TW202411231A - Substituted purinone derivative used as ubiquitin-specific protease inhibitor - Google Patents

Abstract

The present disclosure relates to a substituted purinone derivative used as a ubiquitin-specific protease inhibitor, and in particular to a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.

Description

Substituted purinone derivatives as ubiquitin-specific protease inhibitors

The present invention relates to substituted purinone derivatives used as ubiquitin-specific protease inhibitors, and specifically to compounds represented by formula (I), isomers thereof or pharmaceutically acceptable salts thereof.

USP1 (ubiquitin specific peptidase 1) is a member of the deubiquitinase family. USP1 and its cofactor UAF1 (USP1-associated factor 1) form the USP1-UAF1 complex, which deubiquitinates two key proteins in the FA and TLS pathways, Ub-FANCD2 and Ub-PCNA, thereby initiating DNA cross-link damage repair and promoting cancer cell survival. USP1 is highly expressed in many human tumors and is closely related to the occurrence and development of tumors. It has received widespread attention as a target for tumor treatment.

The genome-wide knockout study based on CRISPR technology showed that USP1 and BRCA1/2 mutations or other homologous recombination repair defects (HRD) have synthetic lethal effects. From the perspective of mechanism of action, USP1 and PARP are key regulatory proteins in the DNA cross-link damage and single-strand damage repair pathways, respectively. The two complement each other to promote DNA damage repair to avoid the production of DNA double-strand breaks with cell-lethal toxicity. Therefore, USP1 is an important target with great clinical value in the field of DNA damage repair.

The present invention provides a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, wherein ^X1 and ^X2 are independently selected from C( ^R1 ) or N; ^X3 , ^X4 , ^X5 and ^X6 are independently selected from C( ^R5 ) or N; each ^R1 and ^R5 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, _-NH2 , -NHC1-12alkyl, -N( _C1-12alkyl ) ₂ , _C1-12alkyl , _{C2-12alkenyl , C2-12alkynyl} , _C1-12alkoxy , _{C1-12alkylthio ,} -COC1-12alkyl, -OC(O) _C1-12alkyl , _-C (O) _OC1-12alkyl , -OC(O) _OC1-12alkyl , _{-SO2C1-12alkyl} , _{-NHSO2C1-12alkyl -12} alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group; the -OH, -SH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O)C _1-12 alkyl, -C(O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C 3-12 wherein R ⁵ on two adjacent carbon atoms and the carbon atom to which they are connected together form a C _5-7 cycloalkenyl, 5-7 heterocycloalkenyl, phenyl or 5-6 heteroaryl which is optionally substituted by one or more substituents; L is selected from -(C(R ³ R ⁴ )) _m -, -O-, -S-, -N(R ⁹ )-, -S(O)- or -S(O) ₂ -; R ² is selected from C _3-12 cycloalkyl, C _6-10 aryl, 5-10 heteroaryl, 3-12 heterocyclo or C _5-7 cycloalkenyl, wherein the C _3-12 cycloalkyl, C 6-10 aryl, 5-10 heteroaryl, 3-12 heterocyclo or C _5-7 cycloalkenyl R ³ and R ⁴ are each independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C 2-12 alkenyl ^, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -COC _{1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl , -SO} 2 C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl _{) 2 -12} alkyl) _{SO2 C1-12 alkyl} , -SO2 _NH2 , _-SO2 NHC1-12 alkyl, _-SO2 N( _C1-12 alkyl) ₂ , _-CONH2 , _-CONHC1-12 alkyl _{, -CON(C1-12 alkyl)2, -NHCOC1-12 alkyl, -N(C1-12 alkyl)COC1-12 alkyl, C3-12 cycloalkyl , C3-12 cycloalkenyl , C6-10 aryl} , 5-10 membered heteroaryl or 3-12 _membered heterocyclic group; the -OH, -SH, _{-NH2 , -NHC1-12 alkyl, -N(C1-12 alkyl)2, C1-12 alkyl, C2-12 alkenyl , C2-12 alkynyl ,} C C _1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O)C _1-12 alkyl, -C(O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C _6-10 membered aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic group are optionally independently substituted by one or more substituents; or ^R3 and ^R4 and the carbon atom to which they are commonly connected together form a carbonyl group; or ^R3 and ^R4 and the carbon atom to which they are commonly connected together form _{a C3-6} cycloalkyl or 3-6 membered heterocycloalkyl group optionally substituted by one or more substituents; or ^R3 and ^R3 , ^R3 and ^R4 , ^R4 and ^R3 , ^R4 and ^R4 on two adjacent carbon atoms and the carbon atom to which they are connected together form a _C3-6 cycloalkyl or 3-6 membered heterocycloalkyl group optionally substituted by one or more substituents; ^R6 is selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, _-NH2 , -NHC C _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O)C _1-12 alkyl, -C(O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C 1-12 alkyl) C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C 1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O)C _1-12 alkyl, _-C (O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl) ₂ R ₇ and R 8 are independently selected from hydrogen _{, halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-12 alkyl , -N(C 1-12 alkyl) 2 , C 3-12 cycloalkyl , C 3-12 cycloalkenyl , C 6-10} aryl, _5-10 membered heteroaryl and 3-12 membered heterocyclic groups, and are optionally substituted with one or more R ^6a ; R ⁷ and R ⁸ are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _3-12 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic groups, respectively. C _1-12 alkyl, C _2-12 alkenyl, C _{2-12 alkynyl, C 1-12} alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O)C _1-12 alkyl, -C(O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl _, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C 1-12 The -OH, -SH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O _{)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl , -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl )SO 2 C 1-12 alkyl , -SO 2 NH 2 , -SO 2} NHC _R7 and R8, together _with the carbon _{atoms to} which _{they are commonly} attached, form a _C3-8 cycloalkyl, a _3-8 membered heterocyclic group or a ^C3-8 cycloalkenyl group which _{is optionally} substituted with one or more substituents; ^R9 is selected from hydrogen or _C1-12 alkyl, and _{the C3-12 cycloalkyl} , _C3-12 cycloalkenyl, _C6-10 aryl, a ^5-10 membered heteroaryl and _{a 3-12} membered heterocyclic group. R ^2a and R ^6a are each independently selected from halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C 2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl _{, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl ,} -OC(O) _{OC 1-12} alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _-1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _{1-12 alkoxy, C 1-12 alkylthio} , -COC _1-12 alkyl, -OC(O)C C _1-12 alkyl, -C(O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C The _6-10 membered aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic group are optionally and independently substituted with one or more substituents; m is selected from 1, 2 or 3.

In some embodiments of the invention, the "substituted by 1 or more" is each independently selected from substituted by 1, 2, 3, 4, 5 or 6.

In some embodiments of the invention, the "substituted by 1 or more" is each independently selected from substituted by 1, 2, 3, 4 or 5.

In some embodiments of the present invention, the "substituted by 1 or more" is each independently selected from substituted by 1, 2, 3 or 4.

In some embodiments of the present invention, the "substituted by 1 or more" is each independently selected from substituted by 1, 2 or 3.

In some embodiments of the present invention, the "substituted by 1 or more" are each independently selected from substituted by 1 or 2.

In some embodiments of the present invention, at least one of X ¹ and X ² is selected from C(R ¹ ).

In some embodiments of the present invention, one of ^X1 and ^X2 is selected from C( ^R1 ), and the other is selected from N.

In some embodiments of the present invention, X ² is selected from C(R ¹ ).

In some embodiments of the present invention, ^X1 is selected from N.

In some embodiments of the present invention, ^X1 is selected from C( ^R1 ), and ^X2 is selected from C( ^R1 ).

In some embodiments of the present invention, X ¹ is selected from N, and X ² is selected from C(R ¹ ).

In some embodiments of the present invention, each R ¹ and R ⁵ are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl) 2 _{-C 1-6} alkyl _{) 2} , _{-NHCOC 1-6 alkyl ,} -N(C _1-6 alkyl)COC _1-6 alkyl, _{C 3-8 cycloalkyl, C 3-8 cycloalkenyl , phenyl} , _5-10 membered heteroaryl and _3-8 membered heterocyclic group are optionally _substituted independently _with one or _more substituents.

In some embodiments of the present invention, each R ¹ and R ⁵ are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl)SO ₂ C _1-3 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-3 alkyl, -SO ₂ N(C _1-3 alkyl) ₂ , -CONH ₂ , -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _{2-3 alkynyl, C 1-3} alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl) 2 -C _1-3 alkyl _{) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl , -N} (C _1-3 alkyl)COC _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, _{5-6 membered} heteroaryl and 3-6 membered heterocyclic group are optionally substituted independently _by one or _more substituents.

In some embodiments of the present invention, each R ¹ and R ⁵ are independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , _{C 1-3} alkyl, C _2-3 alkenyl, C 2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -SO ₂ NH ₂ , -CONH ₂ , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -SO ₂ NH 2 ₂ , -CONH ₂ , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic are optionally and independently substituted by one or more substituents.

In some embodiments of the present invention, each R ¹ and R ⁵ is independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, and the C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl and 3-6 membered heterocyclic group are optionally and independently substituted by one or more substituents.

In some embodiments of the present invention, each R ¹ and R ⁵ are independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, the methyl, ethyl, Isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl are optionally substituted independently with one or more substituents.

In some embodiments of the present invention, each R ¹ and R ⁵ is optionally and independently substituted by one or more groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention, each R ¹ and R ⁵ is optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention, each R ¹ and R ⁵ are independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, the methyl, ethyl, isopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, cyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, the methyl, ethyl, isopropyl, Methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or _NH2 .

In some embodiments of the invention, each R ¹ and R ⁵ are independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azidocyclobutyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azidocyclobutyl are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the invention, each R ¹ and R ⁵ are independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In some embodiments of the invention, each R ¹ and R ⁵ is independently selected from hydrogen, -F, -CN, methyl, methoxy, trifluoromethyl or trifluoromethoxy.

In some embodiments of the present invention, each R ¹ and R ⁵ are independently selected from hydrogen, -F or CN.

In some embodiments of the invention, each R ¹ is independently selected from -F.

In some embodiments of the invention, each R ¹ is independently selected from hydrogen.

In some embodiments of the present invention, ^X1 is selected from CH, and ^X2 is selected from CH.

In some embodiments of the present invention, ^X1 is selected from N, and ^X2 is selected from CH.

In some embodiments of the present invention, ^X1 is selected from C(F), and ^X2 is selected from CH.

In some embodiments of the present invention, ^X1 is selected from C(CN), and ^X2 is selected from CH.

In some embodiments of the present invention, at least two of X ³ , X ⁴ , X ⁵ and X ⁶ are selected from C(R ⁵ ).

In some embodiments of the present invention, X ³ is selected from C(R ⁵ ), and X ⁴ is selected from C(R ⁵ ).

In some embodiments of the present invention, ^X5 is selected from C( ^R5 ), and ^X6 is selected from C( ^R5 ).

In some embodiments of the present invention, ^X3 is selected from C( ^R5 ), ^X4 is selected from C( ^R5 ), ^X5 is selected from C( ^R5 ), and ^X6 is selected from C( ^R5 ).

In some embodiments of the present invention, ^X3 is selected from C( ^R5 ), ^X4 is selected from N, ^X5 is selected from C( ^R5 ), and ^X6 is selected from C( ^R5 ).

In some embodiments of the present invention, ^X3 is selected from N, ^X4 is selected from C( ^R5 ), ^X5 is selected from C( ^R5 ), and ^X6 is selected from C( ^R5 ).

In some embodiments of the present invention, ^X3 is selected from C( ^R5 ), ^X4 is selected from C( ^R5 ), ^X5 is selected from N, and ^X6 is selected from C( ^R5 ).

In some embodiments of the present invention, ^X3 is selected from C( ^R5 ), ^X4 is selected from C( ^R5 ), ^X5 is selected from C( ^R5 ), and ^X6 is selected from N.

In some embodiments of the present invention, ^X3 is selected from N, ^X4 is selected from C( ^R5 ), ^X5 is selected from N, and ^X6 is selected from C( ^R5 ).

In some embodiments of the present invention, ^X3 is selected from C( ^R5 ), ^X4 is selected from N, ^X5 is selected from C( ^R5 ), and ^X6 is selected from N.

In some embodiments of the invention, each R ⁵ is independently selected from hydrogen or -F.

In some embodiments of the present invention, each R ⁵ is independently selected from H.

In some embodiments of the present invention, ^X3 is selected from CH, and ^X4 is selected from CH.

In some embodiments of the present invention, ^X5 is selected from CH, and ^X6 is selected from CH.

In some embodiments of the present invention, ^X3 is selected from CH, ^X4 is selected from CH, ^X5 is selected from CH, and ^X6 is selected from CH.

In some embodiments of the present invention, ^X3 is selected from CH, ^X4 is selected from N, ^X5 is selected from CH, and ^X6 is selected from CH.

In some embodiments of the present invention, ^X3 is selected from CH, ^X4 is selected from CH, ^X5 is selected from CH, and ^X6 is selected from C(F).

