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EP-4741390-A1 - BIARYL RING COMPOUND, INTERMEDIATE THEREOF, PREPARATION METHOD THEREFOR AND USE THEREOF

EP4741390A1EP 4741390 A1EP4741390 A1EP 4741390A1EP-4741390-A1

Abstract

Provided are a biaryl ring compound, an intermediate thereof, a preparation method therefor and a use thereof. Specifically provided are a compound represented by Formula I, a pharmaceutically acceptable salt thereof, or an isotopic compound thereof. The ATPase activity and the inhibitory effect on proteins of the provided biaryl ring compound are greatly improved compared with the prior art.

Inventors

  • HE, Hu
  • GE, Chongxun
  • LIU, SONG
  • SHI, SONG

Assignees

  • Hangzhou Synrx Therapeutics Biomedical Technology Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240902

Claims (14)

  1. A compound of Formula I, a pharmaceutically acceptable salt thereof or an isotopic compound thereof, wherein, m and n are independently 0, 1, 2, 3 or 4; X 1 and X 4 are independently N or CR a ; X 2 and X 3 are independently N or CH; each R a is independently hydrogen, halogen, CN, OH, deuterium, cyano, -NHR f , -C(O)NHR g , C 1-6 alkyl unsubstituted or substituted by one or more R 1-1 , or C 1-6 alkoxy unsubstituted or substituted by one or more R 1-2 ; each of R 1-1 and R 1-2 is independently halogen; R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, amino, -NHC(O)R b , -NHS(O) 2 R c , -S(O) 2 NHR d , -NHR f , -C(O)NHR g , -OR h , -SR i , -C(O)R j , -S(O) 2 R k , -C(O)N(R m ) 2 , C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 , or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; each of R b , R c , R d , R e , R f , R g , R h , R i , R j , R k and R m is independently C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 , or C 1-6 alkyl unsubstituted or substituted by one or more R 1-13 ; each of R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 is independently deuterium, halogen, C 1-6 alkyl, -S(O) 2 C 1-6 alkyl or -P(O)(C 1-6 alkyl) 2 ; each R 2 is independently deuterium, halogen, cyano, amino, hydroxyl, C 1-6 alkyl unsubstituted or substituted by one or more R 2-1 , C 1-6 alkoxy unsubstituted or substituted by one or more R 2-2 , C 2-6 alkenyl unsubstituted or substituted by one or more R 2-3 , C 2-6 alkynyl unsubstituted or substituted by one or more R 2-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 2-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 2-6 , 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 2-13 , -COOR 2-7 , -C(O)R 2-8 , -C(O)N(R 2-9 ) 2 , or N(R 2-12 ) 2 ; each of R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 , R 2-6 and R 2-13 is independently deuterium, hydroxyl, cyano or halogen; each of R 2-7 , R 2-8 , R 2-9 and R 2-12 is independently hydrogen or C 1-6 alkyl; each of R 2-10 and R 2-11 is independently hydroxyl or C 1-6 alkyl; each R 3 is independently C 1-6 alkyl unsubstituted or substituted by one or more R 3-1 , C 2-6 alkenyl unsubstituted or substituted by one or more R 3-2 , C 2-6 alkynyl unsubstituted or substituted by one or more R 3-3 , C 3-6 cycloalkyl unsubstituted or substituted by one or more R 3-4 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-5 , 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 3-6 , -0-5-12 membered heteroaryl, C 6-12 aryl unsubstituted or substituted by one or more R 3-10 , -N(R 3-7 ) 2 or each of R 3-1 , R 3-2 and R 3-3 is independently 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-1 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 3-1-2 or each of R 3-4 , R 3-5 and R 3-9 is independently oxo, halogen, cyano, hydroxyl, C 1-6 alkyl unsubstituted or substituted by one or more R 3-5-1 , C 1-6 alkoxy unsubstituted or substituted by one or more R 3-5-2 , C 3-6 cycloalkyl unsubstituted or substituted by one or more R 3-5-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-5-6 , -N(R 3-5-3 ) 2 , each of R 3-6 and R 3-10 is independently oxo, halogen, cyano, hydroxyl, C 1-6 alkyl unsubstituted or substituted by one or more R 3-6-1 , C 1-6 alkoxy unsubstituted or substituted by one or more R 3-5-2 , C 3-6 cycloalkyl unsubstituted or substituted by one or more R 3-5-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-6-2 , -N(R 3-6-3 ) 2 , each R 3-7 is independently hydrogen, C 1-6 alkyl unsubstituted or substituted by one or more R 3-7-1 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-8-1 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 3-7-2 or each R 3-8 is independently C 1-6 alkyl unsubstituted or substituted by one or more R 3-7-1 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-8-1 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 3-7-2 or each of R 3-1-1 and R 3-1-2 is independently hydroxyl, cyano, halogen or C 1-6 alkyl; each R 3-1-3 is independently 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-3-1 ; each R 3-1-3-1 is independently hydroxyl, cyano, halogen or C 1-6 alkyl; each of R 3-4-1 , R 3-5-3 and R 3-6-3 is independently hydrogen or C 1-6 alkyl; each of R 3-5-1 , R 3-5-2 and R 3-7-1 is independently deuterium, hydroxyl, cyano or halogen; each of R 3-5-4 and R 3-7-3 is independently C 1-6 alkyl or C 3-6 cycloalkyl; each of R 3-5-5 , R 3-5-6 and R 3-6-2 is independently hydroxyl, cyano, halogen or C 1-6 alkyl; each R 3-6-1 is independently hydroxyl, cyano, halogen or C 1-6 alkoxy; each of R 3-7-2 and R 3-8-1 is independently hydroxyl, cyano, halogen or C 1-6 alkyl; and a heteroatom in each of the 3-12 membered heterocycloalkyl, the 4-12 membered heterocycloalkenyl, the 5-12 membered heteroaryl and -O-5-12 membered heteroaryl is independently selected from one, two or three of N, O and S, and the number of heteroatom(s) is independently 1, 2 or 3.
