2022118398-appb-000020
在一些实施方案中，
Figure PCTCN2022118398-appb-000021
选自
Figure PCTCN2022118398-appb-000022
In some embodiments,
Figure PCTCN2022118398-appb-000021
selected from
Figure PCTCN2022118398-appb-000022
在一些实施方案中，
Figure PCTCN2022118398-appb-000023
选自
Figure PCTCN2022118398-appb-000024
In some embodiments,
Figure PCTCN2022118398-appb-000023
selected from
Figure PCTCN2022118398-appb-000024
在一些实施方案中，
Figure PCTCN2022118398-appb-000025
选自
Figure PCTCN2022118398-appb-000026
In some embodiments,
Figure PCTCN2022118398-appb-000025
selected from
Figure PCTCN2022118398-appb-000026
在一些实施方案中，
Figure PCTCN2022118398-appb-000027
选自
Figure PCTCN2022118398-appb-000028
In some embodiments,
Figure PCTCN2022118398-appb-000027
selected from
Figure PCTCN2022118398-appb-000028
在一些实施方案中，
Figure PCTCN2022118398-appb-000029
选自
Figure PCTCN2022118398-appb-000030
In some embodiments,
Figure PCTCN2022118398-appb-000029
selected from
Figure PCTCN2022118398-appb-000030
在一些实施方案中，X选自
Figure PCTCN2022118398-appb-000031
In some embodiments, X is selected from
Figure PCTCN2022118398-appb-000031
在一些实施方案中，环B选自任选被R 3取代的以下基团：5-10元含氮杂芳基、4-7元单环含氮杂环基或6-10元含氮杂环基。 In some embodiments, ring B is selected from the following groups optionally substituted by R : 5-10 membered nitrogen-containing heteroaryl, 4-7 membered monocyclic nitrogen-containing heterocyclyl, or 6-10 membered nitrogen-containing heterocyclyl Ring base.
在一些实施方案中，环B选自任选被R 3取代的以下基团：吡唑基、咪唑基、三唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、氮杂环庚基、
Figure PCTCN2022118398-appb-000032
Figure PCTCN2022118398-appb-000033
In some embodiments, ring B is selected from the following groups optionally substituted by R : pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, aza Cyclobutyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azepanyl,
Figure PCTCN2022118398-appb-000032
Figure PCTCN2022118398-appb-000033
在一些实施方案中，环B选自任选被R 3取代的以下基团：吡唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、氮杂环庚基、
Figure PCTCN2022118398-appb-000034
Figure PCTCN2022118398-appb-000035
In some embodiments, Ring B is selected from the group consisting of pyrazolyl , azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, aza Cycloheptyl,
Figure PCTCN2022118398-appb-000034
Figure PCTCN2022118398-appb-000035
在一些实施方案中，R 3选自卤素、OH、＝O、CN、C 1-C 6烷基、C 1-C 6烷氧基、6-10元芳基或5-10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、6-10元芳基或5-10元杂芳基任选进一步被R 3a取代。 In some embodiments, R is selected from halogen, OH, =O, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 6-10 membered aryl or 5-10 membered heteroaryl , the C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, 6-10 membered aryl group or 5-10 membered heteroaryl group is optionally further substituted by R 3a .
在一些实施方案中，R 3选自卤素、OH、＝O、CN、C 1-C 3烷基、C 1-C 3烷氧基或苯基，所述C 1-C 3烷基、C 1-C 3烷氧基或苯基任选进一步被R 3a取代。 In some embodiments, R 3 is selected from halogen, OH, =O, CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or phenyl, said C 1 -C 3 alkyl, C 1 -C 3 alkoxy or phenyl is optionally further substituted by R 3a .
在一些实施方案中，R 3a选自卤素、OH、＝O或C 1-C 3烷氧基。 In some embodiments, R 3a is selected from halogen, OH, =0 or C 1 -C 3 alkoxy.
在一些实施方案中，R 3a选自F、OH或甲氧基。 In some embodiments, R 3a is selected from F, OH or methoxy.
在一些实施方案中，R 3选自＝O、OH、F、CN、甲基、异丙基、CF 3、羟甲基、甲氧基、
Figure PCTCN2022118398-appb-000036
或苯基。 In some embodiments, R 3 is selected from =O, OH, F, CN, methyl, isopropyl, CF 3 , hydroxymethyl, methoxy,
Figure PCTCN2022118398-appb-000036
or phenyl.
在一些实施方案中，R 3选自＝O、OH、F、CN、甲基、CF 3、羟甲基、甲氧基、
Figure PCTCN2022118398-appb-000037
或苯基。 In some embodiments, R 3 is selected from =O, OH, F, CN, methyl, CF 3 , hydroxymethyl, methoxy,
Figure PCTCN2022118398-appb-000037
or phenyl.
在一些实施方案中，R 4、R 5独立选自H、卤素、OH或任选被R 4a取代的C 1-C 3烷基，或者R 4、R 5一起形成＝O。 In some embodiments, R 4 , R 5 are independently selected from H, halogen, OH, or C 1 -C 3 alkyl optionally substituted by R 4a , or R 4 , R 5 together form =O.
在一些实施方案中，R 4a选自卤素、OH或C 1-C 3烷氧基。 In some embodiments, R 4a is selected from halogen, OH, or C 1 -C 3 alkoxy.
在一些实施方案中，R 4a选自F。 In some embodiments, R 4a is selected from F.
在一些实施方案中，R 4、R 5独立选自H、甲基、CF 3或乙基，或者R 4、R 5一起形成＝O。 In some embodiments, R 4 , R 5 are independently selected from H, methyl, CF 3 or ethyl, or R 4 , R 5 together form =O.
在一些实施方案中，p选自1。In some embodiments, p is selected from 1.
在一些实施方案中，p选自0。In some embodiments, p is selected from zero.
在一些实施方案中，
Figure PCTCN2022118398-appb-000038
选自如下基团：
Figure PCTCN2022118398-appb-000039
Figure PCTCN2022118398-appb-000040
In some embodiments,
Figure PCTCN2022118398-appb-000038
selected from the following groups:
Figure PCTCN2022118398-appb-000039
Figure PCTCN2022118398-appb-000040
在一些实施方案中，环D选自任选被R 6取代的以下基团：C 3-C 6环烷基、5-6元杂芳基、4-7元单环杂环基或6-10元杂环基，并且环D以非N原子与L相连。 In some embodiments, ring D is selected from the following groups optionally substituted by R 6 : C 3 -C 6 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered monocyclic heterocyclyl, or 6- 10-membered heterocyclic group, and the ring D is connected to L through a non-N atom.
在一些实施方案中，环D选自任选被R 6取代的以下基团：环丙基、环丁基、环戊基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、
Figure PCTCN2022118398-appb-000041
吡唑基、咪唑基、噁唑基、异噁唑基、三唑基、噻唑基或异噻唑基。 In some embodiments, ring D is selected from the following groups optionally substituted by R : cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
Figure PCTCN2022118398-appb-000041
Pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl or isothiazolyl.
在一些实施方案中，R 6选自卤素、OH、CN、＝O或任选被R 3a取代的C 1-C 3烷基。 In some embodiments, R 6 is selected from halogen, OH, CN, =O, or C 1 -C 3 alkyl optionally substituted by R 3a .
在一些实施方案中，R 6选自卤素、＝O、OH或C 1-C 3烷基。 In some embodiments, R 6 is selected from halogen, =O, OH, or C 1 -C 3 alkyl.
在一些实施方案中，R 6选自F、＝O或甲基。 In some embodiments, R6 is selected from F, =0 or methyl.
在一些实施方案中，L选自键、-NR 7-、-NR 7CR 8R 9-、-O-或-CR 8R 9-。 In some embodiments, L is selected from a bond, -NR 7 -, -NR 7 CR 8 R 9 -, -O-, or -CR 8 R 9 -.
在一些实施方案中，L选自键、-NR 7-、-NR 7CH 2-、-O-或-CR 8R 9-。 In some embodiments, L is selected from a bond, -NR 7 -, -NR 7 CH 2 -, -O-, or -CR 8 R 9 -.
在一些实施方案中，R 7、R 8和R 9独立选自H、C 1-C 3烷基或OH。 In some embodiments, R 7 , R 8 and R 9 are independently selected from H, C 1 -C 3 alkyl, or OH.
在一些实施方案中，R 7选自H或甲基。 In some embodiments, R7 is selected from H or methyl.
在一些实施方案中，R 8、R 9选自H或甲基。 In some embodiments, R 8 , R 9 are selected from H or methyl.
在一些实施方案中，R 8、R 9选自H。 In some embodiments, R 8 , R 9 are selected from H.
在一些实施方案中，L选自键、-NCH 3-、-NHCH 2-、-NHCH(CH 3)-、-O-或-CH 2-。 In some embodiments, L is selected from a bond, -NCH3- , -NHCH2- , -NHCH( CH3 )-, -O-, or -CH2- .
在一些实施方案中，L选自键、-NCH 3-、-NHCH 2-、-O-或-CH 2-。 In some embodiments, L is selected from a bond, -NCH3- , -NHCH2- , -O-, or -CH2- .
在一些实施方案中，
Figure PCTCN2022118398-appb-000042
选自如下基团：
Figure PCTCN2022118398-appb-000043
Figure PCTCN2022118398-appb-000044
In some embodiments,
Figure PCTCN2022118398-appb-000042
selected from the following groups:
Figure PCTCN2022118398-appb-000043
Figure PCTCN2022118398-appb-000044
在一些实施方案中，X选自如下基团：
Figure PCTCN2022118398-appb-000045
Figure PCTCN2022118398-appb-000046
Figure PCTCN2022118398-appb-000047
In some embodiments, X is selected from the following groups:
Figure PCTCN2022118398-appb-000045
Figure PCTCN2022118398-appb-000046
Figure PCTCN2022118398-appb-000047
在一些实施方案中，X选自
Figure PCTCN2022118398-appb-000048
In some embodiments, X is selected from
Figure PCTCN2022118398-appb-000048
在一些实施方案中，Q为任选被R 10取代的苯基或6元杂芳基。 In some embodiments, Q is phenyl or 6-membered heteroaryl optionally substituted with R 10 .
在一些实施方案中，Q为任选被R 10取代的以下基团：苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基。 In some embodiments, Q is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, optionally substituted by R 10 .
在一些实施方案中，Q为任选被R 10取代的以下基团：苯基、吡啶基、哒嗪基或嘧啶基。 In some embodiments, Q is phenyl, pyridyl, pyridazinyl, or pyrimidinyl, optionally substituted by R 10 .
在一些实施方案中，Q为任选被R 10取代的苯基。 In some embodiments, Q is phenyl optionally substituted with R 10 .
在一些实施方案中，R 10选自卤素、OH、CN、C 1-C 6烷基或C 1-C 6烷氧基，所述C 1-C 6烷基或C 1-C 6烷氧基任选被R 10a取代。 In some embodiments, R 10 is selected from halogen, OH, CN, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, said C 1 -C 6 alkyl or C 1 -C 6 alkoxy The group is optionally substituted by R 10a .
在一些实施方案中，R 10选自卤素、C 1-C 3烷基或C 1-C 3烷氧基，所述C 1-C 3烷基或C 1-C 3烷氧基任选被R 10a取代。 In some embodiments, R 10 is selected from halogen , C 1 -C 3 alkyl or C 1 -C 3 alkoxy, which is optionally replaced by R 10a is substituted.
在一些实施方案中，R 10a选自卤素、OH或C 1-C 3烷基。 In some embodiments, R 10a is selected from halogen, OH, or C 1 -C 3 alkyl.
在一些实施方案中，R 10a选自F或OH。 In some embodiments, R 10a is selected from F or OH.
在一些实施方案中，R 10选自F、Cl、甲基、甲氧基、CH 2OH或CF 3。 In some embodiments, R 10 is selected from F, Cl, methyl, methoxy, CH 2 OH, or CF 3 .
在一些实施方案中，Q为任选被卤素取代的苯基。In some embodiments, Q is phenyl optionally substituted with halo.
在一些实施方案中，Q选自
Figure PCTCN2022118398-appb-000049
其中Z 4和Z 5独立选自CR cR d、NR 11、O、S或SO 2，
Figure PCTCN2022118398-appb-000050
代表单键或双键，并且当
Figure PCTCN2022118398-appb-000051
为双键时，m为1，当
Figure PCTCN2022118398-appb-000052
为单键时，m为1或2。 In some embodiments, Q is selected from
Figure PCTCN2022118398-appb-000049
wherein Z 4 and Z 5 are independently selected from CR c R d , NR 11 , O, S or SO 2 ,
Figure PCTCN2022118398-appb-000050
represents a single or double bond, and when
Figure PCTCN2022118398-appb-000051
When it is a double bond, m is 1, when
Figure PCTCN2022118398-appb-000052
When it is a single bond, m is 1 or 2.
在一些实施方案中，R c、R d和R 11独立选自H、卤素、OH、NH 2或C 1-C 6烷基，所述C 1-C 6烷基任选被R 11a取代，或者R c、R d共同形成＝O，或者R c、R d与其相连的原子共同形成C 3-C 6环烷基，所述C 3-C 6环烷基任选被R 11b取代。 In some embodiments, R c , R d and R 11 are independently selected from H, halogen, OH, NH 2 , or C 1 -C 6 alkyl optionally substituted with R 11a , Or R c , R d jointly form =O, or R c , R d and the atoms connected to them jointly form a C 3 -C 6 cycloalkyl group, and the C 3 -C 6 cycloalkyl group is optionally substituted by R 11b .
在一些实施方案中，R c、R d和R 11独立选自H、卤素、OH或任选被R 11a取代的C 1-C 3烷基，或者R c、R d共同形成＝O，或者R c、R d与其相连的原子共同形成任选被R 11b取代的C 3-C 4环烷基。 In some embodiments, R c , R d and R 11 are independently selected from H, halogen, OH, or C 1 -C 3 alkyl optionally substituted by R 11a , or R c , R d together form =O, or R c , R d and the atoms connected to them together form a C 3 -C 4 cycloalkyl group optionally substituted by R 11b .
在一些实施方案中，R c与R 11及其各自相连的原子共同形成4-7元杂环基，所述4-7元杂环基任选被R 11c取代。 In some embodiments, R c and R 11 and the atoms to which they are each attached together form a 4-7 membered heterocyclyl optionally substituted with R 11c .
在一些实施方案中，R 11a、R 11b和R 11c独立选自卤素、OH、＝O、NH 2或C 1-C 3烷基。 In some embodiments, R 11a , R 11b and R 11c are independently selected from halogen, OH, =0, NH 2 or C 1 -C 3 alkyl.
在一些实施方案中，R 11a、R 11b和R 11c独立选自卤素、OH或＝O。 In some embodiments, R 11a , R 11b , and R 11c are independently selected from halogen, OH, or =O.
在一些实施方案中，R c、R d和R 11独立选自H、卤素或甲基，或者R c、R d共同形成＝O，或者R c、R d与其相连的原子共同形成环丙基。 In some embodiments, R c , R d and R 11 are independently selected from H, halogen, or methyl, or R c , R d together form =O, or R c , R d and the atoms to which they are attached form cyclopropyl .
在一些实施方案中，R c和R d二者及其相连的原子共同形成环丙基。 In some embodiments, both Rc and Rd , together with the atoms to which they are attached, form cyclopropyl.
在一些实施方案中，Z 4和Z 5独立选自CH 2、CF 2、CHCH 3、C(CH 3) 2、NCH 3、C＝O、O、S、S(＝O) 2或
Figure PCTCN2022118398-appb-000053
或者Z 4-Z 5共同形成
Figure PCTCN2022118398-appb-000054
In some embodiments, Z4 and Z5 are independently selected from CH2 , CF2 , CHCH3 , C( CH3 ) 2 , NCH3 , C=O, O, S, S(=O) 2 , or
Figure PCTCN2022118398-appb-000053
Or Z 4 -Z 5 together form
Figure PCTCN2022118398-appb-000054
在一些实施方案中，Q选自
Figure PCTCN2022118398-appb-000055
m为1或2。 In some embodiments, Q is selected from
Figure PCTCN2022118398-appb-000055
m is 1 or 2.
在一些实施方案中，Q选自
Figure PCTCN2022118398-appb-000056
m为1。 In some embodiments, Q is selected from
Figure PCTCN2022118398-appb-000056
m is 1.
在一些实施方案中，Q选自
Figure PCTCN2022118398-appb-000057
In some embodiments, Q is selected from
Figure PCTCN2022118398-appb-000057
在一些实施方案中，Q选自苯基、
Figure PCTCN2022118398-appb-000058
Figure PCTCN2022118398-appb-000059
Figure PCTCN2022118398-appb-000060
Figure PCTCN2022118398-appb-000061
其中a代表Q与母核中的6元环共用的键，b代表Q与母核中的5元环共用的键。 In some embodiments, Q is selected from phenyl,
Figure PCTCN2022118398-appb-000058
Figure PCTCN2022118398-appb-000059
Figure PCTCN2022118398-appb-000060
Figure PCTCN2022118398-appb-000061
Wherein a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
在一些实施方案中，Q选自苯基、
Figure PCTCN2022118398-appb-000062
Figure PCTCN2022118398-appb-000063
Figure PCTCN2022118398-appb-000064
其中a代表Q与母核中的6元环共用的键，b代表Q与母核中的5元环共用的键。 In some embodiments, Q is selected from phenyl,
Figure PCTCN2022118398-appb-000062
Figure PCTCN2022118398-appb-000063
Figure PCTCN2022118398-appb-000064
Wherein a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
在一些实施方案中，Q选自苯基、
Figure PCTCN2022118398-appb-000065
Figure PCTCN2022118398-appb-000066
In some embodiments, Q is selected from phenyl,
Figure PCTCN2022118398-appb-000065
Figure PCTCN2022118398-appb-000066
其中a代表Q与母核中的6元环共用的键，b代表Q与母核中的5元环共用的键。Where a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
在一些实施方案中，Q选自
Figure PCTCN2022118398-appb-000067
Figure PCTCN2022118398-appb-000068
Figure PCTCN2022118398-appb-000069
其中a代表Q与母核中的6元环共用的键，b代表Q与母核中的5元环共用的键。 In some embodiments, Q is selected from
Figure PCTCN2022118398-appb-000067
Figure PCTCN2022118398-appb-000068
Figure PCTCN2022118398-appb-000069
Wherein a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
在一些实施方案中，Q选自
Figure PCTCN2022118398-appb-000070
Figure PCTCN2022118398-appb-000071
Figure PCTCN2022118398-appb-000072
其中a代表Q与母核中的6元环共用的键，b代表Q与母核中的5元环共用的键。 In some embodiments, Q is selected from
Figure PCTCN2022118398-appb-000070
Figure PCTCN2022118398-appb-000071
Figure PCTCN2022118398-appb-000072
Where a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
在一些实施方案中，Q选自苯基、
Figure PCTCN2022118398-appb-000073
其中a代表Q与母核中的6元环共用的键，b代表Q与母核中的5元环共用的键。 In some embodiments, Q is selected from phenyl,
Figure PCTCN2022118398-appb-000073
Where a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
在一些实施方案中，Q选自苯基或
Figure PCTCN2022118398-appb-000074
其中a代表Q与母核中的6元环共用的键，b代表Q与母核中的5元环共用的键。 In some embodiments, Q is selected from phenyl or
Figure PCTCN2022118398-appb-000074
Wherein a represents the bond shared by Q and the 6-membered ring in the parent core, and b represents the bond shared by Q and the 5-membered ring in the parent core.
在一些实施方案中，R 1、R 2与其连接的原子共同形成C 3-C 8环烷基或4-10元杂环基，所述C 3-C 8环烷基或4-10元杂环基任选被R 1b取代。 In some embodiments, R 1 and R 2 together form a C 3 -C 8 cycloalkyl group or a 4-10 membered heterocyclic group, and the C 3 -C 8 cycloalkyl group or a 4-10 membered heterocyclic group Cyclic is optionally substituted by R 1b .
在一些实施方案中，R 1、R 2与其连接的原子共同形成C 3-C 6环烷基或4-7元杂环基，所述C 3-C 6环烷基或4-7元杂环基任选被R 1b取代。 In some embodiments, R 1 and R 2 together form a C 3 -C 6 cycloalkyl or a 4-7 membered heterocyclyl, and the C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl Cyclic is optionally substituted by R 1b .
在一些实施方案中，R 1、R 2与其连接的原子共同形成任选被R 1b取代的如下基团：环丁基、螺[2,3]己基或氧杂环丁基。 In some embodiments, R 1 , R 2 and the atoms to which they are attached together form a group optionally substituted by R 1b : cyclobutyl, spiro[2,3]hexyl, or oxetanyl.
在一些实施方案中，R 1b选自卤素、OH、CN、＝O、NH 2、C 1-C 3烷基或C 1-C 3烷氧基，所述C 1-C 3烷基或C 1-C 3烷氧基任选被R 1c取代。 In some embodiments, R 1b is selected from halogen, OH, CN, =O, NH 2 , C 1 -C 3 alkyl or C 1 -C 3 alkoxy, said C 1 -C 3 alkyl or C 1 -C 3 alkoxy is optionally substituted by R 1c .
在一些实施方案中，R 1b选自卤素、CN、C 1-C 3烷基或C 1-C 3烷氧基，所述C 1-C 3烷基或C 1-C 3烷氧基任选被R 1c取代。 In some embodiments, R 1b is selected from halogen, CN, C 1 -C 3 alkyl or C 1 -C 3 alkoxy, and the C 1 -C 3 alkyl or C 1 -C 3 alkoxy is any is replaced by R 1c .
在一些实施方案中，R 1c选自卤素、OH或CN。 In some embodiments, R 1c is selected from halogen, OH or CN.
在一些实施方案中，R 1c选自CN。 In some embodiments, R 1c is selected from CN.
在一些实施方案中，R 1b选自F、CN、甲基、甲氧基或CH 2CN。 In some embodiments, R 1b is selected from F, CN, methyl, methoxy, or CH 2 CN.
在一些实施方案中，R 1和R 2独立选自H、卤素、CN、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基或4-7元杂环基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基或4-7元杂环基任选被R 1a取代，且所述C 3-C 8环烷基或4-7元杂环基可以是螺环、桥环或并环形式的。 In some embodiments, R 1 and R 2 are independently selected from H, halogen, CN, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 4-7 membered heterocyclic group, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R 1a , and the C 3 -C 8 cycloalkyl or 4-7 membered heterocyclic group may be a spiro ring, bridged ring or in ring form.
在一些实施方案中，R 1和R 2独立选自H、卤素、CN、C 1-C 3烷基、C 1-C 3烷氧基或C 3-C 6环烷基，所述C 1-C 3烷基、C 1-C 3烷氧基或C 3-C 6环烷基任选被R 1a取代。 In some embodiments, R and R are independently selected from H, halogen, CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or C 3 -C 6 cycloalkyl, the C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 3 -C 6 cycloalkyl is optionally substituted by R 1a .
在一些实施方案中，R 1和R 2独立选自H、C 1-C 3烷基或C 3-C 6环烷基，所述C 1-C 3烷基或 C 3-C 6环烷基任选被R 1a取代。 In some embodiments, R 1 and R 2 are independently selected from H, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, said C 1 -C 3 alkyl or C 3 -C 6 cycloalkane The group is optionally substituted by R 1a .
在一些实施方案中，R 1a选自卤素、OH、CN、＝O、NH 2、C 1-C 3烷基或C 1-C 3烷氧基。 In some embodiments, R 1a is selected from halogen, OH, CN, =0, NH 2 , C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.
在一些实施方案中，R 1和R 2独立选自H、甲基、异丙基、环丙基或环丁基，或者R 1、R 2与其连接的原子共同形成如下基团：
Figure PCTCN2022118398-appb-000075
Figure PCTCN2022118398-appb-000076
In some embodiments, R 1 and R 2 are independently selected from H, methyl, isopropyl, cyclopropyl or cyclobutyl, or R 1 , R 2 and the atoms to which they are attached together form the following group:
Figure PCTCN2022118398-appb-000075
Figure PCTCN2022118398-appb-000076
在一些实施方案中，R 1和R 2独立选自H、甲基、异丙基或环丁基，或者R 1、R 2与其连接的原子共同形成如下基团：
Figure PCTCN2022118398-appb-000077
Figure PCTCN2022118398-appb-000078
In some embodiments, R 1 and R 2 are independently selected from H, methyl, isopropyl or cyclobutyl, or R 1 , R 2 and the atoms to which they are attached together form the following group:
Figure PCTCN2022118398-appb-000077
Figure PCTCN2022118398-appb-000078
在一些实施方案中，R 1和R 2独立选自H、甲基或环丁基，或者R 1、R 2与其连接的原子共同形成如下基团：
Figure PCTCN2022118398-appb-000079
In some embodiments, R 1 and R 2 are independently selected from H, methyl or cyclobutyl, or R 1 , R 2 and the atoms to which they are attached together form the following group:
Figure PCTCN2022118398-appb-000079
在一些实施方案中，R 1、R 2与其连接的原子共同形成如下基团：
Figure PCTCN2022118398-appb-000080
Figure PCTCN2022118398-appb-000081
In some embodiments, R 1 , R 2 and the atoms to which they are attached together form the following group:
Figure PCTCN2022118398-appb-000080
Figure PCTCN2022118398-appb-000081
在一些实施方案中，R 1、R 2与其连接的原子共同形成如下基团：
Figure PCTCN2022118398-appb-000082
Figure PCTCN2022118398-appb-000083
In some embodiments, R 1 , R 2 and the atoms to which they are attached together form the following group:
Figure PCTCN2022118398-appb-000082
Figure PCTCN2022118398-appb-000083
在一些实施方案中，R 1、R 2与其连接的原子共同形成如下基团：
Figure PCTCN2022118398-appb-000084
Figure PCTCN2022118398-appb-000085
In some embodiments, R 1 , R 2 and the atoms to which they are attached together form the following group:
Figure PCTCN2022118398-appb-000084
Figure PCTCN2022118398-appb-000085
在一些实施方案中，R 1、R 2与其连接的原子共同形成如下基团：
Figure PCTCN2022118398-appb-000086
In some embodiments, R 1 , R 2 and the atoms to which they are attached together form the following group:
Figure PCTCN2022118398-appb-000086
在一些实施方案中，R 1和R 2独立选自H、甲基、异丙基或环丁基。 In some embodiments, R and R are independently selected from H, methyl, isopropyl, or cyclobutyl.
在一些实施方案中，R 1和R 2独立选自H、甲基或环丁基。 In some embodiments, R and R are independently selected from H, methyl, or cyclobutyl.
在一些实施方案中，W选自-(CR 12R 13)W 1。 In some embodiments, W is selected from -(CR 12 R 13 )W 1 .
在一些实施方案中，R 12、R 13独立选自H、卤素、OH或甲基。 In some embodiments, R 12 , R 13 are independently selected from H, halogen, OH or methyl.
在一些实施方案中，R 12、R 13独立选自H或F。 In some embodiments, R 12 , R 13 are independently selected from H or F.
在一些实施方案中，R 12、R 13均为H。 In some embodiments, both R 12 and R 13 are H.
在一些实施方案中，R 1与R 12及其各自相连的原子和键共同形成任选被R 12a取代的C 3-C 6环烷基。 In some embodiments, R 1 and R 12 together with the atoms and bonds to which they are attached form a C 3 -C 6 cycloalkyl optionally substituted with R 12a .
在一些实施方案中，R 12a选自C 1-C 3烷基。 In some embodiments, R 12a is selected from C 1 -C 3 alkyl.
在一些实施方案中，R 12a选自甲基。 In some embodiments, R 12a is selected from methyl.
在一些实施方案中，R 1与R 12及其各自相连的原子和键共同形成
Figure PCTCN2022118398-appb-000087
In some embodiments, R and R together with the atoms and bonds to which they are attached form
Figure PCTCN2022118398-appb-000087
在一些实施方案中，W选自W 1。 In some embodiments, W is selected from W 1 .
在一些实施方案中，W 1选自任选被R 14取代的4-10元杂环基。 In some embodiments, W is selected from 4-10 membered heterocyclyl optionally substituted by R.
在一些实施方案中，W 1选自任选被R 14取代的5-10元杂芳基。 In some embodiments, W is selected from 5-10 membered heteroaryl optionally substituted by R.
在一些实施方案中，W 1选自任选被R 14取代的5元杂芳基。 In some embodiments, W is selected from 5-membered heteroaryl optionally substituted with R.
在一些实施方案中，W 1选自任选被R 14取代的如下基团：吡咯、噻吩、呋喃、吡唑、咪唑、噻唑、异噻唑、噻二唑、三氮唑、噁唑、异噁唑、噁二唑、
Figure PCTCN2022118398-appb-000088
In some embodiments, W is selected from the following groups optionally substituted by R : pyrrole, thiophene, furan, pyrazole, imidazole, thiazole, isothiazole, thiadiazole, triazole, oxazole, isoxazole Azole, oxadiazole,
Figure PCTCN2022118398-appb-000088
在一些实施方案中，W 1选自任选被R 14取代的如下基团：三氮唑、噁唑、异噁唑或噁二唑。 In some embodiments, W 1 is selected from triazole, oxazole, isoxazole, or oxadiazole, optionally substituted by R 14 .
在一些实施方案中，W 1选自任选被R 14取代的如下基团：
Figure PCTCN2022118398-appb-000089
In some embodiments, W is selected from the following groups optionally substituted by R :
Figure PCTCN2022118398-appb-000089
在一些实施方案中，R 14选自卤素、OH、NH 2、C 1-C 3烷基或C 3-C 6环烷基，所述C 1-C 3烷基或C 3-C 6环烷基任选被R 14a取代。 In some embodiments, R 14 is selected from halogen, OH, NH 2 , C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, said C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl Alkyl is optionally substituted by R 14a .
在一些实施方案中，R 14选自OH、C 1-C 3烷基或C 3-C 6环烷基，所述C 1-C 3烷基或C 3-C 6环烷基任选被R 14a取代。 In some embodiments, R 14 is selected from OH, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, the C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl optionally replaced by R 14a is substituted.
在一些实施方案中，R 14选自甲基或环丙基，所述甲基或环丙基任选被R 14a取代。 In some embodiments, R 14 is selected from methyl or cyclopropyl optionally substituted with R 14a .
在一些实施方案中，R 14a选自卤素、OH或CN。 In some embodiments, R 14a is selected from halogen, OH or CN.
在一些实施方案中，R 14a选自F。 In some embodiments, R 14a is selected from F.
在一些实施方案中，R 14选自甲基、CHF 2或环丙基。 In some embodiments, R 14 is selected from methyl, CHF 2 or cyclopropyl.