In some embodiments of the present invention, ^X3 is selected from N, ^X4 is selected from CH, ^X5 is selected from CH, and ^X6 is selected from CH.

In some embodiments of the present invention, ^X3 is selected from C( ^R5 ), ^X4 is selected from C( ^R5 ), and ^R5 on the two carbon atoms of ^X3 and ^X4 and the carbon atom to which they are attached together form a _C5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl group which is optionally substituted with one or more substituents.

In some embodiments of the present invention, ^X3 is selected from C( ^R5 ), ^X4 is selected from C( ^R5 ), and ^R5 on the two carbon atoms of ^X3 and ^X4 and the carbon atom to which they are attached together form a _C5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or _NH2 .

In some embodiments of the present invention, ^X3 is selected from C( ^R5 ), ^X4 is selected from C( ^R5 ), and ^R5 on the two carbon atoms of ^X3 and ^X4 and the carbon atom to _which they are attached together form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, 2,5-dihydro-furanyl, 2,3-dihydro-furanyl, 2,5-dihydro-thienyl, 2,3-dihydro-thienyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2 The invention may be any of the following: 1,4-dihydro-2H-1,4-thiopyranyl, 3,6-dihydro-2H-thiopyranyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or oxazinyl.

In some embodiments of the present invention, ^X3 is selected from C( ^R5 ), ^X4 is selected from C( ^R5 ), and ^R5 on the two carbon atoms of ^X3 and ^X4 and the carbon atom to which they are attached together form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl or pyrimidinyl group optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or _NH2 .

In some embodiments of the present invention, ^X5 is selected from C( ^R5 ), ^X6 is selected from C( ^R5 ), and ^R5 on the two carbon atoms of ^X5 and ^X6 and the carbon atom to which they are attached together form a _C5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl group which is optionally substituted with one or more substituents.

In some embodiments of the present invention, ^X5 is selected from C( ^R5 ), ^X6 is selected from C( ^R5 ), and ^R5 on the two carbon atoms of ^X5 and ^X6 and the carbon atom to which they are attached together form a _C5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or _NH2 .

In some embodiments of the present invention, ^X5 is selected from C( ^R5 ), ^X6 is selected from C( ^R5 ), and ^R5 on the two carbon atoms of ^X5 and ^X6 and the carbon atom to _which they are attached together form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, 2,5-dihydro-furanyl, 2,3-dihydro-furanyl, 2,5-dihydro-thienyl, 2,3-dihydro-thienyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2 The invention may be any of the following: 1,4-dihydro-2H-1,4-thiopyranyl, 3,6-dihydro-2H-thiopyranyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or oxazinyl.

In some embodiments of the present invention, X ⁵ is selected from C(R ⁵ ), X ⁶ is selected from C(R ⁵ ), and R ⁵ on the two carbon atoms of X ⁵ and X ⁶ and the carbon atom to which they are attached together form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl or pyrimidinyl group optionally substituted with 1, 2 or ₃ groups selected from halogen, OH, CN or NH 2.

In some embodiments of the invention, L is selected from -(C(R ³ R ⁴ )) _m -, -O-, -S-, or -N(R ⁹ )-.

In some embodiments of the invention, R ⁹ is selected from hydrogen, methyl, ethyl or isopropyl.

In some embodiments of the present invention, R ⁹ is selected from hydrogen.

In some embodiments of the invention, L is selected from -(C(R ³ R ⁴ )) _m -, -O-, -S- or -NH-.

In some embodiments of the invention, L is selected from -C(R ³ R ⁴ )- or -C(R ³ R ⁴ )-C(R ³ R ⁴ )-.

In some embodiments of the present invention, each R ³ and R ⁴ is independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl) 2 _{-C 1-6} alkyl _{) 2} , _{-NHCOC 1-6 alkyl ,} -N(C _1-6 alkyl)COC _1-6 alkyl, _{C 3-8 cycloalkyl, C 3-8 cycloalkenyl , phenyl} , _5-10 membered heteroaryl and _3-8 membered heterocyclic group are optionally _substituted independently _with one or _more substituents.

In some embodiments of the present invention, each R ³ and R ⁴ is independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl)SO ₂ C _1-3 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-3 alkyl, -SO ₂ N(C _1-3 alkyl) ₂ , -CONH ₂ , -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _{2-3 alkynyl, C 1-3} alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl) 2 -C _1-3 alkyl _{) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl , -N} (C _1-3 alkyl)COC _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, _{5-6 membered} heteroaryl and 3-6 membered heterocyclic group are optionally substituted independently _by one or _more substituents.

In some embodiments of the present invention, each R ³ and R ⁴ are independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , _{C 1-3} alkyl, C _2-3 alkenyl, C 2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -SO ₂ NH ₂ , -CONH ₂ , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -SO ₂ NH 2 ₂ , -CONH ₂ , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic are optionally and independently substituted by one or more substituents.

In some embodiments of the present invention, each R ³ and R ⁴ is independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , C _1-3 alkyl or C _1-3 alkoxy, and the C _1-3 alkyl and C _1-3 alkoxy are optionally and independently substituted with one or more substituents.

In some embodiments of the invention, each R ³ and R ⁴ is independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally and independently substituted with one or more substituents.

In some embodiments of the present invention, each R ³ and R ⁴ is optionally and independently substituted with one or more groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention, each R ³ and R ⁴ is independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the invention, each R ³ and R ⁴ is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl or ethyl.

In some embodiments of the invention, each R ³ is independently selected from hydrogen, and each R ⁴ is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl or ethyl.

In some embodiments of the invention, each R ³ is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl or ethyl, and each R ⁴ is independently selected from hydrogen.

In some embodiments of the present invention, each R ³ is independently selected from hydrogen, and each R ⁴ is independently selected from hydrogen, methyl or ethyl.

In some embodiments of the present invention, each R ³ is independently selected from hydrogen, methyl or ethyl, and each R ⁴ is independently selected from hydrogen.

In some embodiments of the present invention, each ^R3 is independently selected from methyl, and each ^R4 is independently selected from methyl; or each ^R3 is independently selected from hydrogen, and each ^R4 is independently selected from hydrogen; or each ^R3 is independently selected from hydrogen, and each ^R4 is independently selected from methyl; each ^R3 is independently selected from methyl, and each ^R4 is independently selected from hydrogen; or each ^R3 is independently selected from hydrogen, and each ^R4 is independently selected from ethyl; or each ^R3 is independently selected from ethyl, and each ^R4 is independently selected from hydrogen.

In some embodiments of the invention, ^R3 and ^R4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, thiacyclobutyl, azacyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or oxolinyl, which may be optionally substituted with one or more substituents.

In some embodiments of the present invention, R ³ and R ⁴ together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azacyclobutyl group which is optionally substituted with one or more substituents.

In some embodiments of the present invention, R ³ and R ⁴ together with the carbon atom to which they are commonly attached form a cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azacyclobutyl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention, R ³ and R ⁴ together with the carbon atom to which they are commonly attached form a substituent group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention, R ³ and R ⁴ together with the carbon atom to which they are commonly attached form a cyclopropyl, oxacyclobutyl or azacyclobutyl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention ^, L is selected from -C( ^R3R4 )-C ^{( R3R4} )-, ^R3 and ^R3 , ^R3 and ^R4 , R4 and ^R3 , ^R4 and ^R4 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, ^{pyrazolidinyl} , imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl or isoxazolidinyl group, which is optionally substituted with one or more substituents.

In some embodiments of the present invention ^, L is selected from -C( ^R3R4 )-C ^{( R3R4} )-, and ^R3 and ^R3 , ^R3 and ^R4 , ^R4 and ^R3 , ^R4 and ^R4 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azacyclobutyl group which is optionally substituted with one or more substituents.

In some embodiments of the present invention ^, L is selected from -C( ^R3R4 )-C( ^R3R4 )-, and ^the substituents formed by ^R3 and ^R3 , ^R3 and ^R4 , ^R4 and ^R3 , ^R4 and ^R4 on two adjacent carbon atoms and the carbon atoms to which they are connected are optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or _NH2 .

In some embodiments of the present invention ^, L is selected from -C( ^R3R4 )-C ^{( R3R4} )-, and ^R3 and ^R3 , ^R3 and ^R4 , R4 and ^R3 , ^R4 and ^R4 on two adjacent carbon ^atoms and the carbon atoms to which they are attached together form a cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azocyclobutyl group which is optionally substituted with 1, 2 or ₃ groups selected from halogen, OH, CN or NH2.

In some embodiments of the present invention ^, L is selected from -C( ^R3R4 )-C ^{( R3R4} )-, and ^R3 and ^R3 , ^R3 and ^R4 , R4 and ^R3 , ^R4 and ^R4 on two adjacent carbon ^atoms and the carbon atoms to which they are attached together form a cyclobutyl, oxacyclobutyl or azocyclobutyl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or _NH2 .

In some embodiments of the invention, L is selected from -O-, -S-, -NH-, -CH2-, -CH( _CH3 )-, _-CH2CH2- , -CH(F)-, -CH ₍ Cl ₎ -, -CH(Br)-, -CH(I)-, -CH(CN)-, -CH( _CF3 )-, -CH(OH)-, -CH( _NH2 )-, -C(O)-, , , , , , , -CH(CH ₃ )CH ₂ -, -CH(F)CH ₂ -, -CH(Cl)CH ₂ -, -CH(Br)CH ₂ -, -CH(I)CH ₂ -, -CH(CN)CH ₂ -, -CH(CF ₃ )CH ₂ -, -CH(OH)CH ₂ -, -CH(NH ₂ )CH ₂ -, , , , , or .

In some embodiments of the present invention, L is selected from -O-, -S-, -NH-, _-CH2- , -CH( _CH3 )-, _{-CH2CH2- ,} -C(O)-, , , , , , , or .

In some embodiments of the invention, L is selected from _-CH2- , -CH( _CH3 )- or .

In some embodiments of the invention, L is selected from -CH ₂ -.

In some embodiments of the present invention, when L is selected from -C(R ³ R ⁴ )- or -C(R ³ R ⁴ )-C(R ³ R ⁴ )-, each carbon atom may be a chiral carbon atom, existing in the form of (R) or (S) single mirror image isomer or in the form enriched in one mirror image isomer.

In some embodiments of the present invention, R ² is selected from C _3-8 cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, 3-8 membered heterocyclic group or C _5-6 cycloalkenyl, and the C _3-8 cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, 3-8 membered heterocyclic group and C _5-6 cycloalkenyl are optionally and independently substituted by one or more R ^2a .

In some embodiments of the present invention, R ² is selected from C _3-6 cycloalkyl, phenyl, naphthyl, 5-9 membered heteroaryl, 3-6 membered heterocyclic group or C _5-6 cycloalkenyl, and the C _3-6 cycloalkyl, phenyl, naphthyl, 5-9 membered heteroaryl, 3-6 membered heterocyclic group and C _5-6 cycloalkenyl are optionally and independently substituted by one or more R ^2a .

In some embodiments of the present invention, R ² is selected from C _5-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group or C _5-6 cycloalkenyl, and the C _5-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group and C _5-6 cycloalkenyl are optionally and independently substituted by one or more R ^2a .

In some embodiments of the present invention, R ² is selected from C _5-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms, 5-6 membered heterocyclic group containing 1-3 N atoms or C _5-6 cycloalkenyl, and the C _5-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms, 5-6 membered heterocyclic group containing 1-3 N atoms and C _5-6 cycloalkenyl are optionally and independently substituted by one or more R ^2a .

In some embodiments of the invention, ^R is selected from cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl, oxazinyl, cyclopentenyl or cyclohexenyl, wherein the cyclopentyl R , cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, fluorenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, oxazinyl, cyclopentenyl and cyclohexenyl are optionally and independently substituted with one or more R ^2a .

In some embodiments of the invention, ^R is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl or oxazinyl, and the phenyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl pyridinyl, pyrazinyl, pyrimidinyl and oxazinyl are optionally and independently substituted with one or more ^R.

In some embodiments of the present invention, R ² is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl or pyrimidinyl, and the phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl and pyrimidinyl are optionally and independently substituted with one or more R ^2a .

In some embodiments of the present invention, R ² is selected from phenyl, pyrazolyl, pyridinyl or pyrimidinyl, and the phenyl, pyrazolyl, pyridinyl and pyrimidinyl are optionally and independently substituted with one or more R ^2a .

In some embodiments of the invention, R ² is selected from pyrimidinyl, which is optionally substituted with one or more R ^2a .

In some embodiments of the present invention, ^R is selected from , , , , , , , or , said R ² is optionally independently substituted by one or more R ^2a .

In some embodiments of the present invention, ^R is selected from , , or , said R ² is optionally independently substituted by one or more R ^2a .

In some embodiments of the present invention, ^R is selected from , said R ² is optionally substituted by one or more R ^2a .