  2. The compound of Formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to claim 1, wherein R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b , -NHS(O) 2 R c , -S(O) 2 NHR d , -NHR f , -C(O)NHR g , -OR h , -SR i , -C(O)R j , -S(O) 2 R k -C(O)N(R m ) 2 , C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 , or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; and/or , each of R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 is independently halogen, C 1-6 alkyl, -S(O) 2 C 1-6 alkyl or -P(O)(C 1-6 alkyl) 2 ; preferably, said compound of Formula I satisfies one or two of the following conditions: (1) in each R a , said hydrogen is independently fluorine, chlorine, bromine or iodine; (2) in each R a , C 1-6 alkyl in said C 1-6 alkyl unsubstituted or substituted by one or more R 1-1 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (3) in each R a , C 1-6 alkoxy in said C 1-6 alkoxy unsubstituted or substituted by one or more R 1-2 is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (4) in each of R 1-1 and R 1-2 , said hydrogen is independently fluorine, chlorine, bromine or iodine; (5) in R 1 , said hydrogen is independently fluorine, chlorine, bromine or iodine, for example, fluorine or chlorine, for another example, fluorine; (6) in R 1 , C 1-6 alkyl in said C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl, n-propyl, isopropyl or tert-butyl, for another example, methyl, isopropyl or tert-butyl; (7) in R 1 , C 1-6 alkoxy in said C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, for example, methoxy; (8) in R 1 , C 3-10 cycloalkyl in said C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl or cyclobutyl, for another example, cyclopropyl; (9) in R 1 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 is independently 5-8 membered heterocycloalkyl; (10) in R 1 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 has a heteroatom that is independently N and/or O; (11) in R 1 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 has the number of heteroatom(s) that is independently 1 or 2, for example, 2; (12) in R 1 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 is independently a monocyclic ring, a bridged ring, a fused ring or a spiro ring; in said spiro ring, fused ring or bridged ring, the number of rings can be 2; said spiro ring can be 3-membered spiro 5-membered heterocyclyl, 3-membered spiro 6-membered heterocyclyl, 4-membered spiro 4-membered heterocyclyl, 4-membered spiro 5-membered heterocyclyl, 4-membered spiro 6-membered heterocyclyl, 4-membered spiro 7-membered heterocyclyl, 5-membered spiro 4-membered heterocyclyl, 5-membered spiro 5-membered heterocyclyl, 5-membered spiro 6-membered heterocyclyl, 5-membered spiro 7-membered heterocyclyl, 6-membered spiro 4-membered heterocyclyl, 6-membered spiro 5-membered heterocyclyl or 6-membered spiro 6-membered heterocyclyl, for example, 4-membered spiro 4-membered heterocyclyl; said fused ring can be as set forth in scheme 1 or scheme 2 as follows: in scheme 1: said fused ring is 4-membered fused 5-membered heterocyclyl, 4-membered fused 6-membered heterocyclyl, 5-membered fused 5-membered heterocyclyl, 5-membered fused 6-membered heterocyclyl or 6-membered fused 6-membered heterocyclyl, for example, 5-membered fused 5-membered heterocyclyl; in scheme 2: said fused ring is 3-membered fused 5-membered heterocyclyl, 4-membered fused 5-membered heterocyclyl, 4-membered fused 6-membered heterocyclyl, 5-membered fused 5-membered heterocyclyl, 5-membered fused 6-membered heterocyclyl or 6-membered fused 6-membered heterocyclyl, for example, 3-membered fused 5-membered heterocyclyl or 5-membered fused 5-membered heterocyclyl; said bridged ring can be 4-membered bridged 5-membered heterocyclyl, 4-membered bridged 6-membered heterocyclyl, 5-membered bridged 6-membered heterocyclyl or 6-membered bridged 6-membered heterocyclyl, for example, 4-membered bridged 6-membered heterocyclyl; (13) in R 1 , C 6-12 aryl in said C 6-12 aryl unsubstituted or substituted by one or more R 1-7 is independently phenyl or naphthyl, for example, phenyl; (14) in R 1 , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 is a monocyclic ring; (15) in R 1 , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 is independently 5-6 membered heteroaryl; (16) in R 1 , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 has a heteroatom that is N and/or O, for example, N; (17) in R 1 , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 has the number of heteroatom(s) that is 1 or 2; (18) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , C 3-10 cycloalkyl in said C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl; (19) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 is independently a monocyclic ring, a bridged ring or a fused ring; in said fused ring or bridged ring, the number of rings can be 2; said fused ring can be 4-membered fused 5-membered heterocyclyl, 4-membered fused 6-membered heterocyclyl, 5-membered fused 5-membered heterocyclyl, 5-membered fused 6-membered heterocyclyl or 6-membered fused 6-membered heterocyclyl, for example, 5-membered fused 5-membered heterocyclyl; said bridged ring can be 4-membered bridged 5-membered heterocyclyl, 4-membered bridged 6-membered heterocyclyl, 5-membered bridged 6-membered heterocyclyl or 6-membered bridged 6-membered heterocyclyl, for example, 4-membered bridged 6-membered heterocyclyl; (20) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 is independently 4-8 membered heterocycloalkyl; (21) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 has a heteroatom that is independently N and/or O; (22) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 has the number of heteroatom(s) that is independently 1 or 2; (23) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , C 6-12 aryl in said C 6-12 aryl unsubstituted or substituted by one or more R 1-11 is independently phenyl or naphthyl, for example, phenyl; (24) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 is a monocyclic ring; (25) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 is independently 5-6 membered heteroaryl; (26) in R b , R c , R d , each R e , R f , R g , R h , R i , R j and R k , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 has a heteroatom that is N; (27) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 has the number of heteroatom(s) that is independently 1 or 2; (28) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , C 1-6 alkyl in said C 1-6 alkyl unsubstituted or substituted by one or more R 1-13 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; (29) in each of R 1-3 , R 1-4 R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 , said hydrogen is independently fluorine, chlorine, bromine or iodine, for example, fluorine or chlorine; (30) in each of R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 , each of said C 1-6 alkyl, C 1-6 alkyl in said -S(O) 2 C 1-6 alkyl and C 1-6 alkyl in said -P(O)(C 1-6 alkyl) 