在一些实施方案中，W 1选自如下基团：
Figure PCTCN2022118398-appb-000090
Figure PCTCN2022118398-appb-000091
In some embodiments, W is selected from the following groups:
Figure PCTCN2022118398-appb-000090
Figure PCTCN2022118398-appb-000091
在一些实施方案中，W选自
Figure PCTCN2022118398-appb-000092
In some embodiments, W is selected from
Figure PCTCN2022118398-appb-000092
在一些实施方案中，W选自
Figure PCTCN2022118398-appb-000093
In some embodiments, W is selected from
Figure PCTCN2022118398-appb-000093
在一些实施方案中，Z 1和Z 2独立选自CH或N；Z 3选自C或CH；Y 1、Y 2和Y 3均为CH以及Y 4为CR b；或者Y 1为N，Y 2和Y 3均为CH，以及Y 4为CR b；或者Y 4为N以及Y 1、Y 2和Y 3均为CH；R b选自H、卤素、CN、C 1-C 6烷基、C 1-C 6烷硫基、NH(C 1-C 6烷基)或C 3-C 6环烷基；X选自
Figure PCTCN2022118398-appb-000094
Q选自任选被R 10取代的苯基或选被R 10取代的6元含氮杂芳基，或者Q选自
Figure PCTCN2022118398-appb-000095
其中a代表Q与母核中的6元环共用的键，b代表Q与母核中的5元环共用的键；R 10选自卤素、C 1-C 3烷氧基或任选地被卤素取代的C 1-C 3烷基；R 1、R 2与其连接的原子共同形成任选被R 1b取代的C 3-C 6环烷基或任选被R 1b取代的4-7元杂环基，或者R 1和R 2独立选自H、C 1-C 3烷基或C 3-C 6环烷基；R 1b选自卤素、CN、C 1-C 3烷氧基或任选被-CN取代的C 1-C 3烷基；以及W选自(CR 12R 13) kW 1，R 12、R 13独立选自H或卤素、k选自0或1，W 1为被C 1-C 3烷基取代的三氮唑。 In some embodiments, Z 1 and Z 2 are independently selected from CH or N; Z 3 is selected from C or CH; Y 1 , Y 2 and Y 3 are all CH and Y 4 is CR b ; or Y 1 is N, Both Y 2 and Y 3 are CH, and Y 4 is CR b ; or Y 4 is N and Y 1 , Y 2 and Y 3 are all CH; R b is selected from H, halogen, CN, C 1 -C 6 alkane Group, C 1 -C 6 alkylthio, NH (C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl; X is selected from
Figure PCTCN2022118398-appb-000094
Q is selected from phenyl optionally substituted by R 10 or 6-membered nitrogen-containing heteroaryl optionally substituted by R 10 , or Q is selected from
Figure PCTCN2022118398-appb-000095
Wherein a represents the bond shared by Q and the 6-membered ring in the core, b represents the bond shared by Q and the 5-membered ring in the core; R is selected from halogen, C 1 -C 3 alkoxy or optionally Halogen substituted C 1 -C 3 alkyl; R 1 , R 2 and the atoms they are connected together form a C 3 -C 6 cycloalkyl optionally substituted by R 1b or a 4-7 membered heteroalkyl group optionally substituted by R 1b Cyclic group, or R 1 and R 2 are independently selected from H, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl; R 1b is selected from halogen, CN, C 1 -C 3 alkoxy or optionally C 1 -C 3 alkyl substituted by -CN; and W is selected from (CR 12 R 13 ) k W 1 , R 12 and R 13 are independently selected from H or halogen, k is selected from 0 or 1, and W 1 is selected from C 1 -C 3 alkyl substituted triazoles.
在一些实施方案中，Z 1和Z 2均为CH；Z 3选自C或CH；Y 1、Y 2、Y 3和Y 4均为CH，Y 1、Y 2和Y 3均为CH以及Y 4为CR b，或者Y 1为N，Y 2和Y 3均为CH，以及Y 4为CR b，或者Y 4为N以及Y 1、Y 2和Y 3均为CH；R b选自H、卤素、CN或甲基；X为
Figure PCTCN2022118398-appb-000096
Figure PCTCN2022118398-appb-000097
Q选自
Figure PCTCN2022118398-appb-000098
或任选被卤素取代的苯基，其中a代表Q与母核中的6元环共用的键，b代表Q与母核中的5元环共用的键；R 1、R 2与其连接的原子共同形成被R 1b取代的环丁基，R 1b选自卤素和C 1-C 3烷基，或者R 1和R 2独立选自H或C 3-C 6环烷基；以及W选自 被甲基取代的三氮唑。 In some embodiments, Z 1 and Z 2 are both CH; Z 3 is selected from C or CH; Y 1 , Y 2 , Y 3 and Y 4 are all CH, Y 1 , Y 2 and Y 3 are all CH and Y 4 is CR b , or Y 1 is N, Y 2 and Y 3 are both CH, and Y 4 is CR b , or Y 4 is N and Y 1 , Y 2 and Y 3 are all CH; R b is selected from H, halogen, CN or methyl; X is
Figure PCTCN2022118398-appb-000096
Figure PCTCN2022118398-appb-000097
Q from
Figure PCTCN2022118398-appb-000098
Or phenyl optionally substituted by halogen, wherein a represents the bond shared by Q and the 6-membered ring in the parent nucleus, and b represents the bond shared by Q and the 5-membered ring in the parent nucleus; R 1 , R 2 are connected to the atom Together form cyclobutyl substituted by R 1b , R 1b is selected from halogen and C 1 -C 3 alkyl, or R 1 and R 2 are independently selected from H or C 3 -C 6 cycloalkyl; and W is selected from Methyl-substituted triazoles.
在一些实施方案中，本申请的式(I)化合物或其立体异构体或其药学上可接受的盐选自式(II)化合物或其立体异构体或其药学上可接受的盐：In some embodiments, the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof of the present application is selected from the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt:
Figure PCTCN2022118398-appb-000099
Figure PCTCN2022118398-appb-000099
其中，j选自0、1、2或3，Z 1、Z 2、Y 1、Y 2、Y 3、Y 4、X、W、R 1、R 2和R 10如式(I)中所定义。 Wherein, j is selected from 0, 1, 2 or 3, Z 1 , Z 2 , Y 1 , Y 2 , Y 3 , Y 4 , X, W, R 1 , R 2 and R 10 are as shown in formula (I) definition.
在一些实施方案中，本申请的式(I)化合物或其立体异构体或其药学上可接受的盐选自式(III)化合物或其立体异构体或其药学上可接受的盐：In some embodiments, the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof of the present application is selected from the compound of formula (III) or its stereoisomer or its pharmaceutically acceptable salt:
Figure PCTCN2022118398-appb-000100
Figure PCTCN2022118398-appb-000100
其中，Z 1、Z 2、Z 3、Z 4、Z 5、Y 1、Y 2、Y 3、Y 4、X、W、R 1、R 2和m如式(I)中所定义。 Wherein, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Y 1 , Y 2 , Y 3 , Y 4 , X, W, R 1 , R 2 and m are as defined in formula (I).
在一些实施方案中，本申请的式(I)化合物或其立体异构体或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：In some embodiments, the compound of formula (I) of the present application or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or its pharmaceutically acceptable salt:
Figure PCTCN2022118398-appb-000101
Figure PCTCN2022118398-appb-000101
Figure PCTCN2022118398-appb-000102
Figure PCTCN2022118398-appb-000102
Figure PCTCN2022118398-appb-000103
Figure PCTCN2022118398-appb-000103
Figure PCTCN2022118398-appb-000104
Figure PCTCN2022118398-appb-000104
Figure PCTCN2022118398-appb-000105
Figure PCTCN2022118398-appb-000105
Figure PCTCN2022118398-appb-000106
Figure PCTCN2022118398-appb-000106
Figure PCTCN2022118398-appb-000107
Figure PCTCN2022118398-appb-000107
Figure PCTCN2022118398-appb-000108
Figure PCTCN2022118398-appb-000108
Figure PCTCN2022118398-appb-000109
Figure PCTCN2022118398-appb-000109
另一方面，本申请提供药物组合物，其包含本申请的式(I)化合物、式(II)化合物、式(III)化合物或其立体异构体或其药学上可接受的盐和药学上可接受的辅料。On the other hand, the application provides a pharmaceutical composition, which comprises the compound of formula (I), compound of formula (II), compound of formula (III) or its stereoisomer or pharmaceutically acceptable salt thereof and pharmaceutically Acceptable excipients.
另一方面，本申请提供治疗哺乳动物的由Cbl-b介导的疾病或病症的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(I)化合物、式(II)化合物、式(III)化合物或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 provides a method for treating a disease or condition mediated by Cbl-b in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I), formula (II) to a mammal in need of the treatment, preferably a human being ) compound, compound of formula (III) or its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
另一方面，本申请提供治疗哺乳动物的肿瘤或自身免疫性疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(I)化合物、式(II)化合物、式(III)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物。In another aspect, the present application provides a method for treating tumors or autoimmune diseases in mammals, comprising administering a therapeutically effective amount of a compound of formula (I), compound of formula (II), compound of formula (III) A compound or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
另一方面，本申请提供式(I)化合物、式(II)化合物、式(III)化合物或其立体异构体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哺乳动物，优选人类的由Cbl-b介导的疾病或病症的药物中的用途。In another aspect, the present application provides compounds of formula (I), compounds of formula (II), compounds of formula (III) or their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of prevention or treatment of breastfeeding Use in medicine for diseases or conditions mediated by Cbl-b in animals, preferably humans.
另一方面，本申请提供式(I)化合物、式(II)化合物、式(III)化合物或其立体异构体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哺乳动物，优选人类的肿瘤或自身免疫性疾病的药物中的用途。In another aspect, the present application provides compounds of formula (I), compounds of formula (II), compounds of formula (III) or their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of prevention or treatment of breastfeeding Use in medicine for tumors or autoimmune diseases in animals, preferably humans.
另一方面，本申请提供式(I)化合物、式(II)化合物、式(III)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物在预防或者治疗哺乳动物，优选人类的由Cbl-b介导的疾病或病症中的用途。On the other hand, the application provides compounds of formula (I), compounds of formula (II), compounds of formula (III) or their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the prevention or treatment of mammals , preferably human diseases or disorders mediated by Cbl-b.
另一方面，本申请提供式(I)化合物、式(II)化合物、式(III)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物在预防或者治疗哺乳动物，优选人类的肿瘤或自身免疫性疾病中的用途。On the other hand, the application provides compounds of formula (I), compounds of formula (II), compounds of formula (III) or their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the prevention or treatment of mammals , preferably for use in human tumors or autoimmune diseases.
另一方面，本申请提供用于预防或者治疗哺乳动物，优选人类的由Cbl-b介导的疾病或病症的式(I)化合物、式(II)化合物、式(III)化合物或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 application provides a compound of formula (I), a compound of formula (II), a compound of formula (III) or its stereoisomer for preventing or treating mammals, preferably human, diseases or diseases mediated by Cbl-b. Constructs or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
另一方面，本申请提供用于预防或者治疗哺乳动物，优选人类的肿瘤或自身免疫性疾病的式(I)化合物、式(II)化合物、式(III)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物。In another aspect, the present application provides a compound of formula (I), a compound of formula (II), a compound of formula (III) or its stereoisomer or its A pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
在一些实施方案中，由Cbl-b介导的疾病或病症选自肿瘤或自身免疫性疾病。In some embodiments, the disease or condition mediated by Cbl-b is selected from tumors or autoimmune diseases.
术语定义和说明Definitions and Explanations of Terms
除非另有说明，本申请中所用的术语具有下列含义，本申请中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化 合物的定义等，可以彼此之间任意组合和结合。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 terms used in this application have the following meanings, definitions of groups and terms recorded in this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, examples The definitions of specific compounds in and etc. may be combined and combined with each other arbitrarily. A specific term should not be regarded as indeterminate or unclear if there is no special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
本文中
Figure PCTCN2022118398-appb-000110
表示连接位点。 In this article
Figure PCTCN2022118398-appb-000110
Indicates the junction site.
本文中，由实线和虚线描绘的键
Figure PCTCN2022118398-appb-000111
表示单键或双键。 In this paper, the bonds depicted by solid and dashed lines
Figure PCTCN2022118398-appb-000111
Indicates a single or double bond.
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚楔键
Figure PCTCN2022118398-appb-000112
表示一个立体中心的绝对构型，用黑实键和虚键
Figure PCTCN2022118398-appb-000113
表示一个立体中心的相对构型(如脂环化合物的顺反构型)。 Graphical representations of racemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, with wedge and dotted keys
Figure PCTCN2022118398-appb-000112
Indicates the absolute configuration of a stereocenter with black real and virtual bonds
Figure PCTCN2022118398-appb-000113
Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本申请化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本申请包含化合物的所有互变异构形式。The term "tautomer" refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. Compounds of the present application may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. This application encompasses all tautomeric forms of the compounds.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和非对映异构体。The term "stereoisomer" refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers and diastereomers.
本申请的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键，因此本申请的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，以及其外消旋混合物或其它混合物，例如对映异构体或非对映体富集的混合物，以上所有这些异构体以及它们的混合物都属于本申请化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子，所有取代基中涉及到的这些异构体以及它们的混合物，也均包括在本申请化合物的定义范围之内。本申请的含有不对称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。The compounds of the present application may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present application may exist in specific geometric or stereoisomer forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof fall within the definition of the compounds of the present application. There may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included in Within the definition of the compounds of the present application. The compounds containing asymmetric atoms of the present application can be isolated in optically pure form or racemic form, optically active form can be resolved from racemic mixture, or synthesized by using chiral raw materials or chiral reagents .
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 the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable. When a substituent is oxo (ie, =0), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.
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，是指乙基可以是未被取代的(CH 2CH 3)、单取代的(CH 2CH 2F、CH 2CH 2Cl等)、多取代的(CHFCH 2F、CH 2CHF 2、CHFCH 2Cl、CH 2CHCl 2等)或完全被取代的(CF 2CF 3、CF 2CCl 3、CCl 2CCl 3等)。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 "optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that description includes that said event or circumstance occurs and that it does not. For example, ethyl is "optionally" substituted with halogen , meaning that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted ( CH2CH2F , CH2CH2Cl , etc.), polysubstituted ( CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc. ) or fully substituted ( CF2CF3 , CF2CCl3 , CCl2CCl3 , etc.) . It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
当任何变量(例如R 1a、R 2a)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，如果一个基团被2个R 1a所取代，则每个R 1a都有独立的选项。 When any variable (eg R 1a , R 2a ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. For example, if a group is substituted by 2 R 1a , each R 1a has independent options.
当一个连接基团的数量为0时，比如-(CR 12R 13) 0-，表示该连接基团为键。 When the number of a linking group is 0, such as -(CR 12 R 13 ) 0 -, it means that the linking group is a bond.
当其中一个变量选自化学键或不存在时，表示其连接的两个基团直接相连，比如
Figure PCTCN2022118398-appb-000114
中L代表键时表示该结构实际上是
Figure PCTCN2022118398-appb-000115
When one of the variables is selected from chemical bond or absence, it means that the two groups connected are directly connected, such as
Figure PCTCN2022118398-appb-000114
When L stands for a bond, it means that the structure is actually
Figure PCTCN2022118398-appb-000115
当本文中涉及到的连接基团若没有指明其连接方向，则其连接方向是任意的。例如当结 构单元
Figure PCTCN2022118398-appb-000116
中的L选自“-NR 7CH 2-”时，此时L既可以按照与从左到右的方向连接环D构成“环D-NR 7CH 2-”，也可以按照从右到左的方向连接环D构成“环D-CH 2NR 7-”。 When the linking group mentioned herein does not indicate its linking direction, its linking direction is arbitrary. For example when the structural unit
Figure PCTCN2022118398-appb-000116
When L in is selected from "-NR 7 CH 2 -", at this time L can be connected to ring D from left to right to form "ring D-NR 7 CH 2 -", or it can be connected from right to left The direction of linking ring D constitutes "ring D-CH 2 NR 7 -".
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2022118398-appb-000117
表示R 10可在苯环上的位置1、2、3中任一处发生取代。 When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring. For example, the structural unit
Figure PCTCN2022118398-appb-000117
It means that R 10 can be substituted at any one of positions 1, 2, and 3 on the benzene ring.
本文中的C m-C n是指具有m-n范围中的整数个碳原子。例如“C 1-C 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。 Cm - Cn herein refers to having an integer number of carbon atoms in the range of mn. For example "C 1 -C 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.
术语“烷基”是指通式为C nH 2n+1的烃基，该烷基可以是直链或支链的。术语“C 1-C 6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基的具体实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等。术语“C 1-C 3烷基”可理解为表示具有1、2或3个碳原子的直链或支链饱和一价烃基。所述“C 1-C 6烷基”可以包含“C 1-C 3烷基”。 The term "alkyl" refers to a hydrocarbon group having the general formula C n H 2n+1 , and the alkyl group may be straight or branched. The term "C 1 -C 6 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. The term "C 1 -C 3 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms. The "C 1 -C 6 alkyl group" may include "C 1 -C 3 alkyl group".
术语“烷氧基”是指直链或支链醇类失去羟基上的氢原子产生的一价基团，可理解为“烷基氧基”或“烷基-O-”。术语“C 1-C 6烷氧基”可理解为“C 1-C 6烷基氧基”或“C 1-C 6烷基-O-”；术语“C 1-C 3烷氧基”可理解为“C 1-C 3烷基氧基”或“C 1-C 3烷基-O-”。所述“C 1-C 6烷氧基”可以进一步包含“C 1-C 3烷氧基”。 The term "alkoxy" refers to a monovalent group produced by the loss of a hydrogen atom on a hydroxyl group of a straight-chain or branched alcohol, which can be understood as "alkyloxy" or "alkyl-O-". The term "C 1 -C 6 alkoxy" can be understood as "C 1 -C 6 alkyloxy" or "C 1 -C 6 alkyl-O-"; the term "C 1 -C 3 alkoxy" Can be understood as "C 1 -C 3 alkyloxy" or "C 1 -C 3 alkyl-O-". The "C 1 -C 6 alkoxy" may further include "C 1 -C 3 alkoxy".
术语“环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的碳环。除非另有指示，该碳环通常为3至10元环。术语“C 3-C 10环烷基”应理解为表示饱和的一价单环、并环、螺环或桥环，其具有3、4、5、6、7、8、9或10个碳原子。所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C 3-C 10环烷基”可以包含“C 3-C 8环烷基”，“C 3-C 8环烷基”可以包含“C 3-C 6环烷基”，“C 3-C 6环烷基”可以包含“C 3-C 4环烷基”。术语“C 3-C 6环烷基”可理解为表示饱和的一价单环或双环烃环，其具有3、4、5或6个碳原子，具体实例包括但不限于环丙基、环丁基、环戊基或环己基等。 The term "cycloalkyl" refers to a fully saturated carbocyclic ring in the form of a monocyclic ring, a double ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. The term "C 3 -C 10 cycloalkyl" is understood to mean a saturated monovalent monocyclic, fused, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbons atom. Specific examples of said cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2 .1] heptyl), bicyclo [2.2.2] octyl, adamantyl, spiro [4.5] decanyl, etc. The term "C 3 -C 10 cycloalkyl" may include "C 3 -C 8 cycloalkyl", "C 3 -C 8 cycloalkyl" may include "C 3 -C 6 cycloalkyl", "C 3 -C 6 cycloalkyl" may include "C 3 -C 4 cycloalkyl". The term "C 3 -C 6 cycloalkyl" can be understood as meaning a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms, specific examples include but are not limited to cyclopropyl, cyclo Butyl, cyclopentyl or cyclohexyl, etc.
术语“环烷基氧基”可理解为“环烷基-O-”。The term "cycloalkyloxy" can be understood as "cycloalkyl-O-".
术语“环烯基”是指含有至少一个碳-碳双键的非芳族单环或多环烃基。“C 3-C 6环烯基”是指具有3、4、5或6个碳原子作为环原子且包含至少一个碳-碳双键的非芳族环状烃。C 3-C 6环烯基的具体实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己二烯基等。 The term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon group containing at least one carbon-carbon double bond. "C 3 -C 6 cycloalkenyl" refers to a non-aromatic cyclic hydrocarbon having 3, 4, 5 or 6 carbon atoms as ring atoms and containing at least one carbon-carbon double bond. Specific examples of C 3 -C 6 cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.
术语“杂环基”是指完全饱和的或部分饱和的(整体上不是具有芳香性的杂芳族)一价单环、并环、螺环或桥环基团，其环原子中含有1、2、3、4或5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O) 2-、-S(＝O)-以及任选被取代的-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-、-C(＝NH)-、-S(＝O) 2NH-、S(＝O)NH-或-NHC(＝O)NH-等。术语“4-10元杂环基”是指环原子数目为4、5、6、7、8、9或10的杂环基，且其环原子中含有1、2、3、4或5个独立选自上文所述的杂原子或杂原子团。术语“4-10元含氮杂环基”是指其环原子中至少含1 个N原子的4、5、6、7、8、9或10元杂环基。术语“4-7元单环含氮杂环基”是指单环形式的且环原子中至少含1个N原子的4、5、6或7元杂环基。“4-10元杂环基”包括“6-10元杂环基”，“6-10元杂环基”进一步包括“6-7元杂环基”，其中，4元杂环基的具体实例包括但不限于氮杂环丁烷基、硫杂环丁烷基或氧杂环丁烷基；5元杂环基的具体实例包括但不限于四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、4,5-二氢噁唑基或2,5-二氢-1H-吡咯基；6元杂环基的具体实例包括但不限于四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基或4H-[1,3,4]噻二嗪基；7元杂环基的具体实例包括但不限于二氮杂环庚烷基。所述杂环基还可以是双环基，其中，5,5元双环基的具体实例包括但不限于六氢环戊并[c]吡咯-2(1H)-基；5,6元双环基的具体实例包括但不限于六氢吡咯并[1,2-a]吡嗪-2(1H)-基、5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪基或5,6,7,8-四氢咪唑并[1,5-a]吡嗪基。任选地，所述杂环基可以是上述4-7元杂环基的苯并稠合环基，具体实例包括但不限于二氢异喹啉基等。“4-10元杂环基”可以包含“5-10元杂环基”、“4-7元杂环基”、“5-6元杂环基”、“6-8元杂环基”、“4-10元杂环烷基”、“5-10元杂环烷基”、“4-7元杂环烷基”、“5-6元杂环烷基”、“6-8元杂环烷基”等范围，“4-7元杂环基”进一步可以包含“4-6元杂环基”、“5-6元杂环基”、“4-7元杂环烷基”、“4-6元杂环烷基”、“5-6元杂环烷基”等范围。本申请中尽管有些双环类杂环基部分地含有一个苯环或一个杂芳环，但所述杂环基整体上仍是无芳香性的。 The term "heterocyclic group" refers to a fully saturated or partially saturated (heteroaromatic which is not aromatic as a whole) monovalent monocyclic, cyclic, spiro or bridged ring group containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups (that is, atomic groups containing heteroatoms), the "heteroatoms or heteroatom groups" include but are not limited to nitrogen atoms (N), oxygen atoms (O), sulfur atoms ( S), phosphorus atom (P), boron atom (B), -S(=O) 2 -, -S(=O)- and optionally substituted -NH-, -S(=O)(=NH )-, -C(=O)NH-, -C(=NH)-, -S(=O) 2 NH-, S(=O)NH- or -NHC(=O)NH- and the like. The term "4-10 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1, 2, 3, 4 or 5 independent selected from the heteroatoms or heteroatom groups described above. The term "4-10 membered nitrogen-containing heterocyclic group" refers to a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic group containing at least one N atom in its ring atoms. The term "4-7 membered monocyclic nitrogen-containing heterocyclic group" refers to a 4, 5, 6 or 7-membered heterocyclic group in the form of a monocyclic ring containing at least one N atom. "4-10 membered heterocyclic group" includes "6-10 membered heterocyclic group", "6-10 membered heterocyclic group" further includes "6-7 membered heterocyclic group", wherein, the specific Examples include, but are not limited to, azetidinyl, thietanyl, or oxetanyl; specific examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include, but are not limited to Tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridyl or 4H-[1,3,4]thiadi azinyl; specific examples of 7-membered heterocyclyl include, but are not limited to, diazepanyl. The heterocyclic group can also be a bicyclic group, wherein, specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; 5,6-membered bicyclic group Specific examples include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzofused cyclic group of the above-mentioned 4-7 membered heterocyclic group, specific examples include but not limited to dihydroisoquinolyl and the like. "4-10 membered heterocyclic group" may include "5-10 membered heterocyclic group", "4-7 membered heterocyclic group", "5-6 membered heterocyclic group", "6-8 membered heterocyclic group" , "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered "Heterocycloalkyl" and other ranges, "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocyclyl" , "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl" and other ranges. In the present application, although some bicyclic heterocyclic groups partially contain a benzene ring or a heteroaromatic ring, the heterocyclic groups as a whole are still non-aromatic.
术语“杂环基氧基”可理解为“杂环基-O-”。The term "heterocyclyloxy" can be understood as "heterocyclyl-O-".
术语“杂环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的一价环状基团，其环的环原子中含有1、2、3、4或5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O) 2-、-S(＝O)-以及任选被取代的-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-、-C(＝NH)-、-S(＝O) 2NH-、S(＝O)NH-或-NHC(＝O)NH-等。术语“4-10元杂环烷基”是指环原子数目为4、5、6、7、8、9或10的杂环烷基，且其环原子中含有1、2、3、4或5个独立选自上文所述的杂原子或杂原子团。“4-10元杂环烷基”包括“4-7元杂环烷基”，其中，4元杂环烷基的具体实例包括但不限于吖丁啶基、噁丁环基或噻丁环基；5元杂环烷基的具体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、咪唑烷基或四氢吡唑基；6元杂环烷基的具体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、1,3-二噻烷基或1,4-二噻烷基；7元杂环烷基的具体实例包括但不限于氮杂环庚烷基、氧杂环庚烷基或硫杂环庚烷基。 The term "heterocycloalkyl" refers to a monovalent cyclic group that is fully saturated and exists in the form of a monocyclic ring, a double ring, a bridged ring or a spiro ring, and the ring atoms of the ring contain 1, 2, 3, 4 Or 5 heteroatoms or heteroatom groups (that is, atomic groups containing heteroatoms), the "heteroatoms or heteroatom groups" include but are not limited to nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S), phosphorus atoms (P), boron atom (B), -S(=O) 2 -, -S(=O)- and optionally substituted -NH-, -S(=O)(=NH)-, -C (=O)NH-, -C(=NH)-, -S(=O) 2NH- , S(=O)NH- or -NHC(=O)NH-, etc. The term "4-10 membered heterocycloalkyl" refers to a heterocycloalkyl group with 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1, 2, 3, 4 or 5 independently selected from the heteroatoms or heteroatom groups described above. "4-10 membered heterocycloalkyl" includes "4-7 membered heterocycloalkyl", wherein specific examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl or thibutanyl; Specific examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, or tetrahydrofuranyl. Hydropyrazolyl; Specific examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thiaxanyl , 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, or 1,4-dithianyl; specific examples of 7-membered heterocycloalkyl include, but are not limited to, aza Cycloheptyl, oxepanyl or thiepanyl.
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。芳基可以具有6-14个碳原子或6-10个碳原子。术语“C 6-C 10芳基”应理解为具有6～10个碳原子的一价芳香性的单环或双环基团。特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有10个碳原子的环(“C 10芳基”)，例如萘基。 The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. Aryl groups can have 6-14 carbon atoms or 6-10 carbon atoms. The term "C 6 -C 10 aryl" is understood as a monovalent aromatic monocyclic or bicyclic group having 6 to 10 carbon atoms. In particular rings having 6 carbon atoms ("C 6 aryl"), such as phenyl; or rings having 10 carbon atoms ("C 10 aryl"), such as naphthyl.
术语“芳基氧基”可理解为“芳基-O-”。The term "aryloxy" is understood to mean "aryl-O-".
术语“杂芳基”是指具有芳香性的单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基。术语“5-10元杂芳基”应理解为包括这样的一价单环或双环芳族环系：其具有5、6、7、8、9或10个环原子，特别是5或6或9或10个环原子，且其包含1、2、3、4或5个，优选1、2或3个独立选自N、O和S的杂原子。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基或噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基或异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基等以及它们的苯并衍生物，例如喹啉基、喹唑啉基或异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基或吩噁嗪基等。术语“5-10元含氮杂芳基”是指其环原子中至少含1个N原子的5、6、 7、8、9或10元杂芳基。术语“5-6元杂芳基”指具有5或6个环原子的芳族环系，且其包含1、2或3个，优选1或2个独立选自N、O和S的杂原子。术语“6元杂芳基”指具有6个环原子的芳族环系，且其包含1、2或3个，优选1或2个N作为杂原子。术语“5-10元杂芳基”包含“5-6元杂芳基”。The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazole Linyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthalene Pyridyl, pteridyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, etc. The term "5-10 membered nitrogen-containing heteroaryl" refers to a 5, 6, 7, 8, 9 or 10 membered heteroaryl group containing at least one N atom in its ring atoms. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1, 2 or 3, preferably 1 or 2, heteroatoms independently selected from N, O and S . The term "6-membered heteroaryl" refers to an aromatic ring system having 6 ring atoms and which contains 1, 2 or 3, preferably 1 or 2 N as heteroatoms. The term "5-10 membered heteroaryl" includes "5-6 membered heteroaryl".
术语“杂芳基氧基”可理解为“杂芳基-O-”。The term "heteroaryloxy" is understood to mean "heteroaryl-O-".
术语“卤”或“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。The term "halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
术语“羟基”是指-OH基团。The term "hydroxyl" refers to a -OH group.
术语“氰基”是指-CN基团。The term "cyano" refers to a -CN group.
术语“巯基”是指-SH基团。The term "mercapto" refers to a -SH group.
术语“氨基”是指-NH 2基团。 The term "amino" refers to a -NH2 group.
术语“硝基”是指-NO 2基团。 The term "nitro" refers to a -NO2 group.
术语“治疗有效量”意指(i)治疗特定疾病、病况或病症，(ii)减轻、改善或消除特定疾病、病况或病症的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或病症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 a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying the The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder. 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 a person skilled in the art according to its own knowledge and 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 tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指药学上可接受的酸或碱的盐，包括化合物与无机酸或有机酸形成的盐，以及化合物与无机碱或有机碱形成的盐。The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts formed between compounds and inorganic or organic acids, and salts formed between compounds and inorganic or organic bases.
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发明的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the invention to an organism.
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 stimulating effect on the organism and will 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 and the like.
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 word "comprise" or "comprise" and its English variants such as comprises or comprising should be interpreted in an open and non-exclusive sense, ie "including but not limited to".
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 isotopically labeled compounds of the present application that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally 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 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)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, labeled with3H and14C ) are useful in compound and/or substrate tissue distribution assays. Tritiated ( ie3H ) and carbon-14 ( ie14C ) isotopes are especially preferred for 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 following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
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 composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, 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 administering a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, 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、乳化法、冷冻干燥法等。The pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, emulsifying methods, freeze-drying methods and the like.