In some embodiments of the present invention, each R ^2a and R ^6a is independently selected from halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl) 2 _{-C 1-6} alkyl _{) 2} , _{-NHCOC 1-6 alkyl ,} -N(C _1-6 alkyl)COC _1-6 alkyl, _{C 3-8 cycloalkyl, C 3-8 cycloalkenyl , phenyl} , _5-10 membered heteroaryl and _3-8 membered heterocyclic group are optionally _substituted independently _with one or _more substituents.

In some embodiments of the present invention, each R ^2a and R ^6a is independently selected from halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl)SO ₂ C _1-3 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-3 alkyl, -SO ₂ N(C _1-3 alkyl) ₂ , -CONH ₂ , -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _{2-3 alkynyl, C 1-3} alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl) 2 -C _1-3 alkyl _{) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl , -N(C 1-3 alkyl)COC 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl , phenyl , 5-6 membered} heteroaryl and 3-6 membered heterocyclic group are optionally substituted independently _by one or _more substituents.

In some embodiments of the present invention, each R ^2a and R ^6a is independently selected from halogen, -CN, -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C 2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -SO ₂ NH ₂ , -CONH ₂ , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, _{C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio , -SO 2 NH 2} , -CONH ₂ , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic are optionally and independently substituted by one or more substituents.

In some embodiments of the present invention, each R ^2a and R ^6a is independently selected from halogen, -CN, -OH, -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, and the C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl and 3-6 membered heterocyclic group are optionally and independently substituted by one or more substituents.

In some embodiments of the present invention, each R ^2a and R ^6a is independently selected from halogen, -CN, -OH, -NH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl or isoxazolidinyl, wherein the methyl, ethyl, Isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azacyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl and isoxazolidinyl are optionally and independently substituted with one or more substituents.

In some embodiments of the present invention, each R ^2a and R ^6a is independently selected from halogen, -CN, -OH, -NH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl or azocyclobutyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl and azocyclobutyl are optionally and independently substituted with one or more substituents.

In some embodiments of the present invention, R ^2a and R ^6a are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention, each R ^2a and R ^6a is independently selected from halogen, -CN, -OH, -NH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl or azidocyclobutyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl and azidocyclobutyl are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention, each R ^2a and R ^6a are independently selected from halogen, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy and cyclopropyl are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention, R ^2a is selected from -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, , , , , or .

In some embodiments of the present invention, R ^2a is selected from methyl, isopropyl, methoxy or .

In some embodiments of the present invention, R ^2a is selected from isopropyl, methoxy or .

In some embodiments of the present invention, ^R is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments of the present invention, ^R is selected from , , or .

In some embodiments of the present invention, ^R is selected from .

In some embodiments of the present invention, ^R6 is selected from hydrogen, halogen, -CN, -OH, _{-SH, -COOH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2 , C1-6alkyl , C2-6alkenyl , C2-6alkynyl, C1-6alkoxy, C1-6alkylthio, -COC1-6alkyl, -OC(O)C1-6alkyl, -C(O)OC1-6alkyl , -OC ( O ) OC1-6alkyl , -SO2C1-6alkyl , -NHSO2C1-6alkyl} , -N( _C1-6alkyl ) _{SO2C1-6alkyl , -SO2NH2} , -SO2NHC1-6alkyl _{, -SO2N ( C1-6alkyl} ) _{2 , -CONH2} , -CONHC _-1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic are optionally and independently substituted by one or more R ^6a .

In some embodiments of the present invention, ^R6 is selected from hydrogen, _halogen , -CN, -OH, -SH, -COOH, -NH2, -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl, _C2-3 alkynyl, _C1-3 alkoxy, _C1-3 alkylthio, -COC1-3 alkyl, -OC(O) _{C1-3 alkyl} , -C(O) _OC1-3 alkyl, -OC(O _{) OC1-3} alkyl _{, -SO2C1-3 alkyl , -NHSO2C1-3} alkyl, -N( _C1-3 alkyl) _{SO2C1-3 alkyl , -SO2NH2 ,} -SO2NHC1-3 _alkyl , _-SO2N ( _C1-3 alkyl) ₂ , -CONH2, -CONHC _-1-3 alkyl, -CON( _C1-3 alkyl) ₂ , _-NHCOC1-3 alkyl, -N( _C1-3 alkyl) _COC1-3 alkyl, _C3-6 cycloalkyl, _C3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, _-NH2 , -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl, _C2-3 alkynyl, _C1-3 alkoxy, _C1-3 alkylthio, _-COC1-3 alkyl, -OC(O) _C1-3 alkyl, -C(O _{) OC1-3} alkyl, -OC(O) _OC1-3 alkyl, _-SO2C1-3 alkyl, _-NHSO2C1-3 alkyl, -N _{( C1-3} alkyl) _{SO2C1-3 alkyl} R 6a is optionally substituted with _one or more R 6a in the following examples: -SO ₂ NH ₂ , -SO ₂ NHC _1-3 alkyl, -SO ₂ N(C _1-3 alkyl) ₂ , -CONH ₂ , -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally and independently substituted with one or more R ^6a .

In some embodiments of the present invention, ^R6 is selected from hydrogen, halogen, -CN, -OH, _-NH2 , -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl, _C2-3 alkynyl, _C1-3 alkoxy, _C1-3 alkylthio, _-SO2NH2 , _-CONH2 , _C3-6 cycloalkyl, _C3-6 cycloalkenyl, phenyl, _5-6 membered heteroaryl or _3-6 membered heterocyclic group, wherein -OH, _-NH2 , -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl _{, C2-3 alkynyl, C1-3 alkoxy , C1-3 alkylthio} , _-SO2NH2 , _-CONH2 , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic are optionally and independently substituted by one or more R ^6a .

In some embodiments of the present invention, R ⁶ is selected from hydrogen, halogen, -CN, -OH, -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, and the C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally and independently substituted by one or more R ^6a .

In some embodiments of the present invention, R ⁶ is selected from C _3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, and the C _3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally and independently substituted by one or more R ^6a .

In some embodiments of the present invention, ^R6 is selected from _C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms or 5-6 membered heterocyclic group containing 1-3 N atoms, and the _C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms and 5-6 membered heterocyclic group containing 1-3 N atoms are optionally and independently substituted by one or more ^R6a .

In some embodiments of the invention, R ^is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or oxazinyl, and the cyclopropyl R , cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, fluorenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl and oxazinyl are optionally and independently substituted with one or more R ^6a .

In some embodiments of the present invention, ^R is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl or oxazinyl, and the phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl and oxazinyl are optionally and independently substituted with one or more ^R.

In some embodiments of the present invention, R ⁶ is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl or pyrimidinyl, and the phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl and pyrimidinyl are optionally and independently substituted with one or more R ^6a .

In some embodiments of the present invention, R ⁶ is selected from pyrazolyl or imidazolyl, and the pyrazolyl and imidazolyl are optionally and independently substituted with one or more R ^6a .

In some embodiments of the present invention, ^R is selected from , , , , , , , , , , , , , , , or , said R ⁶ is optionally independently substituted by one or more R ^6a .

In some embodiments of the present invention, ^R is selected from , , , , or , said R ⁶ is optionally independently substituted by one or more R ^6a .

In some embodiments of the present invention, ^R is selected from or , said R ⁶ is optionally independently substituted by one or more R ^6a .

In some embodiments of the present invention, R ^6a is selected from -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, , , , , , or .

In some embodiments of the present invention, R ^6a is selected from methyl, isopropyl, trifluoromethyl, or .

In some embodiments of the invention, R ^6a is selected from isopropyl or trifluoromethyl.

In some embodiments of the present invention, ^R is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments of the present invention, ^R is selected from , , , , or .

In some embodiments of the present invention, ^R is selected from , or .

In some embodiments of the present invention, ^R is selected from .

In some embodiments of the present invention, ^R7 and ^R8 are independently selected from hydrogen, halogen, -CN, _-OH , -SH, -COOH, -NH2, -NHC1-6alkyl, -N( _C1-6alkyl ) ₂ , _C1-6alkyl , _C2-6alkenyl , _C2-6alkynyl , _C1-6alkoxy , _{C1-6alkylthio} , _{-COC1-6alkyl, -OC(O)C1-6alkyl, -C(O)OC1-6alkyl , -OC ( O} ) _{OC1-6alkyl , -SO2C1-6alkyl ,} -NHSO2C1-6alkyl, -N( _{C1-6alkyl ) SO2C1-6alkyl} , _-SO2NH2 , _{-SO2NHC1-6alkyl , -SO2N} ( _C1-6alkyl ) _{2 , -CONH2} , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl) 2 _{-C 1-6} alkyl _{) 2} , _{-NHCOC 1-6 alkyl ,} -N(C _1-6 alkyl)COC _1-6 alkyl, _{C 3-8 cycloalkyl, C 3-8 cycloalkenyl , phenyl} , _5-10 membered heteroaryl and _3-8 membered heterocyclic group are optionally _substituted independently _with one or _more substituents.

In some embodiments of the present invention, ^R7 and ^R8 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, _-NH2 , -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl, _C2-3 alkynyl, _C1-3 alkoxy, _C1-3 alkylthio, _{-COC1-3 alkyl, -OC(O)C1-3 alkyl} , -C(O) _OC1-3 alkyl, _-OC (O) _OC1-3 alkyl, _{-SO2C1-3 alkyl} , _-NHSO2C1-3 alkyl, _-N ( _{C1-3 alkyl)SO2C1-3 alkyl , -SO2NH2} , _-SO2NHC1-3 alkyl _{, -SO2N} ( _C1-3 alkyl) _{2 , -CONH2} , -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _{2-3 alkynyl, C 1-3} alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl) 2 -C _1-3 alkyl _{) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl , -N} (C _1-3 alkyl)COC _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, _{5-6 membered} heteroaryl and 3-6 membered heterocyclic group are optionally substituted independently _by one or _more substituents.

In some embodiments of the present invention, ^R7 and ^R8 are independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _{C2-3 alkenyl} , _{C2-3 alkynyl, C1-3 alkoxy, C1-3 alkylthio , -SO2NH2} , _-CONH2 , _C3-6 cycloalkyl, _C3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein -OH, _-NH2 , _-NHC1-3 alkyl, _-N ( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl, _C2-3 alkynyl, _C1-3 alkoxy _{, C1-3 alkylthio} , _-SO2NH2 , -CONH ₂ , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic are optionally and independently substituted by one or more substituents.

In some embodiments of the present invention, ^R7 and ^R8 are independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , _C1-3 alkyl or _C1-3 alkoxy, and the _C1-3 alkyl and _C1-3 alkoxy are optionally and independently substituted with one or more substituents.

In some embodiments of the present invention, ^R7 and ^R8 are independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally and independently substituted with one or more substituents.

In some embodiments of the present invention, R ⁷ and R ⁸ are optionally and independently substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention, ^R7 and ^R8 are independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or _NH2 .

In some embodiments of the invention, R ⁷ and R ⁸ are each independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In some embodiments of the invention, R ⁷ and R ⁸ are each independently selected from -F, -Cl, -Br, -I, methyl, methoxy or trifluoromethyl.

In some embodiments of the present invention, ^R7 and ^R8 are each independently selected from methyl.

In some embodiments of the present invention, R ⁷ and R ⁸ together with the carbon atom to which they are commonly attached form a C _3-6 cycloalkyl, a 3-6 membered heterocyclic group or a C _3-6 cycloalkenyl group which is optionally substituted with one or more substituents.

In some embodiments of the present invention, R and ^R and the carbon atom to which they are commonly attached together form cyclopropyl, ^cyclobutyl , cyclopentyl, cyclohexyl, oxacyclobutyl, thiacyclobutyl, azacyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, which is optionally substituted with one or more substituents.

In some embodiments of the present invention, ^R7 and ^R8 , together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, oxacyclobutyl, azacyclobutyl, pyrrolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl group, which may be optionally substituted with one or more substituents.

In some embodiments of the present invention, ^R7 and ^R8 and the carbon atom to which they are commonly attached together form a cyclopropyl, cyclobutyl, oxacyclobutyl, azacyclobutyl, pyrrolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or _NH2 .

In some embodiments of the present invention, R ⁷ and R ⁸ together with the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl or tetrahydropyranyl group optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention, ^R7 and ^R8 together with the carbon atom to which they are attached form a group optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or _NH2. , or .

In some embodiments of the present invention, R ⁷ and R ⁸ together with the carbon atom to which they are commonly attached form a substituent group which is optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH ₂ .

In some embodiments of the present invention, ^R7 and ^R8 together with the carbon atom to which they are attached form , , or .

In some embodiments of the present invention, ^R7 and ^R8 together with the carbon atom to which they are attached form .

In some embodiments of the present invention, the "impurities" are each independently selected from oxygen, sulfur and nitrogen impurities, wherein the nitrogen atom is optionally quaternized or oxidized to N(O), and the sulfur atom is optionally oxidized to S(O) or S(O) ₂ .

In some embodiments of the present invention, the "impurities" are each independently selected from oxygen, sulfur and nitrogen impurity atoms, wherein the sulfur impurity atom is optionally oxidized to S(O) or S(O) ₂ .