2 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; (31) in R 1 , "more" in each case refers to 2 or 3, for example, 2; (32) in each R 2 , said hydrogen is independently fluorine, chlorine, bromine or iodine, fluorine or chlorine; (33) in each R 2 , C 1-6 alkyl in said C 1-6 alkyl unsubstituted or substituted by one or more R 2-1 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; (34) in each R 2 , "more" in each case refers to 2 or 3, for example, 2; (35) in each R 2 , C 1-6 alkoxy in said C 1-6 alkoxy unsubstituted or substituted by one or more R 2-2 is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, for example, methoxy; (36) in each of R 2-1 and R 2-2 , said hydrogen is independently fluorine, chlorine, bromine or iodine, for example, fluorine; (37) in each R 3 , C 1-6 alkyl in said C 1-6 alkyl unsubstituted or substituted by one or more R 3-1 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; (38) in each R 3 , 4-12 membered heterocycloalkenyl in said 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 is a monocyclic ring or a fused ring; in said fused ring, the number of rings can be 2; and said fused ring can be 4-membered fused 5 membered heterocycloalkenyl, 4-membered fused 6 membered heterocycloalkenyl, 5-membered fused 5 membered heterocycloalkenyl, 5-membered fused 6 membered heterocycloalkenyl or 6-membered fused 6 membered heterocycloalkenyl, for example, 5-membered fused 6 membered heterocycloalkenyl; (39) in each R 3 , 4-12 membered heterocycloalkenyl in said 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 is independently 5-9 membered heterocycloalkenyl, for example, 5-6 membered heterocycloalkenyl; (40) in each R 3 , 4-12 membered heterocycloalkenyl in said 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 has a heteroatom that is N; (41) in each R 3 , 4-12 membered heterocycloalkenyl in said 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 has the number of heteroatom(s) that is 1 or 2, for example, 1; (42) in each R 3 , 4-12 membered heterocycloalkenyl in said 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 has the number of double bond(s) that is 1 or 2, for example, 2; (43) in each R 3 , C 2-6 alkynyl in said C 2-6 alkynyl unsubstituted or substituted by one or more R 3-3 is independently ethynyl, propinyl or propargyl, for example, ethynyl; (44) in each R 3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-5 is independently a bridged ring or a spiro ring; in said spiro ring or bridged ring, the number of rings can be 2, and said spiro ring can be 3-membered spiro 5-membered heterocyclyl, 3-membered spiro 6-membered heterocyclyl, 4-membered spiro 4-membered heterocyclyl, 4-membered spiro 5-membered heterocyclyl, 4-membered spiro 6-membered heterocyclyl, 4-membered spiro 7-membered heterocyclyl, 5-membered spiro 4-membered heterocyclyl, 5-membered spiro 5-membered heterocyclyl, 5-membered spiro 6-membered heterocyclyl, 5-membered spiro 7-membered heterocyclyl, 6-membered spiro 4-membered heterocyclyl, 6-membered spiro 5-membered heterocyclyl or 6-membered spiro 6-membered heterocyclyl, for example, 3-membered spiro 6 membered heterocycloalkyl; and said bridged ring can be 4-membered bridged 5 membered heterocycloalkyl, 4-membered bridged 6 membered heterocycloalkyl, 5-membered bridged 6 membered heterocycloalkyl or 6-membered bridged 6 membered heterocycloalkyl, for example, 4-membered bridged 6 membered heterocycloalkyl; (45) in each R 3 , 3-12 membered heterocycloalkyl in said 3-12-membered heterocycloalkane unsubstituted or substituted by one or more R 3-5 is independently 6-8 membered heterocycloalkyl; (46) in each R 3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-5 has a heteroatom that is N; (47) in each R 3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-5 has the number of heteroatom(s) that is independently 1 or 2; (48) in each R 3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-5 is 6-8 membered heterocycloalkyl, said 6-8 membered heterocycloalkyl has a heteroatom that is N, and the number of heteroatom(s) is 1 or 2, for example, (49) in each R 3 , C 6-12 aryl in said C 6-12 aryl unsubstituted or substituted by one or more R 3-10 is phenyl or naphthyl, for example, phenyl; (50) in each R 3 , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 3-6 is a monocyclic ring or a fused ring, and in said fused ring, the number of rings can be 2; (51) in each R 3 , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 3-6 is 5-9 membered heteroaryl; (52) in each R 3 , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 3-6 has a heteroatom that is N and/or O; (53) in each R 3 , "more" in each case refers to 2 or 3, for example, 2; (54) in each of R 3-1 and R 3-3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-1 is a monocyclic ring; (55) in each of R 3-1 and R 3-3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-1 is 5-6 membered heterocycloalkyl; (56) in each of R 3-1 and R 3-3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-1 has a heteroatom that is N and/or O, for example, O; (57) in each of R 3-1 and R 3-3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-1 has the number of heteroatom(s) that is 1 or 2, for example, 1; (58) in each of R 3-5 and R 3-9 , said hydrogen is independently fluorine, chlorine, bromine or iodine, for example, fluorine or chlorine; (59) in each of R 3-5 and R 3-9 , C 1-6 alkyl in said C 1-6 alkyl unsubstituted or substituted by one or more R 3-5-1 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example, methyl; (60) in each of R 3-5 and R 3-9 , C 1-6 alkyl in said C 1-6 alkoxy unsubstituted or substituted by one or more R 3-5-1 is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example, methoxy; (61) in each of R 3-6 and R 3-10 , C 1-6 alkyl in said C 1-6 alkyl unsubstituted or substituted by one or more R 3-6-1 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example, methyl; (62) in each R 3-8 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-8-1 is a monocyclic ring; (63) in each R 3-8 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-8-1 is 5-6 membered heterocycloalkyl; (64) in each R 3-8 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-8-1 has a heteroatom that is N and/or O; (65) in each R 3-8 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-8-1 has the number of heteroatom(s) that is 1 or 2, for example, 2; (66) in each R 3-1-3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-3-1 is a monocyclic ring; (67) in each R 3-1-3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-3-1 is 5-6 membered heterocycloalkyl; (68) in each R 3-1-3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-3-1 has a heteroatom that is N and/or O; (69) in each R 3-1-3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-3-1 has the number of heteroatom(s) that is 1 or 2, for example, 2; and (70) in each R 3-5-1 , said hydrogen is independently fluorine, chlorine, bromine or iodine, for example, fluorine.