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 oral form. For oral administration, the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, 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、助流剂或矫味剂等。Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating. Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants 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 composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
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0.01mg/kg到200mg/kg体重，优选为0.05mg/kg到50mg/kg体重，更优选0.1mg/kg到30mg/kg体重，以单独或分开剂量的形式。In all methods of administration of the compound of general formula I described herein, the daily dosage is 0.01 mg/kg to 200 mg/kg body weight, preferably 0.05 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 30 mg /kg body weight, 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、其与其它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, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art In an equivalent alternative, preferred implementations include but are not limited to the examples of the present 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 in the specific embodiments of the present application are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes on the basis of existing embodiments.
在一些实施方案中，本申请通式(II)的部分化合物可以由有机合成领域技术人员通过以下合成路线1来制备：In some embodiments, some compounds of the general formula (II) of the present application can be prepared by those skilled in the field of organic synthesis through the following synthetic route 1:
Figure PCTCN2022118398-appb-000118
Figure PCTCN2022118398-appb-000118
合成路线1Synthetic route 1
其中：X’为卤素；R为C 1-C 3烷基；环B、Z 1、Z 2、Y 1、Y 2、Y 3、Y 4、W、R 1、R 2、R 10和j如式(II)中所定义。 Among them: X' is halogen; R is C 1 -C 3 alkyl; Ring B, Z 1 , Z 2 , Y 1 , Y 2 , Y 3 , Y 4 , W, R 1 , R 2 , R 10 and j as defined in formula (II).
在一些实施方案中，本申请通式(III)的部分化合物可以由有机合成领域技术人员通过以下合成路线2来制备：In some embodiments, some compounds of the general formula (III) of the present application can be prepared by those skilled in the field of organic synthesis through the following synthetic route 2:
Figure PCTCN2022118398-appb-000119
Figure PCTCN2022118398-appb-000119
合成路线2Synthetic route 2
其中：X’为卤素；R为C 1-C 3烷基；环B、Z 1、Z 2、Z 4、Z 5、Y 1、Y 2、Y 3、Y 4、W、R 1和R 2如式(III)中所定义。 Among them: X' is halogen; R is C 1 -C 3 alkyl; Ring B, Z 1 , Z 2 , Z 4 , Z 5 , Y 1 , Y 2 , Y 3 , Y 4 , W, R 1 and R 2 is as defined in formula (III).
在一些实施方案中，本申请通式(II)的部分化合物可以由有机合成领域技术人员通过以下合成路线3来制备：In some embodiments, some compounds of the general formula (II) of the present application can be prepared by those skilled in the field of organic synthesis through the following synthetic route 3:
Figure PCTCN2022118398-appb-000120
Figure PCTCN2022118398-appb-000120
合成路线3Synthetic route 3
其中：X’为卤素；环B、Z 1、Z 2、Y 1、Y 2、Y 3、Y 4、W、R 1、R 2、R 10和j如式(II)中所定义。 Wherein: X' is halogen; ring B, Z 1 , Z 2 , Y 1 , Y 2 , Y 3 , Y 4 , W, R 1 , R 2 , R 10 and j are as defined in formula (II).
实施例Example
下面通过实施例对发明进行详细描述，但并不意味着对本申请的任何不利限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种改变和改进将是显而易见的。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。The invention will be described in detail through the following examples, but it does not mean any unfavorable limitation to the application. The present application has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the application without departing from the spirit and scope of the application. will be obvious. All reagents used in this application are commercially available and used without further purification.
除非另作说明，混合溶剂表示的比例是体积混合比例。除非另作说明，否则，％是指wt％。Unless otherwise specified, the ratios indicated for mixed solvents are volume mixing ratios. Unless otherwise stated, % means wt%.
化合物经手工或
Figure PCTCN2022118398-appb-000121
软件命名，市售化合物采用供应商目录名称。 compound by hand or
Figure PCTCN2022118398-appb-000121
The software is named, and the commercially available compounds adopt the supplier catalog name.
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC 50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。 Compound structures were determined by nuclear magnetic resonance (NMR) and/or mass spectroscopy (MS). The unit of NMR shift is 10 -6 (ppm). The solvents measured by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); concentration.
术语或缩写说明：Explanation of term or abbreviation:
EtOH：乙醇；MeCN：乙腈；TsCl：对甲基苯磺酰氯；TEA：三乙胺；Pd(dppf)Cl 2：[1,1'-双(二苯基膦)二茂铁]二氯化钯；HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；DIEA或DIPEA：N,N-二异丙基乙胺；DMF：N,N-二甲基甲酰胺；PivOH：三甲基乙酸；DEAD：偶氮二甲酸二乙酯；TFE：三氟乙醇；Brettphos Pd G3：甲烷磺酸(2-二环己基膦)-3,6- 二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)；Selectflour：1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐；XphosPdG 2：氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)；Xphos：2-二环己基膦-2',4',6'-三异丙基联苯；THF：四氢呋喃；DCM：二氯甲烷；AcOH：乙酸；DAST：二乙胺基三氟化硫；pyridine：吡啶；dioxane：1,4-二氧六环；LDA：二异丙基氨基锂；Pre-HPLC：制备高效液相色谱；DBU：1,8-二氮杂二环[5.4.0]十一碳-7-烯；SFC：超临界流体色谱；XtalFluor-E：(二乙氨基)二氟锍鎓四氟硼酸盐；trans-Me 2CyDA：反式-N,N'-二甲基1,2-环己二胺。 EtOH: ethanol; MeCN: acetonitrile; TsCl: p-toluenesulfonyl chloride; TEA: triethylamine; Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIEA or DIPEA: N,N-diisopropylethyl Amine; DMF: N,N-dimethylformamide; PivOH: trimethylacetic acid; DEAD: diethyl azodicarboxylate; TFE: trifluoroethanol; Brettphos Pd G3: methanesulfonic acid (2-dicyclohexyl Phosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2- base) palladium(II); Selectflour: 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt; XphosPdG 2 : chloro(2-di Cyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) ; Xphos: 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; THF: tetrahydrofuran; DCM: dichloromethane; AcOH: acetic acid; DAST: diethylaminosulfur trifluoride ; pyridine: pyridine; dioxane: 1,4-dioxane; LDA: lithium diisopropylamide; Pre-HPLC: preparative high performance liquid chromatography; ]undec-7-ene; SFC: supercritical fluid chromatography; XtalFluor-E: (diethylamino) difluorosulfonium tetrafluoroborate; trans-Me 2 CyDA: trans-N,N'-di Methyl 1,2-cyclohexanediamine.
下文的洗脱剂可由两种或多种溶剂形成混合洗脱剂，其比值为各溶剂的体积比，如“0～10％甲醇/二氯甲烷”表示梯度洗脱过程中，混合洗脱剂中的甲醇与二氯甲烷的体积用量比为0:100～10:100。The following eluents can be mixed eluents formed by two or more solvents, and the ratio is the volume ratio of each solvent. For example, "0-10% methanol/dichloromethane" means that in the gradient elution process, mixed eluents The volume ratio of methanol and dichloromethane in the mixture is 0:100～10:100.
实施例1(S)-1-(3-(3-甲基-1-(4-甲基-4H-1,2,4-三氮唑-3-基)环丁基)苯基)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物1)的制备Example 1 (S)-1-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)- Preparation of 4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (Compound 1)
Figure PCTCN2022118398-appb-000122
Figure PCTCN2022118398-appb-000122
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000123
Figure PCTCN2022118398-appb-000123
步骤1：1-(3-溴苯基)-3-甲基环丁基-1-甲酸甲酯(1B)的制备Step 1: Preparation of methyl 1-(3-bromophenyl)-3-methylcyclobutyl-1-carboxylate (1B)
将2-(3-溴苯基)乙酸甲酯(1.49g,6.48mmol)，1,3-二溴-2-甲基丙烷(1.40g,6.48mmol)溶于DMF(20mL)中，0℃下分批加入氢化钠(有效含量60％)(519.76mg,21.66mmol)，加毕，室温下反应2小时。反应液倒入饱和氯化铵水溶液中，加入乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经硅胶柱层析(石油醚:乙酸乙酯＝100:1)纯化得到无色透明液体标题化合物1B(0.77g)。Dissolve 2-(3-bromophenyl)methyl acetate (1.49g, 6.48mmol), 1,3-dibromo-2-methylpropane (1.40g, 6.48mmol) in DMF (20mL), 0°C Sodium hydride (60% effective content) (519.76mg, 21.66mmol) was added in batches, and the reaction was carried out at room temperature for 2 hours after the addition was complete. The reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was subjected to silica gel column chromatography (petroleum ether: ethyl acetate =100:1) Purification gave the title compound 1B (0.77 g) as a colorless transparent liquid.
步骤2：1-(3-溴苯基)-3-甲基环丁基-1-甲酰肼(1C)的制备Step 2: Preparation of 1-(3-bromophenyl)-3-methylcyclobutyl-1-carboxhydrazide (1C)
将1-(3-溴苯基)-3-甲基环丁基-1-甲酸甲酯(770mg,2.72mmol)溶于乙醇(10mL)中，加入一水合肼(2.8mL)，将反应体系在80℃搅拌16小时。将反应液浓缩得到无色透明液体标题化合物1C(0.77g)。Dissolve methyl 1-(3-bromophenyl)-3-methylcyclobutyl-1-carboxylate (770 mg, 2.72 mmol) in ethanol (10 mL), add hydrazine monohydrate (2.8 mL), and dissolve the reaction system Stir at 80°C for 16 hours. The reaction solution was concentrated to obtain the title compound 1C (0.77 g) as a colorless transparent liquid.
MS m/z(ESI):283[M+H] +. MS m/z(ESI):283[M+H] + .
步骤3：2-(1-(3-溴苯基)-3-甲基环丁基-1-羰基)-N-甲基肼基-1-硫代甲酰胺(1D)的制备Step 3: Preparation of 2-(1-(3-bromophenyl)-3-methylcyclobutyl-1-carbonyl)-N-methylhydrazino-1-carbothioamide (1D)
将1-(3-溴苯基)-3-甲基环丁基-1-甲酰肼(770mg,2.72mmol)溶于四氢呋喃(20mL)中，加入异硫氰酸甲酯(596mg,8.16mmol)，将反应体系在80℃搅拌2小时。将反应液浓缩，所得白色固体用乙酸乙酯打浆，过滤，滤液浓缩得到白色固体标题化合物1D(1.1g)。Dissolve 1-(3-bromophenyl)-3-methylcyclobutyl-1-carboxhydrazide (770mg, 2.72mmol) in tetrahydrofuran (20mL), add methyl isothiocyanate (596mg, 8.16mmol ), the reaction system was stirred at 80°C for 2 hours. The reaction solution was concentrated, the obtained white solid was slurried with ethyl acetate, filtered, and the filtrate was concentrated to obtain the title compound 1D (1.1 g) as a white solid.
MS m/z(ESI):356/358[M+H] +. MS m/z(ESI):356/358[M+H] + .
步骤4：5-(1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三氮唑-3-硫醇(1E)的制备Step 4: 5-(1-(3-Bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (1E) preparation
将2-(1-(3-溴苯基)-3-甲基环丁基-1-羰基)-N-甲基肼基-1-硫代甲酰胺(968mg,2.72mmol)溶于四氢呋喃(10mL)，然后加入1mol/L氢氧化钠水溶液(22mL)，混合物在室温下搅拌反应16小时。将反应液用稀盐酸调节至pH＝3，此过程中间有白色固体析出。加入乙酸乙酯溶解，萃取，分液，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，得白色固体标题化合物1E(834mg)。2-(1-(3-bromophenyl)-3-methylcyclobutyl-1-carbonyl)-N-methylhydrazino-1-carbothioamide (968 mg, 2.72 mmol) was dissolved in tetrahydrofuran ( 10 mL), and then 1 mol/L sodium hydroxide aqueous solution (22 mL) was added, and the mixture was stirred and reacted at room temperature for 16 hours. The reaction solution was adjusted to pH=3 with dilute hydrochloric acid, during which a white solid was precipitated. Ethyl acetate was added to dissolve, extracted, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 1E (834 mg) as a white solid.
MS m/z(ESI):338/340[M+H] +. MS m/z(ESI):338/340[M+H] + .
步骤5：3-(1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三氮唑(1F)的制备Step 5: Preparation of 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (1F)
将5-(1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三氮唑-3-硫醇(834mg,2.47mmol)溶于二氯甲烷(15mL)中，0℃下滴加双氧水(35％)(184.42mg,5.42mmol,120μL)的醋酸(3mL)溶液，加毕，室温下反应16小时。将反应液倒入水中，氢氧化钠溶液调节pH＝10，萃取，分液，水相用二氯甲烷萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩至干，通过柱层析(石油醚:乙酸乙酯＝1:1)纯化，得到淡黄色液体标题化合物1F(400mg)。5-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (834mg, 2.47mmol) Dissolve in dichloromethane (15mL), add hydrogen peroxide (35%) (184.42mg, 5.42mmol, 120μL) in acetic acid (3mL) dropwise at 0°C, and react at room temperature for 16 hours. The reaction solution was poured into water, adjusted to pH=10 with sodium hydroxide solution, extracted, separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Purification by column chromatography (petroleum ether:ethyl acetate=1:1) gave the title compound 1F (400 mg) as a pale yellow liquid.
MS m/z(ESI):306/308[M+H] +. MS m/z(ESI):306/308[M+H] + .
步骤6：3-(1-(3-碘苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三氮唑(1G)的制备Step 6: Preparation of 3-(1-(3-iodophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (1G)
向3-(1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三氮唑(200mg,0.65mmol),碘化钠(196mg,0.31mmol)，碘化亚铜(13mg,0.065mmol)以及乙腈(5mL)的混合物中，加入反式-N,N'-二甲基1,2-环己二胺(19mg,0.13mmol)。混合物置换氮气3次，微波加热至100℃并搅拌10小时。反应液冷却至室温，用乙酸乙酯稀释，硅藻土过滤，滤液旋干，粗品进行柱层析(石油醚:乙酸乙酯＝1:1)纯化，得到淡黄色液体标题化合物1G(210mg)。To 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (200mg, 0.65mmol), sodium iodide ( 196mg, 0.31mmol), cuprous iodide (13mg, 0.065mmol) and acetonitrile (5mL) mixture, add trans-N, N'-dimethyl 1,2-cyclohexanediamine (19mg, 0.13mmol ). The mixture was replaced with nitrogen 3 times, microwaved to 100°C and stirred for 10 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through celite, and the filtrate was spin-dried. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the title compound 1G (210 mg) as a light yellow liquid .
MS m/z(ESI):354.2[M+H] +. MS m/z(ESI):354.2[M+H] + .
步骤7：3-溴-1,8-萘二甲酸酐(1H)的制备Step 7: Preparation of 3-bromo-1,8-naphthalic anhydride (1H)
将1,8-萘二甲酸酐(5g,25.23mmol),硫酸银(4.00g,12.83mmol)，加入到浓硫酸(50mL)中，然后缓慢滴加溴素(5.00g,31.29mmol,1.72mL)。混合物在65℃下反应6小时。反应液倒入800mL冰水中析出固体，过滤，固体先用水洗，再用乙醇洗涤，得到9g粗品。往粗品中加入90mL DMSO，50℃搅拌3小时，硅藻土趁热过滤得到滤液，冷却后加入200mL水，析出白色固体，过滤干燥得到白色固体标题化合物1H(4.5g)。Add 1,8-naphthalene dicarboxylic anhydride (5g, 25.23mmol), silver sulfate (4.00g, 12.83mmol) into concentrated sulfuric acid (50mL), then slowly add bromine (5.00g, 31.29mmol, 1.72mL) ). The mixture was reacted at 65°C for 6 hours. The reaction solution was poured into 800 mL of ice water to precipitate a solid, filtered, and the solid was washed with water and then with ethanol to obtain 9 g of crude product. Add 90mL DMSO to the crude product, stir at 50°C for 3 hours, filter with diatomaceous earth to obtain the filtrate, add 200mL water after cooling, precipitate a white solid, filter and dry to obtain the title compound 1H (4.5g) as a white solid.
步骤8：4-溴-苯并[cd]吲哚-2(1H)-酮(1J)的制备Step 8: Preparation of 4-bromo-benzo[cd]indol-2(1H)-one (1J)
将3-溴-1,8-萘二甲酸酐(4.10g,14.06mmol)和盐酸羟胺(977mg,14.06mmol)溶于吡啶(90mL)，所得溶液在120℃下反应2小时。反应液冷却至80℃，然后加入对甲基苯磺酰氯(5.36g,28.12mmol)，升温到120℃后反应2小时。冷却，将反应混合物倒入160mL水中析出固体，过滤，固体先用200mL饱和碳酸氢钠水溶液洗，再用200mL水洗，过滤干燥得到中间体。将中间体加入16mL乙醇和20mL水搅拌。然后缓慢加入52mL 1.4mol/L的氢氧化钠水溶液。升温到100℃后反应3小时，旋干乙醇。向反应液中加入3mL浓盐酸，有固体析出，冷却过滤后滤饼用水洗，干燥得到黄色固体。然后加入300mL乙酸乙酯，室温搅拌过夜，过滤，浓缩滤液，得到白色固体标题化合物1J(1.6g)。3-Bromo-1,8-naphthalic anhydride (4.10 g, 14.06 mmol) and hydroxylamine hydrochloride (977 mg, 14.06 mmol) were dissolved in pyridine (90 mL), and the resulting solution was reacted at 120° C. for 2 hours. The reaction liquid was cooled to 80°C, then p-toluenesulfonyl chloride (5.36g, 28.12mmol) was added, the temperature was raised to 120°C, and the reaction was carried out for 2 hours. After cooling, the reaction mixture was poured into 160 mL of water to precipitate a solid, filtered, and the solid was first washed with 200 mL of saturated aqueous sodium bicarbonate solution, then washed with 200 mL of water, filtered and dried to obtain an intermediate. Add 16 mL of ethanol and 20 mL of water to the intermediate and stir. Then slowly add 52mL of 1.4mol/L sodium hydroxide aqueous solution. Raise the temperature to 100°C and react for 3 hours, then spin dry the ethanol. Add 3 mL of concentrated hydrochloric acid to the reaction solution, and a solid precipitates out. After cooling and filtering, the filter cake is washed with water and dried to obtain a yellow solid. Then 300 mL of ethyl acetate was added, stirred overnight at room temperature, filtered, and the filtrate was concentrated to obtain the title compound 1J (1.6 g) as a white solid.
MS m/z(ESI):248.0，250.0[M+H] +； MS m/z (ESI): 248.0, 250.0 [M+H] + ;
1H NMR(500MHz,DMSO-d 6)δppm 10.89(s,1H),8.45(d,J＝1.5Hz,1H),8.11(d,J＝1.0Hz,1H),7.57-7.50(m,2H),7.00(d,J＝6.5Hz,1H). 1 H NMR (500MHz, DMSO-d 6 ) δppm 10.89(s, 1H), 8.45(d, J=1.5Hz, 1H), 8.11(d, J=1.0Hz, 1H), 7.57-7.50(m, 2H ),7.00(d,J＝6.5Hz,1H).
步骤9：4-乙烯基-苯并[cd]吲哚-2(1H)-酮(1K)的制备Step 9: Preparation of 4-vinyl-benzo[cd]indol-2(1H)-one (1K)
将4-溴-苯并[cd]吲哚-2(1H)-酮(1.5g,4.72mmol),乙烯基硼酸频哪醇酯(872mg,5.66mmol)和碳酸铯(3.07g,9.43mmol)溶于1,4-二氧六环(12mL)和水(4mL)中，氮气置换3次。加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(173mg,0.24mmol)，氮气置换3次，100℃反应过夜。反应液倒入100mL水中，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经柱层析(石油醚:乙酸乙酯＝3:1)纯化得到淡黄色固体标题化合物1K(750mg)。4-Bromo-benzo[cd]indol-2(1H)-one (1.5g, 4.72mmol), vinyl borate pinacol ester (872mg, 5.66mmol) and cesium carbonate (3.07g, 9.43mmol) Dissolve in 1,4-dioxane (12mL) and water (4mL), replace with nitrogen 3 times. Add 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (173 mg, 0.24 mmol), replace with nitrogen three times, and react overnight at 100°C. The reaction solution was poured into 100 mL of water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1) Purification afforded the title compound 1K (750 mg) as a light yellow solid.
LC-MS:MS m/z(ESI):196.2[M+H] +； LC-MS: MS m/z (ESI): 196.2[M+H] + ;
1H NMR(400MHz,Methanol-d 4)δppm 8.19(s,1H),8.07(s,1H),7.58-7.54(m,1H),7.49-7.44(m,1H),7.04(dd,J＝11.2,17.6Hz,1H),6.97(d,J＝6.8Hz,1H),6.02(d,J＝17.6Hz,1H),5.42(d,J＝10.8Hz,1H). 1 H NMR (400MHz, Methanol-d 4 )δppm 8.19(s,1H), 8.07(s,1H), 7.58-7.54(m,1H), 7.49-7.44(m,1H), 7.04(dd,J= 11.2,17.6Hz,1H),6.97(d,J=6.8Hz,1H),6.02(d,J=17.6Hz,1H),5.42(d,J=10.8Hz,1H).
步骤10：4-甲酰基-苯并[cd]吲哚-2(1H)-酮(1L)的制备Step 10: Preparation of 4-formyl-benzo[cd]indol-2(1H)-one (1 L)
在0℃条件下，将高碘酸钠(745mg,3.48mmol)和二水合锇酸钾(53mg,0.17mmol)溶于水(2mL)中，加入4-乙烯基-苯并[cd]吲哚-2(1H)-酮(200mg,870.83μmol)的四氢呋喃(4mL)溶液，混合物室温下反应4小时。反应液倒入100mL水溶液中，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得到淡黄色固体标题化合物1L(150mg)。Sodium periodate (745mg, 3.48mmol) and potassium osmate dihydrate (53mg, 0.17mmol) were dissolved in water (2mL) at 0°C, and 4-vinyl-benzo[cd]indole was added -2(1H)-one (200 mg, 870.83 μmol) in tetrahydrofuran (4 mL) was reacted at room temperature for 4 hours. The reaction solution was poured into 100 mL aqueous solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 1 L (150 mg) of the title compound as a pale yellow solid.
MS m/z(ESI):198.0[M+H] +； MS m/z(ESI):198.0[M+H] + ;
1H NMR(400MHz,Methanol-d 4)δppm 10.25(s,1H),8.71(s,1H),8.46(s,1H),7.76(d,J＝8.4Hz,1H),7.60(d,J＝7.2Hz,1H),7.14(d,J＝6.8Hz,1H). 1 H NMR (400MHz, Methanol-d 4 )δppm 10.25(s,1H),8.71(s,1H),8.46(s,1H),7.76(d,J=8.4Hz,1H),7.60(d,J ＝7.2Hz, 1H), 7.14(d, J＝6.8Hz, 1H).
步骤11：(S)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(1M)的制备Step 11: Preparation of (S)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (1M)
将4-甲酰基-苯并[cd]吲哚-2(1H)-酮(150mg,0.61mmol)，(S)-3-甲基哌啶盐酸盐(99mg,0.73mmol)和三乙胺(123mg,1.22mmol,170μL)溶于二氯甲烷(5mL)。混合物室温搅拌30分钟后，加入醋酸硼氢化钠(387mg,1.83mmol)，室温反应5小时。反应液倒入80mL水中，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经柱层析(二氯甲烷:甲醇＝10:1)纯化得到黄色固体标题化合物1M(170mg)。4-Formyl-benzo[cd]indol-2(1H)-one (150mg, 0.61mmol), (S)-3-methylpiperidine hydrochloride (99mg, 0.73mmol) and triethylamine (123mg, 1.22mmol, 170μL) was dissolved in dichloromethane (5mL). After the mixture was stirred at room temperature for 30 minutes, sodium acetate borohydride (387 mg, 1.83 mmol) was added and reacted at room temperature for 5 hours. The reaction solution was poured into 80 mL of water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=10:1) to obtain Title compound 1M (170 mg) as a yellow solid.
MS m/z(ESI):281.3[M+H] +； MS m/z(ESI):281.3[M+H] + ;
1H NMR(400MHz,CDCl 3)δppm 8.13(s,1H),8.01(s,1H),7.84(s,1H),7.56-7.51(m,1H),7.45(dd,J＝7.2,8.8Hz,1H),6.94(d,J＝7.2Hz,1H),3.75(d,J＝2.8Hz,2H),2.88-2.79(m,2H),2.01-1.93(m,1H),1.73(s,2H),1.65-1.55(m,4H),0.84(d,J＝6.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δppm 8.13(s, 1H), 8.01(s, 1H), 7.84(s, 1H), 7.56-7.51(m, 1H), 7.45(dd, J=7.2, 8.8Hz ,1H),6.94(d,J=7.2Hz,1H),3.75(d,J=2.8Hz,2H),2.88-2.79(m,2H),2.01-1.93(m,1H),1.73(s, 2H),1.65-1.55(m,4H),0.84(d,J＝6.0Hz,3H).
步骤12：(S)-1-(3-(3-甲基-1-(4-甲基-4H-1,2,4-三氮唑-3-基)环丁基)苯基)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物1)的制备Step 12: (S)-1-(3-(3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)- Preparation of 4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (Compound 1)
向(S)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(50mg,0.18mmol)、3-(1-(3-碘苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三氮唑(76mg,0.22mmol)、碳酸铯(174mg,0.54mmol)以及1,4-二氧六环(5mL)的混合物中，加入Brettphos Pd G3(16mg,0.018mmol)。混合物置换氮气3次，加热至100℃并搅拌过夜。反应液冷却至室温，用乙酸乙酯稀释，硅藻土过滤，滤液旋干，粗品相继进行正相柱层析(二氯甲烷:甲醇＝10:1)以及反相柱层析(色谱柱：
Figure PCTCN2022118398-appb-000124
快速硅胶柱，洗脱剂：70％乙腈水溶液)纯化，得到淡黄色固体标题化合物1(6.7mg)。 To (S)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (50mg, 0.18mmol), 3-(1-( 3-iodophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (76mg, 0.22mmol), cesium carbonate (174mg, 0.54mmol) and 1, To the mixture of 4-dioxane (5 mL) was added Brettphos Pd G3 (16 mg, 0.018 mmol). The mixture was replaced with nitrogen 3 times, heated to 100°C and stirred overnight. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was spin-dried. The crude product was subjected to normal phase column chromatography (dichloromethane:methanol=10:1) and reverse phase column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000124
Purification by flash silica gel column, eluent: 70% acetonitrile in water) gave the title compound 1 (6.7 mg) as a pale yellow solid.
MS m/z(ESI):506.4[M+H] +. MS m/z(ESI):506.4[M+H] + .
1H NMR(400MHz,DMSO-d 6)δppm 8.50(s,1H),8.40(s,1H),8.32(s,1H),7.80(d,J＝8.5Hz,1H),7.63(t,J＝7.8Hz,2H),7.56–7.44(m,3H),7.06(d,J＝7.2Hz,1H),4.63(s,2H),3.44(d,J＝11.9Hz,1H),3.34(brs,1H),2.98–2.82(m,3H),2.70–2.55(m,4H),1.87–1.62(m,4H), 1.14–1.01(m,4H),0.87(d,J＝6.5Hz,3H). 1 H NMR (400MHz,DMSO-d 6 )δppm 8.50(s,1H),8.40(s,1H),8.32(s,1H),7.80(d,J=8.5Hz,1H),7.63(t,J =7.8Hz,2H),7.56–7.44(m,3H),7.06(d,J=7.2Hz,1H),4.63(s,2H),3.44(d,J=11.9Hz,1H),3.34(brs ,1H),2.98–2.82(m,3H),2.70–2.55(m,4H),1.87–1.62(m,4H), 1.14–1.01(m,4H),0.87(d,J＝6.5Hz,3H ).
实施例2 1-(3-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-(((S)-3-甲基哌啶-1-基)甲基)-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(化合物2)的制备Example 2 1-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-((( Preparation of S)-3-methylpiperidin-1-yl)methyl)-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (Compound 2)
Figure PCTCN2022118398-appb-000125
Figure PCTCN2022118398-appb-000125
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000126
Figure PCTCN2022118398-appb-000126
步骤1：N-(6-溴-1,2,3,4-四氢萘-1-基)吡啶甲酰胺(2B)的制备Step 1: Preparation of N-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)pyridinecarboxamide (2B)
室温下，将6-溴-1,2,3,4-四氢萘-1-胺(2A，0.8g,3.5mmol)溶解于到N,N-二甲基甲酰胺(10mL)中，依次加入2-吡啶甲酸(522.7mg,4.3mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.0g,5.3mmol)和N,N-二异丙基乙胺(1.4g,10.6mmol),反应1小时后加入乙酸乙酯(50ml)，并用水(30mlx3)洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩。所得残余物经反相硅胶柱色谱法(色谱柱：
Figure PCTCN2022118398-appb-000127
快速硅胶柱，水:乙腈＝95:5-5:95)纯化，冻干后得固体标题化合物(933mg)。 At room temperature, 6-bromo-1,2,3,4-tetrahydronaphthalene-1-amine (2A, 0.8g, 3.5mmol) was dissolved in N,N-dimethylformamide (10mL), followed by Add 2-pyridinecarboxylic acid (522.7mg, 4.3mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.0g, 5.3 mmol) and N,N-diisopropylethylamine (1.4g, 10.6mmol), add ethyl acetate (50ml) after reacting for 1 hour, and wash with water (30mlx3), the organic phase is dried with anhydrous sodium sulfate, filtered , the filtrate was concentrated. The resulting residue was subjected to reverse-phase silica gel column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000127
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified, and the title compound (933 mg) was obtained as a solid after lyophilization.
MS m/z(ESI):331[M+H] +. MS m/z(ESI):331[M+H] + .
步骤2：4-溴-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(2C)的制备Step 2: Preparation of 4-bromo-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (2C)
室温下，将化合物N-(6-溴-1,2,3,4-四氢萘-1-基)吡啶甲酰胺(2B，350mg,1.1mmol)、四水醋酸钴(52.6mg,0.2mmol)、碳酸银(532.2mg,3.2mol)、偶氮二甲酸二乙酯(368.1mg,2.1mmol)和三甲基乙酸(107.9mg,1.1mmol)加入到反应管中，加入三氟乙醇(TFE)(6mL),体系加热到120℃，反应24小时，冷却至室温，过滤，所得残余物经反相硅胶柱色谱法(色谱柱：
Figure PCTCN2022118398-appb-000128
快速硅胶柱，水:乙腈＝95：5-5:95)纯化冻干后得固体标题化合物(100mg)。 At room temperature, compound N-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)pyridinecarboxamide (2B, 350mg, 1.1mmol), cobalt acetate tetrahydrate (52.6mg, 0.2mmol ), silver carbonate (532.2mg, 3.2mol), diethyl azodicarboxylate (368.1mg, 2.1mmol) and trimethylacetic acid (107.9mg, 1.1mmol) were added to the reaction tube, and trifluoroethanol (TFE ) (6mL), the system was heated to 120°C, reacted for 24 hours, cooled to room temperature, filtered, and the residue obtained was subjected to reverse phase silica gel column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000128
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified and lyophilized to obtain the title compound (100 mg) as a solid.