In some embodiments of the present invention, m is selected from 1.

In some embodiments of the present invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ⁷ , R ⁸ or R ⁹ are optionally substituted by one or more substituents selected from the group consisting of -OH, -SH, halogen, -NH ₂ , nitro, nitroso, -CN, an azido group, a sulfonyl group, a sulfonyl group, a sulfonamide group, a carboxyl group, a carboxaldehyde group, an imine group, an alkyl group, a halogenated-alkyl group, a cycloalkyl group, a halogenated-cycloalkyl group, an alkenyl group, a halogenated-alkenyl group, a cycloalkenyl group, a halogenated-cycloalkenyl group, an alkynyl group, a halogenated-alkynyl group, a cycloalkynyl group, a halogenated-cycloalkynyl group, a heteroalkyl group, a halogenated-heteroalkyl group, an alkoxy group, an alkylthio group, an aryl group, an aromatic group, a The invention also includes a 3-D-type acrolein group, ...

In some embodiments of the present invention, the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (I) is selected from the compound represented by formula (I-1), Wherein, ^X1 , ^X2 , ^X3 , ^X4 , ^X5 , ^X6 , ^R2 , ^R3 , ^R4 and ^R6 are defined as the compound shown in formula (I); the carbon atom to which ^R3 and ^R4 are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or in a form enriched in one mirror image isomer.

In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-2) Wherein, X ⁴ is selected from CH or N; X ¹ , X ² , R ² , L and R ⁶ are as defined for the compound represented by formula (I).

In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-3) Wherein, X ⁴ is selected from CH or N; X ¹ , R ² , L and R ⁶ are as defined for the compound represented by formula (I).

In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-4) Wherein, ^X4 is selected from CH or N; ^X1 , ^R2 , ^R3 , ^R4 and ^R6 are defined as the compound shown in formula (I); the carbon atom to which ^R3 and ^R4 are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or a form enriched in one mirror image isomer.

In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-5) wherein X ⁴ is selected from CH or N; Y ¹ , Y ² and Y ³ are independently selected from CH or N; X ¹ , R ³ , R ⁴ , R ⁶ and R ^2a are as defined in the compound of formula (I); the carbon atom to which R ³ and R ⁴ are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or in a form enriched in one mirror image isomer.

In some embodiments of the present invention, ^Y1 is selected from N.

In some embodiments of the present invention, ^Y1 and ^Y3 are both selected from N.

In some embodiments of the invention, Y ¹ , Y ² and Y ³ are all selected from CH.

In some embodiments of the present invention, ^Y1 is selected from N, and ^Y2 and ^Y3 are both selected from CH.

In some embodiments of the present invention, ^Y1 and ^Y3 are both selected from N, and ^Y2 is selected from CH.

In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-6) wherein ^X4 is selected from CH or N; ^Y1 , ^Y2 and ^Y3 are as defined in the compound shown in formula (I-5); ^X1 , ^R3 , ^R4 , ^R2a and ^R6a are as defined in the compound shown in formula (I); the carbon atom to which ^R3 and ^R4 are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or in a form enriched in one mirror image isomer.

In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-7) wherein ^X4 is selected from CH or N; ^Y1 , ^Y2 and ^Y3 are as defined in the compound shown in formula (I-5); ^X1 , ^R3 , ^R4 , ^R2a and ^R6a are as defined in the compound shown in formula (I); the carbon atom to which ^R3 and ^R4 are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or in a form enriched in one mirror image isomer.

Some other embodiments of the present invention are obtained by any combination of the above variables.

On the other hand, the present invention also provides a compound of the following formula, an isomer thereof or a pharmaceutically acceptable salt thereof, .

On the other hand, the present invention also provides a compound of the following formula, an isomer thereof or a pharmaceutically acceptable salt thereof, .

On the other hand, the present invention also provides a pharmaceutical composition containing a therapeutically or prophylactically effective amount of the compound of the present invention, its isomers or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition of the present invention also includes a pharmaceutically acceptable adjuvant.

On the other hand, the present invention also provides the use of the compound, its isomer or pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of a drug for treating or preventing diseases associated with the inhibition of ubiquitin-specific protease 1 (USP1).

On the other hand, the present invention also provides a method for treating or preventing a disease associated with the inhibition of ubiquitin-specific protease 1 (USP1), comprising administering a therapeutically or preventively effective amount of the compound of the present invention, its isomers or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof to a mammal (preferably a human) in need of such treatment or prevention.

On the other hand, the present invention also provides the use of the compound of the present invention, its isomer or pharmaceutically acceptable salt or its pharmaceutical composition in the treatment or prevention of diseases related to the inhibition of ubiquitin-specific protease 1 (USP1).

On the other hand, the present invention also provides the compound of the present invention, its isomers, or its pharmaceutically acceptable salt, or its pharmaceutical composition for treating or preventing diseases associated with the inhibition of ubiquitin-specific protease 1 (USP1).

On the other hand, in some embodiments of the present invention, the disease associated with the inhibition of ubiquitin-specific protease 1 (USP1) is selected from tumors or cancers (such as breast cancer ).

The compounds of the present invention are inhibitors of a completely new structure of ubiquitin-specific protease 1 (USP1), which have a good inhibitory effect on the signal transduction of ubiquitin-specific protease 1 (USP1). The compounds of the present invention have good inhibitory effects in vivo and in vitro, including but not limited to good inhibitory effects on in vitro enzyme activity and cell activity, good liver microsomal stability, good pharmacokinetic properties, good in vivo efficacy, etc., and can be developed into new USP1 inhibitor drugs. Related definitions

Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to the corresponding trade name or its active ingredient.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from the compounds having specific substituents discovered in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with sufficient amounts of base in pure solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with sufficient amounts of acid in pure solution or in a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or alkaline groups by conventional chemical methods. Generally, such salts are prepared by reacting free acid or alkaline forms of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-mirror isomers, ( R )- and ( S )-mirror isomers, diastereoisomers, ( D )-isomers, ( L )-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereoisomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present invention.

Unless otherwise specified, a solid wedge key ( ) and the Dashed Wedge Key ( ) represents the absolute configuration of a stereocenter, with a straight solid line key ( ) and the straight dash key ( ) represents the relative configuration of the stereocenter.

The compounds and intermediates of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also called proton shift tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which the proton can migrate between two ring nitrogens. Valence tautomers include interconversions via reorganization of some bonding electrons.

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on a chemically feasible basis.

The “substituent” described herein includes all substituents mentioned herein, for example, the terms “C _1-12 alkyl”, “C _{1-12 alkoxy”, “C 1-12} alkylthio”, “C _2-12 alkenyl”, “C _2-12 alkynyl”, “halogen”, “C _3-12 cycloalkyl”, “C _3-12 cycloalkenyl”, “ _3-6 membered heterocycloalkyl”, “C _6-10 aryl”, “5-10 membered heteroaryl”, “3-12 membered heterocyclo” and the like, and the corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the “substituent” include hydroxyl, oxalyl, halogen, amine, nitro, nitroso, cyano, azido, sulfonamide, sulfonyl, sulfonyl, thiophene ... group, carboxyl group, carboxaldehyde group, imine group, alkyl group, halogenated-alkyl group, cycloalkyl group, halogenated-cycloalkyl group, alkenyl group, halogenated-alkenyl group, cycloalkenyl group, halogenated-cycloalkenyl group, alkynyl group, halogenated-alkynyl group, cycloalkynyl group, halogenated-cycloalkynyl group, heteroalkyl group, halogenated-heteroalkyl group, alkoxy group, alkylthio group, aryl group, aryloxy group, arylthio group, aralkyl group, an arylalkoxy group, an arylalkylthio group, a heteroaryl group, a heteroaryloxy group, a heteroarylthio group, a heteroarylalkyl group, a heteroarylalkoxy group, a heteroarylalkylthio group, a heterocyclic group, a heterocyclic oxy group, a heterocyclic thio group, a heterocyclic alkylene group, a heterocyclic alkoxy group, a heterocyclic alkylthio group, an acyl group, an acyloxy group, a carbamate group, an amide group, a urea group, an epoxide group, ester group, oxo and thio, etc., wherein the group is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amine, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, carboxyl, -C(O)O-alkyl, - OC(O)-alkyl, -C(O) _NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) ₂ , -NHC(O)-alkyl, -C(O) _{-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH - alkyl ,} -S(O) _2N (alkyl) ₂ , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclo, heterocycloalkylalkylene, heterocycloalkyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

In some embodiments herein, the substituent is selected from hydroxyl, oxalyl, halogen, amine, nitro, nitroso, cyano, azido, sulfonyl, sulfonamide, carboxyl, aldehyde, imine, _C1-12 alkyl, halogenated- _C1-12 alkyl, 3-12 membered cycloalkyl, halogenated-3-12 membered cycloalkyl, _C2-12 alkenyl, halogenated- _C2-12 alkenyl, 3-12 membered cycloalkenyl, halogenated-3-12 membered cycloalkenyl, _C2-12 alkynyl, halogenated- _C2-12 alkynyl, 8-12 membered cycloalkynyl, halogenated-8-12 membered cycloalkynyl, _C1-12 heteroalkyl, halogenated-C _1-12 membered heteroalkyl, C _1-12 membered alkoxy, C _1-12 membered alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC _1-12 alkylene, 6-10 membered arylC _{1-12 alkoxy, 6-10 membered arylC 1-12 alkylthio} , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroaryl alkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclic group, 3-12 membered heterocyclic groupoxy, 3-12 membered heterocyclic groupthio, 3-12 membered heterocyclic groupC The substituents may be a C _1-12 alkylene group, a 3-12 membered heterocyclic C _1-12 alkoxy group, a 3-12 membered heterocyclic C _1-12 alkylthio group, a C _1-12 acyl group, a C _1-12 acyloxy group, a carbamate group, a C _1-12 amide group, a urea group, an epoxy group, a C _2-12 ester group, an oxo group, and a thioxo group, etc., wherein the substituents are optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amine, nitro, halogen, cyano, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, halogenated C _1-12 alkoxy, C _1-12 alkylamino, di-C _1-12 alkylamino, halogenated C _1-12 alkylamino, halogenated di-C 1-12 _1-12 alkylamino, carboxyl, -C(O)O- C _1-12 alkyl, -OC(O)- C _1-12 alkyl, -C(O)NH ₂ , -C(O)NH-C _1-12 alkyl, -C(O)N(C _1-12 alkyl) ₂ , -NHC(O)- C _1-12 alkyl, -C(O)- C _1-12 alkyl, -S(O)-C _1-12 alkyl, -S(O) ₂ -C _1-12 alkyl, -S(O) ₂ NH ₂ , -S(O) ₂ NH-C _1-12 alkyl, -S(O) ₂ N(C _1-12 alkyl) ₂ , 3-12 membered cycloalkyl, 3-12 membered cycloalkylC 1-12 The present invention may be a _1-12 membered alkylene group, a 3-12 membered cycloalkyloxy group, a 3-12 membered heterocycloyl group, a 3-12 membered heterocycloalkylC _1-12 alkylene group, a 3-12 membered heterocycloalkyloxy group, a 3-12 membered heterocycloalkyl group, a 3-12 membered heterocycloalkylC _1-12 alkylene group, a 3-12 membered heterocycloalkyloxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroarylC 1-12 alkylene group, a 5-10 membered heteroaryloxy group, a 6-10 membered aryl group, a 6-10 membered arylC _1-12 alkylene group, or a 6-10 membered aryloxy group.

When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and each occurrence of R is an independent choice. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.

When a linker group is listed without specifying its direction of attachment, the direction of attachment is arbitrary, e.g. The connecting group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right. , or by connecting Ring A and Ring B in the opposite direction of the reading order from left to right. Combinations of linking groups, substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected to become a group of corresponding valence. The chemical bonds connecting the site to other groups can be represented by straight solid bonds ( ), straight dashed line key( ), or a wavy line ( ) represents. For example, the straight solid bond in -OCH ₃ represents the connection with other groups through the oxygen atom in the group; The straight dashed bonds in the figure indicate that the two ends of the nitrogen atom in the group are connected to other groups. The wavy line in the figure indicates that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group. or Indicates that any linkable site on the pyridinyl group can be linked to other groups via a chemical bond, including at least , , , These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that position will decrease by one and become the corresponding monovalent piperidinyl group.

Unless otherwise specified, the term "C _1-12 alkyl" by itself or as part of another substituent refers to a straight or branched saturated hydrocarbon group consisting of 1 to 12 carbon atoms. The C _1-12 alkyl may be a C _1-6 alkyl or a C _1-3 alkyl. Unless otherwise specified, the term "C _1-6 alkyl" is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C _1-6 alkyl includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ and C ₅ alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of _C1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), butyl (including n -butyl, isobutyl, s -butyl and t -butyl), pentyl (including n -pentyl, isopentyl and neopentyl), hexyl and the like.