  3. The compound of Formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to claim 2, which satisfies one or more of the following conditions: (1) in R 1 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 is independently 5-8 membered heterocycloalkyl, said 5-8 membered heterocycloalkyl has a heteroatom that is N and/or O, and the number of heteroatom(s) is 1 or 2, for example, for another example, (2) in R 1 , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 is 5-6 membered heteroaryl, said 5-6 membered heteroaryl has a heteroatom that is N and/or O, and the number of heteroatom(s) is 1 or 2, for example, preferably, in R 1 , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 is 5-6 membered heteroaryl, said 5-6 membered heteroaryl has a heteroatom that is N, and the number of heteroatom(s) is 1 or 2, for example, (3) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 is independently 4-8 membered heterocycloalkyl, said 4-8 membered heterocycloalkyl has a heteroatom that is N and/or O, and the number of heteroatom(s) is 1 or 2, for example, (4) in R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 is independently 5-6 membered heteroaryl, said 5-6 membered heteroaryl has a heteroatom that is N, and the number of heteroatom(s) is 1 or 2, for example, (5) in each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 , said -S(O) 2 C 1-6 alkyl is (6) in each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 , -P(O)(C 1-6 alkyl) 2 is (7) in each R 2 , said C 1-6 alkyl substituted by one or more R 2-1 is (8) in each R 3 , 4-12 membered heterocycloalkenylin said 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 is independently 5-9 membered heterocycloalkenyl, said 5-9 membered heterocycloalkenyl has a heteroatom that is N, the number of heteroatom(s) is 1 or 2, and in said 5-9 membered heterocycloalkenyl, the number of double bond(s) is 1 or 2, for example, (9) in each R 3 , 5-12 membered heteroaryl in said 5-12 membered heteroaryl unsubstituted or substituted by one or more R 3-6 is 5-9 membered heteroaryl, said 5-9 membered heteroaryl has a heteroatom that is N and/or O, and the number of heteroatom(s) is 1, 2 or 3, for example, or for another example, (10) in each of R 3-1 and R 3-3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-1 is 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl has a heteroatom that is N and/or O, and the number of heteroatom(s) is 1 or 2, for example, (11) in each R 3-8 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-8-1 is 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl has a heteroatom that is N and/or O, and the number of heteroatom(s) is 1 or 2, for example, (12) in each R 3-1-3 , 3-12 membered heterocycloalkyl in said 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-3-1 is 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl has a heteroatom that is N and/or O, and the number of heteroatom(s) is 1 or 2, for example, (13) in each of R 3-5 and R 3-9 , said C 1-6 alkyl substituted by one or more R 3-5-1 is
  4. The compound of Formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to any one of claims 1 to 3, which satisfies one or more of the following conditions: (1) R a is hydrogen; (2) X 2 is N; (3) X 3 is N; (4) R b is as set forth in scheme 1 or scheme 2 as follows: in scheme 1: R b is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 ; preferably, R b is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 or C 6-12 aryl unsubstituted or substituted by one or more R 1-11 ; more preferably, R b is unsubstituted C 3-10 cycloalkyl or unsubstituted C 6-12 aryl; in scheme 2: R b is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 or C 1-6 alkyl unsubstituted or substituted by one or more R 1-13 ; preferably, R b is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 or C 1-6 alkyl unsubstituted or substituted by one or more R 1-13 ; more preferably, R b is unsubstituted C 3-10 cycloalkyl, unsubstituted C 6-12 aryl or unsubstituted C 1-6 alkyl, most preferably, R b is unsubstituted C 1-6 alkyl; (5) R c is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 or 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 ; preferably, R c is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 ; more preferably, R c is unsubstituted C 3-10 cycloalkyl; (6) R d is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 or 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 ; preferably, R d is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 ; more preferably, R d is unsubstituted C 3-10 cycloalkyl; (7) R e is C 1-6 alkyl unsubstituted or substituted by one or more R 1-13 ; preferably, R e is unsubstituted C 1-6 alkyl; (8) R f is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 ; preferably, R f is 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 ; more preferably, R f is unsubstituted 3-12 membered heterocycloalkyl, unsubstituted C 6-12 aryl or unsubstituted 5-12 membered heteroaryl; (9) R g is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 or 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 ; preferably, R g is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 ; more preferably, R g is unsubstituted C 3-10 cycloalkyl; (10) R h is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 ; preferably, R h is as set forth in scheme 1 or scheme 2 as follows: in scheme 1: R h is 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 ; more preferably, R h is unsubstituted 3-12 membered heterocycloalkyl, unsubstituted C 6-12 aryl or unsubstituted 5-12 membered heteroaryl; in scheme 2: R h is unsubstituted C 3-10 cycloalkyl, unsubstituted 3-12 membered heterocycloalkyl or unsubstituted C 6-12 aryl or unsubstituted 5-12 membered heteroaryl; (11) R i is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 or C 6-12 aryl unsubstituted or substituted by one or more R 1-11 ; preferably, R i is 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 or C 6-12 aryl unsubstituted or substituted