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CN-121991092-A - Tri-fused ring derivative inhibitor, preparation method and application thereof

CN121991092ACN 121991092 ACN121991092 ACN 121991092ACN-121991092-A

Abstract

The invention relates to a tricyclic derivative inhibitor, a preparation method and application thereof. In particular, the invention relates to tricyclic derivative compounds, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of cancer.

Inventors

  • WU JIANRUI
  • GAO PENG
  • ZHANG YANG
  • ZHENG LULU
  • CHEN WEI

Assignees

  • 江苏豪森药业集团有限公司
  • 上海翰森生物医药科技有限公司

Dates

Publication Date
20260508
Application Date
20251106
Priority Date
20241106

Claims (12)

  1. 1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: M 1 is selected from-N-or-CR a -; M 2 is selected from-N-or-CR b -, preferably-CR b -; M 3 is selected from N or C, preferably N; Ring A is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, or 5-14 membered heteroaryl, preferably C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 fused ring alkyl, 6-10 membered fused ring, C 6-10 aryl, or 5-10 membered heteroaryl; L 1 is selected from the group consisting of a bond, -CR aa R bb -、-C(O)-、-NR cc C(O)、-S(O) m1 -or-NR cc -, preferably-CR aa R bb -、-C(O)-、-S(O) m1 -or-NR cc -; L 2 is selected from the group consisting of bond, -CR aa R bb -、-C(O)-、-S(O) m1 -or NR cc , preferably, -CR aa R bb -、-C(O)-、-S(O) m1 -or NR cc ; R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, - (CR cc R dd ) n1 -C 3-12 cycloalkyl, - (CR cc R dd ) n1 -3-12 membered heterocyclyl, - (CR cc R dd ) n1 -C 6-12 aryl, - (CR cc R dd ) n1 -5-12 membered heteroaryl 、-SF 5 、-OR e 、-NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-N=S(O)R e R f 、-S(O)R e (=NR f ) or-P (O) R e R f ), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, c 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl and =cr gg R hh , preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, - (CR cc R dd ) n1 -C 3-8 cycloalkyl, - (CR cc R dd ) n1 -3-8 membered heterocyclyl, - (CR cc R dd ) n1 -C 6-10 aryl), - (CR cc R dd ) n1 -5-10 membered heteroaryl, -OR e 、-NR e R f 、-C(O)R e 、-C(O)NR e R f OR-P (O) R e R f , said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, one or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; or R 1 is linked with R a 、R b or R c to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, Substituted by one or more substituents selected from C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably forming C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, one or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, c 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl 、-(CH 2 ) n2 OR ee 、-(CH 2 ) n2 NR ee R ff 、-(CH 2 ) n2 C(O)R ee 、-(CH 2 ) n2 C(O)NR ee R ff 、-(CH 2 ) n2 P(O)R ee R ff or = CR ee R ff , said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, c 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, One or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; R 3 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -Y 1 -C 3-12 cycloalkyl, -Y 1 -3-12 membered heterocyclyl, -Y 1 -C 6-12 aryl, -Y 1 -5-12 membered heteroaryl 、-SF 5 、-OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h 、-C(=NR i )NR g R h or =r g R h , said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and one or more substituents of = CR e R f , preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, A C 3-8 cycloalkyl, a 3-8 membered heterocyclyl, a C 6-10 aryl, a 5-10 membered heteroaryl, and =cr e R f ; Or any two R 3 are linked to their adjacent atoms to form C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 aryl and 5-to 12-membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, c 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably forms C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, Fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; R a 、R b 、R c 、R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl 、-(CH 2 ) n2 OR ee 、-(CH 2 ) n2 NR ee R ff 、-(CH 2 ) n2 C(O)R ee 、-(CH 2 ) n2 C(O)OR ee 、-(CH 2 ) n2 C(O)NR ee R ff 、-(CH 2 ) n2 N=S(O)R ee R ff 、-(CH 2 ) n2 S(O)R ee (=NR ff ) or- (CH 2 ) n2 P(O)R ee R ff ), said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl and =CR gg R hh , preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; Y 1 is selected from the group consisting of bond 、-O-、-S-、-C(O)、-NR j -、-C(O)NR j -、-NR j C(O)-、-S(O) 2 NR j -、-NR j S(O) 2 -、C 1-6 alkylene, -O-C 1-6 alkylene-, -C 1-6 alkylene-O-, -NR j -C 1-6 alkylene-, -C 1-6 alkylene-NR j -、C 2-6 alkenylene or C 2-6 alkynylene, said C 1-6 alkylene, C 2-6 alkenylene and C 2-6 alkynylene, optionally interrupted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, c 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, one or more substituents of