MS m/z(ESI):252[M+H] +. MS m/z(ESI):252[M+H] + .
步骤3：4-乙烯基-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(2D)的制备Step 3: Preparation of 4-vinyl-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (2D)
室温下，将(4-溴-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(100.0mg,396.7μmol)、乙烯三氟硼酸钾(79.7mg,595.0μmol)、碳酸钾(109.6mg,133.2μmmol)、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(31.2mg，39.7μmol)和2-二环己基膦-2',4',6'-三异丙基联苯(37.8mg,79.3μmol)加入反应管，置换氩气，加入无水1,4-二氧六环(2ml)和水(0.5ml)，体系加热到100℃，反应1小时，冷却至室温，过滤，所得残余物经浓缩得粗品(79mg)。At room temperature, (4-bromo-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (100.0mg, 396.7μmol), potassium ethylene trifluoroborate (79.7mg, 595.0μmol), potassium carbonate (109.6mg, 133.2μmmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2- (2'-amino-1,1'-biphenyl)]palladium(II) (31.2 mg, 39.7 μmol) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl ( 37.8mg, 79.3μmol) into the reaction tube, replace the argon, add anhydrous 1,4-dioxane (2ml) and water (0.5ml), heat the system to 100°C, react for 1 hour, cool to room temperature, filter , the resulting residue was concentrated to give a crude product (79mg).
MS m/z(ESI):200[M+H] +. MS m/z(ESI):200[M+H] + .
步骤4：2-氧代-1,2,6,7,8,8a-六氢苯并[cd]吲哚-4-甲醛(2E)的制备Step 4: Preparation of 2-oxo-1,2,6,7,8,8a-hexahydrobenzo[cd]indole-4-carbaldehyde (2E)
室温下，将(4-乙烯基-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(2D，79.0mg,396.5μmol)溶解入四氢呋喃(5ml)和水(5ml)中，冷却至0℃，加入高碘酸钠(339.2mg,1.60mmol)和四水锇酸钾(13.2mg,39.7μmol)，升温至室温，反应30分钟，加入乙酸乙酯(30ml)，分别用饱和亚硫酸钠水溶液和饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，得粗品(79mg)。(4-vinyl-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (2D, 79.0 mg, 396.5 μmol) was dissolved in THF (5 ml) and In water (5ml), cooled to 0°C, sodium periodate (339.2mg, 1.60mmol) and potassium osmate tetrahydrate (13.2mg, 39.7μmol) were added, warmed to room temperature, reacted for 30 minutes, added ethyl acetate ( 30ml), washed with saturated aqueous sodium sulfite solution and saturated brine, respectively, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product (79mg).
MS m/z(ESI):202[M+H] +. MS m/z(ESI):202[M+H] + .
步骤5：4-(((S)-3-甲基哌啶-1-基)甲基)-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(2F)的制备Step 5: 4-(((S)-3-Methylpiperidin-1-yl)methyl)-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one Preparation of (2F)
室温下，将2-氧代-1,2,6,7,8,8a-六氢苯并[cd]吲哚-4-甲醛(2E，79mg,392.6μmol)溶解入二氯甲烷(10ml)中，加入乙酸钾(77mg,785.2μmol)和(S)-3-甲基哌啶盐酸盐(79.9mg，588.9μmol)，体系室温下搅拌10分钟，加入醋酸硼氢化钠(166.4mg,785.2μmol)，反应在45℃下搅拌过夜后浓缩干，加入乙酸乙酯(30ml)并用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤浓缩干后所得残余物经反相硅胶柱色谱法(色谱柱：
Figure PCTCN2022118398-appb-000129
快速硅胶柱，水:乙腈＝95：5-5:95)纯化，冻干后得固体标题化合物(47mg)。 2-Oxo-1,2,6,7,8,8a-hexahydrobenzo[cd]indole-4-carbaldehyde (2E, 79mg, 392.6μmol) was dissolved in dichloromethane (10ml) at room temperature Add potassium acetate (77mg, 785.2μmol) and (S)-3-methylpiperidine hydrochloride (79.9mg, 588.9μmol), stir the system at room temperature for 10 minutes, add sodium acetate borohydride (166.4mg, 785.2 μmol), the reaction was stirred overnight at 45°C and then concentrated to dryness, added ethyl acetate (30ml) and washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue obtained was subjected to reversed-phase silica gel column chromatography (Column:
Figure PCTCN2022118398-appb-000129
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified, and the title compound (47 mg) was obtained as a solid after lyophilization.
MS m/z(ESI):285[M+H] +. MS m/z(ESI):285[M+H] + .
步骤6：1-(3-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-(((S)-3-甲基哌啶-1-基)甲基)-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(化合物2)的制备Step 6: 1-(3-(3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-((( Preparation of S)-3-methylpiperidin-1-yl)methyl)-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (Compound 2)
室温下，将4-(((S)-3-甲基哌啶-1-基)甲基)-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(2F，17.0mg,59.4μmol)、3-(1-(3-碘苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三氮唑(1G，20.0mg,65.3μmol)、碳酸钾(16.4mg,118.7μmmol)和碘化亚铜(2.3mg，11.9μmol)加入反应管，置换氩气，加入无水N,N-二甲基甲酰胺(2ml)和反式-N,N'-二甲基1,2-环己二胺(4.2mg，29.7μmol)，体系加热到100℃，反应2小时，冷却至室温，过滤，所得残余物经反相硅胶柱色谱法(色谱柱：
Figure PCTCN2022118398-appb-000130
快速硅胶柱，水:乙腈＝95：5-5:95)纯化，冻干后得固体标题化合物(0.7mg)。 At room temperature, 4-(((S)-3-methylpiperidin-1-yl)methyl)-6,7,8,8a-tetrahydrobenzo[cd]indole-2(1H)- Ketone (2F, 17.0 mg, 59.4 μmol), 3-(1-(3-iodophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole ( 1G, 20.0mg, 65.3μmol), potassium carbonate (16.4mg, 118.7μmmol) and cuprous iodide (2.3mg, 11.9μmol) were added to the reaction tube, argon was replaced, and anhydrous N,N-dimethylformamide was added (2ml) and trans-N,N'-dimethyl 1,2-cyclohexanediamine (4.2mg, 29.7μmol), the system was heated to 100°C, reacted for 2 hours, cooled to room temperature, filtered, the obtained residue Through reverse phase silica gel column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000130
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified, and the title compound (0.7 mg) was obtained as a solid after lyophilization.
MS m/z(ESI):510.1[M+H] +； MS m/z(ESI):510.1[M+H] + ;
1H-NMR(400MHz,DMSO-d 6)δ7.58(s,1H),7.48–7.31(m,4H),7.28(s,1H),7.07(d,J＝7.8Hz,1H),5.05(d,J＝7.1Hz,1H),3.44(s,2H),3.17(s,3H),2.96(d,J＝17.7Hz,1H),2.78(s,2H),2.69–2.62(m,3H),2.47(s,2H),2.18(s,2H),1.98(s,2H),1.83–1.75(m,1H),1.54(d,J＝22.9Hz,4H),1.40(s,1H),1.02(d,J＝4.6Hz,3H),0.97–0.89(m,1H),0.74(d,J＝4.4Hz,4H). 1 H-NMR (400MHz, DMSO-d 6 )δ7.58(s,1H),7.48–7.31(m,4H),7.28(s,1H),7.07(d,J＝7.8Hz,1H),5.05 (d,J=7.1Hz,1H),3.44(s,2H),3.17(s,3H),2.96(d,J=17.7Hz,1H),2.78(s,2H),2.69–2.62(m, 3H), 2.47(s, 2H), 2.18(s, 2H), 1.98(s, 2H), 1.83–1.75(m, 1H), 1.54(d, J=22.9Hz, 4H), 1.40(s, 1H ), 1.02(d,J=4.6Hz,3H),0.97–0.89(m,1H),0.74(d,J=4.4Hz,4H).
实施例3(S)-6-氟-1-(3-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物3)的制备Example 3 (S)-6-fluoro-1-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)benzene base)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 3)
Figure PCTCN2022118398-appb-000131
Figure PCTCN2022118398-appb-000131
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000132
Figure PCTCN2022118398-appb-000132
步骤1：(S)-三氟(3-甲基哌啶-1-基)甲基硼酸钾(3B)的制备Step 1: Preparation of potassium (S)-trifluoro(3-methylpiperidin-1-yl)methylborate (3B)
向(S)-3-甲基哌啶盐酸盐(3A，540mg,3.98mmol)、(溴甲基)三氟硼酸钾(960mg,4.78mmol)、碳酸钾(605mg,4.38mmol)以及碘化钾(67mg,0.40mmol)中加入无水四氢呋喃 (10mL)，抽换氮气3次。混合物在氮气保护下加热至回流并搅拌12小时。反应液冷却至室温，加入100mL丙酮，过滤，固体用丙酮洗，把滤液蒸干得到浅黄色胶状标题化合物粗品420mg，该粗品直接用于下一步反应。To (S)-3-methylpiperidine hydrochloride (3A, 540mg, 3.98mmol), potassium (bromomethyl) trifluoroborate (960mg, 4.78mmol), potassium carbonate (605mg, 4.38mmol) and potassium iodide ( 67mg, 0.40mmol) was added anhydrous tetrahydrofuran (10mL), and the nitrogen gas was replaced 3 times. The mixture was heated to reflux and stirred under nitrogen for 12 hours. The reaction solution was cooled to room temperature, 100 mL of acetone was added, filtered, the solid was washed with acetone, and the filtrate was evaporated to dryness to obtain 420 mg of the crude product of the title compound in the form of light yellow gum, which was directly used in the next reaction.
MS m/z(ESI):162.1[M-KF+H] +. MS m/z(ESI):162.1[M-KF+H] + .
步骤2：4-溴-6-氟苯并[cd]吲哚-2(1H)-酮(3C)的制备Step 2: Preparation of 4-bromo-6-fluorobenzo[cd]indol-2(1H)-one (3C)
室温下，将4-溴苯并[cd]吲哚-2(1H)-酮(1J，0.2g,0.8mmol)溶解于N,N-二甲基甲酰胺(5mL)中，依次加入乙酸(48.4mg,0.8mmol)和1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(Selectflour)(428.4mg,1.2mmol)，体系加热到50℃，反应8小时后，冷却至室温，加入乙酸乙酯(50ml)，并用水(30ml x3)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩。所得残余物经反相硅胶柱色谱法(色谱柱：
Figure PCTCN2022118398-appb-000133
快速硅胶柱，水:乙腈＝95:5-5:95)纯化，冻干后得固体标题化合物(40.0mg)。 At room temperature, 4-bromobenzo[cd]indol-2(1H)-one (1J, 0.2g, 0.8mmol) was dissolved in N,N-dimethylformamide (5mL), and acetic acid ( 48.4mg, 0.8mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectflour) (428.4mg, 1.2mmol), The system was heated to 50°C, reacted for 8 hours, cooled to room temperature, added ethyl acetate (50ml), and washed with water (30ml x3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was subjected to reverse-phase silica gel column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000133
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified, and the title compound (40.0 mg) was obtained as a solid after lyophilization.
MS m/z(ESI):266[M+H] +. MS m/z(ESI):266[M+H] + .
步骤3：(S)-6-氟-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(3D)的制备Step 3: Preparation of (S)-6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (3D)
室温下，将化合物4-溴-6-氟苯并[cd]吲哚-2(1H)-酮(3C，40.0mg,150.0μmol)、(S)-三氟((3-甲基哌啶-1-基)甲基)硼酸钾(98.6mg,450μmol)、XphosPdG 2(23.6mg,30.1μmol)、Xphos(28.7mg,60.1μmol)和碳酸钾(83.1mg,601.4μmol)加入到反应管中，置换氩气，加入1,4-二氧六环(2mL)和水(0.5mL)，体系加热到100℃，反应2小时，冷却至室温，过滤，所得残余物经反相硅胶柱色谱法(色谱柱：
Figure PCTCN2022118398-appb-000134
快速硅胶柱，水:乙腈＝95：5-5:95)纯化冻干后得固体标题化合物(20mg)。 At room temperature, the compound 4-bromo-6-fluorobenzo[cd]indol-2(1H)-one (3C, 40.0 mg, 150.0 μmol), (S)-trifluoro((3-methylpiperidine -1-yl)methyl)potassium borate (98.6 mg, 450 μmol), XphosPdG2 (23.6 mg, 30.1 μmol), Xphos (28.7 mg, 60.1 μmol) and potassium carbonate (83.1 mg, 601.4 μmol) were added to the reaction tube , replace argon, add 1,4-dioxane (2mL) and water (0.5mL), heat the system to 100 ° C, react for 2 hours, cool to room temperature, filter, and the resulting residue is subjected to reverse phase silica gel column chromatography (Column:
Figure PCTCN2022118398-appb-000134
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified and lyophilized to give the title compound (20 mg) as a solid.
MS m/z(ESI):299[M+H] +. MS m/z(ESI):299[M+H] + .
步骤4：(S)-6-氟-1-(3-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物3)的制备Step 4: (S)-6-Fluoro-1-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)benzene base)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 3)
室温下，将(S)-6-氟-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(3D，20.0mg,66.6μmol)、3-(1-(3-碘苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三氮唑(1G，23.5mg,66.6μmol)、碳酸钾(18.4mg，133.2μmol)和碘化亚铜(2.5mg，13.3μmol)加入反应管，置换氩气，加入无水N,N-二甲基甲酰胺(2ml)和反式-N,N'-二甲基1,2-环己二胺(4.7mg，33.3μmol),体系加热到100℃，反应2小时，冷却至室温，过滤，所得残余物经反相硅胶柱色谱法(色谱柱：
Figure PCTCN2022118398-appb-000135
快速硅胶柱，水:乙腈＝95:5-5:95)纯化，冻干后得固体标题化合物(6.9mg)。 At room temperature, (S)-6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (3D, 20.0mg, 66.6μmol), 3-(1-(3-iodophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (1G, 23.5mg, 66.6μmol ), potassium carbonate (18.4mg, 133.2μmol) and cuprous iodide (2.5mg, 13.3μmol) were added to the reaction tube, argon was replaced, and anhydrous N,N-dimethylformamide (2ml) and trans- N,N'-Dimethyl 1,2-cyclohexanediamine (4.7mg, 33.3μmol), the system was heated to 100°C, reacted for 2 hours, cooled to room temperature, filtered, and the residue obtained was subjected to reverse-phase silica gel column chromatography (Column:
Figure PCTCN2022118398-appb-000135
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified, and the title compound (6.9 mg) was obtained as a solid after lyophilization.
MS m/z(ESI):524.0[M+H] +； MS m/z(ESI):524.0[M+H] + ;
1H-NMR(400MHz,DMSO-d 6)δ8.32(s,1H),8.20(d,J＝7.2Hz,2H),7.63–7.25(m,5H),6.89(dd,J＝7.8,2.9Hz,1H),3.83–3.74(m,2H),3.26(s,3H),2.89(s,2H),2.77(t,J＝11.4Hz,2H),2.57(d,J＝6.5Hz,2H),1.96(t,J＝10.3Hz,1H),1.72–1.40(m,6H),1.09(d,J＝5.4Hz,3H),0.92–0.78(m,4H). 1 H-NMR (400MHz, DMSO-d 6 ) δ8.32(s, 1H), 8.20(d, J=7.2Hz, 2H), 7.63–7.25(m, 5H), 6.89(dd, J=7.8, 2.9Hz, 1H), 3.83–3.74(m, 2H), 3.26(s, 3H), 2.89(s, 2H), 2.77(t, J=11.4Hz, 2H), 2.57(d, J=6.5Hz, 2H), 1.96(t, J=10.3Hz, 1H), 1.72–1.40(m, 6H), 1.09(d, J=5.4Hz, 3H), 0.92–0.78(m, 4H).
实施例4(S)-6-氟-1-(4-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物54)的制备Example 4 (S)-6-fluoro-1-(4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine Preparation of -2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 54)
Figure PCTCN2022118398-appb-000136
Figure PCTCN2022118398-appb-000136
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000137
Figure PCTCN2022118398-appb-000137
步骤1：1-(2-氯吡啶-4-基)-3-甲基环丁基甲酸(54B)的制备Step 1: Preparation of 1-(2-chloropyridin-4-yl)-3-methylcyclobutylcarboxylic acid (54B)
将2-(2-氯吡啶-4-基)乙酸乙酯(1.9g,9.52mmol)，1,3-二溴-2-甲基丙烷(2.47g,11.42mmol)溶于DMF(100mL)中，0℃下分批加入氢化钠(有效含量60％)(913.6mg,38.07mmol)，加毕，室温下反应4小时。反应液倒入饱和氯化铵水溶液中，加入乙酸乙酯萃取，有机相蒸干，粗品用50mL甲醇溶解，加入20mL氢氧化钠水溶液(2mol/L)，反应液搅拌2小时，然后用4mol/L的盐酸中和至pH约为7。蒸干溶剂，反相硅胶柱色谱法(色谱柱：
Figure PCTCN2022118398-appb-000138
快速硅胶柱，水:乙腈＝95:5-5:95)纯化，冻干后得标题化合物54B(910mg)。 Ethyl 2-(2-chloropyridin-4-yl)acetate (1.9 g, 9.52 mmol), 1,3-dibromo-2-methylpropane (2.47 g, 11.42 mmol) were dissolved in DMF (100 mL) , Add sodium hydride (60% effective content) (913.6mg, 38.07mmol) in batches at 0°C, after the addition is complete, react at room temperature for 4 hours. The reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was evaporated to dryness, the crude product was dissolved in 50 mL of methanol, 20 mL of sodium hydroxide aqueous solution (2mol/L) was added, the reaction solution was stirred for 2 hours, and then mixed with 4 mol/L L of hydrochloric acid to neutralize to a pH of about 7. Solvent was evaporated to dryness, reversed-phase silica gel column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000138
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified, and the title compound 54B (910 mg) was obtained after lyophilization.
MS m/z(ESI):226[M+H] +. MS m/z(ESI):226[M+H] + .
步骤2：1-((1-(2-氯吡啶-4-基)-3-甲基环丁基羰基)氨基)-3-甲基硫脲(54C)的制备Step 2: Preparation of 1-((1-(2-chloropyridin-4-yl)-3-methylcyclobutylcarbonyl)amino)-3-methylthiourea (54C)
将1-(2-氯吡啶-4-基)-3-甲基环丁基甲酸(910mg,4.03mmol)、1-氨基-3-甲基硫脲(508.87mg,4.84mmol)以及N,N-二异丙基乙胺(1.56g,12.10mmol)溶于无水DMF(20mL)中，用冰水浴降至5℃，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.67g,4.44mmol)，氮气保护下室温搅拌2小时。将反应液浓缩，粗品用反相硅胶柱色谱法(色谱柱：
Figure PCTCN2022118398-appb-000139
快速硅胶柱，水:乙腈＝95:5-5:95)纯化，冻干后得标题化合物54C(1.1g)。 1-(2-chloropyridin-4-yl)-3-methylcyclobutylcarboxylic acid (910mg, 4.03mmol), 1-amino-3-methylthiourea (508.87mg, 4.84mmol) and N,N -Diisopropylethylamine (1.56g, 12.10mmol) was dissolved in anhydrous DMF (20mL), cooled to 5°C with an ice-water bath, added 2-(7-azabenzotriazole)-N,N , N',N'-tetramethylurea hexafluorophosphate (1.67g, 4.44mmol), stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was concentrated, and the crude product was subjected to reverse-phase silica gel column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000139
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified, and the title compound 54C (1.1 g) was obtained after lyophilization.
MS m/z(ESI):313[M+H] +. MS m/z(ESI):313[M+H] + .
步骤3：5-(1-(2-氯吡啶-4-基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑-3-硫醇(54D)的制备Step 3: 5-(1-(2-Chloropyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (54D ) preparation
将1-((1-(2-氯吡啶-4-基)-3-甲基环丁基羰基)氨基)-3-甲基硫脲(1.1g,3.52mmol)溶于四氢呋喃(40mL)，然后加入2mol/L氢氧化钠水溶液(20mL)，混合物在室温下搅拌2小时。将反应液用稀盐酸调节至pH＝3，乙酸乙酯萃取，分液，浓缩，得粗品，直接用于下一步反应。1-((1-(2-Chloropyridin-4-yl)-3-methylcyclobutylcarbonyl)amino)-3-methylthiourea (1.1 g, 3.52 mmol) was dissolved in tetrahydrofuran (40 mL), Then 2 mol/L aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was adjusted to pH = 3 with dilute hydrochloric acid, extracted with ethyl acetate, separated and concentrated to obtain a crude product, which was directly used in the next reaction.
步骤4：2-氯-4-(3-甲基-1-(4-甲基-4H-1,2,4-三氮唑-3-基)环丁基)吡啶(54E)的制备Step 4: Preparation of 2-chloro-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (54E)
将步骤3所得54D粗品溶于二氯甲烷(50mL)中，0℃下滴加双氧水(35％)(598.05mg,17.58mmol)的醋酸(4mL)溶液，加毕，室温下反应4小时。将反应液倒入水中，氢氧化钠水溶液调节pH＝10，萃取，分液，水相用二氯甲烷萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩至干，粗品用反相硅胶柱色谱法(色谱柱：
Figure PCTCN2022118398-appb-000140
快速硅胶柱，水:乙腈＝95:5-5:95)纯化，冻干后得标题化合物54E(730mg)。 The crude product 54D obtained in step 3 was dissolved in dichloromethane (50 mL), and a solution of hydrogen peroxide (35%) (598.05 mg, 17.58 mmol) in acetic acid (4 mL) was added dropwise at 0°C, and the reaction was carried out at room temperature for 4 hours. Pour the reaction solution into water, adjust the pH to 10 with aqueous sodium hydroxide solution, extract, separate the liquids, extract the aqueous phase with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to dryness. Phase silica gel column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000140
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified, and the title compound 54E (730 mg) was obtained after lyophilization.
MS m/z(ESI):263[M+H] +. MS m/z(ESI):263[M+H] + .
步骤5：(S)-6-氟-1-(4-(3-甲基-1-(4-甲基-4H-1,2,4-三氮唑-3-基)环丁基)吡啶-2-基)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物54)的制备Step 5: (S)-6-Fluoro-1-(4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl) Preparation of pyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 54)
室温下，将(S)-6-氟-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(3D，20.0mg,66.6μmol)、2-氯-4-(3-甲基-1-(4-甲基-4H-1,2,4-三氮唑-3-基)环丁基)吡啶(54E，23.5mg,66.6μmol)、碳酸钾(18.4mg，133.2μmol)和碘化亚铜(2.5mg，13.3μmol)加入反应管，置换氩气，加入无水N,N-二甲基甲酰胺(2ml)和反式-N,N'-二甲基1,2-环己二胺(4.7mg，33.3μmol)，体系加热到100℃，反应2小时，冷却至室温，过滤，所得残余物经反相硅胶柱色谱法(色谱柱：
Figure PCTCN2022118398-appb-000141
快速硅胶柱，水:乙腈＝95:5-5:95)纯化，冻干后得标题化合物(5.7mg)。 At room temperature, (S)-6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (3D, 20.0mg, 66.6μmol), 2-chloro-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (54E, 23.5mg ,66.6μmol), potassium carbonate (18.4mg, 133.2μmol) and cuprous iodide (2.5mg, 13.3μmol) were added to the reaction tube, argon was replaced, and anhydrous N,N-dimethylformamide (2ml) and Trans-N,N'-dimethyl 1,2-cyclohexanediamine (4.7 mg, 33.3 μmol), the system was heated to 100 ° C, reacted for 2 hours, cooled to room temperature, filtered, and the resulting residue was subjected to reverse phase silica gel Column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000141
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified, and the title compound (5.7 mg) was obtained after lyophilization.
MS m/z(ESI):525.4[M+H] +. MS m/z(ESI):525.4[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ8.60-8.53(m,1H),8.38(s,1H),8.23-8.15(m,2H),8.12(s,1H),7.93-7.86(m,1H),7.42-7.33(m,1H),7.31-7.25(m,1H),3.77(s,2H),3.26(s,3H),2.94-2.83(m,2H),2.81-2.70(m,2H),2.69-2.59(m,3H),2.02-1.89(m,1H),1.73-1.56(m,4H),1.54-1.40(m,1H),1.14-1.07(m,3H),0.83-0.78(m,4H). 1 H-NMR (400MHz,DMSO-d 6 )δ8.60-8.53(m,1H),8.38(s,1H),8.23-8.15(m,2H),8.12(s,1H),7.93-7.86( m,1H),7.42-7.33(m,1H),7.31-7.25(m,1H),3.77(s,2H),3.26(s,3H),2.94-2.83(m,2H),2.81-2.70( m,2H),2.69-2.59(m,3H),2.02-1.89(m,1H),1.73-1.56(m,4H),1.54-1.40(m,1H),1.14-1.07(m,3H), 0.83-0.78(m,4H).
实施例5(S)-6-氟-1-(5-(3-甲基-1-(4-甲基-4H-1,2,4-三氮唑-3-基)环丁基)吡啶-3-基)-4-((3-甲基哌啶-1-基)甲基)苯并吲哚-2(1H)-酮(化合物55)的制备Example 5 (S)-6-fluoro-1-(5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl) Preparation of pyridin-3-yl)-4-((3-methylpiperidin-1-yl)methyl)benzindol-2(1H)-one (compound 55)
Figure PCTCN2022118398-appb-000142
Figure PCTCN2022118398-appb-000142
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000143
Figure PCTCN2022118398-appb-000143
步骤1：1-(5-溴吡啶-3-基)-3-甲基环丁基-1-甲酸甲酯(55A)的制备Step 1: Preparation of methyl 1-(5-bromopyridin-3-yl)-3-methylcyclobutyl-1-carboxylate (55A)
将2-(5-溴吡啶-3-基)乙酸甲酯(2.27g,9.87mmol)，1,3-二溴-2-甲基丙烷(2.56g,11.84mmol)溶于DMF(15mL)中，0℃下分批加入氢化钠(有效含量60％)(790mg,19.75mmol)，加毕，室温下反应2小时。反应液倒入饱和氯化铵水溶液中，加入乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经硅胶柱层析(石油醚:乙酸乙酯＝100:1)纯化，得到标题化合物55A(1.3g)。Methyl 2-(5-bromopyridin-3-yl)acetate (2.27g, 9.87mmol), 1,3-dibromo-2-methylpropane (2.56g, 11.84mmol) were dissolved in DMF (15mL) , Add sodium hydride (60% effective content) (790mg, 19.75mmol) in batches at 0°C, after the addition is complete, react at room temperature for 2 hours. The reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was subjected to silica gel column chromatography (petroleum ether: ethyl acetate =100:1) Purification gave the title compound 55A (1.3 g).
步骤2：1-(5-溴吡啶-3-基)-3-甲基环丁基-1-甲酰肼(55B)的制备Step 2: Preparation of 1-(5-bromopyridin-3-yl)-3-methylcyclobutyl-1-carboxhydrazide (55B)
将1-(5-溴吡啶-3-基)-3-甲基环丁基-1-甲酸甲酯(1.3g,4.58mmol)溶于乙醇(15mL)中，加入一水合肼(12.340g,209.53mmol,85％有效含量)，将反应体系在80℃搅拌16小时。将反应液浓缩得到标题化合物55B(1.3g)。Dissolve 1-(5-bromopyridin-3-yl)-3-methylcyclobutyl-1-carboxylic acid methyl ester (1.3g, 4.58mmol) in ethanol (15mL), add hydrazine monohydrate (12.340g, 209.53mmol, 85% effective content), the reaction system was stirred at 80°C for 16 hours. The reaction solution was concentrated to obtain the title compound 55B (1.3 g).
MS m/z(ESI):283.7/285.7[M+H] +. MS m/z(ESI):283.7/285.7[M+H] + .
步骤3：2-(1-(5-溴吡啶-3-基)-3-甲基环丁基-1-羰基)-N-甲基肼基-1-硫代甲酰胺(55C)的制备Step 3: Preparation of 2-(1-(5-bromopyridin-3-yl)-3-methylcyclobutyl-1-carbonyl)-N-methylhydrazino-1-carbothioamide (55C)
将1-(5-溴吡啶-3-基)-3-甲基环丁基-1-甲酰肼(1.3g,4.58mmol)溶于四氢呋喃(15mL)中，加入异硫氰酸甲酯(1.00g,13.73mmol)，将反应体系在80℃搅拌3小时。将反应液浓缩，所得固体用乙酸乙酯打浆，过滤，浓缩得到标题化合物55C(1.5g)。1-(5-Bromopyridin-3-yl)-3-methylcyclobutyl-1-carboxhydrazide (1.3 g, 4.58 mmol) was dissolved in tetrahydrofuran (15 mL), and methyl isothiocyanate ( 1.00g, 13.73mmol), the reaction system was stirred at 80°C for 3 hours. The reaction solution was concentrated, and the resulting solid was slurried with ethyl acetate, filtered, and concentrated to give the title compound 55C (1.5 g).
MS m/z(ESI):357.0/359.0[M+H] +. MS m/z(ESI):357.0/359.0[M+H] + .
步骤4：5-(1-(5-溴吡啶-3-基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三氮唑-3-硫醇(55D)的制备Step 4: 5-(1-(5-bromopyridin-3-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol ( 55D) Preparation
将2-(1-(5-溴吡啶-3-基)-3-甲基环丁基-1-羰基)-N-甲基肼基-1-硫代甲酰胺(1.5g,4.20mmol)溶于四氢呋喃(20mL)，然后加入1mol/L氢氧化钠水溶液(25mL)，混合物在室温下搅拌反应12小时。将反应液用1mol/L稀盐酸调节至pH＝3，此过程中间有固体析出。加入乙酸乙酯溶解，萃取，分液，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩，得标题化合物55D(1.4g)。2-(1-(5-bromopyridin-3-yl)-3-methylcyclobutyl-1-carbonyl)-N-methylhydrazino-1-carbothioamide (1.5g, 4.20mmol) Dissolve in tetrahydrofuran (20 mL), then add 1 mol/L sodium hydroxide aqueous solution (25 mL), and stir the mixture at room temperature for 12 hours. The reaction solution was adjusted to pH = 3 with 1 mol/L dilute hydrochloric acid, and solids were precipitated during the process. Ethyl acetate was added to dissolve, extracted, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 55D (1.4 g).
MS m/z(ESI):339.0/341.0[M+H] +. MS m/z(ESI):339.0/341.0[M+H] + .