by one or more R 1-11 ; more preferably, R i is unsubstituted 3-12 membered heterocycloalkyl or unsubstituted C 6-12 aryl; (12) R j is C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 ; preferably, R j is 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 ; more preferably, R j is unsubstituted 3-12 membered heterocycloalkyl or unsubstituted 5-12 membered heteroaryl; (13) R k is C 6-12 aryl unsubstituted or substituted by one or more R 1-11 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 or C 1-6 alkyl unsubstituted or substituted by one or more R 1-13 ; preferably, R k is 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 or C 1-6 alkyl unsubstituted or substituted by one or more R 1-13 ; more preferably, R k is unsubstituted 5-12 membered heteroaryl or unsubstituted C 1-6 alkyl; (14) each R 1-3 is independently halogen; (15) each R 1-4 is independently halogen; (16) each R 1-5 is independently halogen or C 1-6 alkyl; preferably, each R 1-5 is independently C 1-6 alkyl; (17) each R 1-6 is independently halogen or C 1-6 alkyl; preferably, each R 1-6 is independently C 1-6 alkyl; (18) each R 1-7 is independently halogen or C 1-6 alkyl; preferably, each R 1-7 is independently halogen; (19) each R 1-8 is independently C 1-6 alkyl, -S(O) 2 C 1-6 alkyl or -P(O)(C 1-6 alkyl) 2 ; preferably, R 1-8 is independently C 1-6 alkyl; (20) R 1 is as set forth in scheme 1 or a scheme 2 as follows: in scheme 1: R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b , -NHS(O) 2 R c , -S(O) 2 NHR d , -NHR f , -C(O)NHR g , -OR h , -SR i , - C(O)R j , -S(O) 2 R k , C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 , or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; preferably, R 1 is hydrogen, C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 , or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; more preferably, R 1 is hydrogen, C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 , or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; most preferably, R 1 is hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 alkoxy, unsubstituted C 3-10 cycloalkyl, unsubstituted C 6-12 aryl or unsubstituted 5-12 membered heteroaryl; in scheme 2: R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, amino, -NHC(O)R b , -NHS(O) 2 R c , - S(O) 2 NHR d , -NHR f , -C(O)NHR g , -OR h , -SR i , -C(O)R j , -S(O) 2 R k , C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; preferably, R 1 is hydrogen, halogen, amino, -NHC(O)R b , C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; more preferably, R 1 is hydrogen, halogen, amino, -NHC(O)R b , unsubstituted C 1-6 alkyl, unsubstituted C 1-6 alkoxy, unsubstituted C 3-10 cycloalkyl, 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; most preferably, R 1 is hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 alkoxy, unsubstituted C 3-10 cycloalkyl, unsubstituted 3-12 membered heterocycloalkyl, unsubstituted C 6-12 aryl, or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; (21) m is 1, 2 or 3; preferably, m is 1 or 2; more preferably, m is 2; (22) n is 1, 2 or 3; preferably, n is 1; (23) each of R 2-1 and R 2-2 is independently halogen; (24) each R 2 is independently halogen, C 1-6 alkyl unsubstituted or substituted by one or more R 2-1 or C 1-6 alkoxy; preferably unsubstituted or substituted by one or more R 2-2 , each R 2 is independently halogen, C 1-6 alkyl substituted by one or more R 2-1 , or unsubstituted C 1-6 alkoxy; (25) each R 3-1 is independently (26) each R 3-1-3 is independently unsubstituted 3-12 membered heterocycloalkyl; (27) each R 3-3 is independently 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-1 ; preferably, each R 3-3 is independently unsubstituted 3-12 membered heterocycloalkyl; (28) each R 3-5 is independently oxo or C 1-6 alkyl unsubstituted or substituted by one or more R 3-5-1 ; preferably, each R 3-5 is independently oxo or unsubstituted C 1-6 alkyl; (29) each R 3-6 is independently cyano or C 1-6 alkyl unsubstituted or substituted by one or more R 3-6-1 ; preferably, each R 3-6 is independently cyano or unsubstituted C 1-6 alkyl; (30) each R 3-10 is independently hydroxyl; (31) each R 3-8 is independently 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-8-1 ; preferably, each R 3-8 is independently unsubstituted 3-12 membered heterocycloalkyl; (32) each R 3-9 is independently oxo, halogen, cyano, hydroxyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 3-5-1 or C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 3-5-2 ; preferably, each R 3-9 is independently oxo, halogen, C 1-6 alkyl unsubstituted or substituted by one or more \R 3-5-1 , or C 1-6 alkoxy unsubstituted or substituted by one or more R 3-5-2 ; more preferably, each R 3-9 is independently oxo, halogen, C 1-6 alkyl substituted by one or more R 3-5-1 , or unsubstituted C 1-6 alkoxy; most preferably, each R 3-9 is independently oxo or halogen; (33) each R 3-5-1 is independently halogen; (34) each R 3 is independently C 1-6 alkyl unsubstituted or substituted by one or more R 3-1 , C 2-6 alkynyl unsubstituted or substituted by one or more R 3-3 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-5 , 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 3-6 , C 6-12 aryl unsubstituted or substituted by one or more R 3-10 or preferably, each R 3 is independently C 1-6 alkyl unsubstituted or substituted by one or more R 3-1 , C 3-6 cycloalkyl unsubstituted or substituted by one or more R 3-4 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-5 or 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 ; more preferably, each R 3 is independently C 1-6 alkyl unsubstituted or substituted by one or more R 3-1 or 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 ; most preferably, each R 3 is independently unsubstituted C 1-6 alkyl or 4-12 membered heterocycloalkenyl substituted by one or more R 3-9 , for example, 4-12 membered heterocycloalkenyl substituted by one or more R 3-9 ; and (35) X 4 is N.