the 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl groups are substituted; R g 、R h 、R i and R j are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, c 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; Or R g is linked to R h to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, and 5-12 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, and 5-12 membered heteroaryl; R aa 、R bb 、R cc and R dd are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, c 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, c 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; r gg and R hh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, c 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; x is selected from 0,1, 2,3, 4, 5 or 6;y is selected from 0,1, 2,3, 4, 5 or 6, m1 is selected from 0,1 or2, m2 is selected from 0,1 or2, n1 is selected from 0,1, 2,3 or 4, and n2 is selected from 0,1, 2,3 or 4.
  2. 2. The compound of claim 1, a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is a pharmaceutically acceptable salt of the compound Selected from the group consisting of 、 、 、 Or (b) 。
  3. 3. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, further characterized by a compound of the general formula (III-E): L 5 is selected from the group consisting of bond 、-O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O) 2 NR N -、-NR N S(O) 2 -、=CR 9a R 9b 、C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-12 cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene or 5-12 membered heteroarylene, said C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-12 cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene and 5-12 membered heteroarylene, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, c 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably selected from the group consisting of a 、-O-、-S-、-C(O)-、-NR N -、-C(O)NR N -、-NR N C(O)-、-S(O) 2 NR N -、-NR N S(O) 2 -、C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene or 5-12 membered heteroarylene, said C 1-6 alkylene, C 2-6 alkenylene, C 2-6 Alkylene, C 3-12 cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene and 5-12 membered heteroarylene, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, c 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, One or more substituents of C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, and 5-12 membered heteroaryl; L 6 is selected from the group consisting of bond 、-O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O) 2 NR N -、-NR N S(O) 2 -、=CR 9a R 9b 、C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-12 cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene or 5-12 membered heteroarylene, said C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-12 cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene and 5-12 membered heteroarylene, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, c 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably selected from the group consisting of a 、-O-、-S-、-C(O)、-NR N -、-C(O)NR N -、-NR N C(O)-、-S(O) 2 NR N -、-NR N S(O) 2 -、C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene or 5-12 membered heteroarylene, said C 1-6 alkylene, C 2-6 alkenylene, C 2-6 Alkylene, C 3-12 cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene and 5-12 membered heteroarylene, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, c 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, One or more substituents of C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, and 5-12 membered heteroaryl; L 7 is selected from the group consisting of bond 、-O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O) 2 NR N -、-NR N S(O) 2 -、=CR 9a R 9b 、C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-12 cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene or 5-12 membered heteroarylene, said C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-12 cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene and 5-12 membered heteroarylene, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, c 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably selected from the group consisting of a 、-O-、-S-、-C(O)、-NR N -、-C(O)NR N -、-NR N C(O)-、-S(O) 2 NR N -、-NR N S(O) 2 -、C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene or 5-12 membered heteroarylene, said C 1-6 alkylene, C 2-6 alkenylene, C 2-6 Alkylene, C 3-12 cycloalkylene, 3-12 membered heterocyclylene, C 6-12 arylene and 5-12 membered heteroarylene, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, c 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, One or more substituents of C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl.