Unless otherwise specified, the term "C _1-12 alkylene" by itself or as part of another substituent means a linear or branched divalent hydrocarbon radical consisting of 1 to 12 carbon atoms, including those having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C _1-6 alkylene" refers to an alkylene radical containing 1 to 6 carbon atoms. Non-limiting examples of alkylene radicals include, but are not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ - or -CH ₂ CH(CH ₃ )-), butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ - or -CH ₂ CH ₂ CH(CH ₃ )-), and the like. The alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, amine, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, cycloalkyl, cycloalkyloxy, heterocyclo, heterocyclooxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

Unless otherwise specified, the term "C _1-12 alkoxy" refers to an alkyl group containing 1 to 12 carbon atoms that is attached to the rest of the molecule via an oxygen atom. The C _1-12 alkoxy group may be a C _1-6 alkoxy group or a C _1-3 alkoxy group. Unless otherwise specified, the term "C _1-6 alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms that is attached to the rest of the molecule via an oxygen atom. The C _1-6 alkoxy group includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ and C ₅ alkoxy groups, etc. Examples of C _1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy and tert-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy and the like.

Unless otherwise specified, the term "C _1-12 alkylthio" means an alkyl group containing 1 to 12 carbon atoms that is attached to the rest of the molecule via a sulfur atom. The C _1-12 alkylthio group may be a C _1-6 alkylthio group or a C _1-3 alkylthio group. Unless otherwise specified, the term "C _1-6 alkylthio" means an alkyl group containing 1 to 6 carbon atoms that is attached to the rest of the molecule via a sulfur atom. The C _1-6 alkylthio group includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ and C ₅ alkylthio groups, etc. Examples of _C1-6 alkylthio include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio and tert-butylthio), pentylthio (including n-pentylthio, isopentylthio and neopentylthio), hexylthio and the like.

Unless otherwise specified, "C _2-12 alkenyl" is used to represent a linear or branched carbon hydrogen group consisting of 2 to 12 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position of the group. The C _2-12 alkenyl group can be a C _2-6 alkenyl group, a C _2-3 alkenyl group or a C _2-3 alkenyl group. The C _2-4 alkenyl group includes C _2-3 , C ₄ , C ₃ and C ₂ alkenyl groups, etc.; the C _2-4 alkenyl group can be monovalent, divalent or polyvalent. Examples of C _2-4 alkenyl groups include but are not limited to ethenyl, propenyl, butenyl, butadienyl, etc. Unless otherwise specified, "C _2-3 alkenyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. The C _2-3 alkenyl group includes C ₃ and C ₂ alkenyl groups; the C _2-3 alkenyl group may be monovalent, divalent or polyvalent. Examples of C _2-3 alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

Unless otherwise specified, "C _2-12 alkynyl" is used to represent a linear or branched carbon hydrogen group consisting of 2 to 12 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. The C _2-12 alkynyl group includes C _2-6 , C _2-3 , C ₄ , C ₃ and C ₂ alkynyl groups, etc. It may be monovalent, divalent or polyvalent. Examples of C _2-3 alkynyl groups include, but are not limited to, ethynyl, propynyl, etc.

Unless otherwise stated, the term "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine, or iodine atom.

Unless otherwise specified, _Cn-n+m or _Cn - _Cn+m includes any specific case of n to n+m carbon atoms, for example, _C1-12 includes _C1 , _C2 , _C3 , _C4 , _C5 , _C6 , _C7 , _C8 , _C9 , _C10 , _C11 , and _C12 , and also includes any range from n to n+m, for example, _C1-12 includes _C1-3 , _C1-6 , C1-9, _C3-6 , _C3-9 , _C3-12 , _C6-9 , _C6-12 , and C13 _{. Similarly} , n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

Unless otherwise specified, "C _3-12 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, which is a monocyclic and bicyclic system, and the C _3-12 cycloalkyl includes C _3-8 , C _3-6 and C _5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C _3-12 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

Unless otherwise specified, the term "C _3-12 cycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic hydrocarbon group consisting of 3 to 12 ring atoms containing at least one carbon-carbon double bond, which may be monovalent, divalent or polyvalent. The C _3-12 cycloalkenyl includes C _3-6 cycloalkenyl, C _5-6 cycloalkenyl, etc. Examples of C _3-6 cycloalkenyl include but are not limited to , or .

Unless otherwise specified, the term "5-7 membered heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 5 to 7 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, N or Se, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, cyclic and bridged rings, and any ring of this system is non-aromatic. It can be monovalent, divalent or polyvalent. In addition, for the "5-7 membered heterocycloalkenyl", a hetero atom may occupy the position where the heterocycloalkenyl is connected to the rest of the molecule. The 5-7 membered heterocycloalkenyl includes 5-6 membered heterocycloalkenyl. Examples of 5-6 membered heterocycloalkenyl include but are not limited to , , , or .

Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It is a monocyclic system. In addition, with respect to the "3-6 membered heterocycloalkyl", the heteroatom may occupy the connection position of the heterocycloalkyl to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 3-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl, etc. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, cyclopropyl oxadiazole, cyclopropyl thiodiazole, cyclopropyl aziride, cyclobutyl aziride, cyclobutyl oxadiazole, cyclobutyl thiodiazole, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl), tetrahydrothienyl 1,1,-dioxide-3-yl, tetrahydrothienyl 1,1,-dioxide-2-yl, tetrahydrofuran ...2-yl, tetrahydrofuranyl ( The invention also includes but is not limited to tetrahydrofuran-2-yl, tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydroxazinyl, homopiperazinyl or homopiperidinyl, etc.

Unless otherwise specified, the term "C _6-10 aryl" means a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated π electron system, which can be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. It can be monovalent, divalent or polyvalent. C _6-10 aryl includes C ₉ , C ₁₀ and C ₆ aryl. Examples of C _6-10 aryl include but are not limited to phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

Unless otherwise specified, the term "5-10 membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π electron system, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, N or Se, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It can be monovalent, divalent or polyvalent. The 5-10 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N -pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N -imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl ( 1H -1,2,3-triazolyl, 2H -1,2,3-triazolyl, 1H -1,2,4-triazolyl and 4H -1, -1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidine The invention may be substituted or alternatively selected from the group consisting of 2-pyrimidinyl, 4-pyrimidinyl, benzothiazolyl, 5-benzothiazolyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, isoquinolyl, 1-isoquinolyl, 5-isoquinolyl, quinoxalinyl, 2-quinoxalinyl, 5-quinoxalinyl, quinolyl, 3-quinolyl, 6-quinolyl, etc.

The term "3-12 member heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 12 member ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Non-limiting examples of heterocyclic groups include, but are not limited to, oxirane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc. The heterocyclic group is optionally substituted with one or more of the following groups: oxo, hydroxyl, amine, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) _NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) ₂ , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) ₂ -alkyl, -S(O) _2NH2 , -S(O) _{2NH -} alkyl, -S(O) _2N (alkyl) ₂ The 3-12 membered heterocycloalkyl group includes 3-8 membered, 3-6 membered, 4-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups, etc. Examples of “3-12 membered heterocycloalkyl” and “3-6 membered heterocycloalkyl” include, but are not limited to, azacyclobutyl, oxacyclobutyl, thiacyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including The invention also includes but is not limited to 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydroxazinyl, homopiperazinyl, homopiperidinyl or dioxacycloheptanyl, etc.

The term "treatment" means administering the compounds or formulations of the present invention to improve or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) inhibiting a disease or disease state, i.e., curbing its development; (ii) relieving a disease or disease state, i.e., causing the disease or disease state to regress.

The term "prevention" means that the compounds or formulations of the present invention are administered to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

The term "therapeutically or prophylactically effective amount" means an amount of a compound of the present invention that (i) treats a specific disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a specific disease, condition or disorder, or (iii) prevents or delays a specific disease, condition or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically or prophylactically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art based on his or her own knowledge and the content of the present invention.

The therapeutic or preventive dose of the compounds of the present invention may be based on, for example, the specific use for treatment or prevention, the mode of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present invention in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. In certain embodiments, the dosage range is about 0.001 mg/kg to about 1000 mg/kg of body weight/day. The dosage is likely to depend on such variables as the type and degree of development of the disease or condition, the general health of the specific patient, the relative biological efficacy of the selected compound, the formulation and its route of administration. The effective dose can be obtained by extrapolation of dose-response curves derived from in vitro or animal model test systems.

The word "comprise" or "comprises" and its English variants such as comprises or comprising should be construed in an open, non-exclusive sense, ie, "including but not limited to".

"Drug composition" means a composition containing one or more compounds of the present invention, their isomers or pharmaceutically acceptable salts thereof, and other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a drug composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thereby exert biological activity.

The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with a suitable pharmaceutically acceptable adjuvant, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation.

The pharmaceutical composition of the present invention can be produced by methods well known in the art.

The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

The chemical reactions of the specific embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention and the reagents and materials required. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

The raw materials or intermediates used in the embodiments of the present invention can be obtained from the market or prepared by methods of the prior art.

An important consideration in planning synthetic routes in this field is the selection of an appropriate protecting group for a reactive functional group (such as an amine group in the present invention), for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

In some embodiments, some compounds of the present invention can be prepared by organic synthesis technicians by referring to the following methods: wherein ^X1 , ^X2 , ^X3 , ^X4 , ^X5 , ^X6 , L, ^R2 , ^R6 , ^R7 and ^R8 are as described above for the compound of formula (I); and Y is selected from halogen, -OH, methylsulfonyloxy, phenylsulfonyloxy or p-toluenesulfonyloxy.

In some embodiments of the present application, Y is selected from -Cl, -Br, -I, -OH, methylsulfonyloxy or p-toluenesulfonyloxy.

In some embodiments of the present application, Y is selected from -Cl.

For the sake of clarity, the present invention is further described with examples, but the examples are not intended to limit the scope of the present invention. All reagents used in the present invention are commercially available and can be used without further purification.

Specific implementation methods

The present invention is described in detail below through examples, but it does not mean any adverse limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Preparation Example 1

Compound A-1 (3.2 g) was dissolved in tetrahydrofuran (100 mL). Under nitrogen protection, diisopropylamine (4.01 g) was added at -20°C, and then n-butyl lithium (2.4 M in n-hexane, 31.2 mL) was added, and stirred for half an hour. The temperature was raised to 0°C, and after stirring for 30 minutes, 1,2-dibromoethane (10.64 g) was added dropwise, and the mixture was transferred to room temperature and stirred overnight. A saturated aqueous ammonium chloride solution was added, and the solution was vacuum filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Vacuum filtered, concentrated, and purified by column chromatography to obtain 740 mg of compound 1-1.

MS (ESI, [M+H] ⁺ ) m/z: 196.07.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.94 (s, 1H), 8.13 (d, J = 1.5 Hz, 1H), 1.83 (q, J = 4.0 Hz, 2H), 1.62 (q, J = 4.0 Hz, 2H). Preparation Example 2

Compound A-2 (500 mg) was dissolved in tetrahydrofuran (15 mL). Under nitrogen protection, diisopropylamine (0.63 g) was added at -20°C, and then n-butyl lithium (2.4 M in n-hexane, 4.9 mL) was added, and stirred for half an hour. The temperature was raised to 0°C, and after stirring for 30 minutes, 1,2-dibromoethane (1.67 g) was added dropwise, and the mixture was transferred to room temperature and stirred for reaction overnight. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Vacuum filtration was performed, and the crude product was added to petroleum ether for slurry (30 mL). Vacuum filtration was performed to obtain 0.4 g of compound 2-1.

MS (ESI, [M+H] ⁺ ) m/z: 195.07.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.19 (s, 1H), 7.92 (s, 1H), 6.95 (s, 1H), 1.75 (q, J = 3.9 Hz, 2H), 1.55 (q, J = 3.9 Hz, 2H). Example 1 Step 1: Preparation of intermediate 1-2

Intermediate 1-1 (680 mg), B-1 (1.5 g), potassium carbonate (1.4 g) and N , N -dimethyldiamide (10 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution in sequence and dried over anhydrous sodium sulfate. The mixture was vacuum filtered, concentrated, and purified by silica gel column chromatography to obtain 1.5 g of intermediate 1-2 .

MS (ESI, [M+H]+) m/z: 550.15.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.24 (s, 1H), 8.16 (d, J = 1.4 Hz, 1H), 7.85 – 7.72 (m, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.40 (s, 2H), 5.01 (s, 2H), 3.63 – 3.50 (m, 2H), 1.96 - 1.94 (m, 2H), 1.76 - 1.73 (m, 2H), 0.82 (dd, J = 8.6, 7.4 Hz, 2H), -0.09 (s, 9H). Step 2: Preparation of intermediate 1-3

Intermediate 1-2 (700 mg), C-1 (494 mg), cesium carbonate (1.24 g), tetrakistriphenylphosphine palladium (147 mg), dioxane (10 mL) and water (0.5 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 2 hours. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution in turn and dried over anhydrous sodium sulfate. The mixture was vacuum filtered, concentrated, and purified by silica gel column chromatography to obtain 0.49 g of intermediate 1-3 .