步骤5：3-溴-5-(3-甲基-1-(4-甲基-4H-1,2,4-三氮唑-3-基)环丁基)吡啶(55E)的制备Step 5: Preparation of 3-bromo-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (55E)
将5-(1-(5-溴吡啶-3-基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三氮唑-3-硫醇(1.3g,3.83mmol)溶于二氯甲烷(15mL)中，0℃下滴加双氧水(浓度35％)(9.2g,81.15mmol)的醋酸(3mL)溶液，加毕，室温下反应12小时。将反应液倒入水中，氢氧化钠水溶液调节pH＝10，萃取，分液，水相用二氯甲烷萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩至干，残留物进行反相柱层析(色谱柱：
Figure PCTCN2022118398-appb-000144
快速硅胶柱，水:乙腈＝95:5-5:95)纯化，得到标题化合物55E(521mg)。 5-(1-(5-bromopyridin-3-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (1.3g , 3.83mmol) was dissolved in dichloromethane (15mL), a solution of hydrogen peroxide (concentration 35%) (9.2g, 81.15mmol) in acetic acid (3mL) was added dropwise at 0°C, after the addition was complete, the reaction was carried out at room temperature for 12 hours. Pour the reaction solution into water, adjust the pH to 10 with aqueous sodium hydroxide solution, extract, separate the liquids, extract the aqueous phase with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness. The residue was subjected to reverse phase column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000144
Flash silica gel column, water: acetonitrile = 95:5-5:95) was purified to obtain the title compound 55E (521 mg).
步骤6：(S)-6-氟-1-(5-(3-甲基-1-(4-甲基-4H-1,2,4-三氮唑-3-基)环丁基)吡啶-3-基)-4-((3-甲基哌啶-1-基)甲基)苯并吲哚-2(1H)-酮(化合物55)的制备Step 6: (S)-6-Fluoro-1-(5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl) Preparation of pyridin-3-yl)-4-((3-methylpiperidin-1-yl)methyl)benzindol-2(1H)-one (compound 55)
参照实施例4步骤5的合成方法，不同的是将步骤4中的54E替换为55E(309mg，1mmol)，同法制得化合物55(270mg)。Referring to the synthesis method in Step 5 of Example 4, except that 54E in Step 4 was replaced by 55E (309 mg, 1 mmol), the same method was used to obtain Compound 55 (270 mg).
MS m/z(ESI):525.5[M+H] +； MS m/z(ESI):525.5[M+H] + ;
1H-NMR(400MHz,DMSO-d 6)δ8.81(1H,d,J＝12.4Hz),8.66(1H,s),8.45(1H,d,J＝31.2Hz),8.28(2H,d,J＝4.8Hz),8.01(1H,d,J＝60.2Hz),7.40(1H,dd,J＝11.6,7.8Hz),7.05(1H,dd,J＝7.8,2.7Hz),3.94–3.79(2H,m),3.40-3.35(3H,m),3.10(2H,t,J＝44.8Hz),2.83(2H,t,J＝11.2Hz),2.69(3H,t,J＝13.8Hz),2.48–2.36(1H,m),2.03(1H,t,J＝10.3Hz),1.72–1.48(4H,m),1.17(3H,t,J＝7.2Hz),0.90(4H,dd,J＝20.1,8.3Hz). 1 H-NMR (400MHz, DMSO-d 6 ) δ8.81 (1H, d, J = 12.4Hz), 8.66 (1H, s), 8.45 (1H, d, J = 31.2Hz), 8.28 (2H, d ,J=4.8Hz),8.01(1H,d,J=60.2Hz),7.40(1H,dd,J=11.6,7.8Hz),7.05(1H,dd,J=7.8,2.7Hz),3.94–3.79 (2H,m),3.40-3.35(3H,m),3.10(2H,t,J=44.8Hz),2.83(2H,t,J=11.2Hz),2.69(3H,t,J=13.8Hz) ,2.48–2.36(1H,m),2.03(1H,t,J=10.3Hz),1.72–1.48(4H,m),1.17(3H,t,J=7.2Hz),0.90(4H,dd,J =20.1,8.3Hz).
化合物55经SFC拆分后，得化合物55A(t R＝5.99min)和化合物55B(t R＝5.61min)，SFC方法如下： Compound 55 was resolved by SFC to obtain compound 55A (t R =5.99min) and compound 55B (t R =5.61min), and the SFC method was as follows:
仪器：CAS-SH-ANA-SFC-G(Agilent UPCC with DAD detector)；Instrument: CAS-SH-ANA-SFC-G (Agilent UPCC with DAD detector);
柱子：ChiralPak AD-3柱长150mm，内径4.6mm,粒径3μm；Column: ChiralPak AD-3 column length 150mm, inner diameter 4.6mm, particle size 3μm;
流动相A：CO 2,流动相B：EtOH(含0.05％DEA)； Mobile phase A: CO 2 , mobile phase B: EtOH (containing 0.05% DEA);
梯度：流动相B从5％到40％用时4分钟，并保持40％洗脱2分钟，然后用5％流动相B洗脱2分钟；流速：2.5mL/min；Gradient: mobile phase B from 5% to 40% for 4 minutes, and maintain 40% elution for 2 minutes, then elution with 5% mobile phase B for 2 minutes; flow rate: 2.5mL/min;
柱温：35℃；Column temperature: 35°C;
自动背压调节器(ABPR)：100bar。Automatic Back Pressure Regulator (ABPR): 100bar.
化合物55A：Compound 55A:
MS m/z(ESI):525.5[M+H] +； MS m/z(ESI):525.5[M+H] + ;
1H-NMR(400MHz,DMSO-d 6)δ8.77(1H,d,J＝2.1Hz),8.60(1H,d,J＝2.0Hz),8.35(1H,s),8.23(2H,d,J＝4.8Hz),8.03(1H,d,J＝2.1Hz),7.35(1H,dd,J＝11.6,7.9Hz),7.00(1H,dd,J＝7.8,2.8Hz),3.80(2H,s),3.30(3H,s),2.97(2H,s),2.77(2H,t,J＝11.1Hz),2.62(3H,d,J＝6.5Hz),1.97(1H,t,J＝10.2Hz),1.70–1.45(5H,m),1.10(3H d,J＝5.2Hz),0.85(4H,m). 1 H-NMR (400MHz, DMSO-d 6 ) δ8.77 (1H, d, J = 2.1Hz), 8.60 (1H, d, J = 2.0Hz), 8.35 (1H, s), 8.23 (2H, d ,J=4.8Hz),8.03(1H,d,J=2.1Hz),7.35(1H,dd,J=11.6,7.9Hz),7.00(1H,dd,J=7.8,2.8Hz),3.80(2H ,s),3.30(3H,s),2.97(2H,s),2.77(2H,t,J＝11.1Hz),2.62(3H,d,J＝6.5Hz),1.97(1H,t,J＝ 10.2Hz), 1.70–1.45(5H,m), 1.10(3H d,J=5.2Hz), 0.85(4H,m).
化合物55B：Compound 55B:
MS m/z(ESI):525.5[M+H] +； MS m/z(ESI):525.5[M+H] + ;
1H-NMR(400MHz,DMSO-d 6)δ8.74(1H,d,J＝2.2Hz),8.47–8.41(2H,m),8.22(2H,d,J＝5.6Hz),7.87(1H,t,J＝2.1Hz),7.35(1H,dd,J＝11.6,7.8Hz),6.99(1H,dd,J＝7.8,2.8Hz),3.80(2H,s),3.34(3H,s),3.18(2H,d,J＝3.7Hz),2.77(2H,t,J＝11.5Hz),2.38(3H,d,J＝6.9Hz),1.97(1H,t,J＝9.9Hz),1.71–1.50(5H,m),1.13(3H,d,J＝5.5Hz),0.82(4H,d,J＝6.2Hz). 1 H-NMR (400MHz, DMSO-d 6 ) δ8.74 (1H, d, J = 2.2Hz), 8.47–8.41 (2H, m), 8.22 (2H, d, J = 5.6Hz), 7.87 (1H ,t,J=2.1Hz),7.35(1H,dd,J=11.6,7.8Hz),6.99(1H,dd,J=7.8,2.8Hz),3.80(2H,s),3.34(3H,s) ,3.18(2H,d,J=3.7Hz),2.77(2H,t,J=11.5Hz),2.38(3H,d,J=6.9Hz),1.97(1H,t,J=9.9Hz),1.71 –1.50(5H,m),1.13(3H,d,J=5.5Hz),0.82(4H,d,J=6.2Hz).
实施例6：6-氟-1-(4-(3-甲基-2-(4-甲基-4H-1,2,4-三唑-3-基)丁烷-2-基)吡啶-2-基)-4-(((S)-3- 甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物56)的制备Example 6: 6-fluoro-1-(4-(3-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)butane-2-yl)pyridine Preparation of -2-yl)-4-(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 56)
Figure PCTCN2022118398-appb-000145
Figure PCTCN2022118398-appb-000145
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000146
Figure PCTCN2022118398-appb-000146
步骤1：2-(2-氯吡啶-4-基)-3-甲基丁酸乙酯的制备Step 1: Preparation of ethyl 2-(2-chloropyridin-4-yl)-3-methylbutyrate
将2-(2-氯吡啶-4-基)乙酸乙酯(2.0g,10.0mmol)溶于DMF(40mL)中，0℃下加入氢化钠(有效含量60％)(1.6g,40.07mmol)，然后加入2-溴丙烷(1.26g,10.2mmol)，室温下反应6小时。反应液倒入饱和氯化铵水溶液中，加入乙酸乙酯萃取，有机相蒸干，粗品通过硅胶柱色谱法纯化(PE/EtOAc＝25/0到3/1)，得标题化合物(1.2g，5.0mmol)。Dissolve ethyl 2-(2-chloropyridin-4-yl)acetate (2.0g, 10.0mmol) in DMF (40mL), add sodium hydride (effective content 60%) (1.6g, 40.07mmol) at 0°C , and then added 2-bromopropane (1.26g, 10.2mmol), and reacted at room temperature for 6 hours. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was evaporated to dryness, and the crude product was purified by silica gel column chromatography (PE/EtOAc=25/0 to 3/1) to obtain the title compound (1.2 g, 5.0 mmol).
MS m/z(ESI):242[M+H] +. MS m/z(ESI):242[M+H] + .
步骤2：2-(2-氯吡啶-4-基)-2,3-二甲基丁酸乙酯的制备Step 2: Preparation of ethyl 2-(2-chloropyridin-4-yl)-2,3-dimethylbutyrate
室温下，将2-(2-氯吡啶-4-基)-3-甲基丁酸乙酯(2.1g,8.69mmol)溶解入无水DMF(20mL)中，氮气下，加入碘甲烷(2.47g,17.38mmol)和NaH(1.04g,26.06mmol,有效含量60％)，室温搅拌2小时。加水淬灭，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥、过滤，浓缩得粗品(2g)。At room temperature, 2-(2-chloropyridin-4-yl)-3-methylbutyric acid ethyl ester (2.1g, 8.69mmol) was dissolved in anhydrous DMF (20mL), under nitrogen, iodomethane (2.47 g, 17.38mmol) and NaH (1.04g, 26.06mmol, effective content 60%), stirred at room temperature for 2 hours. Add water to quench, extract with ethyl acetate, combine organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product (2 g).
MS m/z(ESI):256[M+H] +. MS m/z(ESI):256[M+H] + .
步骤3：2-(2-氯吡啶-4-基)-2,3-二甲基丁酸的制备Step 3: Preparation of 2-(2-chloropyridin-4-yl)-2,3-dimethylbutanoic acid
室温下，将2-(2-氯吡啶-4-基)-2,3-二甲基丁酸乙酯(2.0g,7.82mmol)溶解入甲醇(10mL)中，加入水(10mL)，四氢呋喃(10mL)和氢氧化锂(374.57mg,15.64mmol)，加热至50℃反应16小时。反应完毕冷却至室温，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，残余物通过硅胶柱色谱法(PE/EtOAc＝1/0至3/1)纯化，得标题化合物(1.0g)。Dissolve ethyl 2-(2-chloropyridin-4-yl)-2,3-dimethylbutanoate (2.0g, 7.82mmol) in methanol (10mL) at room temperature, add water (10mL), tetrahydrofuran (10mL) and lithium hydroxide (374.57mg, 15.64mmol), heated to 50°C for 16 hours. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE/EtOAc=1/0 to 3/1) to obtain the title compound (1.0g).
MS m/z(ESI):228[M+H] +. MS m/z(ESI):228[M+H] + .
步骤4：2-(2-(2-氯吡啶-4-基)-2,3-二甲基丁酰)-N-甲基肼甲硫代酰胺的制备Step 4: Preparation of 2-(2-(2-chloropyridin-4-yl)-2,3-dimethylbutyryl)-N-methylhydrazinemethylthioamide
参照实施例4步骤2的合成方法，不同的是将步骤2中的54B替换为2-(2-氯吡啶-4-基)-2,3-二甲基丁酸(550mg，2.2mmol)，同法制得标题化合物(691mg，2.2mmol)。Referring to the synthesis method of step 2 of Example 4, the difference is that 54B in step 2 is replaced by 2-(2-chloropyridin-4-yl)-2,3-dimethylbutanoic acid (550mg, 2.2mmol), The title compound (691 mg, 2.2 mmol) was obtained in the same manner.
步骤5：5-(2-(2-氯吡啶-4-基)-3-甲基丁烷-2-基)-4-甲基-4H-1,2,4-三唑-3-硫醇的制备Step 5: 5-(2-(2-Chloropyridin-4-yl)-3-methylbutan-2-yl)-4-methyl-4H-1,2,4-triazole-3-sulfur Preparation of Alcohol
参照实施例4步骤3的合成方法，不同的是将步骤3中的54C替换为2-(2-(2-氯吡啶-4- 基)-2,3-二甲基丁酰)-N-甲基肼甲硫代酰胺(550mg，1.75mmol)，同法制得标题化合物(580mg)。Referring to the synthetic method of Example 4 Step 3, the difference is that 54C in Step 3 is replaced by 2-(2-(2-chloropyridin-4-yl)-2,3-dimethylbutyryl)-N- Methylhydrazine methyl thioamide (550mg, 1.75mmol), the title compound (580mg) was obtained by the same method.
步骤6：2-氯-4-(3-甲基-2-(4-甲基-4H-1,2,4-三唑-3-基)丁烷-2-基)吡啶的制备Step 6: Preparation of 2-chloro-4-(3-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)butan-2-yl)pyridine
参照实施例4步骤4的合成方法，不同的是将步骤4中的54D替换为5-(2-(2-氯吡啶-4-基)-3-甲基丁烷-2-基)-4-甲基-4H-1,2,4-三唑-3-硫醇(580mg，1.62mmol)，同法制得标题化合物(220mg，0.83mmol)。With reference to the synthetic method of Example 4 step 4, the difference is that 54D in step 4 is replaced by 5-(2-(2-chloropyridin-4-yl)-3-methylbutan-2-yl)-4 -Methyl-4H-1,2,4-triazole-3-thiol (580mg, 1.62mmol), the title compound (220mg, 0.83mmol) was obtained by the same method.
步骤7：6-氟-1-(4-(3-甲基-2-(4-甲基-4H-1,2,4-三唑-3-基)丁烷-2-基)吡啶-2-基)-4-(((S)-3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物56)的制备Step 7: 6-Fluoro-1-(4-(3-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)butan-2-yl)pyridine- Preparation of 2-yl)-4-(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 56)
参照实施例4步骤5的合成方法，不同的是将步骤4中的54E替换为2-氯-4-(3-甲基-2-(4-甲基-4H-1,2,4-三唑-3-基)丁烷-2-基)吡啶(9mg)，同法制得标题化合物(2.7mg)。Referring to the synthetic method of step 5 of Example 4, the difference is that 54E in step 4 is replaced by 2-chloro-4-(3-methyl-2-(4-methyl-4H-1,2,4-tri (Azol-3-yl)butan-2-yl)pyridine (9 mg), and the title compound (2.7 mg) was obtained in the same manner.
MS m/z(ESI):527.3[M+H] +； MS m/z(ESI):527.3[M+H] + ;
1H-NMR(400MHz,DMSO-d 6)δ8.58(d,J＝4.8Hz,1H),8.39(s,1H),8.25(s,1H),8.21(s,1H),7.96-7.92(m,2H),7.45-7.40(m,1H),7.15-7.11(m,1H),3.82(s,2H),3.22(s,3H),2.97-2.88(m,2H),2.83–2.72(m,4H),2.03–1.98(m,1H),1.71(s,3H),1.68–1.63(m,2H),1.04(d,J＝6.5Hz,3H),0.88-0.84(m,7H). 1 H-NMR (400MHz, DMSO-d 6 ) δ8.58(d, J=4.8Hz, 1H), 8.39(s, 1H), 8.25(s, 1H), 8.21(s, 1H), 7.96-7.92 (m,2H),7.45-7.40(m,1H),7.15-7.11(m,1H),3.82(s,2H),3.22(s,3H),2.97-2.88(m,2H),2.83–2.72 (m,4H),2.03–1.98(m,1H),1.71(s,3H),1.68–1.63(m,2H),1.04(d,J＝6.5Hz,3H),0.88-0.84(m,7H ).
实施例7(S)-6-氟-1-(6-甲基-4-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物57)的制备Example 7 (S)-6-fluoro-1-(6-methyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) Preparation of cyclobutyl)pyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 57)
Figure PCTCN2022118398-appb-000147
Figure PCTCN2022118398-appb-000147
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000148
Figure PCTCN2022118398-appb-000148
步骤1：2-(2-氯-6-甲基吡啶-4-基)乙酸甲酯的制备Step 1: Preparation of methyl 2-(2-chloro-6-methylpyridin-4-yl)acetate
将2-氯-4,6-二甲基吡啶(10g,70.62mmol)溶解入无水四氢呋喃(100ml)中，干冰乙醇浴冷却，往溶液中滴加LDA(2M,88.2ml)，搅拌一小时。碳酸二甲酯(9.54g,105.93mmol)加入，升至0℃，并在0℃反应两小时，饱和氯化铵水溶液(10ml)加入淬灭反应，浓缩除掉四氢呋喃，乙酸乙酯(50mlx2)萃取，无水硫酸钠干燥后过滤，滤液浓缩得粗品，粗品经硅胶柱色谱法(PE:EA＝1:0至3:1)纯化，得2-(2-氯-6-甲基吡啶-4-基)乙酸甲酯(5.4g)。Dissolve 2-chloro-4,6-lutidine (10g, 70.62mmol) into anhydrous tetrahydrofuran (100ml), cool in a dry ice ethanol bath, add LDA (2M, 88.2ml) dropwise to the solution, and stir for one hour . Dimethyl carbonate (9.54g, 105.93mmol) was added, raised to 0°C, and reacted at 0°C for two hours, saturated ammonium chloride aqueous solution (10ml) was added to quench the reaction, concentrated to remove tetrahydrofuran, ethyl acetate (50mlx2) Extracted, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=1:0 to 3:1) to obtain 2-(2-chloro-6-picoline- 4-yl) methyl acetate (5.4 g).
MS m/z(ESI):200[M+H] +. MS m/z(ESI):200[M+H] + .
步骤2：1-(2-氯-6-甲基吡啶-4-基)-3-甲基环丁基甲酸的制备Step 2: Preparation of 1-(2-chloro-6-methylpyridin-4-yl)-3-methylcyclobutylcarboxylic acid
参照实施例4步骤1的合成方法，不同的是将步骤1中的2-(2-氯吡啶-4-基)乙酸乙酯替换为2-(2-氯-6-甲基吡啶-4-基)乙酸甲酯(5.4g,27.14mmol)，同法制得标题化合物(2.9g,12.1mmol)。With reference to the synthetic method of Example 4 step 1, the difference is that 2-(2-chloropyridin-4-yl) ethyl acetate in step 1 is replaced by 2-(2-chloro-6-methylpyridine-4- base) methyl acetate (5.4g, 27.14mmol), and the title compound (2.9g, 12.1mmol) was obtained by the same method.
步骤3：2-(1-(2-氯-6-甲基吡啶-4-基)-3-甲基环丁基羰基)-N-甲基肼甲硫代酰胺的制备Step 3: Preparation of 2-(1-(2-chloro-6-methylpyridin-4-yl)-3-methylcyclobutylcarbonyl)-N-methylhydrazinemethylthioamide
参照实施例4步骤2的合成方法，不同的是将步骤2中的54B替换为1-(2-氯-6-甲基吡啶-4-基)-3-甲基环丁基甲酸(2.9g,12.1mmol)，同法制得标题化合物(2.81g,8.60mmol)。With reference to the synthetic method of Example 4 step 2, the difference is that 54B in step 2 is replaced by 1-(2-chloro-6-methylpyridin-4-yl)-3-methylcyclobutylcarboxylic acid (2.9g , 12.1mmol), the title compound (2.81g, 8.60mmol) was obtained by the same method.
步骤4：5-(1-(2-氯-6-甲基吡啶-4-基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑-3-硫醇的制备Step 4: 5-(1-(2-Chloro-6-methylpyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3 - Preparation of thiols
参照实施例4步骤3的合成方法，不同的是将步骤3中的1-((1-(2-氯吡啶-4-基)-3-甲基环丁基羰基)氨基)-3-甲基硫脲替换为2-(1-(2-氯-6-甲基吡啶-4-基)-3-甲基环丁基羰基)-N-甲基肼甲硫代酰胺(2.81g,8.6mmol)，同法制得标题化合物(2.26g,7.33mmol)。With reference to the synthetic method of Example 4 step 3, the difference is that the 1-((1-(2-chloropyridin-4-yl)-3-methylcyclobutylcarbonyl)amino)-3-methyl The thiourea was replaced by 2-(1-(2-chloro-6-methylpyridin-4-yl)-3-methylcyclobutylcarbonyl)-N-methylhydrazinemethylthioamide (2.81g, 8.6 mmol), the title compound (2.26g, 7.33mmol) was obtained by the same method.
步骤5：2-氯-6-甲基-4-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶的制备Step 5: Preparation of 2-chloro-6-methyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine
参照实施例4步骤4的合成方法，不同的是将步骤4中的54D替换为5-(1-(2-氯-6-甲基吡啶-4-基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑-3-硫醇(500mg，1.62mmol)，同法制得标题化合物(200mg,0.72mmol)。Referring to the synthetic method of Example 4 step 4, the difference is that 54D in step 4 is replaced by 5-(1-(2-chloro-6-methylpyridin-4-yl)-3-methylcyclobutyl) -4-Methyl-4H-1,2,4-triazole-3-thiol (500mg, 1.62mmol), the title compound (200mg, 0.72mmol) was obtained by the same method.
步骤6：(S)-6-氟-1-(6-甲基-4-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物57)的制备Step 6: (S)-6-Fluoro-1-(6-methyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) Preparation of cyclobutyl)pyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 57)
参照实施例4步骤5的合成方法，不同的是将步骤5中的54E替换为2-氯-6-甲基-4-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(9mg)，同法制得标题化合物(3.2mg)。With reference to the synthetic method of Example 4 step 5, the difference is that 54E in step 5 is replaced by 2-chloro-6-methyl-4-(3-methyl-1-(4-methyl-4H-1, 2,4-Triazol-3-yl)cyclobutyl)pyridine (9 mg), and the title compound (3.2 mg) was obtained in the same manner.
MS m/z(ESI):539.3[M+H] +； MS m/z(ESI):539.3[M+H] + ;
1H-NMR(400MHz,DMSO-d 6)δ8.43(s,1H),8.22(d,J＝13.4Hz,2H),7.96(m,2H),7.42(dd,J＝11.6,8.1Hz,1H),7.13(s,1H),3.81(s,2H),3.29(s,3H),2.95–2.74(m,4H),2.67(m,3H),2.59(s,3H),2.35(m,1H),1.99(t,J＝9.9Hz,1H),1.74-1.46(m,4H),1.13(d,J＝5.0Hz,3H),0.92-0.79(m,4H). 1 H-NMR (400MHz, DMSO-d 6 ) δ8.43(s, 1H), 8.22(d, J=13.4Hz, 2H), 7.96(m, 2H), 7.42(dd, J=11.6, 8.1Hz ,1H),7.13(s,1H),3.81(s,2H),3.29(s,3H),2.95–2.74(m,4H),2.67(m,3H),2.59(s,3H),2.35( m,1H),1.99(t,J=9.9Hz,1H),1.74-1.46(m,4H),1.13(d,J=5.0Hz,3H),0.92-0.79(m,4H).
实施例8(S)-6-氟-1-(3-(3-氟-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物58)的制备Example 8 (S)-6-fluoro-1-(3-(3-fluoro-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) ring Preparation of butyl)phenyl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 58)
Figure PCTCN2022118398-appb-000149
Figure PCTCN2022118398-appb-000149
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000150
Figure PCTCN2022118398-appb-000150
步骤1：顺式-1-(3-溴苯基)-3-羟基环丁羧酸的制备Step 1: Preparation of cis-1-(3-bromophenyl)-3-hydroxycyclobutanecarboxylic acid
于干燥三颈烧瓶中，称入2-(3-溴苯基)乙酸(15g,69.75mmol)，置换氩气，加入无水四氢呋喃(150ml)，冰水浴冷却，滴加异丙基溴化镁(2M,77.95ml)，升至室温，搅拌1小时，加入2-(氯甲基)噁丙环(12g,129.74mmol,10.15ml)，室温下，搅拌3小时，再次滴加异丙基溴化镁(2M,77.95ml)，室温下反应过夜。反应加入2M盐酸至pH为1-2为止，二氯甲 烷(800mlx3)萃取，合并有机相，浓缩得粗品，粗品经硅胶柱色谱法(0-50％EA/PE)纯化，得标题化合物(13.92g,47.35mmol)。In a dry three-necked flask, weigh 2-(3-bromophenyl)acetic acid (15g, 69.75mmol), replace the argon, add anhydrous tetrahydrofuran (150ml), cool in an ice-water bath, add isopropylmagnesium bromide dropwise (2M, 77.95ml), raised to room temperature, stirred for 1 hour, added 2-(chloromethyl)oxapropane (12g, 129.74mmol, 10.15ml), stirred for 3 hours at room temperature, added dropwise isopropyl bromide again Magnesium chloride (2M, 77.95ml), react overnight at room temperature. Add 2M hydrochloric acid to the reaction until the pH is 1-2, extract with dichloromethane (800mlx3), combine the organic phases, and concentrate to obtain the crude product, which is purified by silica gel column chromatography (0-50% EA/PE) to obtain the title compound (13.92 g, 47.35 mmol).
MS m/z(ESI):271[M+H] +. MS m/z(ESI):271[M+H] + .
1H NMR(400MHz,DMSO-d 6)d 12.38(br.s.,1H),7.55-7.49(m,1H),7.48-7.43(m,1H),7.36-7.29(m,2H),5.26-5.12(m,1H),3.90-3.83(m,1H),2.78-2.73(m,2H),2.55-2.52(m,2H). 1 H NMR (400MHz,DMSO-d 6 )d 12.38(br.s.,1H),7.55-7.49(m,1H),7.48-7.43(m,1H),7.36-7.29(m,2H),5.26 -5.12(m,1H),3.90-3.83(m,1H),2.78-2.73(m,2H),2.55-2.52(m,2H).
步骤2：顺式-2-(1-(3-溴苯基)-3-羟基环丁基羰基)-N-甲基肼甲硫代酰胺的制备Step 2: Preparation of cis-2-(1-(3-bromophenyl)-3-hydroxycyclobutylcarbonyl)-N-methylhydrazinemethylthioamide
参照实施例4步骤2的合成方法，不同的是将步骤2中的54B替换为顺式-1-(3-溴苯基)-3-羟基环丁羧酸(294mg,1.08mmol)，同法制得标题化合物(171mg,0.48mmol)。Referring to the synthesis method in step 2 of Example 4, the difference is that 54B in step 2 is replaced by cis-1-(3-bromophenyl)-3-hydroxycyclobutanecarboxylic acid (294mg, 1.08mmol), the same method The title compound (171 mg, 0.48 mmol) was obtained.
步骤3：顺式-3-(3-溴苯基)-3-(5-巯基-4-甲基-4H-1,2,4-三唑-3-基)环丁醇的制备Step 3: Preparation of cis-3-(3-bromophenyl)-3-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanol
参照实施例4步骤3的合成方法，不同的是将步骤3中的54C替换为顺式-2-(1-(3-溴苯基)-3-羟基环丁基羰基)-N-甲基肼甲硫代酰胺(161mg,0.45mmol)，同法制得标题化合物(122mg,0.36mmol)。Referring to the synthesis method of step 3 of Example 4, the difference is that 54C in step 3 is replaced by cis-2-(1-(3-bromophenyl)-3-hydroxycyclobutylcarbonyl)-N-methyl Hydrazinemethylthioamide (161mg, 0.45mmol), the title compound (122mg, 0.36mmol) was obtained by the same method.
步骤4：顺式-3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁醇的制备Step 4: Preparation of cis-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanol
参照实施例4步骤4的合成方法，不同的是将步骤4中的54D替换为顺式-3-(3-溴苯基)-3-(5-巯基-4-甲基-4H-1,2,4-三唑-3-基)环丁醇(1.1g,3.23mmol)，同法制得标题化合物(328mg,1.06mmol)。Referring to the synthetic method of step 4 of Example 4, the difference is that 54D in step 4 is replaced by cis-3-(3-bromophenyl)-3-(5-mercapto-4-methyl-4H-1, 2,4-Triazol-3-yl)cyclobutanol (1.1g, 3.23mmol), and the title compound (328mg, 1.06mmol) was obtained by the same method.
步骤5：3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁酮的制备Step 5: Preparation of 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanone
将顺式-3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁醇(1g,3.24mmol)溶解入二氯甲烷(50ml)中，冰水浴冷却，分批加入Dess-Martin试剂(2.75g，6.49mmol)，升至室温反应1小时，用饱和亚硫酸钠水溶液(5ml)淬灭，过滤，分液，二氯甲烷(50mlx3)萃取，合并有机相，浓缩得粗品，粗品经过反相柱纯化(色谱柱：
Figure PCTCN2022118398-appb-000151
快速硅胶柱，水:乙腈＝95:5-5:95)得标题化合物(830mg，2.71mmol)。 Dissolve cis-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanol (1 g, 3.24 mmol) in dichloro In methane (50ml), cooled in an ice-water bath, added Dess-Martin reagent (2.75g, 6.49mmol) in batches, raised to room temperature for 1 hour, quenched with saturated aqueous sodium sulfite (5ml), filtered, separated, dichloromethane (50mlx3) extraction, combined organic phase, concentrated to get crude product, crude product was purified by reverse phase column (chromatographic column:
Figure PCTCN2022118398-appb-000151
Flash silica gel column, water: acetonitrile = 95:5-5:95) to obtain the title compound (830 mg, 2.71 mmol).
MS m/z(ESI):306[M+H] +. MS m/z(ESI):306[M+H] + .
步骤6：3-(3-溴苯基)-1-甲基-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁醇的制备Step 6: Preparation of 3-(3-bromophenyl)-1-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanol
于干燥三颈烧瓶中，称入3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁酮(300mg,979.89μmol)，置换氩气，加入干燥四氢呋喃(10ml)，冰水浴冷却，加入甲基溴化镁(2M，1.96mmol，0.98ml)，升至室温反应过夜。用水(3ml)淬灭，浓缩得粗品，粗品经反相柱纯化(色谱柱：
Figure PCTCN2022118398-appb-000152
快速硅胶柱，水:乙腈＝95:5-5:95)得标题化合物(55mg,170.70μmol)。 In a dry three-necked flask, weigh 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanone (300mg, 979.89μmol ), replaced with argon, added dry tetrahydrofuran (10ml), cooled in an ice-water bath, added methylmagnesium bromide (2M, 1.96mmol, 0.98ml), raised to room temperature and reacted overnight. Quenched with water (3ml), concentrated to give the crude product, the crude product was purified by reverse phase column (chromatographic column:
Figure PCTCN2022118398-appb-000152
Flash silica gel column, water: acetonitrile = 95:5-5:95) to obtain the title compound (55 mg, 170.70 μmol).
