WO2023036330A1 - Composé tricyclique utile en tant qu'inhibiteur de cbl-b - Google Patents

Composé tricyclique utile en tant qu'inhibiteur de cbl-b 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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alkyl
membered
cycloalkyl
group
optionally substituted
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PCT/CN2022/118398
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English (en)
Chinese (zh)
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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/zh
Publication of WO2023036330A1 publication Critical patent/WO2023036330A1/fr

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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

La présente invention concerne un composé de formule (I) utile en tant qu'inhibiteur de Cbl-b, ou un stéréoisomère ou un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation, une composition pharmaceutique contenant le composé de formule (I) ou un stéréoisomère ou un sel pharmaceutiquement acceptable de celui-ci, et l'utilisation du composé de formule (I) ou d'un stéréoisomère ou d'un sel pharmaceutiquement acceptable de celui-ci dans la prévention ou le traitement de maladies ou d'affections médiées par Cbl-b, telles que des tumeurs ou des maladies auto-immunes.
PCT/CN2022/118398 2021-09-13 2022-09-13 Composé tricyclique utile en tant qu'inhibiteur de cbl-b WO2023036330A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023205180A1 (fr) 2022-04-19 2023-10-26 Nurix Therapeutics, Inc. Biomarqueurs pour cbl, et compositions et procédés pour leur utilisation
WO2023217067A1 (fr) * 2022-05-09 2023-11-16 上海先博生物科技有限公司 Cellule effectrice immunitaire modifiée et utilisation correspondante en association avec un inhibiteur de cbl-b
WO2023250097A1 (fr) 2022-06-22 2023-12-28 Nurix Therapeutics, Inc. Polythérapies avec des composés inhibiteurs de cbl-b et des agents antiémétiques
WO2024017201A1 (fr) * 2022-07-18 2024-01-25 Insilico Medicine Ip Limited Inhibiteurs de cbl-b et leurs procédés d'utilisation

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023205180A1 (fr) 2022-04-19 2023-10-26 Nurix Therapeutics, Inc. Biomarqueurs pour cbl, et compositions et procédés pour leur utilisation
WO2023217067A1 (fr) * 2022-05-09 2023-11-16 上海先博生物科技有限公司 Cellule effectrice immunitaire modifiée et utilisation correspondante en association avec un inhibiteur de cbl-b
WO2023250097A1 (fr) 2022-06-22 2023-12-28 Nurix Therapeutics, Inc. Polythérapies avec des composés inhibiteurs de cbl-b et des agents antiémétiques
WO2024017201A1 (fr) * 2022-07-18 2024-01-25 Insilico Medicine Ip Limited Inhibiteurs de cbl-b et leurs procédés d'utilisation

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