  4. 4. A compound according to any one of claims 1 to 3, a stereoisomer or a pharmaceutically acceptable salt thereof, further characterized by a compound represented by the general formula (IV-E): M 5 is selected from N or CR 3a ;M 6 is selected from N or CR 3b ; R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 aryl or 5-to 12-membered heteroaryl, said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, c 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, one or more substituents of the 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl groups are substituted; R 3a 、R 3b 、R 3d and R 3e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl 、-SF 5 、-OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h or-C (=NR i )NR g R h ) said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and = one or more substituents in CR e R f ; R 3c is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl 、-SF 5 、-OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h or-C (=nr i )NR g R h ), said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, and = CR e R f .
  5. 5. A compound according to any one of claims 1 to 4, wherein ring A is selected from the group consisting of 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl and 6-membered heteroaryl, more preferably 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) ; Or, ring B is selected from 3-6 membered heterocycloalkenyl or 3-6 membered heterocycloalkenyl 5-6 membered heteroaryl, preferably 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  6. 6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, further characterized by the general formula (VI-a) or (VI-B): M 5 is selected from N or CR 3a ; M 6 is selected from N or CR 3b ; R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 aryl or 5-to 12-membered heteroaryl, said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, c 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, one or more substituents of the 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl groups are substituted; R 3a 、R 3b 、R 3d and R 3e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl 、-SF 5 、-OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h or-C (=NR i )NR g R h ) said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and = one or more substituents in CR e R f ; R 3c is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl 、-SF 5 、-OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h or-C (=nr i )NR g R h ), said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, and = CR e R f ; n11 is selected from 0,1 or 2.
  7. 7. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein, L 6 is selected from the group consisting of-O-, -S-, -C (O) NR N -、C 1-3 alkylene or C 2-4 alkenylene, the C 1-3 alkylene and C 2-4 alkenylene, optionally substituted with one or more substituents from the group consisting of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; n8 is selected from 1,2 or 3, n9 is selected from 0, 1 or 2; Or, R 2 or R 2c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl or-C (O) NR ee R ff , said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, cyano-substituted C 1-3 alkyl and C 3-8 cycloalkyl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, One or more substituents of C 1-3 haloalkyl, cyano-substituted C 1-3 alkyl and C 3-8 cycloalkyl; R ee and R ff are each independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl or cyano substituted C 1-3 alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, trifluoromethyl, 、 Or (b) ; Or, R c is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl or cyano-substituted C 1-3 alkyl; Or, R a is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl or cyano substituted C 1-3 alkyl, preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuteromethyl, difluoromethyl or trifluoromethyl.
  8. 8. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the compound has the structure: Or (b) 。
  9. 9. A pharmaceutical composition comprising a therapeutically effective amount of a compound as set forth in any one of claims 1 to 8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  10. 10. The use of a compound according to any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 in the manufacture of a medicament for a PRMT5 inhibitor.
  11. 11. The use of a compound according to any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of cancer, wherein the cancer is an MTAP-related cancer.
  12. 12. The use according to claim 11, wherein the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated multiforme sarcoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, renal cancer, endometrial cancer, ovarian tumor, prostate cancer, diffuse large B-cell lymphoma, non-hodgkin's lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer or cholangiocarcinoma, the lung cancer is selected from non-small cell lung cancer, lung squamous cell carcinoma or lung adenocarcinoma, the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