MS m/z(ESI):322[M+H] +. MS m/z(ESI):322[M+H] + .
步骤7：3-(1-(3-溴苯基)-3-氟-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑的制备Step 7: Preparation of 3-(1-(3-bromophenyl)-3-fluoro-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole
于干燥反应管中，将3-(3-溴苯基)-1-甲基-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁醇(55mg,170.70μmol)溶解入二氯甲烷(3ml)，冰水浴下加入DAST(41.27mg,256.05μmol)，反应1小时后，用饱和碳酸氢钠水溶液(1ml)淬灭反应，浓缩得粗品，粗品经反相柱纯化(色谱柱：
Figure PCTCN2022118398-appb-000153
快速硅胶柱，水:乙腈＝95:5-5:95)，冻干后得标题化合物(20mg,61.69μmol)。 In a dry reaction tube, add 3-(3-bromophenyl)-1-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanol (55mg , 170.70μmol) was dissolved into dichloromethane (3ml), and DAST (41.27mg, 256.05μmol) was added under an ice-water bath. After reacting for 1 hour, the reaction was quenched with saturated aqueous sodium bicarbonate (1ml), concentrated to obtain a crude product, and the crude product was subjected to Reverse-phase column purification (chromatographic column:
Figure PCTCN2022118398-appb-000153
Flash silica gel column, water: acetonitrile = 95:5-5:95), and lyophilized to obtain the title compound (20 mg, 61.69 μmol).
MS m/z(ESI):324[M+H] +. MS m/z(ESI):324[M+H] + .
步骤8：(S)-6-氟-1-(3-(3-氟-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物58)的制备Step 8: (S)-6-Fluoro-1-(3-(3-fluoro-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) ring Preparation of butyl)phenyl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 58)
参照实施例4步骤5的合成方法，不同的是将步骤5中的54E替换为3-(1-(3-溴苯基)-3-氟-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(11mg)，同法制得标题化合物(4.7mg)。Referring to the synthesis method of step 5 of Example 4, the difference is that 54E in step 5 is replaced by 3-(1-(3-bromophenyl)-3-fluoro-3-methylcyclobutyl)-4-methanol -4H-1,2,4-triazole (11mg), and the title compound (4.7mg) was obtained by the same method.
MS m/z(ESI):542.3[M+H] +； MS m/z(ESI):542.3[M+H] + ;
1H-NMR(400MHz,DMSO-d 6)δ8.36(s,1H),8.23(d,J＝5.6Hz,2H),7.66(s,1H),7.65-7.60(m,1H),7.55-7.50(m,1H),7.45-7.40(m,1H),7.40-7.30(m,1H),6.93-6.89(m,1H),3.82(s,2H),3.31(s,3H),3.20-3.10(m,2H),2.85-2.75(m,3H),2.05-1.9(m,1H),1.75-1.60(m,6H),1.50-1.40(m,3H),0.9-0.8(m,4H). 1 H-NMR(400MHz,DMSO-d 6 )δ8.36(s,1H),8.23(d,J=5.6Hz,2H),7.66(s,1H),7.65-7.60(m,1H),7.55 -7.50(m,1H),7.45-7.40(m,1H),7.40-7.30(m,1H),6.93-6.89(m,1H),3.82(s,2H),3.31(s,3H),3.20 -3.10(m,2H),2.85-2.75(m,3H),2.05-1.9(m,1H),1.75-1.60(m,6H),1.50-1.40(m,3H),0.9-0.8(m, 4H).
实施例9：(S)-1-(3-氯-5-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-6-氟-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物59)的制备Example 9: (S)-1-(3-chloro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl) Preparation of phenyl)-6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 59)
Figure PCTCN2022118398-appb-000154
Figure PCTCN2022118398-appb-000154
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000155
Figure PCTCN2022118398-appb-000155
步骤1：2-(3-溴-5-氯苯基)乙酸(59A)的制备Step 1: Preparation of 2-(3-bromo-5-chlorophenyl)acetic acid (59A)
将2-(3-溴-5-氯苯基)乙腈(1g,4.33mmol)溶解入乙醇(10mL)中，加入4M氢氧化钠水溶液(3mL)，加热至回流7小时，冷却至室温，蒸除乙醇，加入浓盐酸调节pH至1，乙酸乙酯(50mL x 3)萃取,合并有机相，无水硫酸钠干燥，过滤浓缩得粗品标题化合物59A(972mg)，直接用于下步反应。Dissolve 2-(3-bromo-5-chlorophenyl)acetonitrile (1g, 4.33mmol) in ethanol (10mL), add 4M aqueous sodium hydroxide solution (3mL), heat to reflux for 7 hours, cool to room temperature, evaporate Remove ethanol, add concentrated hydrochloric acid to adjust the pH to 1, extract with ethyl acetate (50mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude title compound 59A (972mg), which is directly used in the next reaction.
MS m/z(ESI):247.0/249[M-H] -； MS m/z(ESI):247.0/249[MH] - ;
步骤2：2-(3-溴-5-氯苯基)乙酸乙酯(59B)的制备Step 2: Preparation of ethyl 2-(3-bromo-5-chlorophenyl)acetate (59B)
将2-(3-溴-5-氯苯基)乙酸(972mg,3.89mmol)溶解入乙醇(10mL)中，加入氯化亚砜(46mg,0.39mmol)，加热至回流1小时，冷却至室温，蒸除乙醇，加入乙酸乙酯(50mL)，饱和碳酸氢钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤浓缩得粗品标题化合物59B(1.29g)，直接用于下步反应。Dissolve 2-(3-bromo-5-chlorophenyl)acetic acid (972mg, 3.89mmol) in ethanol (10mL), add thionyl chloride (46mg, 0.39mmol), heat to reflux for 1 hour, and cool to room temperature , evaporated to remove ethanol, added ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude title compound 59B (1.29 g), which was directly used in the next reaction.
MS m/z(ESI):331/333[M+H] +； MS m/z(ESI):331/333[M+H] + ;
步骤3至步骤6：3-(1-(3-溴-5-氯苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(59G)的制备Step 3 to Step 6: 3-(1-(3-Bromo-5-chlorophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (59G) preparation of
参照实施例4步骤1至步骤4的合成方法，不同的是将54A替换为59B(1.29g,3.89mmol)，同法制得标题化合物59G(113mg)。Referring to the synthesis method of Step 1 to Step 4 of Example 4, except that 54A was replaced by 59B (1.29 g, 3.89 mmol), the title compound 59G (113 mg) was obtained in the same way.
MS m/z(ESI):340/342[M+H] +； MS m/z(ESI):340/342[M+H] + ;
步骤7：(S)-1-(3-氯-5-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-6-氟-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物59)的制备Step 7: (S)-1-(3-chloro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)benzene base)-6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 59)
参照实施例4步骤5的合成方法，不同的是将54E替换为59G(11.38mg,33.44μmol)，与3D(10mg,33.44μmol)反应，最终得到标题化合物59(11mg)。Referring to the synthesis method in Step 5 of Example 4, the difference was that 54E was replaced by 59G (11.38 mg, 33.44 μmol) and reacted with 3D (10 mg, 33.44 μmol) to finally obtain the title compound 59 (11 mg).
MS m/z(ESI):558.24[M+H] +； MS m/z(ESI):558.24[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ8.20(d,J＝7.9Hz,2H),7.65(m,1H),7.52(s,1H),7.40–7.22(m,3H),6.93(d,J＝7.8Hz,1H),3.79(s,2H),3.33(s,3H),2.96-2.85(m,2H),2.80-2.70(m,2H),2.60-2.55(m,2H),2.35-2.25(m,1H),2.00-1.90(m,1H),1.70–1.47(m,5H),1.1-1.0(m,3H),0.85-0.75(m,4H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.20 (d, J=7.9Hz, 2H), 7.65 (m, 1H), 7.52 (s, 1H), 7.40–7.22 (m, 3H), 6.93 ( d,J＝7.8Hz,1H),3.79(s,2H),3.33(s,3H),2.96-2.85(m,2H),2.80-2.70(m,2H),2.60-2.55(m,2H) ,2.35-2.25(m,1H),2.00-1.90(m,1H),1.70–1.47(m,5H),1.1-1.0(m,3H),0.85-0.75(m,4H).
实施例10：(S)-3-(6-氟-4-((3-甲基哌啶-1-基)甲基)-2-羰基苯并[cd]吲哚-1(2H)-基)-5-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯甲腈(化合物60)的制备Example 10: (S)-3-(6-fluoro-4-((3-methylpiperidin-1-yl)methyl)-2-carbonylbenzo[cd]indole-1(2H)- Preparation of -5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)benzonitrile (compound 60)
Figure PCTCN2022118398-appb-000156
Figure PCTCN2022118398-appb-000156
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000157
Figure PCTCN2022118398-appb-000157
步骤1：3-氯-5-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯甲腈(60A)的制备Step 1: Preparation of 3-chloro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)benzonitrile (60A)
将3-(1-(3-溴-5-氯苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(30mg,88.23μmol)，Pd(PPh 3) 4(5mg,4.41μmol)和Zn(CN) 2(20.65mg,176.46μmol)称入反应管中，置换氩气，加入无水DMF(1mL)加热到130℃，反应三小时，冷却至室温，反相柱(柱子：Welch Xtimate C18柱长150mm，内径30mm,粒径5μm；流动相A：水(含0.225％NH 3),流动相B：乙腈；梯度：流动相B从5％到95％用时18分钟)纯化，收集产物冻干得标题产物60A(12.6mg)。 3-(1-(3-bromo-5-chlorophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (30mg, 88.23μmol), Pd (PPh 3 ) 4 (5mg, 4.41μmol) and Zn(CN) 2 (20.65mg, 176.46μmol) were weighed into a reaction tube, replaced with argon, added anhydrous DMF (1mL) and heated to 130°C, and reacted for three hours. Cool to room temperature, reverse-phase column (column: Welch Xtimate C18 column length 150mm, inner diameter 30mm, particle size 5μm; mobile phase A: water (containing 0.225% NH 3 ), mobile phase B: acetonitrile; gradient: mobile phase B from 5 % to 95% in 18 minutes) and the collected product was lyophilized to give the title product 60A (12.6 mg).
MS m/z(ESI):287.1[M+H] +； MS m/z(ESI):287.1[M+H] + ;
步骤2：(S)-3-(6-氟-4-((3-甲基哌啶-1-基)甲基)-2-羰基苯并[cd]吲哚-1(2H)-基)-5-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯甲腈(化合物60)的制备Step 2: (S)-3-(6-fluoro-4-((3-methylpiperidin-1-yl)methyl)-2-carbonylbenzo[cd]indol-1(2H)-yl Preparation of )-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)benzonitrile (compound 60)
参照实施例4步骤5的合成方法，不同的是将54E替换为60A(9.59mg,33.44μmol)，与3D(10mg,33.44μmol)反应，最终得到标题化合物60(4.7mg)。Referring to the synthesis method in Step 5 of Example 4, the difference is that 54E was replaced by 60A (9.59 mg, 33.44 μmol) and reacted with 3D (10 mg, 33.44 μmol) to finally obtain the title compound 60 (4.7 mg).
MS m/z(ESI):549.7[M+H] +； MS m/z(ESI):549.7[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ8.33(s,1H),8.21(d,J＝6.4Hz,2H),8.03(s,1H),7.89(s,1H),7.84(s,1H),7.38-7.28(m,1H),6.99(d,J＝8.1Hz,1H),3.79(s,2H),3.27(s,3H),2.98-2.90(m,2H),2.78-2.70(m,2H),2.60-2.55(m,2H),2.35-2.33(m,1H),2.00-1.90(m,1H),1.67–1.46(m,5H),1.08(s,3H),0.88-0.70(m,4H). 1 H NMR (400MHz, DMSO-d 6 )δ8.33(s, 1H), 8.21(d, J=6.4Hz, 2H), 8.03(s, 1H), 7.89(s, 1H), 7.84(s, 1H),7.38-7.28(m,1H),6.99(d,J＝8.1Hz,1H),3.79(s,2H),3.27(s,3H),2.98-2.90(m,2H),2.78-2.70 (m,2H),2.60-2.55(m,2H),2.35-2.33(m,1H),2.00-1.90(m,1H),1.67–1.46(m,5H),1.08(s,3H),0.88 -0.70(m,4H).
实施例11：顺式-6-氟-1-(3-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-(((1-甲基环丁基)氨基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物61)的制备Example 11: cis-6-fluoro-1-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl )cyclobutyl)phenyl)-4-(((1-methylcyclobutyl)amino)methyl)benzo[cd]indol-2(1H)-one (compound 61)
Figure PCTCN2022118398-appb-000158
Figure PCTCN2022118398-appb-000158
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000159
Figure PCTCN2022118398-appb-000159
步骤1：顺式-3-(1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三氮唑(1F-P1)的制备Step 1: cis-3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (1F-P1) preparation
将化合物1F(2g,6.54mmol)进行制备分离纯化(柱子：Welch Xtimate C18柱长150mm，内径30mm,粒径5μm；流动相A：水(含0.225％NH 3),流动相B：乙腈；梯度：流动相B从5％到95％用时18分钟)，得标题化合物1F-P1(610mg)。 Compound 1F (2g, 6.54mmol) was prepared, separated and purified (column: Welch Xtimate C18 column length 150mm, inner diameter 30mm, particle size 5μm; mobile phase A: water (containing 0.225% NH 3 ), mobile phase B: acetonitrile; gradient : mobile phase B from 5% to 95% in 18 minutes), the title compound 1F-P1 (610 mg) was obtained.
MS m/z(ESI):305.7,307.7[M+H] +； MS m/z(ESI):305.7,307.7[M+H] + ;
1H NMR(400MHz,CDCl 3)δ7.97(s,1H),7.54-7.51(m,1H),7.41-7.37(m,1H),7.25-7.18(m,2H),3.18(s,3H),2.85-2.75(m,2H),2.70-2.58(m,3H),1.13(d,J＝4.0Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ7.97(s,1H),7.54-7.51(m,1H),7.41-7.37(m,1H),7.25-7.18(m,2H),3.18(s,3H ),2.85-2.75(m,2H),2.70-2.58(m,3H),1.13(d,J＝4.0Hz,3H).
步骤2至步骤3：6-氟-4-(((1-甲基环丁基)氨基)甲基)苯并[cd]吲哚-2(1H)-酮(61B)的制备Step 2 to Step 3: Preparation of 6-fluoro-4-(((1-methylcyclobutyl)amino)methyl)benzo[cd]indol-2(1H)-one (61B)
参照实施例3步骤1和步骤3的合成方法，不同的是将3A替换为1-甲基环丁烷-1-胺盐酸(100mg，822.37μmol)，经两步反应，同法制得标题化合物61B(15mg)。Referring to the synthesis method of Step 1 and Step 3 of Example 3, the difference is that 3A is replaced by 1-methylcyclobutane-1-amine hydrochloride (100 mg, 822.37 μmol), and the title compound 61B is prepared in the same way through two-step reactions (15 mg).
MS m/z(ESI):285.1[M+H] +； MS m/z(ESI):285.1[M+H] + ;
步骤4：顺式-6-氟-1-(3-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-(((1-甲基环丁基)氨基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物61)的制备Step 4: cis-6-fluoro-1-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) Preparation of cyclobutyl)phenyl)-4-(((1-methylcyclobutyl)amino)methyl)benzo[cd]indol-2(1H)-one (compound 61)
参照实施例4步骤5的合成方法，不同的是将54E替换为1F-P1(5.4mg,17.59μmol)，3D替换为61B(5mg,17.59μmol)，同法制得标题化合物61(1.2mg)。Referring to the synthesis method in Step 5 of Example 4, except that 54E was replaced by 1F-P1 (5.4 mg, 17.59 μmol) and 3D was replaced by 61B (5 mg, 17.59 μmol), the title compound 61 (1.2 mg) was obtained in the same way.
MS m/z(ESI):510.3[M+H] +； MS m/z(ESI):510.3[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ8.34–8.23(m,3H),7.61–7.46(m,3H),7.38(d,J＝7.8Hz,1H),7.30-7.25(m,1H),6.9-6.8(d,J＝7.8Hz,1H),3.97(s,2H),3.25(s,3H),3.20-3.15(m,1H),2.95-2.85(m,2H),2.60-2.55(m,2H),2.28-2.20(m,1H),2.05-1.95(m,2H),1.76–1.61(m,4H),1.26(s,3H),1.08(d,J＝4.7Hz,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.34–8.23(m,3H),7.61–7.46(m,3H),7.38(d,J=7.8Hz,1H),7.30-7.25(m,1H ),6.9-6.8(d,J＝7.8Hz,1H),3.97(s,2H),3.25(s,3H),3.20-3.15(m,1H),2.95-2.85(m,2H),2.60- 2.55(m,2H),2.28-2.20(m,1H),2.05-1.95(m,2H),1.76–1.61(m,4H),1.26(s,3H),1.08(d,J＝4.7Hz, 3H).
实施例12：1-(3-((S)-环丙基(4-甲基-4H-1,2,4-三唑-3-基)甲基)苯基)-6-氟-4-(((S)-3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮和1-(3-((R)-环丙基(4-甲基-4H-1,2,4-三唑-3-基)甲基)苯基)-6-氟-4-(((S)-3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物62、化合物63)的制备Example 12: 1-(3-((S)-cyclopropyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-6-fluoro-4 -(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one and 1-(3-((R)-cyclopropyl( 4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-6-fluoro-4-(((S)-3-methylpiperidin-1-yl) Preparation of methyl)benzo[cd]indol-2(1H)-one (compound 62, compound 63)
Figure PCTCN2022118398-appb-000160
Figure PCTCN2022118398-appb-000160
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000161
Figure PCTCN2022118398-appb-000161
步骤1：2-(3-溴苯基)-2-重氮乙酸甲酯(62A)的制备Step 1: Preparation of methyl 2-(3-bromophenyl)-2-diazoacetate (62A)
将2-(3-溴苯基)乙酸甲酯(5g，21.83mmol)和1,8-二氮杂二环[5.4.0]十一碳-7-烯(9.97g，65.48mmol，9.77mL)加入乙腈(49.98mL)中，降温到0℃，在氮气保护下向反应液中滴加将4-乙酰氨基苯磺酰叠氮(6.29g，26.19mmol)。将反应液升温至25℃并在氮气保护下搅拌3小时。反应结束后，加入饱和氯化铵水溶液(20mL)并用乙酸乙酯萃取3次。萃取所得有机相用无水硫酸钠干燥，过滤，减压蒸馏得到粗产品，粗产品经过正相柱层析(石油醚：乙酸乙酯＝10:1)纯化，得到固体标题化合物62A(5.5g)。Methyl 2-(3-bromophenyl)acetate (5g, 21.83mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (9.97g, 65.48mmol, 9.77mL ) was added into acetonitrile (49.98mL), cooled to 0°C, and 4-acetamidobenzenesulfonyl azide (6.29g, 26.19mmol) was added dropwise to the reaction solution under nitrogen protection. The reaction solution was warmed up to 25°C and stirred for 3 hours under nitrogen protection. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added and extracted 3 times with ethyl acetate. The extracted organic phase was dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product, which was purified by normal phase column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the solid title compound 62A (5.5 g ).
MS m/z:254.8,256.8[M+H] +. MS m/z:254.8,256.8[M+H] + .
1H NMR(400MHz，DMSO-d 6)δ7.77(s,1H)，7.45(d，J＝7.0Hz,1H)，7.42-7.34(m,2H)，3.81(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.77(s, 1H), 7.45(d, J=7.0Hz, 1H), 7.42-7.34(m, 2H), 3.81(s, 3H).
步骤2：2-(3-溴苯基)-2-环丙基乙酸甲酯(62B)的制备Step 2: Preparation of methyl 2-(3-bromophenyl)-2-cyclopropylacetate (62B)
往二氯甲烷(20mL)中加入环丙基硼酸(1.35g，15.68mmol)、2-(3-溴苯基)-2-重氮乙酸甲酯(2g，7.84mmol)和碳酸钠(831.5mg，7.84mmol)，置换三次氮气，在光反应仪(450nm)25℃下搅拌12小时。反应结束后，减压蒸馏得到粗产品，粗产品经过正相柱层析(石油醚：乙酸乙酯＝10:1)纯化，得到固体标题化合物62B(1.2g)。To dichloromethane (20 mL) was added cyclopropylboronic acid (1.35 g, 15.68 mmol), methyl 2-(3-bromophenyl)-2-diazoacetate (2 g, 7.84 mmol) and sodium carbonate (831.5 mg , 7.84mmol), nitrogen was replaced three times, and stirred at 25°C for 12 hours in a photoreactor (450nm). After the reaction, the crude product was obtained by distillation under reduced pressure. The crude product was purified by normal phase column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound 62B (1.2 g) as a solid.
MS m/z(ESI):269.01[M+H] +&271.01[M+H] +. MS m/z(ESI):269.01[M+H] + &271.01[M+H] + .
步骤3：2-(3-溴苯基)-2-环丙基乙酸(62C)的制备Step 3: Preparation of 2-(3-bromophenyl)-2-cyclopropylacetic acid (62C)
将2-(3-溴苯基)-2-环丙基乙酸甲酯(480mg，1.78mmol)加到水(5mL)和四氢呋喃(5mL)的混合液中，再加入氢氧化锂(299.34mg，7.13mmol)，室温下搅拌3小时。反应结束后，旋蒸除去四氢呋喃，用乙酸乙酯萃取3次，水相用1M的盐酸调pH到3～4，再用乙酸乙酯萃取3次，有机相减压浓缩至干得到固体标题化合物62C(215mg)。Add methyl 2-(3-bromophenyl)-2-cyclopropylacetate (480mg, 1.78mmol) to a mixture of water (5mL) and tetrahydrofuran (5mL), then add lithium hydroxide (299.34mg, 7.13 mmol), stirred at room temperature for 3 hours. After the reaction, THF was removed by rotary evaporation, extracted three times with ethyl acetate, the aqueous phase was adjusted to pH 3-4 with 1M hydrochloric acid, extracted three times with ethyl acetate, and the organic phase was concentrated to dryness under reduced pressure to obtain the title compound as a solid 62C (215 mg).
MS m/z(ESI):255.01[M+H] +&257.01[M+H] +. MS m/z(ESI):255.01[M+H] + &257.01[M+H] + .
步骤4：1-[(2-(3-溴苯基)-2-环丙基乙酰基)氨基]-3-甲基硫脲(62D)的制备Step 4: Preparation of 1-[(2-(3-bromophenyl)-2-cyclopropylacetyl)amino]-3-methylthiourea (62D)
向DMF(2mL)中加入DIPEA(519.28mg，4.02mmol，699.83μL)、2-(3-溴苯基)-2-环丙基乙酸(205mg，803.58μmol)、4-甲基氨基硫脲(211.27mg，2.01mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(460.09mg，1.21mmol)。在室温下搅拌6个小时。反应结束后，用水稀释，再用乙酸乙酯萃取3次。有机相用无水硫酸钠干燥，过滤，旋蒸得到粗产品。粗产品经过正相柱层析(石油醚：乙酸乙酯＝0:1)纯化，得到固体标题产物62D(0.11g)。To DMF (2 mL) was added DIPEA (519.28 mg, 4.02 mmol, 699.83 μL), 2-(3-bromophenyl)-2-cyclopropylacetic acid (205 mg, 803.58 μmol), 4-methylthiosemicarbazide ( 211.27 mg, 2.01 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (460.09 mg, 1.21 mmol). Stir at room temperature for 6 hours. After the reaction was completed, it was diluted with water and extracted 3 times with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain a crude product. The crude product was purified by normal phase column chromatography (petroleum ether: ethyl acetate = 0:1) to obtain the title product 62D as a solid (0.11 g).
MS m/z(ESI):342.02[M+H] +&344.02[M+H] +. MS m/z(ESI):342.02[M+H] + &344.02[M+H] + .
步骤5：5-[(3-溴苯基)环丙基甲基]-4-甲基-4H-1,2,4-三氮唑-3-硫醇(62E)的制备Step 5: Preparation of 5-[(3-bromophenyl)cyclopropylmethyl]-4-methyl-4H-1,2,4-triazole-3-thiol (62E)
将1-[(2-(3-溴苯基)-2-环丙基乙酰基)氨基]-3-甲基硫脲(110mg，321.40μmol)加入到氢氧化钠水溶液(1M，3mL)中。反应液在室温下搅拌12小时。反应结束后，用1M的盐酸调pH到3～4。用乙酸乙酯萃取3次，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸得到固体标题产物62E(77mg)。1-[(2-(3-Bromophenyl)-2-cyclopropylacetyl)amino]-3-methylthiourea (110 mg, 321.40 μmol) was added to aqueous sodium hydroxide (1M, 3 mL) . The reaction was stirred at room temperature for 12 hours. After the reaction, adjust the pH to 3-4 with 1M hydrochloric acid. Extracted with ethyl acetate three times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the title product 62E (77 mg) as a solid.
步骤6：3-[(3-溴苯基)环丙基甲基]-4-甲基-4H-1,2,4-三氮唑(62F)的制备Step 6: Preparation of 3-[(3-bromophenyl)cyclopropylmethyl]-4-methyl-4H-1,2,4-triazole (62F)
将5-[(3-溴苯基)环丙基甲基]-4-甲基-4H-1,2,4-三氮唑-3-硫醇(77mg，237.48μmol)加入到二氯甲烷(2mL)和醋酸(285.22mg，4.75mmol)中，冷却至0℃。再逐滴加入双氧水(40.39mg，391.84μmol，33％纯度)，恢复至室温下搅拌12小时。反应结束后，加入饱和亚硫酸氢钠水溶液和饱和碳酸氢钠水溶液，调pH到8左右。用二氯甲烷萃取，有机相用饱和亚硫酸氢钠洗，无水硫酸钠干燥，过滤，减压浓缩至干得到固体标题产物62F(62mg)。5-[(3-Bromophenyl)cyclopropylmethyl]-4-methyl-4H-1,2,4-triazole-3-thiol (77 mg, 237.48 μmol) was added to dichloromethane (2mL) and acetic acid (285.22mg, 4.75mmol), and cooled to 0°C. Hydrogen peroxide (40.39 mg, 391.84 μmol, 33% purity) was added dropwise, returned to room temperature and stirred for 12 hours. After the reaction, add saturated aqueous sodium bisulfite and saturated aqueous sodium bicarbonate to adjust the pH to about 8. Extracted with dichloromethane, the organic phase was washed with saturated sodium bisulfite, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title product 62F as a solid (62 mg).
步骤7：(R)-((3-溴苯基)环丙基甲基)-4-甲基-4H-1,2,4-三唑和(S)-((3-溴苯基)环丙基甲基)-4-甲基-4H-1,2,4-三唑的制备Step 7: (R)-((3-bromophenyl)cyclopropylmethyl)-4-methyl-4H-1,2,4-triazole and (S)-((3-bromophenyl) Preparation of cyclopropylmethyl)-4-methyl-4H-1,2,4-triazole
将((3-溴苯基)环丙基甲基)-4-甲基-4H-1,2,4-三唑(97mg)经过超临界流体色谱纯化分离(柱子：DAICEL CHIRALPAK IC柱长250mm，内径30mm,粒径10μm；流动相A：甲醇(含0.1％氨水)，流动相B：超临界二氧化碳；梯度：流动相B从35％到35％；流速：80mL/min；)得到淡黄色油状标题化合物(62F-P1，42.8mg)与无色油状标题化合物(62F-P2，41.4mg)。然后通过以下手性HPLC分析方法分别对两标题产物进行进一步分析。((3-bromophenyl)cyclopropylmethyl)-4-methyl-4H-1,2,4-triazole (97mg) was purified and separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK IC column length 250mm , inner diameter 30mm, particle diameter 10μm; mobile phase A: methanol (containing 0.1% ammonia water), mobile phase B: supercritical carbon dioxide; gradient: mobile phase B from 35% to 35%; flow rate: 80mL/min;) to obtain light yellow Oily title compound (62F-P1, 42.8 mg) and colorless oily title compound (62F-P2, 41.4 mg). The two title products were then further analyzed separately by the following chiral HPLC analysis method.
手性HPLC分析方法：Chiral HPLC analysis method:
色谱柱：Chiralpak IC-3柱长100mm，内径4.6mm，粒径3μm；流动相：A:CO 2B:甲醇(含0.05％DEA)；梯度：流动相B从5％至40％用时4分钟，并保持40％洗脱0.5分钟，然后用5％流动相B洗脱1.5分钟；流速：2.8mL/min；柱温：35℃；ABPR：1500psi Chromatographic column: Chiralpak IC-3 column length 100mm, inner diameter 4.6mm, particle size 3μm; mobile phase: A: CO 2 B: methanol (containing 0.05% DEA); gradient: mobile phase B from 5% to 40% takes 4 minutes , and maintain 40% elution for 0.5 minutes, then elution with 5% mobile phase B for 1.5 minutes; flow rate: 2.8mL/min; column temperature: 35 ° C; ABPR: 1500psi
62F-P1:62F-P1:
手性HPLC出峰时间为3.96min；Chiral HPLC peak time is 3.96min;
MS m/z(ESI):293.9/291.9[M+H] +； MS m/z(ESI):293.9/291.9[M+H] + ;
1H NMR(400MHz,CDCl 3)δ8.04(s,1H),7.42-7.37(m,2H),7.22-7.13(m,2H),3.34(s,3H),3.30(d,J＝9.6Hz,1H),1.73-1.62(m,1H),0.83-0.63(m,2H),0.38-0.28(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.04(s, 1H), 7.42-7.37(m, 2H), 7.22-7.13(m, 2H), 3.34(s, 3H), 3.30(d, J=9.6 Hz,1H),1.73-1.62(m,1H),0.83-0.63(m,2H),0.38-0.28(m,2H).
62F-P2:62F-P2:
手性HPLC出峰时间为4.48min；Chiral HPLC peak time is 4.48min;
MS m/z(ESI):293.9/291.9[M+H] +； MS m/z(ESI):293.9/291.9[M+H] + ;
1H NMR(400MHz,CDCl 3)δ8.04(s,1H),7.42-7.37(m,2H),7.21-7.12(m,2H),3.34(s,3H),3.30(d,J＝9.6Hz,1H),1.74-1.61(m,1H),0.82-0.64(m,2H),0.38-0.30(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.04(s, 1H), 7.42-7.37(m, 2H), 7.21-7.12(m, 2H), 3.34(s, 3H), 3.30(d, J=9.6 Hz,1H),1.74-1.61(m,1H),0.82-0.64(m,2H),0.38-0.30(m,2H).