MS (ESI, [M+H] ⁺ ) m/z: 664.40.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.67 (s, 1H), 8.46 (s, 1H), 8.16 (s, 1H), 7.76 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 5.38 (s, 2H), 5.04 (s, 2H), 3.85 (s, 3H), 3.56 (t, J = 8.1 Hz, 2H), 1.98 (q, J = 4.2 Hz, 2H), 1.82 – 1.69 (m, 3H), 1.03 (t, J = 3.6 Hz, 2H), 0.86 - 0.81 (m, 4H), -0.09 (s, 9H). Step 3: Preparation of intermediates 1-4

Mix the intermediate 1-3 (400 mg) and tetrahydrofuran (5 mL), add triethylsilane (0.96 mL) and trifluoroacetic acid (7.43 mL) in sequence, and stir at room temperature for 16 hours. Add saturated sodium bicarbonate to adjust the pH to neutral, extract with ethyl acetate, and dry with anhydrous sodium sulfate. Filter under vacuum, concentrate, and purify by silica gel column chromatography to obtain 0.13 g of intermediate 1-4 .

MS (ESI, [M+H] ⁺ ) m/z: 534.31.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.18 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 7.92 – 7.89 (m, 3H), 7.45 (d, J = 8.2 Hz, 2H), 5.00 (s, 2H), 3.85 (s, 3H), 1.99 - 1.97 (m, 2H), 1.76 - 1.74 (m, 2H), 1.73 – 1.70 (m, 1H), 1.04 - 1.02 (m, 2H), 0.86 - 0.83 (m, 2H). Step 4: Preparation of compound 1

Intermediate 1-4 (110 mg), cesium carbonate (336 mg), N , N -dimethylformamide (5 mL) were mixed, isopropyl iodide (140 mg) was added, and the mixture was stirred at 80°C for 16 hours. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was vacuum filtered and concentrated, and the crude product was purified by column chromatography to obtain 0.031 g of compound 1 .

MS (ESI, [M+H] ⁺ ) m/z: 576.37.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.66 (s, 1H), 8.15 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 1.3 Hz, 1H), 5.11 (s, 2H), 4.53 (h, J = 6.7 Hz, 1H), 3.95 (s, 3H), 1.93 (q, J = 4.3 Hz, 2H), 1.78 - 1.72 (m, 3H), 1.44 (d, J = 6.7 Hz, 6H), 1.25 – 1.22 (m, 2H), 0.90 - 0.87 (m, 2H). Embodiment 2 Step 1: Preparation of intermediate 2-1

Intermediate 1-1 (200 mg), B-2 (309 mg), potassium carbonate (424 mg) and N,N-dimethylformamide (10 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 0.36 g of intermediate 2-1 .

MS (ESI, [M+H] ⁺ ) m/z: 434.25.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.25 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 6.75 (s, 1H), 5.03 (s, 2H), 2.41 – 2.31 (m, 3H), 1.96 (q, J = 4.1 Hz, 2H), 1.75 (q, J = 4.0 Hz, 2H). Step 2: Preparation of compound 2

Intermediate 2-1 (200 mg), compound C- 1 (179 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine (32.6 mg), tripotassium phosphate (294 mg), dioxane (10 mL) and water (0.1 mL) were mixed, heated to 90°C under nitrogen atmosphere, stirred and reacted for 2 hours. Vacuum filtration, concentration, and silica gel column chromatography were performed to obtain 0.064 g of compound 2 .

MS (ESI, [M+H] ⁺ ) m/z: 548.23.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.66 (s, 1H), 8.47 (s, 1H), 7.60 – 7.47 (m, 4H), 6.75 (s, 1H), 5.06 (s, 2H), 3.84 (s, 3H), 2.32 (s, 3H), 1.99 (q, J = 4.0 Hz, 2H), 1.76 (q, J = 3.9 Hz, 2H), 1.72 - 1.69 (m, 1H), 1.04 - 1.01 (m, 2H), 0.85 – 0.83 (m, 2H). Example 3 Step 1: Preparation of intermediate 3-1

Intermediate 1-1 (100 mg), B-3 (154 mg), potassium carbonate (212 mg) and N , N -dimethylformamide (5 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 0.15 g of compound 3-1 .

MS (ESI, [M+H] ⁺ ) m/z: 434.25.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.25 (s, 1H), 7.93 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 5.02 (s, 2H), 3.77 (s, 3H), 1.96 (dd, J = 8.2, 4.1 Hz, 2H), 1.75 (dd, J = 8.1, 3.9 Hz, 2H). Step 2: Preparation of compound 3

Intermediate 3-1 (150 mg), C-2 (150 mg), tris(dibenzylideneacetone)dipalladium (33 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (31 mg), tripotassium phosphate (220 mg), dioxane (7 mL) and water (2 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 2 hours. The mixture was vacuum filtered, concentrated and purified by silica gel column chromatography to obtain 0.06 g of compound 3 .

MS (ESI, [M+H] ⁺ ) m/z: 519.21.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.62 (d, J = 3.4 Hz, 1H), 8.48 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.38 – 7.27 (m, 1H), 5.08 (s, 2H), 3.76 (s, 3H), 3.63 (dt, J = 13.2, 6.6 Hz, 1H), 1.99 (d, J = 3.8 Hz, 2H), 1.77 (d, J = 3.8 Hz, 2H), 1.13 (d, J = 6.7 Hz, 6H). Example 4 Step 1: Preparation of compound 4

Intermediate 2-1 (130 mg), C-2 (99 mg), tris(dibenzylideneacetone)dipalladium (27.4 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (28.5 mg), tripotassium phosphate (191 mg), dioxane (7 mL) and water (0.5 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 2 hours. The mixture was vacuum filtered, concentrated and purified by silica gel column chromatography to obtain 0.02 g of compound 4 .

MS (ESI, [M+H] ⁺ ) m/z: 519.30.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.62 (dd, J = 4.7, 1.8 Hz, 1H), 8.48 (s, 1H), 7.98 (dd, J = 7.8, 1.9 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.32 (dd, J = 7.8, 4.7 Hz, 1H), 6.74 (s, 1H), 5.10 (s, 2H), 3.62 (p, J = 6.7 Hz, 1H), 2.32 (s, 3H), 1.99 (q, J = 4.1 Hz, 2H), 1.78 (q, J = 4.0 Hz, 2H), 1.12 (d, J = 6.6 Hz, 6H). Example 5 Step 1: Preparation of intermediate 5-1

Intermediate 1-1 (100 mg), B-4 (155 mg), potassium carbonate (141 mg) and N , N -dimethylformamide (2 mL) were mixed and reacted at room temperature overnight. Water and ethyl acetate were added, the aqueous phase was separated, extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. Vacuum filtration was performed, and the crude product was concentrated and purified by column chromatography to obtain 185 mg of intermediate 5-1 .

MS (ESI, [M+H] ⁺ ) m/z: 435.27.

¹ HNMR (500 MHz, DMSO-d ₆ ): δ 8.66 (d, J =1.5Hz, 1H), 8.24 (s, 1H), 8.06 (d, J =8.0Hz, 1H), 7.99 (s, 1H), 7.88 (dd, J ₁ =8.3Hz, J ₂ =2.3Hz, 1H), 5.04 (s, 2H), 4.07 (s, 3H), 1.96-1.94 (m, 2H), 1.76-1.74 (m, 2H). Step 2: Preparation of Compound 5

Intermediate 5-1 (150 mg), C-3 (113 mg), tris(dibenzylideneacetone)dipalladium (32 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (33 mg), tripotassium phosphate (220 mg), dioxane (5 mL) and water (1 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 1 hour. The mixture was vacuum filtered, concentrated and purified by silica gel column chromatography to obtain 38 mg of compound 5 .

MS (ESI, [M+H] ⁺ ) m/z: 519.33.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.66 (s, 1H), 8.45 (s, 1H), 8.06 (d, J =8.5 Hz, 1H), 7.98 (s, 1H), 7.87 (d, J =7.5 Hz, 1H), 7.53 (d, J =7.5 Hz, 1H), 7.43-7.40 (m, 2H), 7.27 (t, J =6.5 Hz, 1H), 5.10 (s, 2H), 4.06 (s, 3H), 3.46-3.41 (m, 1H), 1.97 (d, J =3.5 Hz, 2H), 1.76 (d, J =3.5 Hz, 2H), 1.08 (d, J =7.0 Hz, 6H). Embodiment 6 Step 1: Preparation of intermediate 6-1

Intermediate 2-1 (350 mg), intermediate B-5 (599 mg), potassium carbonate (746 mg) and N , N -dimethylformamide (10 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 0.46 g of intermediate 6-1 .

MS (ESI, [M+H] ⁺ ) m/z: 461.26.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.16 (d, J = 1.4 Hz, 1H), 8.02 (s, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.47 (dd, J = 8.3, 1.9 Hz, 2H), 7.35 (s, 1H), 5.09 (s, 2H), 4.49 – 4.43 (m, 1H), 1.89 (q, J = 4.0 Hz, 2H), 1.70 (q, J = 3.9 Hz, 2H), 1.39 (d, J = 6.7 Hz, 6H). Step 2: Preparation of compound 6

Intermediate 6-1 (150 mg), C-1 (126 mg), tris(dibenzylideneacetone)dipalladium (29.8 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (31.0 mg), tripotassium phosphate (138 mg), dioxane (7 mL) and water (0.7 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 2 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution in turn and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under vacuum, and the crude product was purified by column chromatography to obtain 65 mg of compound 6 .

MS (ESI, [M+H] ⁺ ) m/z: 575.29.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.62 (s, 1H), 8.29 (s, 1H), 8.23 – 8.12 (m, 1H), 7.59 – 7.54 (m, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.33 (s, 1H), 5.09 (s, 2H), 4.43 (p, J = 6.7 Hz, 1H), 3.77 (s, 3H), 1.92 (q, J = 4.0 Hz, 2H), 1.72 (q, J = 3.8 Hz, 3H), 1.39 (d, J = 6.5 Hz, 6H), 0.99 (t, J = 3.6 Hz, 2H), 0.85 – 0.75 (m, 2H). Example 7 Step 1: Preparation of intermediate 7-1

Intermediate 1-1 (200 mg), B-6 (480 mg), potassium carbonate (424 mg) and N , N -dimethylformamide (5 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered under vacuum, concentrated, and the crude product was purified by column chromatography to obtain 0.42 g of intermediate 7-1.

MS (ESI, [M+H]+) m/z: 476.26.

¹ HNMR (500 MHz, DMSO- d ₆ ) δ .

1HNMR (500 MHz,DMSO-d ₆ ) δ 8.23 (s, 1H), 8.17 (d, J = 0.9 Hz, 1H), 7.56 – 7.51 (m, 4H), 5.75 (q, J = 7.2 Hz, 1H), 4.47 (dt, J = 13.3, 6.7 Hz, 1H), 1.94-1.93 (m, 5H), 1.74 – 1.70 (m, 2H), 1.40 (d, J = 6.6 Hz, 6H). Step 2: Preparation of compound 7

Intermediate 7-1 (370 mg), C-1 (800 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (100 mg), potassium phosphate (400 mg), dioxane (15 mL) and water (3 mL) were mixed, heated to 90°C under nitrogen atmosphere and stirred for 2 hours. Vacuum filtration, concentration, and silica gel column chromatography were performed to obtain 0.28 g of compound 7 .

MS (ESI, [M+H] ⁺ ) m/z: 590.15.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.66 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 7.54 (q, J = 8.5 Hz, 4H), 5.80 (t, J = 7.2 Hz, 1H), 4.44 (dt, J = 13.3, 6.6 Hz, 1H), 3.84 (s, 3H), 1.96 (dd, J = 14.2, 5.7 Hz, 5H), 1.81 – 1.64 (m, 3H), 1.39 (d, J = 6.6 Hz, 6H), 1.25 (t, J = 5.8 Hz, 2H), 1.02 (d, J = 4.3 Hz, 2H). Embodiment 8 Step 1: Preparation of intermediate 8-1

Intermediate 1-1 (100 mg), B-7 (171 mg), potassium carbonate (141 mg) and N , N -dimethylformamide (2 mL) were mixed and reacted at room temperature for 2 hours. Water and ethyl acetate were added, the aqueous phase was separated, extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. Vacuum filtration was performed, and the crude product was concentrated and purified by column chromatography to obtain 155 mg of intermediate 8-1 .

MS (ESI, [M+H] ⁺ ) m/z: 463.25.

¹ HNMR (500 MHz, DMSO-d ₆ ) δ 8.85 (d, J=2.0Hz, 1H), 8.24-8.23 (m, 2H), 8.03 (d, J =8.5Hz, 1H), 7.90 (dd, J1 =8.3Hz, J2 =2.3Hz, 1H), 5.75-5.69 (m, 1H), 5.05 (s, 2H), 1.96-1.94 (m, 2H), 1.76-1.74 (m, 2H), 1.44 (d, J =6.5Hz, 6H). Step 2: Preparation of Compound 8

Intermediate 8-1 (150 mg), (2-isopropylpyridin-3-yl)boronic acid (107 mg), tris(dibenzylideneacetone)dipalladium (30 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (31 mg), tripotassium phosphate (206 mg), dioxane (5 mL) and water (1 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 2 hours. The mixture was vacuum filtered, concentrated and purified by silica gel column chromatography to obtain 73 mg of compound 8 .