Description

Tri-fused ring derivative inhibitor, preparation method and application thereof Technical Field The invention belongs to the field of drug synthesis, and particularly relates to a tricyclic derivative inhibitor, and a preparation method and application thereof. Background Protein arginase methyltransferases (PRMTs) are classified into three major classes, type I, type II, and type III, based on catalytic activity and type of product. Type I mainly comprises PRMT1/2/3/4/6/8, which catalyzes the formation of Asymmetric Dimethylarginine (ADMA) by the substrate, type II comprises PRMT5/9, which catalyzes the formation of Symmetric Dimethylarginine (SDMA) by the substrate, and type III only comprises PRMT7, which is responsible for catalyzing the formation of monomethylarginine (MMA) by the substrate. PRMT5 uses S-adenosyl-L-methionine (SAM) as methyl donor, transfers methyl to DNA, RNA, histone and other substrates, and the arginine residue of the substrates is symmetrically and dimethyl to generate SDMA, so as to regulate and control a plurality of key cell processes including transcription, translation and DNA repair, maintain cell homeostasis, and simultaneously can participate in regulating and controlling the growth and survival pathways of tumor cells and promote tumorigenesis and development. Elevated expression of PRMT5 has also been shown to be associated with poor prognosis for a variety of cancers, a very potential epigenetic target. Methylthioadenosine phosphorylase (MTAP) catalyzes the production of methionine from Methylthioadenosine (MTA), which is critical to maintaining normal cellular function. Deletion mutations in the MTAP gene compete for intracellular accumulation of MTA, MTA and substrate SAM of PRMT5, decrease PRMT5 activity, and produce a large amount of PRMT5-MTA complex. Deletion of MTAP gene can increase dependence of tumor on PRMT5, inhibit PRMT5 from playing a role of 'synthetic death' in MTAP deleted tumor, and PARP inhibitor based on 'synthetic death' theory has been greatly successful in accurate treatment field of tumor field. MTAP gene is adjacent to the most common tumor suppressor gene CDKN2A in human cancers and is often co-deleted with CDKN2A, and the co-deletion accounts for 10% -15% of all cancers, mainly occurs in non-small cell lung cancer (12% -20%), glioma (53%), pancreatic cancer (30%), DLBCL (20%), and has a huge market prospect. At present, no PRMT5 inhibitor is marketed, and early PRMT5 inhibitors are nonselective substrate SAM competitive inhibitors, and have serious clinical blood toxic and side effects and small safety window. Clinical progress with the primary PRMT5 inhibitors GSK-3326595, JNJ-64619178 and PF-06939999 was poor. The new generation PRMT5 inhibitor of the target PRMT5-MTA complex is effective only on MTAP-deficient and MTA-enriched tumors, has higher selectivity on MTAP wild type, reduces blood toxicity in mechanism, is verified in preclinical research, and is expected to greatly improve the safety window. The patent relates to a novel PRMT5-MTA selective inhibitor which only has activity on MTAP-deleted cells, has weak inhibition on MTAP wild type cells, and can avoid side effects such as blood toxicity and the like caused by clinical nonselective PRMT5 inhibitors on MTAP wild type inhibition. The high-selectivity PRMT5-MTA inhibitor can be used as a novel PRMT5-MTA inhibitor for treating various tumors, cancers and other diseases. Disclosure of Invention The invention aims to provide a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure: M 1 is selected from-N-or-CR a -; m 2 is selected from-N-or-CR b -; M 3 is selected from N or C, preferably N; Ring A is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, or 5-14 membered heteroaryl, preferably C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 fused ring alkyl, 6-10 membered fused ring, C 6-10 aryl, or 5-10 membered heteroaryl; L 1 is selected from the group consisting of bond, -CR aaRbb-、-C(O)-、-NRccC(O)、-S(O)m1 -or NR cc, preferably, -CR aaRbb-、-C(O)-、-S(O)m1 -or NR cc; L 2 is selected from the group consisting of bond, -CR aaRbb-、-C(O)-、-S(O)m1 -or NR cc, preferably, -CR aaRbb-、-C(O)-、-S(O)m1 -or NR cc; R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, - (CR ccRdd)n1-C3-12 cycloalkyl, - (CR ccRdd)n1 -3-12 membered heterocyclyl, - (CR ccRdd)n1-C6-12 aryl, - (CR ccRdd)n1 -5-12 membered heteroaryl 、-SF5、-ORe、-NReRf、-C(O)Re、-C(O)ORe、-C(O)NReRf、-N=S(O)ReRf、-S(O)Re(=N