步骤8：1-(3-((S)-环丙基(4-甲基-4H-1,2,4-三唑-3-基)甲基)苯基)-6-氟-4-(((S)-3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮与1-(3-((R)-环丙基(4-甲基-4H-1,2,4-三唑-3-基)甲基)苯基)-6-氟-4-(((S)-3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物62、化合物63)的制备Step 8: 1-(3-((S)-Cyclopropyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-6-fluoro-4- (((S)-3-Methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one and 1-(3-((R)-cyclopropyl(4 -Methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-6-fluoro-4-(((S)-3-methylpiperidin-1-yl)methyl base) benzo[cd]indol-2(1H)-one (compound 62, compound 63) preparation
参照实施例4步骤5的合成方法，不同的是将54E替换为62F-P1(4.9mg,16.72μmol)，与3D(5mg,16.72μmol)反应，最终得到标题化合物62(6.4mg)。Referring to the synthesis method in Step 5 of Example 4, the difference was that 54E was replaced by 62F-P1 (4.9 mg, 16.72 μmol) and reacted with 3D (5 mg, 16.72 μmol) to finally obtain the title compound 62 (6.4 mg).
MS m/z(ESI):510.3[M+H] +； MS m/z(ESI):510.3[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ8.36(s,1H),8.19(d,J＝6.4Hz,2H),7.60–7.46(m,3H),7.32(d,J＝16.5Hz,2H),6.92(d,J＝7.9Hz,1H),3.78(s,2H),3.68(d,J＝9.7Hz,1H),3.45(s,3H),2.76(t,J＝11.7Hz,2H),1.96(s,1H),1.72–1.48(m,6H),0.86–0.79(m,4H),0.7-0.5(m,2H),0.4-0.3(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.36(s, 1H), 8.19(d, J=6.4Hz, 2H), 7.60–7.46(m, 3H), 7.32(d, J=16.5Hz, 2H), 6.92(d, J=7.9Hz, 1H), 3.78(s, 2H), 3.68(d, J=9.7Hz, 1H), 3.45(s, 3H), 2.76(t, J=11.7Hz, 2H),1.96(s,1H),1.72–1.48(m,6H),0.86–0.79(m,4H),0.7-0.5(m,2H),0.4-0.3(m,2H).
参照实施例4步骤5的合成方法，不同的是将54E替换为62F-P2(4.9mg,16.72μmol)，与3D(5mg,16.72μmol)反应，最终得到标题化合物63(6.5mg)。Referring to the synthesis method in Step 5 of Example 4, the difference was that 54E was replaced by 62F-P2 (4.9 mg, 16.72 μmol) and reacted with 3D (5 mg, 16.72 μmol) to finally obtain the title compound 63 (6.5 mg).
MS m/z(ESI):510.3[M+H] +； MS m/z(ESI):510.3[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ8.36(s,1H),8.19(d,J＝6.4Hz,2H),7.60–7.46(m,3H),7.32(d,J＝16.5Hz,2H),6.92(d,J＝7.9Hz,1H),3.78(s,2H),3.68(d,J＝9.7Hz,1H),3.45(s,3H),2.76(t,J＝11.7Hz,2H),1.96(s,1H),1.72–1.48(m,6H),0.86–0.79(m,4H),0.7-0.5(m,2H),0.4-0.3(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.36(s, 1H), 8.19(d, J=6.4Hz, 2H), 7.60–7.46(m, 3H), 7.32(d, J=16.5Hz, 2H), 6.92(d, J=7.9Hz, 1H), 3.78(s, 2H), 3.68(d, J=9.7Hz, 1H), 3.45(s, 3H), 2.76(t, J=11.7Hz, 2H),1.96(s,1H),1.72–1.48(m,6H),0.86–0.79(m,4H),0.7-0.5(m,2H),0.4-0.3(m,2H).
实施例13：反式-6-氟-1-(3-((1R,3S)-3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-(((S)-3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物64)的制备Example 13: trans-6-fluoro-1-(3-((1R,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl) Preparation of cyclobutyl)phenyl)-4-(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 64)
Figure PCTCN2022118398-appb-000162
Figure PCTCN2022118398-appb-000162
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000163
Figure PCTCN2022118398-appb-000163
步骤1：反式-3-(1-(3-溴苯基)-3-氟环丁基)-4-甲基-4H-1,2,4-三唑(64A)的制备Step 1: Preparation of trans-3-(1-(3-bromophenyl)-3-fluorocyclobutyl)-4-methyl-4H-1,2,4-triazole (64A)
顺式-3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁醇(100mg,324.49μmol)溶解入二氯甲烷(5mL)，冷却至0℃，氩气环境下，滴加二乙胺基三氟化硫(78.46mg,486.74μmol)，搅拌1小时，饱和NaHCO 3水溶液(1mL)淬灭，浓缩，反相柱纯化(色谱柱：
Figure PCTCN2022118398-appb-000164
快速硅胶柱；流动相：乙腈/水＝7：3)得标题化合物64A(51mg)。 cis-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanol (100 mg, 324.49 μmol) was dissolved in dichloromethane (5mL), cooled to 0°C, under argon atmosphere, diethylaminosulfur trifluoride (78.46mg, 486.74μmol) was added dropwise, stirred for 1 hour, quenched with saturated NaHCO 3 aqueous solution (1mL), concentrated, reversed phase Column purification (chromatographic column:
Figure PCTCN2022118398-appb-000164
Flash silica gel column; mobile phase: acetonitrile/water=7:3) to obtain the title compound 64A (51 mg).
MS m/z(ESI):310.03/312.03[M+H] +. MS m/z(ESI):310.03/312.03[M+H] + .
步骤2：反式-6-氟-1-(3-(反式-3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-(((S)-3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物64)的制备Step 2: trans-6-fluoro-1-(3-(trans-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl) Preparation of phenyl)-4-(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 64)
参照实施例4步骤5的合成方法，不同的是将54E替换为64A(5.2mg,16.72μmol)，与3D(5mg,16.72μmol)反应，最终得到标题化合物64(8.5mg)。Referring to the synthesis method in Step 5 of Example 4, the difference is that 54E was replaced by 64A (5.2 mg, 16.72 μmol) and reacted with 3D (5 mg, 16.72 μmol) to finally obtain the title compound 64 (8.5 mg).
MS m/z(ESI):528.3[M+H] +； MS m/z(ESI):528.3[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ8.45(s,1H),8.24(s,2H),7.63(t,J＝7.8Hz,1H),7.54(d,J＝8.0Hz,1H),7.47(s,1H),7.40–7.28(m,2H),6.94(d,J＝7.7Hz,1H),5.25-4.95(m,1H),3.90-3.70(m,2H),3.60-3.50(m,2H),3.33(s,3H),3.0-2.8(m,4H),2.09–1.96(m,2H),1.70-1.50(m,4H),0.88-0.79(t,J＝7.8Hz,4H). 1 H NMR (400MHz,DMSO-d 6 )δ8.45(s,1H),8.24(s,2H),7.63(t,J=7.8Hz,1H),7.54(d,J=8.0Hz,1H) ,7.47(s,1H),7.40–7.28(m,2H),6.94(d,J＝7.7Hz,1H),5.25-4.95(m,1H),3.90-3.70(m,2H),3.60-3.50 (m,2H),3.33(s,3H),3.0-2.8(m,4H),2.09–1.96(m,2H),1.70-1.50(m,4H),0.88-0.79(t,J＝7.8Hz ,4H).
实施例14(S)-1-(3-(3,3-二氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-6-氟-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物65)的制备Example 14 (S)-1-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl) - Preparation of 6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 65)
Figure PCTCN2022118398-appb-000165
Figure PCTCN2022118398-appb-000165
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000166
Figure PCTCN2022118398-appb-000166
步骤1：3-(1-(3-溴苯基)-3,3-二氟环丁基)-4-甲基-4H-1,2,4-三唑(65A)的制备Step 1: Preparation of 3-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole (65A)
在冰浴下，将三乙胺氟化氢(663.0mg,3.92mmol)加入二氯甲烷(5.0mL)中，置换4次氩气气体保护，然后在氩气流的吹扫下向溶液中依次加入(二乙氨基)二氟锍鎓四氟硼酸盐(897.5mg,3.92mmol)和3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1-酮(400.0mg,1.31mmol)。然后将反应液缓慢升温至室温并搅拌2.0小时。反应结束后，将反应液冷却至0℃，加入饱和氯化铵水溶液淬灭反应(60mL)，二氯甲烷萃取(50mL×3)。有机相用无水硫酸钠干燥，过滤并减压浓缩至干得到粗产品。粗品用反相柱层析(色谱柱：
Figure PCTCN2022118398-appb-000167
快速硅胶柱；流动相：乙腈/水＝60：40)，得到标题化合物65A(20.0mg)。 Under ice bath, triethylamine hydrogen fluoride (663.0mg, 3.92mmol) was added into dichloromethane (5.0mL), replaced by argon gas protection for 4 times, and then added to the solution successively under the purging of argon flow (two Ethylamino) difluorosulfonium tetrafluoroborate (897.5mg, 3.92mmol) and 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazole-3 -yl)cyclobutan-1-one (400.0 mg, 1.31 mmol). Then the reaction solution was slowly warmed to room temperature and stirred for 2.0 hours. After the reaction, the reaction solution was cooled to 0° C., quenched by adding saturated ammonium chloride aqueous solution (60 mL), and extracted with dichloromethane (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was subjected to reverse phase column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000167
Flash silica gel column; mobile phase: acetonitrile/water=60:40) to obtain the title compound 65A (20.0 mg).
MS m/z(ESI):328.0/330.0[M+H] +。 MS m/z (ESI): 328.0/330.0 [M+H] + .
步骤2：(S)-1-(3-(3,3-二氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-6-氟-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物65)的制备Step 2: (S)-1-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl) - Preparation of 6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (compound 65)
在氩气氛围下，向3-(1-(3-溴苯基)-3,3-二氟环丁基)-4-甲基-4H-1,2,4-三唑(10.0mg,30.47μmol)的N,N-二甲基甲酰胺(1.0mL)溶液中依次加入反式-N,N'-二甲基1,2-环己二胺(4.77mg,33.5μmol)、碘化亚铜(3.19mg,16.76μmol)、碳酸钾(4.63mg,33.52μmol)和(S)-6-氟-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(11.0mg,33.52μmol)，所得混合物在氮气保护下加热至100℃，搅拌2.0小时。反应完毕后冷却至室温，过滤，减压浓缩得到的粗产品经制备高效液相色谱柱(柱子：Welch Xtimate C18柱长150mm，内径30mm,粒径5μm；流动相A：水(含0.225％NH 3),流动相B：乙腈；梯度：流动相B从5％到95％用时18分钟)分离，得标题化合物65(4.62mg，收率：25.26％)。 Under argon atmosphere, 3-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole (10.0mg, 30.47μmol) of N,N-dimethylformamide (1.0mL) solution was sequentially added trans-N,N'-dimethyl 1,2-cyclohexanediamine (4.77mg, 33.5μmol), iodide Cuprous (3.19 mg, 16.76 μmol), potassium carbonate (4.63 mg, 33.52 μmol) and (S)-6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd ] indole-2(1H)-one (11.0mg, 33.52μmol), the resulting mixture was heated to 100°C under nitrogen protection, and stirred for 2.0 hours. After completion of the reaction, cool to room temperature, filter, and concentrate under reduced pressure to obtain the thick product through the preparation of a high performance liquid chromatography column (column: Welch Xtimate C18 column length 150mm, internal diameter 30mm, particle diameter 5 μ m; mobile phase A: water (containing 0.225% NH 3 ), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) separation to obtain the title compound 65 (4.62 mg, yield: 25.26%).
MS m/z(ESI):546.44[M+H] +； MS m/z(ESI):546.44[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ8.42(s,1H),8.18(d,J＝6.5Hz,2H),7.61(t,J＝7.8Hz,1H),7.54(d,J＝6.7Hz,2H),7.38–7.25(m,2H),6.94–6.86(m,1H),3.77(d,J＝5.7Hz,2H),3.71(d,J＝13.4Hz,1H),3.48(d,J＝12.9Hz,2H),2.75(t,J＝11.6Hz,2H),1.97(d,J＝11.1Hz,2H),1.62(t,J＝17.2Hz,4H),1.48(d,J＝12.9Hz,2H),0.85(d,J＝6.6Hz,1H),0.80(d,J＝6.0Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.42(s, 1H), 8.18(d, J=6.5Hz, 2H), 7.61(t, J=7.8Hz, 1H), 7.54(d, J= 6.7Hz, 2H), 7.38–7.25(m, 2H), 6.94–6.86(m, 1H), 3.77(d, J=5.7Hz, 2H), 3.71(d, J=13.4Hz, 1H), 3.48( d, J=12.9Hz, 2H), 2.75(t, J=11.6Hz, 2H), 1.97(d, J=11.1Hz, 2H), 1.62(t, J=17.2Hz, 4H), 1.48(d, J＝12.9Hz, 2H), 0.85(d, J＝6.6Hz, 1H), 0.80(d, J＝6.0Hz, 3H).
19F NMR(376MHz,DMSO-d 6)δ-86.72(t,J＝12.6Hz),-129.64(d,J＝11.9Hz). 19 F NMR (376MHz, DMSO-d 6 ) δ-86.72(t, J=12.6Hz), -129.64(d, J=11.9Hz).
实施例15 6-氟-1-(3-(2-(4-甲基-4H-1,2,4-三唑-3-基)氧杂环丁烷-2-基)苯基)-4-(((S)-3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物66)的制备Example 15 6-fluoro-1-(3-(2-(4-methyl-4H-1,2,4-triazol-3-yl)oxetane-2-yl)phenyl)- Preparation of 4-(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (Compound 66)
Figure PCTCN2022118398-appb-000168
Figure PCTCN2022118398-appb-000168
合成路线：synthetic route:
Figure PCTCN2022118398-appb-000169
Figure PCTCN2022118398-appb-000169
步骤1：2-(2-溴乙氧基)-2-(3-溴苯基)乙酸甲酯(66A)的制备Step 1: Preparation of methyl 2-(2-bromoethoxy)-2-(3-bromophenyl)acetate (66A)
将2-(3-溴苯基)-2-重氮基乙酸甲酯(1.0g,3.92mmol)溶于无水二氯甲烷(5.0mL)中。在0℃冰浴下，将溶液滴加到溶有溴乙醇(499mg,3.92mmol)和二聚醋酸铑(173mg,0.392mmol)的二氯甲烷(5.0mL)混合物中。反应液缓慢升温至室温并搅拌1小时。TLC监测反应完全后，过滤，滤液减压蒸馏得到粗产品。粗产品用反相柱层析(色谱柱：
Figure PCTCN2022118398-appb-000170
快速硅胶柱；流动相：乙腈/水＝55：45)，得到标题化合物66A(1.10g)。 Dissolve methyl 2-(3-bromophenyl)-2-diazoacetate (1.0 g, 3.92 mmol) in anhydrous dichloromethane (5.0 mL). The solution was added dropwise to a mixture of bromoethanol (499 mg, 3.92 mmol) and rhodium diacetate (173 mg, 0.392 mmol) in dichloromethane (5.0 mL) in an ice bath at 0°C. The reaction solution was slowly warmed to room temperature and stirred for 1 hour. After the reaction was complete as monitored by TLC, it was filtered, and the filtrate was distilled under reduced pressure to obtain a crude product. Crude product is used reverse-phase column chromatography (chromatographic column:
Figure PCTCN2022118398-appb-000170
Flash silica gel column; mobile phase: acetonitrile/water=55:45) to obtain the title compound 66A (1.10 g).
步骤2：2-(3-溴苯基)氧杂环丁烷-2-羧酸甲酯(66B)的制备Step 2: Preparation of methyl 2-(3-bromophenyl)oxetane-2-carboxylate (66B)
将NaH(102.0mg,2.84mmol)加入到封管中，置换4次氩气保护，在冰浴下，加入DMF(1.0mL)，然后将66A(1.0g,2.84mmol)溶于DMF(9.0mL)并缓慢滴加到封管中，滴加完毕后，将反应液缓慢升温至室温并搅拌2.0小时。反应结束后，将反应液滴加到冰水(100.0mL)中，用乙酸乙酯萃取(10.0mL×3)。有机相用无水硫酸钠干燥，减压蒸馏得到标题产物66B(695.0mg)，无需进一步纯化，直接用于下一步反应。NaH (102.0mg, 2.84mmol) was added to the sealed tube, and the argon protection was replaced 4 times. Under ice cooling, DMF (1.0mL) was added, and then 66A (1.0g, 2.84mmol) was dissolved in DMF (9.0mL ) and slowly added dropwise into the sealed tube, after the dropwise addition, the reaction solution was slowly warmed up to room temperature and stirred for 2.0 hours. After the reaction, the reaction solution was added dropwise into ice water (100.0 mL), and extracted with ethyl acetate (10.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain the title product 66B (695.0 mg), which was directly used in the next reaction without further purification.
步骤3：2-(3-溴苯基)氧杂环丁烷-2-羧酸(66C)的制备Step 3: Preparation of 2-(3-bromophenyl)oxetane-2-carboxylic acid (66C)
在室温下，将66B(695.0mg,2.56mmol)溶于乙腈(10.0mL)中，加入氢氧化钠的水溶液(10.0mL,3.0M),65℃下反应1.0小时。反应结束后，降温至0℃，加入饱和的柠檬酸水溶液并调节pH至3，用二氯甲烷萃取三次。有机相用无水硫酸钠进行干燥，过滤，并减压蒸馏得到标题粗产品66C(594.0mg)，无需进一步纯化，直接用于下一步反应。Dissolve 66B (695.0 mg, 2.56 mmol) in acetonitrile (10.0 mL) at room temperature, add aqueous sodium hydroxide solution (10.0 mL, 3.0 M), and react at 65°C for 1.0 hour. After the reaction, the temperature was lowered to 0° C., a saturated aqueous solution of citric acid was added to adjust the pH to 3, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the title crude product 66C (594.0 mg), which was directly used in the next reaction without further purification.
MS m/z(ESI):255.0/257.0[M-H] -。 MS m/z (ESI): 255.0/257.0 [MH] - .
步骤4：2-(2-(3-溴苯基)氧杂环丁烷-2-羰基)-N-甲基肼-1-硫代酰胺(66D)的制备Step 4: Preparation of 2-(2-(3-bromophenyl)oxetane-2-carbonyl)-N-methylhydrazine-1-thioamide (66D)
将66C(594.0mg,2.31mmol)、4-甲基氨基硫脲(292.0mg,2.77mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.05g,2.77mmol)、磷酸钾(1.05g,2.77mmol)和DIPEA(896.0mg,6.93mmol,1.21mL)加入到DMF(6.0mL)中，室温下反应1.0小时。反应结束后，加入水(60.0mL)并用二氯甲烷(6.0mL×3)萃取。萃取所得有机相用无水硫酸钠干燥，过滤，减压蒸馏得到标题产物66D(720.0m)，无需进一步纯化，直接用于下一步反应。66C (594.0mg, 2.31mmol), 4-methylthiosemicarbazide (292.0mg, 2.77mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (1.05g, 2.77mmol), potassium phosphate (1.05g, 2.77mmol) and DIPEA (896.0mg, 6.93mmol, 1.21mL) were added to DMF (6.0mL) and reacted at room temperature for 1.0 hour . After the reaction was completed, water (60.0 mL) was added and extracted with dichloromethane (6.0 mL×3). The extracted organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the title product 66D (720.0m), which was directly used in the next reaction without further purification.
MS m/z(ESI):344.0/346.0[M+H] +。 MS m/z (ESI): 344.0/346.0 [M+H] + .
步骤5：5-(2-(3-溴苯基)氧杂环丁烷-2-基)-4-甲基-4H-1,2,4-三唑-3-硫醇(66E)的制备Step 5: 5-(2-(3-Bromophenyl)oxetan-2-yl)-4-methyl-4H-1,2,4-triazole-3-thiol (66E) preparation
将66D(720.0mg,2.09mmol)加入氢氧化钠的水溶液(10.0mL,3.0M)中，反应在80℃下反应1.0小时。反应结束后，将反应降温至0℃，加入饱和的柠檬酸水溶液并调节pH至酸性，用二氯甲烷萃取三次。萃取所得有机相用无水硫酸钠干燥，过滤，减压蒸馏得到标题产物66E(614.0mg)，无需进一步纯化，直接用于下一步反应。66D (720.0 mg, 2.09 mmol) was added into an aqueous solution of sodium hydroxide (10.0 mL, 3.0 M), and the reaction was carried out at 80° C. for 1.0 hour. After the reaction was completed, the temperature of the reaction was lowered to 0° C., a saturated aqueous solution of citric acid was added to adjust the pH to acidic, and the mixture was extracted three times with dichloromethane. The extracted organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the title product 66E (614.0 mg), which was directly used in the next reaction without further purification.
MS m/z(ESI):326.0/328.0[M+H] +。 MS m/z (ESI): 326.0/328.0 [M+H] + .
步骤6：3-(2-(3-溴苯基)氧杂环丁烷-2-基)-4-甲基-4H-1,2,4-三唑(66F)的制备Step 6: Preparation of 3-(2-(3-bromophenyl)oxetan-2-yl)-4-methyl-4H-1,2,4-triazole (66F)
在室温下，将66E(614.0mg,1.88mmol)溶于二氯甲烷(6.0mL)中，依次向反应液中依次缓慢滴加冰醋酸(0.5mL)和过氧化氢(3.0mL)。反应在室温下反应1.0小时。反应结束后，加入水(60.0mL)并用二氯甲烷(6.0mL×3)萃取。萃取所得有机相用无水硫酸钠干燥，过滤，滤液减压蒸馏得到标题产物66F(500.0mg)，无需进一步纯化，直接用于下一步反应。MS m/z(ESI):294.0/296.0[M+H] +。 66E (614.0 mg, 1.88 mmol) was dissolved in dichloromethane (6.0 mL) at room temperature, and glacial acetic acid (0.5 mL) and hydrogen peroxide (3.0 mL) were slowly added dropwise to the reaction solution successively. The reaction was allowed to react at room temperature for 1.0 hour. After the reaction was completed, water (60.0 mL) was added and extracted with dichloromethane (6.0 mL×3). The extracted organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain the title product 66F (500.0 mg), which was directly used in the next reaction without further purification. MS m/z (ESI): 294.0/296.0 [M+H] + .
步骤7：6-氟-1-(3-(2-(4-甲基-4H-1,2,4-三唑-3-基)氧杂环丁烷-2-基)苯基)-4-(((S)-3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(化合物66)的制备Step 7: 6-Fluoro-1-(3-(2-(4-methyl-4H-1,2,4-triazol-3-yl)oxetan-2-yl)phenyl)- Preparation of 4-(((S)-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (Compound 66)
在氩气氛围下，向3-(2-(3-溴苯基)氧杂环丁烷-2-基)-4-甲基-4H-1,2,4-三唑(9.86mg,33.52μmol)的N,N-二甲基甲酰胺(1.0mL)溶液中依次加入反式-N,N'-二甲基1,2-环己二胺(4.77mg,3.19μmol)、碘化亚铜(3.19mg,16.76μmol)、碳酸钾(4.63mg,33.52μmol)和(S)-6-氟-4-((3-甲基哌啶-1-基)甲基)苯并[cd]吲哚-2(1H)-酮(10.0mg,33.52μmol)，所得混合物在氮气保护下加热至100℃，搅拌2.0小时。反应完毕后冷却至室温，过滤，减压浓缩得到的粗产品经制备高效液相色谱柱(柱子：Welch Xtimate C18柱长150mm，内径30mm,粒径5μm；流动相A：水(0.225％NH 3),流动相B：乙腈；梯度：流动相B从5％到95％用时18分钟)分离，得标题化合物66(1.85mg)。 Under argon atmosphere, 3-(2-(3-bromophenyl)oxetan-2-yl)-4-methyl-4H-1,2,4-triazole (9.86mg, 33.52 μmol) of N,N-dimethylformamide (1.0mL) solution, add trans-N,N'-dimethyl 1,2-cyclohexanediamine (4.77mg, 3.19μmol), ethylene iodide Copper (3.19 mg, 16.76 μmol), potassium carbonate (4.63 mg, 33.52 μmol) and (S)-6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd] Indole-2(1H)-one (10.0 mg, 33.52 μmol), the resulting mixture was heated to 100° C. under nitrogen protection, and stirred for 2.0 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the crude product obtained by concentrating under reduced pressure was prepared through a high performance liquid chromatography column (column: Welch Xtimate C18 column length 150mm, internal diameter 30mm, particle diameter 5 μm; mobile phase A: water (0.225%NH 3 ), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) separation to obtain the title compound 66 (1.85 mg).
MS m/z(ESI):512.45[M+H] +； MS m/z(ESI):512.45[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ8.48(s,1H),8.19(d,J＝7.0Hz,2H),7.67–7.54(m,3H),7.31(d,J＝7.3Hz,2H),6.94(s,1H),4.65(s,2H),3.89(s,1H),3.78(s,2H),2.87(d,J＝90.5Hz,4H),1.96(s,2H),1.64(s,4H),1.46(s,1H),0.84(s,1H),0.80(d,J＝5.4Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.48(s, 1H), 8.19(d, J=7.0Hz, 2H), 7.67–7.54(m, 3H), 7.31(d, J=7.3Hz, 2H),6.94(s,1H),4.65(s,2H),3.89(s,1H),3.78(s,2H),2.87(d,J=90.5Hz,4H),1.96(s,2H), 1.64(s,4H),1.46(s,1H),0.84(s,1H),0.80(d,J=5.4Hz,3H).
参考上述实施例的合成方法以及前述通用合成路线1、2和3，合成如下化合物，其结构和质谱数据为：With reference to the synthetic methods of the above examples and the aforementioned general synthetic routes 1, 2 and 3, the following compounds were synthesized, whose structure and mass spectrum data are:
Figure PCTCN2022118398-appb-000171
Figure PCTCN2022118398-appb-000171
Figure PCTCN2022118398-appb-000172
Figure PCTCN2022118398-appb-000172
Figure PCTCN2022118398-appb-000173
Figure PCTCN2022118398-appb-000173
Figure PCTCN2022118398-appb-000174
Figure PCTCN2022118398-appb-000174
Figure PCTCN2022118398-appb-000175
Figure PCTCN2022118398-appb-000175
Figure PCTCN2022118398-appb-000176
Figure PCTCN2022118398-appb-000176
生物学活性及相关性质测试例Biological activity and related properties test cases
测试例1 Cbl-b活性实验Test example 1 Cbl-b activity experiment
实验目的：测试化合物对Cbl-b蛋白与UbcH5B-Ub相互作用抑制活性The purpose of the experiment: to test the inhibitory activity of the compound on the interaction between Cbl-b protein and UbcH5B-Ub
实验方法：Eu-Ubquitin(Cisbio)与UbcH5B(ENZO)，E1(ENZO)在37℃孵育4小时制备Eu-Ubquitin-UbcH5B。Eu-Ubquitin-UbcH5B分装于-80℃保存。Cbl-b活性实验在384孔板(Perkin Elmer)中进行。100nL 3倍梯度稀释化合物(终浓度为10μM-0.5nM，起始浓度10μM，进行3倍稀释，10个点，第10个点是0.5nM)与5μL 50nM Biotin-Cbl-b蛋白(Sigma)在室温孵育1小时，反应缓冲液为50mM HEPES pH 7.0(Gibco),100mM NaCl(Sigma),0.01％Triton X-100(Sigma),0.01％BSA(Sigma)以及l mM DTT(Invitrogen)。在反应板中加入5μL Src混合液(40nM Src(R&D),2mM ATP(Sigma)，10mM MgCl 2(Sigma))，室温孵育3小时。在反应板中加入10μL检测液(12.5nM Strepdividin-XL665(Cisbio)，500nM Eu-Ubquitin-UbcH5B，120nM EDTA(Invitrogen)，0.004％BSA(Sigma))，室温孵育过夜，在Envision(Perkin Elmer)上读取HTRF信号(665/615)。使用IDBS XLfit计算IC 50。 Experimental method: Eu-Ubquitin (Cisbio) was incubated with UbcH5B (ENZO), E1 (ENZO) at 37°C for 4 hours to prepare Eu-Ubquitin-UbcH5B. Store Eu-Ubquitin-UbcH5B at -80°C. Cbl-b activity assays were performed in 384-well plates (Perkin Elmer). 100nL 3-fold serial dilution compound (final concentration is 10μM-0.5nM, initial concentration 10μM, 3-fold dilution, 10 points, the 10th point is 0.5nM) and 5μL 50nM Biotin-Cbl-b protein (Sigma) in Incubate at room temperature for 1 hour, and the reaction buffer is 50 mM HEPES pH 7.0 (Gibco), 100 mM NaCl (Sigma), 0.01% Triton X-100 (Sigma), 0.01% BSA (Sigma) and 1 mM DTT (Invitrogen). Add 5 μL of Src mixture (40 nM Src (R&D), 2 mM ATP (Sigma), 10 mM MgCl 2 (Sigma)) to the reaction plate and incubate at room temperature for 3 hours. Add 10 μL of detection solution (12.5nM Strepdividin-XL665 (Cisbio), 500nM Eu-Ubquitin-UbcH5B, 120nM EDTA (Invitrogen), 0.004% BSA (Sigma)) to the reaction plate, incubate overnight at room temperature, on the Envision (Perkin Elmer) Read HTRF signal (665/615). IC50 was calculated using IDBS XLfit.
实验结果如表1所示。The experimental results are shown in Table 1.
表1Table 1
化合物编号Compound number IC 50(nM) IC 50 (nM)
11 49.849.8
22 107.5107.5
33 21.321.3
5454 59.559.5
5555 25.325.3
5757 66.866.8
5858 58.458.4
5959 34.434.4
6060 17.817.8
6161 16.516.5
6363 16.616.6
6464 66.566.5
6565 66.466.4
9494 16.516.5
测试例2 Jurkat T激活实验Test example 2 Jurkat T activation experiment
实验目的：测试化合物对Jurkat T细胞IL-2释放激活作用The purpose of the experiment: to test the effect of the compound on the release and activation of Jurkat T cells IL-2
实验方法：96孔细胞板(Corning)使用2μg/mL Anti-Human CD3 Clone OKT3(BD)37℃包被4小时。3倍梯度稀释化合物(终浓度为10μM-4.6nM，起始浓度10μM，进行3倍稀释，8个点，第8个点是4.6nM)与220μL 1.11x10 6/mL Jurkat T细胞(ATCC)孵育1小时，加入5μL 45μg/mL Anti-Human CD28Clone CD28.2(BD)，混合均匀，转移100μL至前述CD3包被细胞板中，37℃细胞培养箱培养48小时，收上清使用IL-2ELISA试剂盒(BD)检测IL-2释放量。使用Prism分析EC 50。 Experimental method: 96-well cell plate (Corning) was coated with 2 μg/mL Anti-Human CD3 Clone OKT3 (BD) at 37° C. for 4 hours. 3-fold serially diluted compound (final concentration 10μM-4.6nM, initial concentration 10μM, 3-fold dilution, 8 points, the 8th point is 4.6nM) was incubated with 220μL 1.11x10 6 /mL Jurkat T cells (ATCC) For 1 hour, add 5 μL of 45 μg/mL Anti-Human CD28Clone CD28.2 (BD), mix well, transfer 100 μL to the aforementioned CD3-coated cell plate, incubate at 37°C for 48 hours, collect the supernatant and use IL-2ELISA reagent Cassette (BD) detects IL-2 release. EC50 was analyzed using Prism.