MS (ESI, [M+H] ⁺ ) m/z: 548.25.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.67 (d, J =1.5 Hz, 1H), 8.62 (dd, J ₁ =4.8 Hz, J ₂ =1.8 Hz, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.04 (d, J =8.5 Hz, 1H), 7.98 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.90 (dd, J ₁ =8.3 Hz, J ₂ =2.3 Hz, 1H), 7.33 (dd, J ₁ =7.5 Hz, J ₂ =2.3 Hz, 1H), 5.75-5.70 (m, 1H), 5.12 (s, 2H), 3.63-3.57 (m, 1H), 2.00-1.98 (m, 2H), 1.80-1.77 (m, 2H), 1.44 (d, J =6.5Hz, 6H), 1.10 (d, J =7.0Hz, 6H). Example 9 Step 1: Preparation of intermediate 9-1

Intermediate 1-1 (120 mg), B-8 (225 mg), potassium carbonate (265 mg) and N , N -dimethylformamide (3 mL) were mixed and stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 0.22 g of intermediate 9-1 .

MS (ESI, [M+H] ⁺ ) m/z: 480.26.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.25 (s, 1H), 8.24 (s, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 10.7 Hz, 1H), 7.29 (d, J = 9.4 Hz, 1H), 5.05 (s, 2H), 4.15 (dt, J = 13.2, 6.5 Hz, 1H), 1.96 (dd, J = 8.2, 4.1 Hz, 2H), 1.76 (dd, J = 8.1, 3.9 Hz, 2H), 1.35 (d, J = 6.6 Hz, 6H). Step 2: Preparation of compound 9

Intermediate 9-1 (180 mg), C-1 (500 mg), 4-triphenylphosphine palladium (50 mg), cesium carbonate (320 mg), dioxane (7 mL) and water (2 mL) were mixed, heated to 90°C under nitrogen atmosphere, stirred and reacted for 2 hours. Vacuum filtration, concentration, and silica gel column chromatography were performed to purify the product to obtain 0.11 g of compound 9 .

MS (ESI, [M+H] ⁺ ) m/z: 594.22.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.66 (s, 1H), 8.47 (s, 1H), 8.23 (s, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.39 (d, J = 10.3 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 5.07 (s, 2H), 4.11 (dt, J = 13.2, 6.5 Hz, 1H), 3.83 (s, 3H), 1.99 (dd, J = 8.0, 4.0 Hz, 2H), 1.77 (dd, J = 7.9, 3.8 Hz, 2H), 1.72 (td, J = 8.0, 4.1 Hz, 1H), 1.34 (d, J = 6.6 Hz, 6H), 1.10 – 0.96 (m, 2H), 0.86 – 0.80 (m, 2H). Example 10 Step 1: Preparation of intermediate 10-1

Intermediate 1-1 (200 mg), B-5 (371 mg), potassium carbonate (47.7 mg), dioxane (424 mg) and N,N -dimethylacetamide (10 mL) were mixed and heated to 80°C under nitrogen atmosphere and stirred for 1 hour. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution in sequence and dried over anhydrous sodium sulfate. The mixture was vacuum filtered, concentrated, and purified by silica gel column chromatography to obtain 371 mg of intermediate 10-1.

MS (ESI, [M+H]+) m/z: 462.27.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.24 (s, 1H), 8.16 (d, J = 0.8 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.02 (s, 2H), 4.46 (hept, J = 6.5 Hz, 1H), 1.96 (dd, J = 8.2, 4.1 Hz, 2H), 1.75 (dd, J = 8.1, 3.9 Hz, 2H), 1.39 (d, J = 6.6 Hz, 6H). Step 2: Preparation of compound 10

Intermediate 10-1 (100 mg), C-4 (108 mg), potassium phosphate (69 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (15 mg), dioxane (10 mL), and water (0.5 mL) were mixed, heated to 100°C under nitrogen atmosphere, stirred and reacted for 4 h. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was vacuum filtered, concentrated, and purified by silica gel column chromatography to obtain 25 mg of compound 10 .

MS (ESI, [M+H] ⁺ ) m/z: 550.23.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.46 (s, 1H), 8.15 (s, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.36 (s, 1H), 5.34 – 5.24 (m, 1H), 5.09 (s, 2H), 4.47 – 4.38 (m, 1H), 2.12 (s, 3H), 1.98 (dd, J = 8.0, 4.0 Hz, 2H), 1.78 (dd, J = 7.9, 3.8 Hz, 2H), 1.38 (d, J = 6.6 Hz, 6H), 1.29 (d, J = 6.6 Hz, 6H). Example 11 Step 1: Preparation of intermediate 11-1

Intermediate 3-1 (250 mg), B-5 (400 mg), potassium carbonate (600 mg) and N , N -dimethylformamide (6 mL) were mixed and stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 0.44 g of intermediate 11-1 .

MS (ESI, [M+H] ⁺ ) m/z: 464.18.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.53 (s, 1H), 8.17 (s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 4.95 (s, 2H), 4.47 (dt, J = 13.3, 6.6 Hz, 1H), 1.43 (s, 6H), 1.40 (d, J = 6.6 Hz, 6H). Step 2: Preparation of compound 11

Intermediate 11-1 (220 mg), C-1 (200 mg), tetrakis(triphenylphosphine)palladium (50 mg), cesium carbonate (420 mg), dioxane (5 mL) and water (1 mL) were mixed, heated to 90°C under nitrogen atmosphere, stirred and reacted for 2 hours. Vacuum filtration, concentration and silica gel column chromatography were performed to obtain 0.06 g of compound 11 .

MS (ESI, [M+H] ⁺ ) m/z: 578.31.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.75 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 4.98 (s, 2H), 4.44 (dt, J = 13.3, 6.6 Hz, 1H), 3.84 (s, 3H), 1.77 – 1.68 (m, 1H), 1.48 (s, 6H), 1.39 (d, J = 6.6 Hz, 6H), 1.04 – 0.98 (m, 2H), 0.81 (dt, J = 11.5, 3.3 Hz, 2H). Embodiment 12 Step 1: Preparation of intermediate 12-2

Compound 12-1 (50 g), ( E )-1-ethoxyvinyl-2-boronic acid pinacol ester (36.4 g), lithium hydroxide monohydrate (23.10 g), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (13.4 g) and N , N -dimethylformamide (500 mL) were mixed and heated to 80 ^° C for 2 hours under nitrogen protection. The filtrate was filtered by vacuum filtration through diatomaceous earth, diluted with water and ethyl acetate, extracted with ethyl acetate, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Vacuum filtration, concentration, and purification by silica gel column chromatography gave 32 g of intermediate 12-2 .

MS: (ESI, [M+H]+) m/z: 217.27.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.78 (s, 1H), 7.04 (d, J = 12.7 Hz, 1H), 6.36 (s, 2H), 5.78 (d, J = 12.7 Hz, 1H), 3.93 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.0 Hz, 3H). Step 2: Preparation of intermediate 12-3

Dissolve the intermediate 12-2 (2.5 g) in methanol (50 mL), add hydrochloric acid (9.27 mL) dropwise, and stir at 70°C for 2 hours. Cool to room temperature, add saturated sodium bicarbonate solution dropwise under ice bath to adjust pH to neutral, extract with ethyl acetate, wash with water and saturated sodium chloride solution in sequence, and dry over anhydrous sodium sulfate. Filter under vacuum and concentrate to obtain 1.7 g of intermediate 12-3 .

MS: (ESI, [M+H] ⁺ ) m/z: 171.04.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.38 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 3.2 Hz, 1H), 6.73 (t, J = 3.3 Hz, 1H). Step 3: Preparation of intermediate 12-4

Dissolve the intermediate 12-3 (1.0 g) in tert-butyl alcohol (50 mL), add pyridinium tribromide (4.69 g) in batches, and stir in an oil bath at 40°C overnight. Concentrate under reduced pressure to remove the solvent, add water and ethyl acetate to dilute, extract with ethyl acetate, wash with water and saturated sodium chloride solution in sequence, and dry over anhydrous sodium sulfate. Filter under vacuum and concentrate to obtain 1.6 g of intermediate 12-4 .

MS: (ESI, [MH] ^- ) m/z: 340.75.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.68 (s, 1H), 8.49 (s, 1H). Step 4: Preparation of intermediate 12-5

Dissolve the intermediate 12-4 (1.5 g) in tetrahydrofuran (10 mL), add zinc powder (1.4 g), add glacial acetic acid (5 mL) dropwise in an ice bath, stir and react for 30 minutes, then filter through diatomaceous earth. Dilute the filtrate with water and ethyl acetate, extract with ethyl acetate, and dry over anhydrous sodium sulfate. Filter through vacuum, concentrate, and purify by silica gel column chromatography to obtain 540 mg of intermediate 12-5 .

MS: (ESI, [M+H] ⁺ ) m/z: 187.1.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.62 (s, 1H), 7.96 (d, J = 1.0 Hz, 1H), 3.67 (d, J = 1.1 Hz, 2H). Step 5 : Preparation of intermediate 12-6

The intermediate 12-5 (0.5 g) was dissolved in tetrahydrofuran (5 mL). Under nitrogen protection, lithium diisopropylamine (2 M in tetrahydrofuran, 8 mL) was added dropwise at -20°C. After stirring for 1 hour, a solution of vinyl sulfate (1.0 g) in tetrahydrofuran (5 mL) was added dropwise. The mixture was transferred to room temperature and stirred overnight. A saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After vacuum filtration, concentration, and purification by silica gel column chromatography, 35 mg of the intermediate 12-6 was obtained.

MS: (ESI, [M+H] ⁺ ) m/z: 213.13.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 7.84 (s, 1H), 1.82 (q, J = 3.9 Hz, 2H), 1.61 (q, J = 3.9 Hz, 2H). Step 6: Preparation of intermediate 12-7

Intermediate 12-6 (40 mg), B-5 (85 mg), potassium carbonate (78 mg) and N , N -dimethylformamide (6 mL) were mixed and stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 64 mg of intermediate 12-7 .

MS (ESI, [M+H] ⁺ ) m/z: 479.24.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.17 (d, J = 1.3 Hz, 1H), 7.96 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.16 (s, 2H), 4.46 (p, J = 6.7 Hz, 1H), 1.98 (q, J = 4.0 Hz, 2H), 1.78 (q, J = 4.0 Hz, 2H), 1.40 (d, J = 6.6 Hz, 6H). Step 7: Preparation of compound 12

Intermediate 12-7 (55 mg), C-1 (67 mg), tris(dibenzylideneacetone)dipalladium (15 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (15 mg), cesium carbonate (112 mg), dioxane (5 mL) and water (1 mL) were mixed, heated to 90°C under nitrogen atmosphere, stirred and reacted overnight. Vacuum filtration, concentration and silica gel column chromatography were performed to obtain 20 mg of compound 12 .

MS (ESI, [M+H] ⁺ ) m/z: 593.29.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.64 (s, 1H), 7.98 (d, J = 1.1 Hz, 1H), 7.52 - 7.48 (m, 4H), 7.40 (d, J = 1.3 Hz, 1H), 5.28 - 5.14 (m, 2H), 4.53 (hept, J = 6.7 Hz, 1H), 3.90 (s, 3H), 1.98 - 1.96 (m, 2H), 1.83 - 1.79 (m, 2H), 1.70 - 1.65 (m, 1H), 1.44 (dd, J = 6.7, 1.5 Hz, 6H), 1.28 - 1.23 (m, 1H), 1.18 - 1.13 (m, 1H), 0.96 - 0.91 (m, 1H), 0.86 - 0.80 (m, 1H). Experimental Example 1 : In vitro cell proliferation inhibitory activity 1.1 Determination of MDA-MB-436 cell proliferation inhibitory activity

Take MDA-MB-436 cells in good growth state, collect them into centrifuge tubes, adjust the cell density to 10 ⁴ cells/mL, inoculate them into 96-well culture plates (100 μL/well), culture them in a cell culture incubator overnight, use a nanoliter sample loader to add compounds to the samples, so that the final concentration of the compound is 1000 nM-0.457 nM, 2 replicate wells, and set up controls at the same time. After 7 days of continuous culture in the cell culture incubator, the test reagent CCK-8 (supplier: Tongren Chemical, 10 μL/well) was added. After 2 hours of culture in the cell culture incubator, the absorbance was measured at 450 nm using the Envision ELISA reader. The four-parameter analysis was performed to fit the dose-effect curve and calculate the IC ₅₀ .