  5. The compound of Formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to any one of claims 1 to 4, wherein said compound of Formula I is as set forth in scheme 1, scheme 2, scheme 3, scheme 4, scheme 5, scheme 6 or scheme 7 as follows: in scheme 1: m and n are independently 1, 2 or 3; X 1 is N or CH; X 2 is N or CH; X 3 is N; X 4 is N or CH; R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b , -NHS(O) 2 R c , -S(O) 2 NHR d , NHR f , -C(O) NHR g , -OR h , -SR i , -C(O)R j , -S(O) 2 R k , C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; R b , R c , R d , each R e , R f , R g , R h , R i , R j and R k are each independently C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 or C 1-6 alkyl unsubstituted or substituted by one or more R 1-13 ; each of R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 is independently halogen, C 1-6 alkyl, - S(O) 2 C 1-6 alkyl or -P(O)(C 1-6 alkyl) 2 ; each R 2 is independently halogen, C 1-6 alkyl unsubstituted or substituted by one or more R 2-1 or C 1-6 alkoxy unsubstituted or substituted by one or more R 2-2 ; each of R 2-1 and R 2-2 is independently halogen; each R 3 is independently C 1-6 alkyl unsubstituted or substituted by one or more R 3-1 , C 2-6 alkynyl unsubstituted or substituted by one or more R 3-3 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-5 , 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 3-6 , C 6-12 aryl unsubstituted or substituted by one or more R 3-10 or each R 3-1 is independently each R 3-3 is independently 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-1 ; each R 3-5 is independently oxo or C 1-6 alkyl unsubstituted or substituted by one or more R 3-5-1 ; each R 3-6 is independently cyano or C 1-6 alkyl unsubstituted or substituted by one or more R 3-6-1 ; each R 3-9 is independently oxo, halogen, C 1-6 alkyl unsubstituted or substituted by one or more R 3-5-1 or C 1-6 alkoxy unsubstituted or substituted by one or more R 3-5-2 ; each R 3-8 is independently 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-8-1 ; each R 3-10 is independently hydroxyl; each R 3-1-1 is independently hydroxyl, cyano, halogen or C 1-6 alkyl; each R 3-1-3 is independently unsubstituted 3-12 membered heterocycloalkyl; each of R 3-5-1 and R 3-5-2 is independently deuterium, hydroxyl, cyano or halogen; each R 3-6-1 is independently hydroxyl, cyano, halogen or C 1-6 alkoxy; each R 3-8-1 is independently hydroxyl, cyano, halogen or C 1-6 alkyl; each of 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl has a heteroatom that is independently selected from one, two or three of N, O and S, and the number of heteroatom(s) is independently 1, 2 or 3; in scheme 2: m is 1 or 2; n is 1; X 1 is N or CH; X 2 is N or CH; X 3 is N; X 4 is N; R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b , -NHS(O) 2 R c , -S(O) 2 NHR d , NHR f , -C(O) NHR g , -OR h , -SR i , -C(O)R j , -S(O) 2 R k , C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 , or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; R b , R c , R d , each R e , R f , R g , R h , R i , R j and R k are each independently C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 , or C 1-6 alkyl unsubstituted or substituted by one or more R 1-13 ; each of R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 is independently halogen, C 1-6 alkyl, - S(O) 2 C 1-6 alkyl or -P(O)(C 1-6 alkyl) 2 ; each R 2 is independently halogen, C 1-6 alkyl unsubstituted or substituted by one or more R 2-1 or C 1-6 alkoxy unsubstituted or substituted by one or more R 2-2 ; each of R 2-1 and R 2-2 is independently halogen; each R 3 is independently unsubstituted C 1-6 alkyl or 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 ; each R 3-9 is independently oxo or halogen; each of 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl has a heteroatom that is independently selected from one, two or three of N, O and S, and the number of heteroatom(s) is independently 1, 2 or 3; in scheme 3: m is 1 or 2; n is 1; X 1 is N or CH; X 2 , X 3 and X 4 are N; R 1 is hydrogen, C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 , or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; each of R 1-3 and R 1-4 is independently halogen; each of R 1-5 , R 1-6 , R 1-7 and R 1-8 is independently halogen or C 1-6 alkyl; each R 2 is independently halogen, C 1-6 alkyl unsubstituted or substituted by one or more R 2-1 or C 1-6 alkoxy unsubstituted or substituted by one or more R 2-2 ; each of R 2-1 and R 2-2 is independently halogen; each R 3 is independently unsubstituted C 1-6 alkyl or 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 ; each R 3-9 is independently oxo or halogen; each of 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl has a heteroatom that is independently selected from one, two or three of N, O and S, and the number of heteroatom(s) is independently 1, 2 or 3; in scheme 4: m and n are independently 1, 2 or 3; X 1 is N or CH; X 2 is N or CH; X 3 is N; X 4 is N or CH; R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, amino, -NHC(O)R b , -NHS(O) 2 R c , -S(O) 2 NHR d , -NHR f , -C(O) NHR g , -OR h , -SR i , -C(O)R j , -S(O) 2 R k , C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 , or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; R b , R c , R d , each R e , R f , R g , R h , R i , R j and R k are each independently C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-9 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-10 , C 6-12 aryl unsubstituted or substituted by one or more R 1-11 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-12 , or C 1-6 alkyl unsubstituted or substituted by one or more R 1-13 ; each of R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 is independently halogen, C 1-6 alkyl, - S(O) 2 C 1-6 alkyl or -P(O)(C 1-6 