实验结果如表2所示。The experimental results are shown in Table 2.
表2Table 2
化合物编号Compound number EC 50(nM) EC50 (nM)
11 616.7616.7
33 318.7318.7
5555 264.1264.1
55A55A 164.3164.3
55B55B 162.2162.2
6363 427.2427.2
9494 355.7355.7

Claims (20)

  1. 式(I)化合物或其立体异构体或其药学上可接受的盐，A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022118398-appb-100001
    Figure PCTCN2022118398-appb-100001
    其中，in,
    Z 1和Z 2独立选自CR a或N； Z and Z are independently selected from CR a or N;
    Z 3选自C、CH或N； Z is selected from C, CH or N;
    Y 1、Y 2、Y 3和Y 4独立选自CR b或N； Y 1 , Y 2 , Y 3 and Y 4 are independently selected from CR b or N;
    X选自卤素、CN、OH、COOH、CONH 2、C 1-C 6烷基、C 1-C 6烷氧基、
    Figure PCTCN2022118398-appb-100002
    Figure PCTCN2022118398-appb-100003
    其中C 1-C 6烷基或C 1-C 6烷氧基任选被R e取代，环B选自任选被R 3取代的以下基团：4-10元含氮杂环基或5-10元含氮杂芳基，环D选自任选被R 6取代的以下基团：C 3-C 10环烷基、4-10元杂环基、苯基或5-10元杂芳基，并且环D以非N原子与L相连，L选自键、-NR 7-、-NR 7CR 8R 9-、-O-、-C(＝O)-、-C(＝O)NH-或-CR 8R 9-；     X is selected from halogen, CN, OH, COOH, CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy,
    Figure PCTCN2022118398-appb-100002
    Figure PCTCN2022118398-appb-100003
    wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted by R e , ring B is selected from the following groups optionally substituted by R 3 : 4-10 membered nitrogen-containing heterocyclic group or 5 -10-membered nitrogen-containing heteroaryl, ring D is selected from the following groups optionally substituted by R 6 : C 3 -C 10 cycloalkyl, 4-10-membered heterocyclic group, phenyl or 5-10-membered heteroaryl group, and the ring D is connected to L by a non-N atom, and L is selected from a bond, -NR 7 -, -NR 7 CR 8 R 9 -, -O-, -C(=O)-, -C(=O) NH-or-CR 8 R 9 -;
    R b选自H、卤素、OH、CN、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、NHC(O)(C 1-C 6烷基)、NHS(O) 2(C 1-C 6烷基)、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 3-C 6环烷基-NH-、N(C 3-C 6环烷基) 2、NHC(O)-C 3-C 6环烷基、NHS(O) 2-C 3-C 6环烷基、4-7元杂环基、4-7元杂环基氧基、4-7元杂环基-NH-、N(4-7元杂环基) 2、NHC(O)-4-7元杂环基、NHS(O) 2-4-7元杂环基、C 6-C 10芳基、C 6-C 10芳基氧基、C 6-C 10芳基-NH-、N(C 6-C 10芳基) 2、NHC(O)-C 6-C 10芳基、NHS(O) 2-C 6-C 10芳基、5-10元杂芳基、5-10元杂芳基氧基或5-10元杂芳基-NH-、N(5-10元杂芳基) 2、NHC(O)-5-10元杂芳基、NHS(O) 2-5-10元杂芳基，其中所述的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 3-C 6环烷基、4-7元杂环基、C 6-C 10芳基或5-10元杂芳基任选被R 2a取代； R b is selected from H, halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, NH 2 , NH(C 1 -C 6 alkyl ), N(C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHS(O) 2 (C 1 -C 6 alkyl), C 3 -C 6 cycloalkane group, C 3 -C 6 cycloalkyl-O-, C 3 -C 6 cycloalkyl-NH-, N(C 3 -C 6 cycloalkyl) 2 , NHC(O)-C 3 -C 6 ring Alkyl, NHS(O) 2 -C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, N(4 -7-membered heterocyclyl) 2 , NHC(O)-4-7-membered heterocyclyl, NHS(O) 2 -4-7-membered heterocyclyl, C 6 -C 10 aryl, C 6 -C 10 aryl Oxygen, C 6 -C 10 aryl-NH-, N(C 6 -C 10 aryl) 2 , NHC(O)-C 6 -C 10 aryl, NHS(O) 2 -C 6 -C 10- aryl, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy or 5-10-membered heteroaryl-NH-, N(5-10-membered heteroaryl) 2 , NHC(O)- 5-10 membered heteroaryl, NHS(O) 2 -5-10 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio Base, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by R 2a ;
    或者两个R b与其相连的C原子共同形成C 3-C 6环烯基、苯基、4-7元杂环基或5-6元杂芳基，所述C 3-C 6环烯基、苯基、4-7元杂环基或5-6元杂芳基任选被R 2a取代； Or two R b and the C atoms connected to them jointly form a C 3 -C 6 cycloalkenyl group, a phenyl group, a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, and the C 3 -C 6 cycloalkenyl group , phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally substituted by R 2a ;
    R a、R 4、R 5、R 7、R 8和R 9彼此独立地选自H、卤素、OH、C 1-C 6烷基或C 1-C 6烷氧基，所述C 1-C 6烷基或C 1-C 6烷氧基任选被R 4a取代； R a , R 4 , R 5 , R 7 , R 8 and R 9 are independently selected from H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, and the C 1 - C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted by R 4a ;
    或者R 8、R 9及其相连的原子一起形成C 3-C 6环烷基或4-7元杂环基，或者R 4、R 5及其相连的原子一起形成C 3-C 6环烷基或4-7元杂环基，所述C 3-C 6环烷基或4-7元杂环基任选进一步被R 8a取代，或者R 4、R 5一起形成＝O； Or R 8 , R 9 and their connected atoms together form a C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group, or R 4 , R 5 and their connected atoms together form a C 3 -C 6 cycloalkane A group or a 4-7 membered heterocyclic group, the C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group is optionally further substituted by R 8a , or R 4 and R 5 together form =O;
    R 3和R 6独立地选自卤素、CN、＝O、NO 2、C 1-C 6烷基、OR 6a、SR 6a、N(R 6a) 2、S(O) 2R 6a、S(O) 2N(R 6a) 2、S(O)R 6a、S(O)N(R 6a) 2、C(O)R 6a、C(O)OR 6a、C(O)N(R 6a) 2、C(O)N(R 6a)OR 6a、OC(O)R 6a、OC(O)N(R 6a) 2、N(R 6a)C(O)OR 6a、N(R 6a)C(O)R 6a、N(R 6a)C(O)N(R 6a) 2、N(R 6a)C(NR 6a)N(R 6a) 2、N(R 6a)S(O) 2N(R 6a) 2、N(R 6a)S(O) 2R 6a、C 3-C 10环烷基、4-7元杂环基、 6-10元芳基或5-10元杂芳基，其中C 1-C 6烷基、C 3-C 10环烷基、4-7元杂环基、6-10元芳基或5-10元杂芳基任选进一步被R 3a取代； R 3 and R 6 are independently selected from halogen, CN, =O, NO 2 , C 1 -C 6 alkyl, OR 6a , SR 6a , N(R 6a ) 2 , S(O) 2 R 6a , S( O) 2 N(R 6a ) 2 , S(O)R 6a , S(O)N(R 6a ) 2 , C(O)R 6a , C(O)OR 6a , C(O)N(R 6a ) 2 , C(O)N(R 6a )OR 6a , OC(O)R 6a , OC(O)N(R 6a ) 2 , N(R 6a )C(O)OR 6a , N(R 6a ) C(O)R 6a , N(R 6a )C(O)N(R 6a ) 2 , N(R 6a )C(NR 6a )N(R 6a ) 2 , N(R 6a )S(O) 2 N(R 6a ) 2 , N(R 6a )S(O) 2 R 6a , C 3 -C 10 cycloalkyl, 4-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl A group, wherein C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally further substituted by R 3a ;
    R 6a选自H、C 1-C 6烷基、苯基、4-7元杂环基或5-6元杂芳基，所述C 1-C 6烷基、苯基、4-7元杂环基或5-6元杂芳基任选进一步被R 6b取代，或者一个N原子上的2个R 6a与其相连的N一起形成4-7元杂环基或5-6元杂芳基，所述4-7元杂环基或5-6元杂芳基任选进一步被R 6b取代； R 6a is selected from H, C 1 -C 6 alkyl, phenyl, 4-7 membered heterocyclic group or 5-6 membered heteroaryl, said C 1 -C 6 alkyl, phenyl, 4-7 membered Heterocyclyl or 5-6 membered heteroaryl is optionally further substituted by R 6b , or 2 R 6a on one N atom form a 4-7 membered heterocyclic group or 5-6 membered heteroaryl together with the N connected to it , the 4-7 membered heterocyclic group or 5-6 membered heteroaryl group is optionally further substituted by R 6b ;
    R 3a、R 4a、R 6b和R e独立选自卤素、OH、CN、＝O、NH 2、COOH或C 1-C 6烷氧基； R 3a , R 4a , R 6b and Re are independently selected from halogen, OH, CN, =O, NH 2 , COOH or C 1 -C 6 alkoxy;
    Q为苯基或6元杂芳基，所述苯基或6元杂芳基任选被R 10取代； Q is phenyl or 6-membered heteroaryl, and said phenyl or 6-membered heteroaryl is optionally substituted by R 10 ;
    或者Q为如下所示基团：
    Figure PCTCN2022118398-appb-100004
    其中Z 4和Z 5独立选自CR cR d、NR 11、O、S、或S(＝O) 2，
    Figure PCTCN2022118398-appb-100005
    代表单键或双键，并且当
    Figure PCTCN2022118398-appb-100006
    为双键时，m为1，当
    Figure PCTCN2022118398-appb-100007
    为单键时m为1或2；     Or Q is a group as shown below:
    Figure PCTCN2022118398-appb-100004
    wherein Z 4 and Z 5 are independently selected from CR c R d , NR 11 , O, S, or S(=O) 2 ,
    Figure PCTCN2022118398-appb-100005
    represents a single or double bond, and when
    Figure PCTCN2022118398-appb-100006
    When it is a double bond, m is 1, when
    Figure PCTCN2022118398-appb-100007
    When it is a single bond, m is 1 or 2;
    R 10选自卤素、OH、NH 2、CN、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基或4-7元杂环基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基或4-7元杂环基任选被R 10a取代； R 10 is selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclic group, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl are optionally substituted by R 10a ;
    R 2a和R 10a独立选自卤素、OH、CN、＝O、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 2a and R 10a are independently selected from halogen, OH, CN, =O, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl , halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy;
    R c、R d和R 11独立选自H、卤素、OH、CN、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 1-C 6烷基或C 1-C 6烷氧基，其中所述的C 1-C 6烷基或C 1-C 6烷氧基任选被R 11a取代，或者R c、R d共同形成＝O，或者R c、R d与其相连的原子共同形成C 3-C 10环烷基或4-7元杂环基，所述C 3-C 10环烷基或4-7元杂环基任选被R 11b取代； R c , R d and R 11 are independently selected from H, halogen, OH, CN, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Alkyl or C 1 -C 6 alkoxy, wherein said C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted by R 11a , or R c and R d jointly form =O, Or R c , R d and the atoms connected to them jointly form a C 3 -C 10 cycloalkyl group or a 4-7 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or a 4-7 membered heterocyclic group is optionally replaced by R 11b is substituted;
    或者R c与R 11及其各自相连的原子共同形成4-7元杂环基，所述4-7元杂环基任选被R 11c取代； Or R c and R 11 and their respective connected atoms together form a 4-7 membered heterocyclic group, and the 4-7 membered heterocyclic group is optionally substituted by R 11c ;
    R 11a、R 11b和R 11c独立地选自卤素、OH、＝O、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2或C 1-C 6烷基； R 11a , R 11b and R 11c are independently selected from halogen, OH, =O, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 or C 1 -C 6 alkyl;
    R 1和R 2独立选自H、卤素、CN、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基或4-10元杂环基，其中所述的C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基或4-10元杂环基任选被R 1a取代， R 1 and R 2 are independently selected from H, halogen, CN, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclic group, wherein said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 Cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R 1a ,
    或者R 1、R 2与其连接的原子共同形成C 3-C 10环烷基或4-10元杂环基，所述C 3-C 10环烷基或4-10元杂环基任选被R 1b取代； Or R 1 , R 2 and the atoms they connect together form a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group is optionally replaced by R 1b replaces;
    R 1a和R 1b独立选自卤素、OH、CN、＝O、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 1-C 6烷基或C 1-C 6烷氧基，所述C 1-C 6烷基或C 1-C 6烷氧基任选进一步被R 1c取代； R 1a and R 1b are independently selected from halogen, OH, CN, =O, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl or C 1 -C 6 alkoxy, the C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally further substituted by R 1c ;
    R 1c选自卤素、OH、CN、＝O、NH 2或COOH； R 1c is selected from halogen, OH, CN, =O, NH 2 or COOH;
    W选自(CR 12R 13) kW 1，所述W 1选自5-10元杂芳基或4-10元杂环基，所述5-10元杂芳基、4-10元杂环基任选被R 14取代，R 12、R 13独立选自H、卤素、OH、C 1-C 6烷基或C 1-C 6烷氧基，R 14选自卤素、OH、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基，其中所述的C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基任选被R 14a取代； W is selected from (CR 12 R 13 ) k W 1 , said W 1 is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclic group, said 5-10 membered heteroaryl, 4-10 membered heterocyclic group The ring group is optionally substituted by R 14 , R 12 and R 13 are independently selected from H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, R 14 is selected from halogen, OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl, wherein The C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R 14a ;
    或者R 1与R 12及其各自相连的原子和键共同形成C 3-C 6环烷基或4-7元杂环基，所述C 3-C 6环烷基或4-7元杂环基任选被R 12a取代； Or R 1 and R 12 and their respective connected atoms and bonds together form a C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group, the C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group The group is optionally substituted by R 12a ;
    R 8a和R 12a独立地选自卤素、OH、CN、C 1-C 6烷基或C 1-C 6烷氧基，所述C 1-C 6烷基或C 1-C 6烷氧基任选进一步被卤素取代，R 14a选自卤素、＝O、OH、CN或C 1-C 6烷基； R 8a and R 12a are independently selected from halogen, OH, CN, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, the C 1 -C 6 alkyl or C 1 -C 6 alkoxy Optionally further substituted by halogen, R 14a is selected from halogen, =O, OH, CN or C 1 -C 6 alkyl;
    p和k独立地选自0或1。p and k are independently selected from 0 or 1.
  2. 如权利要求1所述的化合物，其中Z 1和Z 2独立选自CH或N；或者，Z 1和Z 2均为CH；或者Z 1为CH以及Z 2为N；或者Z 1为N以及Z 2为CH。 The compound of claim 1, wherein Z 1 and Z 2 are independently selected from CH or N; or, Z 1 and Z 2 are both CH; or Z 1 is CH and Z 2 is N; or Z 1 is N and Z2 is CH.
  3. 如权利要求1或2所述的化合物，其中Y 1、Y 2、Y 3和Y 4均为CR b；或者，Y 1和Y 2 独立选自CR b或N，Y 3和Y 4均为CR b；或者，Y 1和Y 2均为N，Y 3和Y 4均为CR b；或者，Y 1为N，Y 2、Y 3和Y 4均为CR b；或者，Y 4为N，Y 1、Y 2和Y 3均为CR b；R b选自H、卤素、OH、CN、C 1-C 6烷基、C 1-C 6烷硫基、C 1-C 6烷氧基、NH 2、NH(C 1-C 6烷基)、N(C 1-C 6烷基) 2、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 3-C 6环烷基-NH-、4-7元杂环基-O-、4-7元杂环基-NH-或5-10元杂芳基，其中所述的C 1-C 6烷基、C 1-C 6烷硫基、C 1-C 6烷氧基、C 3-C 6环烷基、4-7元杂环基或5-10元杂芳基任选被R 2a取代；或者，R b选自H、卤素或任选被R 2a取代的以下基团：甲基、乙氧基、NHCH 3、NHEt、NH(i-Pr)、吡唑基、环丙基-O-、环丁基-NH-或氧杂环丁基-O-。 The compound as claimed in claim 1 or 2, wherein Y 1 , Y 2 , Y 3 and Y 4 are all CR b ; or, Y 1 and Y 2 are independently selected from CR b or N, and Y 3 and Y 4 are all CR b ; or, Y 1 and Y 2 are N, Y 3 and Y 4 are CR b ; or, Y 1 is N, Y 2 , Y 3 and Y 4 are all CR b ; or, Y 4 is N , Y 1 , Y 2 and Y 3 are all CR b ; R b is selected from H, halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy group, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-O-, C 3 -C 6 cycloalkyl-NH-, 4-7 membered heterocyclyl-O-, 4-7 membered heterocyclyl-NH- or 5-10 membered heteroaryl, wherein the C 1 -C 6 Alkyl, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl or 5-10 membered heteroaryl are optionally replaced by R 2a alternatively, R b is selected from H, halogen, or the following groups optionally substituted by R 2a : methyl, ethoxy, NHCH 3 , NHEt, NH(i-Pr), pyrazolyl, cyclopropyl- O-, cyclobutyl-NH- or oxetanyl-O-.
  4. 如权利要求1-3中任一项所述的化合物，其中X选自
    Figure PCTCN2022118398-appb-100008
    The compound according to any one of claims 1-3, wherein X is selected from
    Figure PCTCN2022118398-appb-100008
  5. 如权利要求1-4中任一项所述的化合物，其中环B选自任选被R 3取代的以下基团：5-10元含氮杂芳基、4-7元单环含氮杂环基或6-10元含氮杂环基；或者， The compound as claimed in any one of claims 1-4, wherein ring B is selected from the following groups optionally substituted by R 3 : 5-10 membered nitrogen-containing heteroaryl, 4-7 membered monocyclic nitrogen-containing heteroaryl Cyclic group or 6-10 membered nitrogen-containing heterocyclic group; or,
    环B选自任选被R 3取代的以下基团：吡唑基、咪唑基、三唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、氮杂环庚基、
    Figure PCTCN2022118398-appb-100009
    Figure PCTCN2022118398-appb-100010
    Ring B is selected from the following groups optionally substituted by R : pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, azetidinyl, tetrahydro Pyrrolyl, piperidinyl, piperazinyl, morpholinyl, azepanyl,
    Figure PCTCN2022118398-appb-100009
    Figure PCTCN2022118398-appb-100010
  6. 如权利要求1-5中任一项所述的化合物，其中R 3选自卤素、OH、＝O、CN、C 1-C 6烷基、C 1-C 6烷氧基、6-10元芳基或5-10元杂芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、6-10元芳基或5-10元杂芳基任选进一步被R 3a取代；或者， The compound according to any one of claims 1-5, wherein R 3 is selected from halogen, OH, =O, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 6-10 yuan Aryl or 5-10 membered heteroaryl, said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 6-10 membered aryl or 5-10 membered heteroaryl is optionally further represented by R 3a replace; or,
    R 3选自＝O、OH、F、CN、甲基、异丙基、CF 3、羟甲基、甲氧基、
    Figure PCTCN2022118398-appb-100011
    或苯基。     R 3 is selected from =O, OH, F, CN, methyl, isopropyl, CF 3 , hydroxymethyl, methoxy,
    Figure PCTCN2022118398-appb-100011
    or phenyl.
  7. 如权利要求1-6中任一项所述的化合物，其中R 4、R 5独立选自H、卤素、OH或任选被R 4a取代的C 1-C 3烷基；或者，R 4、R 5独立选自H、甲基、CF 3或乙基；或者R 4、R 5一起形成＝O。 The compound according to any one of claims 1-6, wherein R 4 , R 5 are independently selected from H, halogen, OH, or C 1 -C 3 alkyl optionally substituted by R 4a ; or, R 4 , R 5 is independently selected from H, methyl, CF 3 or ethyl; or R 4 , R 5 together form =O.
  8. 如权利要求1-4中任一项所述的化合物，其中环D选自任选被R 6取代的以下基团：C 3-C 6环烷基、5-6元杂芳基、4-7元单环杂环基或6-10元杂环基，并且环D以非N原子与L相连；或者 The compound according to any one of claims 1-4, wherein ring D is selected from the following groups optionally substituted by R 6 : C 3 -C 6 cycloalkyl, 5-6 membered heteroaryl, 4- 7-membered monocyclic heterocyclic group or 6-10 membered heterocyclic group, and the ring D is connected to L through a non-N atom; or
    环D选自任选被R 6取代的以下基团：环丙基、环丁基、环戊基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、
    Figure PCTCN2022118398-appb-100012
    吡唑基、咪唑基、噁唑基、异噁唑基、三唑基、噻唑基或异噻唑基。     Ring D is selected from the following groups optionally substituted by R: cyclopropyl , cyclobutyl, cyclopentyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
    Figure PCTCN2022118398-appb-100012
    Pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl or isothiazolyl.
  9. 如权利要求1-4或8中任一项所述的化合物，其中R 6选自卤素、OH、CN、＝O或任 选被R 3a取代的C 1-C 3烷基；或者，R 6选自卤素、＝O、OH或C 1-C 3烷基；或者，R 6选自F、＝O或甲基。 The compound according to any one of claims 1-4 or 8, wherein R is selected from halogen, OH, CN, =O or C 1 -C 3 alkyl optionally substituted by R 3a ; or, R 6 is selected from halogen, =O, OH or C 1 -C 3 alkyl; alternatively, R 6 is selected from F, =O or methyl.
  10. 如权利要求1-4或8-9中任一项所述的化合物，其中L选自键、-NR 7-、-NR 7CR 8R 9-、-O-或-CR 8R 9-，其中优选地，R 7、R 8和R 9独立选自H、C 1-C 3烷基或OH；更优选地，R 7选自H或甲基，以及R 8、R 9选自H；或者，L选自键、-NCH 3-、-NHCH 2-、-NHCH(CH 3)-、-O-或-CH 2-。 The compound according to any one of claims 1-4 or 8-9, wherein L is selected from a bond, -NR 7 -, -NR 7 CR 8 R 9 -, -O- or -CR 8 R 9 -, Among them, preferably, R 7 , R 8 and R 9 are independently selected from H, C 1 -C 3 alkyl or OH; more preferably, R 7 is selected from H or methyl, and R 8 and R 9 are selected from H; Alternatively, L is selected from a bond, -NCH3- , -NHCH2- , -NHCH( CH3 )-, -O- or -CH2- .
  11. 如权利要求1-10中任一项所述的化合物，其中Q为任选被R 10取代的苯基或6元杂芳基；或者，Q为任选被R 10取代的以下基团：苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基；或者，Q为任选被卤素取代的苯基。 The compound according to any one of claims 1-10, wherein Q is phenyl or 6-membered heteroaryl optionally substituted by R 10 ; or, Q is the following group optionally substituted by R 10 : benzene or, Q is phenyl optionally substituted with halogen.
  12. 如权利要求1-11中任一项所述的化合物，其中R 10选自卤素、OH、CN、C 1-C 6烷基或C 1-C 6烷氧基，所述C 1-C 6烷基或C 1-C 6烷氧基任选被R 10a取代；或者，R 10选自F、Cl、甲基、甲氧基、CH 2OH或CF 3。 The compound according to any one of claims 1-11, wherein R 10 is selected from halogen, OH, CN, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, and said C 1 -C 6 Alkyl or C 1 -C 6 alkoxy is optionally substituted by R 10a ; alternatively, R 10 is selected from F, Cl, methyl, methoxy, CH 2 OH or CF 3 .
  13. 如权利要求1-12中任一项所述的化合物，其中Q选自
    Figure PCTCN2022118398-appb-100013
    其中Z 4和Z 5独立选自CR cR d、NR 11、O、S或SO 2，
    Figure PCTCN2022118398-appb-100014
    代表单键或双键，并且当
    Figure PCTCN2022118398-appb-100015
    为双键时，m为1，当
    Figure PCTCN2022118398-appb-100016
    为单键时，m为1或2，     The compound according to any one of claims 1-12, wherein Q is selected from
    Figure PCTCN2022118398-appb-100013
    wherein Z 4 and Z 5 are independently selected from CR c R d , NR 11 , O, S or SO 2 ,
    Figure PCTCN2022118398-appb-100014
    represents a single or double bond, and when
    Figure PCTCN2022118398-appb-100015
    When it is a double bond, m is 1, when
    Figure PCTCN2022118398-appb-100016
    When it is a single bond, m is 1 or 2,
    优选地，R c、R d和R 11独立选自H、卤素、OH、NH 2或C 1-C 6烷基，所述C 1-C 6烷基任选被R 11a取代，或者R c、R d共同形成＝O，或者R c、R d与其相连的原子共同形成C 3-C 6环烷基，所述C 3-C 6环烷基任选被R 11b取代。 Preferably, R c , R d and R 11 are independently selected from H, halogen, OH , NH 2 or C 1 -C 6 alkyl optionally substituted by R 11a , or R c , R d jointly form =O, or R c , R d and the atoms connected to them jointly form a C 3 -C 6 cycloalkyl group, and the C 3 -C 6 cycloalkyl group is optionally substituted by R 11b .
  14. 如权利要求1-13中任一项所述的化合物，其中R 1、R 2与其连接的原子共同形成C 3-C 8环烷基或4-10元杂环基，所述C 3-C 8环烷基或4-10元杂环基任选被R 1b取代；或者， The compound according to any one of claims 1-13, wherein R 1 , R 2 and the atoms they are connected to together form a C 3 -C 8 cycloalkyl group or a 4-10 membered heterocyclic group, and the C 3 -C 8 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R 1b ; or,
    R 1、R 2与其连接的原子共同形成任选被R 1b取代的如下基团：环丁基、螺[2,3]己基或氧杂环丁基。 R 1 , R 2 and the atoms they are connected together form the following group optionally substituted by R 1b : cyclobutyl, spiro[2,3]hexyl or oxetanyl.
  15. 如权利要求1-14中任一项所述的化合物，其中W选自-(CR 12R 13)W 1或-W 1；W 1选自任选被R 14取代的4-10元杂环基或5-10元杂芳基；或者， The compound according to any one of claims 1-14, wherein W is selected from -(CR 12 R 13 )W 1 or -W 1 ; W 1 is selected from 4-10 membered heterocycles optionally substituted by R 14 base or 5-10 membered heteroaryl; or,
    W 1选自任选被R 14取代的如下基团：吡咯、噻吩、呋喃、吡唑、咪唑、噻唑、异噻唑、噻二唑、三氮唑、噁唑、异噁唑、噁二唑、
    Figure PCTCN2022118398-appb-100017
     W is selected from the following groups optionally substituted by R : pyrrole, thiophene, furan, pyrazole, imidazole, thiazole, isothiazole, thiadiazole, triazole, oxazole, isoxazole, oxadiazole,
    Figure PCTCN2022118398-appb-100017
    R 14优选地选自卤素、OH、NH 2、C 1-C 3烷基或C 3-C 6环烷基，所述C 1-C 3烷基或C 3-C 6环烷基任选被R 14a取代。 R 14 is preferably selected from halogen, OH, NH 2 , C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, which C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl is optionally Replaced by R 14a .
  16. 如权利要求1所述的化合物，其中所述式(I)化合物选自如下化合物之一或其立体异构体或其药学上可接受的盐：The compound as claimed in claim 1, wherein the compound of formula (I) is selected from one of the following compounds or its stereoisomer or pharmaceutically acceptable salt thereof:
    Figure PCTCN2022118398-appb-100018
    Figure PCTCN2022118398-appb-100018
    Figure PCTCN2022118398-appb-100019
    Figure PCTCN2022118398-appb-100019
    Figure PCTCN2022118398-appb-100020
    Figure PCTCN2022118398-appb-100020
    Figure PCTCN2022118398-appb-100021
    Figure PCTCN2022118398-appb-100021
    Figure PCTCN2022118398-appb-100022
    Figure PCTCN2022118398-appb-100022
    Figure PCTCN2022118398-appb-100023
    Figure PCTCN2022118398-appb-100023
    Figure PCTCN2022118398-appb-100024
    Figure PCTCN2022118398-appb-100024
    Figure PCTCN2022118398-appb-100025
    Figure PCTCN2022118398-appb-100025
    Figure PCTCN2022118398-appb-100026
    Figure PCTCN2022118398-appb-100026
  17. 药物组合物，其包含权利要求1-16中任一项所述的式(I)化合物或其立体异构体或其药学上可接受的盐和药学上可接受的辅料。A pharmaceutical composition comprising the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials according to any one of claims 1-16.
  18. 用于治疗哺乳动物的由Cbl-b介导的疾病或病症的方法，其包括对有需要的所述哺乳动物，优选人类，给予治疗有效量的权利要求1-16中任一项所述的式(I)化合物或其立体异构体或其药学上可接受的盐或权利要求17所述的药物组合物，所述由Cbl-b介导的疾病或病症优选为肿瘤或自身免疫性疾病。A method for treating a disease or disorder mediated by Cbl-b in a mammal, comprising administering a therapeutically effective amount of any one of claims 1-16 to said mammal in need, preferably a human. The compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition described in claim 17, the disease or disease mediated by Cbl-b is preferably tumor or autoimmune disease .
  19. 用于预防或治疗哺乳动物，优选人类的由Cbl-b介导的疾病或病症的权利要求1-16中任一项所述的式(I)化合物或其立体异构体或其药学上可接受的盐或权利要求17所述的药物组合物，所述由Cbl-b介导的疾病或病症优选为肿瘤或自身免疫性疾病。For the prevention or treatment of mammals, preferably humans, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable compound according to any one of claims 1-16 for diseases or diseases mediated by Cbl-b Acceptable salts or the pharmaceutical composition according to claim 17, the disease or disease mediated by Cbl-b is preferably a tumor or an autoimmune disease.
  20. 权利要求1-16中任一项所述的式(I)化合物或其立体异构体或其药学上可接受的盐或权利要求17所述的药物组合物在制备用于治疗或者预防哺乳动物，优选人类的由Cbl-b介导的疾病或病症的药物中的用途，所述由Cbl-b介导的疾病或病症优选为肿瘤或自身免疫性疾病。The compound of formula (I) described in any one of claims 1-16 or its stereoisomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition described in claim 17 is used for the treatment or prevention of mammalian , preferably a human Cbl-b-mediated disease or disease in medicine, and the Cbl-b-mediated disease or disease is preferably a tumor or an autoimmune disease.
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