alkyl) 2 ; each R 2 is independently halogen, C 1-6 alkyl unsubstituted or substituted by one or more R 2-1 , or C 1-6 alkoxy unsubstituted or substituted by one or more R 2-2 ; each of R 2-1 and R 2-2 is independently halogen; each R 3 is independently C 1-6 alkyl unsubstituted or substituted by one or more R 3-1 , C 2-6 alkynyl unsubstituted or substituted by one or more R 3-3 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-5 , 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 , 5-12 membered heteroaryl unsubstituted or substituted by one or more R 3-6 , C 6-12 aryl unsubstituted or substituted by one or more R 3-10 or each R 3-1 is independently each R 3-3 is independently 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-1-1 ; each R 3-5 is independently oxo or C 1-6 alkyl unsubstituted or substituted by one or more R 3-5-1 ; each R 3-6 is independently cyano or C 1-6 alkyl unsubstituted or substituted by one or more R 3-6-1 ; each R 3-9 is independently oxo, halogen, C 1-6 alkyl unsubstituted or substituted by one or more R 3-5-1 or C 1-6 alkoxy unsubstituted or substituted by one or more R 3-5-2 ; each R 3-8 is independently 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 3-8-1 ; each R 3-10 is independently hydroxyl; each R 3-1-1 is independently hydroxyl, cyano, halogen or C 1-6 alkyl; each R 3-1-3 is independently unsubstituted 3-12 membered heterocycloalkyl; each of R 3-5-1 and R 3-5-2 is independently deuterium, hydroxyl, cyano or halogen; each R 3-6-1 is independently hydroxyl, cyano, halogen or C 1-6 alkoxy; each R 3-8-1 is independently hydroxyl, cyano, halogen or C 1-6 alkyl; each of 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl has a heteroatom that is independently selected from one, two or three of N, O and S, and the number of heteroatom(s) is independently 1, 2 or 3; in scheme 5: m is 1 or 2; n is 1; X 1 is N or CH; X 2 , X 3 and X 4 are N; R 1 is hydrogen, halogen, amino, -NHC(O)R b , C 1-6 alkyl unsubstituted or substituted by one or more R 1-3 , C 1-6 alkoxy unsubstituted or substituted by one or more R 1-4 , C 3-10 cycloalkyl unsubstituted or substituted by one or more R 1-5 , 3-12 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-6 , C 6-12 aryl unsubstituted or substituted by one or more R 1-7 or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; each of R 1-3 and R 1-4 is independently halogen; each of R 1-5 , R 1-6 , R 1-7 and R 1-8 is independently halogen or C 1-6 alkyl; R b is unsubstituted C 1-6 alkyl; each R 2 is independently halogen, C 1-6 alkyl unsubstituted or substituted by one or more R 2-1 or C 1-6 alkoxy unsubstituted or substituted by one or more R 2-2 ; each of R 2-1 and R 2-2 is independently halogen; each R 3 is independently unsubstituted C 1-6 alkyl or 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 ; each R 3-9 is independently oxo or halogen; each of 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl has a heteroatom that is independently selected from one, two or three of N, O and S, and the number of heteroatom(s) is independently 1, 2 or 3; in scheme 6: m is 1 or 2; n is 1; X 1 is N or CH; X 2 , X 3 and X 4 are N; R 1 is hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 alkoxy, unsubstituted C 3-10 cycloalkyl, unsubstituted 3-12 membered heterocycloalkyl, unsubstituted C 6-12 aryl or 5-12 membered heteroaryl unsubstituted or substituted by one or more R 1-8 ; each R 1-8 is independently C 1-6 alkyl; each R 2 is independently halogen, C 1-6 alkyl unsubstituted or substituted by one or more R 2-1 or C 1-6 alkoxy unsubstituted or substituted by one or more R 2-2 ; each of R 2-1 and R 2-2 is independently halogen; R 3 is 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 ; each R 3-9 is independently oxo or halogen; each of 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl has a heteroatom that is independently selected from one, two or three of N, O and S, and the number of heteroatom(s) is independently 1, 2 or 3; in scheme 7: m is 1 or 2; n is 1; X 2 and X 3 are N; each R 2 is independently halogen, C 1-6 alkyl unsubstituted or substituted by one or more R 2-1 or C 1-6 alkoxy unsubstituted or substituted by one or more R 2-2 ; each of R 2-1 and R 2-2 is independently halogen; R 3 is 4-12 membered heterocycloalkenyl unsubstituted or substituted by one or more R 3-9 ; each R 3-9 is independently oxo or halogen; and each 4-12 membered heterocycloalkenyl has a heteroatom that is independently selected from one, two or three of N, O and S, and the number of heteroatom(s) is independently 1, 2 or 3.
  6. The compound of Formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to any one of claims 1 to 5 , which satisfies one or more of the following conditions: (1) R 1 is as set forth in scheme 1 or scheme 2 as follows: in scheme 1: R 1 is hydrogen, deuterium, cyano, hydroxyl, fluorine, methyl, preferably, R 1 is hydrogen, methyl, in scheme 2: R 1 is hydrogen, deuterium, cyano, hydroxyl, fluorine, methyl, or preferably, R 1 is hydrogen, methyl, (2) R 2 is F or Cl; and (3) R 3 is methyl, preferably, R 3 is or methyl, for example,
  7. The compound of Formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to claim 6, which satisfies one or more of the following conditions: (1) is as set forth in scheme 1 or scheme 2 as follows, in scheme 1 preferably, in scheme 2: preferably, more preferably, most preferably, and (2) or preferably,
  8. The compound of Formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to claim 1, wherein said compound of Formula I is any one of the following compounds: and
  9. A pharmaceutical composition, comprising: (1) a substance A, which is the compound of Formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to any one of claims 1 to 8; and (2) a pharmaceutical excipient.
  10. Use of a substance A or the pharmaceutical composition according to claim 9 in preparation of a polymerase theta inhibitor, wherein said substance A is the compound of formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to any one of claims 1 to 8.
  11. Use of a substance A or the pharmaceutical composition according to claim 9 in preparation of a medicament, wherein said substance A is the compound of Formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to any one of claims 1 to 8; and said medicament is used for treatment and/or prevention of lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer or colon cancer.
  12. Use of a substance A or the pharmaceutical composition according to claim 9 in preparation of a medicament for treatment and/or prevention of polymerase theta-related diseases, wherein said substance A is the compound of Formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to any one of claims 1 to 8; and said polymerase theta-related diseases comprise lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer or colon cancer.
  13. A compound of Formula II, or a salt thereof: wherein R v is halogen; preferably, said compound of Formula II is
  14. A method for treating a disease or a polymerase theta-related disease, comprising a step of: administering a substance A or the pharmaceutical composition according to claim 9 to a subject, wherein said substance A is the compound of Formula I, the pharmaceutically acceptable salt thereof or the isotopic compound thereof according to any one of claims 1 to 8; and said disease and said polymerase theta-related disease are independently lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer or colon cancer.

Description

This application claims priorities to Chinese Patent Application No. 202311124367X filed on September 1, 2023, Chinese Patent Application No. 2023114104077 filed on October 27, 2023, and Chinese Patent Application No. 2023118384594 filed on December 28, 2023. The present application makes reference to the full texts of the Chinese Patent Applications above. FIELD OF THE INTVENTION The present invention relates to a biaryl cyclic compound, intermediates thereof, a preparation method therefor and use thereof. BACKGROUND OF THE INVENTION DNA damage is an important mechanism for many chemotherapy drugs to exert anti-tumor effects. DNA double-strand breaks (DSBs) are one of the most common types of damage in cells, which can be directly caused by ionizing radiation or induced by ultraviolet light, reactive oxygen species (ROS), or other mutagens, such as common chemotherapy drugs like cisplatin, 5-FU, and etoposide. Unrepaired DNA damage may lead to functional blockage such as cell transcription and replication, inducing apoptosis or necrosis, and clearance by immune cells. In tumor cells, there is an efficient damage repair pathway or alternative repair pathway. It is one of the important strategies for cancer treatment to target the key proteins of the DNA damage repair pathway, allowing for the constant accumulation of unrepaired DNA damage to eventually lead to cell death. The DNA DSBs are typically repaired in three ways, including non-homologous end joining (NHEJ), homologous recombination (HR), and alternative non-homologous end joining (Alt-NHEJ, also known as microhomology-mediated end joining (MMEJ) or theta-mediated end joining (TMEJ)). Here, the HR repair pathway only occurs in phases G2 and S to complete error-free repair in the presence of sister chromatids. In mammals, more than 90% of DSB damage is repaired by the NHEJ pathway. This repair is error-prone, resulting in the deletion mutation of < 30 bp, or the insertion mutation of < 5 bp, or the micro-homologous sequence of < 2 bp. Recent studies have shown that, in the case of HR and/or NHEJ deficiency, cells are highly dependent on the third way, i.e., MMEJ, to repair the broken DNAs. Inhibition of MMEJ leads to apoptosis. MMEJ, which is also an error-prone repair pathway, relies on DNA polymerase theta to link theta mediated end joining (TMEJ) sequences, thereby completing the repair of DNA double-strand breaks. DNA polymerase theta (Pol theta or Pol θ), a key protein in the MMEJ repair pathway, is a unique multifunctional polymerase composed of an N-terminus helicase domain, a central domain, and a C-terminus polymerase domain. Basic studies have found that the polymerase domain is essential for DNA extension of DSB damage repair sites, and the helicase domain and the central domain play a key role in the recognition and binding of Pol θ to a substrate. Pol θ can eliminate the interaction between DNA and damage repair complexes (such as competition with RAD51 for binding to single-stranded DNA) and inhibit the HR repair pathway. In addition, the helicase domain of Pol θ is also involved in DNA replication blockage, and its function deficiency leads to increased replication pressure and apoptosis of tumor cells. Pol θ is not expressed or expressed at a low level in normal tissue cells, but is highly expressed in a variety of tumors such as lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, and colon cancer, and it is associated with worse prognosis. Pol θ is overexpressed in more than 70% of breast cancers. These facts indicate that Pol θ may play an important role in these cancers and is a potential tumor-specific target. Studies on knockdown or knockout of Pol θ in tumor cells have found that Pol θ deficiency can sensitize these cells to ionizing radiation, induce DSB production, enhance replication fork instability, and make tumor cells sensitive to genotoxic agents, which may enhance the effect of radiotherapy and chemotherapy, and Pol θ is a potential drug target. The studies have also found that Pol θ shows a synthetic lethality effect with HR deficiency, and its small molecule inhibitors can kill HR-deficient tumor cells in vitro and in vivo. In particular, in tumors resistant to PARP inhibitors (Olaparib, etc.) with HR deficiency reverse mutations, Pol θ inhibitors can sensitize cells to PARPi again, providing valuable therapeutic opportunities. In addition, given that Pol θ is a key protein in the MMEJ pathway, its functional impairment also leads to intensified genomic instability in cancer cells and increased somatic mutations, facilitating the production of tumor neoantigens. In addition, Pol θ has been reported to be involved in cGAS-STING-mediated immune activation. Hence, targeting Pol θ also has the potential to enhance immunotherapy. In summary, Pol θ is a target with great potential for cancer treatment, and in the treatment of lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, colon