The experimental results are shown in Table 1, where A represents: 0 nM < IC ₅₀ ≤ 50 nM; B represents: 50 nM < IC ₅₀ ≤ 100 nM; C represents: 100 nM < IC ₅₀ ≤ 1000 nM; D represents: 1000 nM < IC _50. Table 1 MDA-MB-436 cell proliferation inhibitory activity Compound IC ₅₀ (nM) Embodiment 1 A Embodiment 2 A Embodiment 3 B Embodiment 4 C Embodiment 5 C Embodiment 6 A Embodiment 7 A Embodiment 8 C Embodiment 9 A Embodiment 10 A Embodiment 11 A Embodiment 12 B Experimental Example 2 : In vitro enzyme inhibitory activity 2.1 USP1/UAF1 enzyme inhibitory activity determination

USP1/UAF1 protein solution (concentration 10 nM) was added to the test wells at 10 μl per well. Different compounds dissolved in DMSO were added to the test wells using a nanoliter sample loader to make the final concentration of the compound 1000 nM-0.24 nM. Two replicate wells were set up at the same time. After the above system was incubated at room temperature for 30 minutes, Ub-Rhodamine (concentration 300 nM) was added to the test wells at 10 μL per well. After 90 minutes of reaction at room temperature, the culture plate was read and detected using a PerkinElmer Envision multi-function ELISA reader (Ex. 490 nm/ Em. 520 nm), and IC ₅₀ was calculated using a four-parameter fit.

The experimental results are shown in Table 2, where A represents: 0 nM＜IC ₅₀ ≤50 nM; B represents: 50 nM＜IC ₅₀ ≤100 nM; C represents: 100 nM＜IC ₅₀ ≤1000 nM; D represents: 1000 nM＜IC _50. Table 2 USP1/UAF1 enzyme inhibitory activity Compound IC ₅₀ (nM) Embodiment 2 A Embodiment 6 A Embodiment 7 A Embodiment 8 A Embodiment 9 C Embodiment 11 A Embodiment 12 A

The compounds of the present invention have good USP1/UAF1 enzyme inhibitory activity. Experimental Example 3 : In vitro liver microsome metabolic stability

The liver microsome incubation sample was prepared by mixing PBS buffer (pH7.4), liver microsome solution (0.5 mg/ml), test compound and NADPH ⁺ MgCl ₂ solution at 37°C and 300 rpm for 1 hour. The 0 hour sample was prepared by mixing PBS buffer (pH7.4), liver microsome solution (0.5 mg/ml), test compound. The sample was added with acetonitrile solution containing internal standard and protein precipitation was performed to prepare supernatant, which was diluted and used for LC/MS/MS determination.

The experimental results are shown in Table 3. Table 3 Metabolic stability of in vitro liver microsomes Compound Microsome stability 60 min residual HLM Embodiment 1 101.21% Embodiment 2 82.58% Embodiment 6 92.02% Embodiment 7 88.85% Embodiment 8 95.91% Embodiment 11 99.86% Embodiment 12 92.38%

The compounds of the present invention have good in vitro liver microsome stability. Test Example 4 : Determination of in vivo pharmacokinetic properties

ICR mice, weighing 18-22 g, were randomly divided into groups after 3-5 days of adaptation, with 9 mice in each group, and were intragastrically administered with the test compound solution at a dose of 10 mg/kg.

Blood was collected from the eye sockets at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h to prepare plasma samples for testing.

30 µL of plasma sample and standard sample were taken, and acetonitrile solution containing internal standard was added to obtain supernatant after protein precipitation. After dilution, it was used for LC/MS/MS determination.

The non-compartmental model was used to fit the pharmacokinetic parameters.

The compounds of the present invention have good in vivo pharmacokinetic properties.

Claims (16)

A compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, wherein ^X1 and ^X2 are independently selected from C( ^R1 ) or N; ^X3 , ^X4 , ^X5 and ^X6 are independently selected from C( ^R5 ) or N; each ^R1 and ^R5 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, _-NH2 , -NHC1-12alkyl, -N( _C1-12alkyl ) ₂ , _C1-12alkyl , _{C2-12alkenyl , C2-12alkynyl} , _C1-12alkoxy , _{C1-12alkylthio ,} -COC1-12alkyl, -OC(O) _C1-12alkyl , _-C (O) _OC1-12alkyl , -OC(O) _OC1-12alkyl , _{-SO2C1-12alkyl} , _{-NHSO2C1-12alkyl -12} alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group; the -OH, -SH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O)C _1-12 alkyl, -C(O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C 3-12 wherein R ⁵ on two adjacent carbon atoms and the carbon atom to which they are connected together form a C _5-7 cycloalkenyl, 5-7 heterocycloalkenyl, phenyl or 5-6 heteroaryl which is optionally substituted by one or more substituents; L is selected from -(C(R ³ R ⁴ )) _m -, -O-, -S-, -N(R ⁹ )-, -S(O)- or -S(O) ₂ -; R ² is selected from C _3-12 cycloalkyl, C _6-10 aryl, 5-10 heteroaryl, 3-12 heterocyclo or C _5-7 cycloalkenyl, wherein the C _3-12 cycloalkyl, C 6-10 aryl, 5-10 heteroaryl, 3-12 heterocyclo or C _5-7 cycloalkenyl R ³ and R ⁴ are each independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C 2-12 alkenyl ^, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -COC _{1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl , -SO} 2 C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl _{) 2 -12} alkyl) _{SO2 C1-12 alkyl} , -SO2 _NH2 , _-SO2 NHC1-12 alkyl, _-SO2 N( _C1-12 alkyl) ₂ , _-CONH2 , _-CONHC1-12 alkyl _{, -CON(C1-12 alkyl)2, -NHCOC1-12 alkyl, -N(C1-12 alkyl)COC1-12 alkyl, C3-12 cycloalkyl , C3-12 cycloalkenyl , C6-10 aryl} , 5-10 membered heteroaryl or 3-12 _membered heterocyclic group; the -OH, -SH, _{-NH2 , -NHC1-12 alkyl, -N(C1-12 alkyl)2, C1-12 alkyl, C2-12 alkenyl , C2-12 alkynyl ,} C C _1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O)C _1-12 alkyl, -C(O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C _6-10 membered aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic group are optionally independently substituted by one or more substituents; or ^R3 and ^R4 and the carbon atom to which they are commonly connected together form a carbonyl group; or ^R3 and ^R4 and the carbon atom to which they are commonly connected together form _{a C3-6} cycloalkyl or 3-6 membered heterocycloalkyl group optionally substituted by one or more substituents; or ^R3 and ^R3 , ^R3 and ^R4 , ^R4 and ^R3 , ^R4 and ^R4 on two adjacent carbon atoms and the carbon atom to which they are connected together form a _C3-6 cycloalkyl or 3-6 membered heterocycloalkyl group optionally substituted by one or more substituents; ^R6 is selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, _-NH2 , -NHC C _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O)C _1-12 alkyl, -C(O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C 1-12 alkyl) C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C 1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O)C _1-12 alkyl, _-C (O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl) ₂ R ₇ and R 8 are independently selected from hydrogen _{, halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-12 alkyl , -N(C 1-12 alkyl) 2 , C 3-12 cycloalkyl , C 3-12 cycloalkenyl , C 6-10} aryl, _5-10 membered heteroaryl and 3-12 membered heterocyclic groups, and are optionally substituted with one or more R ^6a ; R ⁷ and R ⁸ are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _3-12 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic groups, respectively. C _1-12 alkyl, C _2-12 alkenyl, C _{2-12 alkynyl, C 1-12} alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O)C _1-12 alkyl, -C(O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl _, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C 1-12 The -OH, -SH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl, -OC(O _{)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl , -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl )SO 2 C 1-12 alkyl , -SO 2 NH 2 , -SO 2} NHC _R7 and R8, together _with the carbon _{atoms to} which _{they are commonly} attached, form a _C3-8 cycloalkyl, a _3-8 membered heterocyclic group or a ^C3-8 cycloalkenyl group which _{is optionally} substituted with one or more substituents; ^R9 is selected from hydrogen or _C1-12 alkyl, and _{the C3-12 cycloalkyl} , _C3-12 cycloalkenyl, _C6-10 aryl, a ^5-10 membered heteroaryl and _{a 3-12} membered heterocyclic group. R ^2a and R ^6a are each independently selected from halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C 2-12 alkynyl, C _1-12 alkoxy, C _1-12 alkylthio, -COC _1-12 alkyl _{, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl ,} -OC(O) _{OC 1-12} alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _-1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-12 alkyl, -N(C _1-12 alkyl) ₂ , C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _{1-12 alkoxy, C 1-12 alkylthio} , -COC _1-12 alkyl, -OC(O)C C _1-12 alkyl, -C(O)OC _1-12 alkyl, -OC(O)OC _1-12 alkyl, -SO ₂ C _1-12 alkyl, -NHSO ₂ C _1-12 alkyl, -N(C _1-12 alkyl)SO ₂ C _1-12 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-12 alkyl, -SO ₂ N(C _1-12 alkyl) ₂ , -CONH ₂ , -CONHC _1-12 alkyl, -CON(C _1-12 alkyl) ₂ , -NHCOC _1-12 alkyl, -N(C _1-12 alkyl)COC _1-12 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkenyl, C The _6-10 membered aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic group are optionally and independently substituted with one or more substituents; m is selected from 1, 2 or 3. The compound represented by formula (I) as described in claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein at least one of ^X1 and ^X2 is selected from C( ^R1 ); preferably, one of ^X1 and ^X2 is selected from C( ^R1 ) and the other is selected from N. The compound represented by formula (I) as described in claim 2, its isomer or pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) -OH, -SH _{, -NH 2 , -NHC 1-6} alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio _, -COC _{1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl , -OC ( O} )OC _{1-6 alkyl} , -SO ₂ C _{1-6 alkyl , -NHSO 2} C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group are optionally and independently substituted with one or more substituents; preferably, each R ¹ is independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C 2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl)SO ₂ C _1-3 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-3 alkyl, -SO _{2 N} (C _1-3 alkyl) ₂ , -CONH ₂ , -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C _3-6 cycloalkyl, C 2-3 alkyl _3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, _-NH2 , _-NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl, _{C2-3 alkynyl, C1-3 alkoxy, C1-3 alkylthio ,} -COC1-3 alkyl, -OC(O) _C1-3 alkyl, -C(O _{) OC1-3} alkyl, -OC(O) _OC1-3 alkyl _{, -SO2C1-3} alkyl _{, -NHSO2C1-3} alkyl, -N( _C1-3 alkyl) _SO2C1-3 alkyl _{, -SO2NH2 , -SO2NHC1-3 alkyl, -SO2N(C1-3 alkyl)2 , -CONH2 ,} -CONHC Preferably, each R 1 is independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _{2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -SO 2 NH 2 , -CONH 2 , C 3-6 cycloalkyl , C 3-6 cycloalkenyl , phenyl} ^, _{5-6 membered heteroaryl and 3-6 membered heterocyclic group .} The -OH, _-NH2 , -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _{C2-3 alkenyl ,} C2-3 alkynyl, _C1-3 alkoxy, _C1-3 alkylthio, _-SO2NH2 , _-CONH2 , _C3-6 cycloalkyl, _C3-6 cycloalkenyl, phenyl, _5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally substituted independently _by one or more substituents. The compound represented by formula (I) as described in claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein at least two of ^X3 , ^X4 , ^X5 and ^X6 are selected from C( ^R5 ); preferably, ^X3 is selected from C( ^R5 ) and ^X4 is selected from C( ^R5 ); or preferably, ^X5 is selected from C( ^R5 ) and ^X6 is selected from C( ^R5 ). The compound represented by formula (I) as described in claim 4, its isomer or pharmaceutically acceptable salt thereof, wherein each R ⁵ is independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) -OH, -SH _{, -NH 2 , -NHC 1-6} alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio _, -COC _{1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl , -OC ( O} )OC _{1-6 alkyl} , -SO ₂ C _{1-6 alkyl , -NHSO 2} C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group are optionally and independently substituted with one or more substituents; preferably, each R ⁵ is independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C 2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl)SO ₂ C _1-3 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-3 alkyl, -SO _{2 N} (C _1-3 alkyl) ₂ , -CONH ₂ , -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C _3-6 cycloalkyl, C 2-3 alkyl _3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, _-NH2 , _-NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl, _{C2-3 alkynyl, C1-3 alkoxy, C1-3 alkylthio ,} -COC1-3 alkyl, -OC(O) _C1-3 alkyl, -C(O _{) OC1-3} alkyl, -OC(O) _OC1-3 alkyl _{, -SO2C1-3} alkyl _{, -NHSO2C1-3} alkyl, -N( _C1-3 alkyl) _SO2C1-3 alkyl _{, -SO2NH2 , -SO2NHC1-3 alkyl, -SO2N(C1-3 alkyl)2 , -CONH2 ,} -CONHC Preferably, each R 5 is independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, _{C 2-3} alkynyl, C _1-3 alkoxy, _{C 1-3 alkylthio, -SO 2 NH 2 , -CONH 2 , C 3-6 cycloalkyl, C 3-6 cycloalkenyl , phenyl , 5-6 membered heteroaryl and} ^3-6 _{membered heterocyclic group} . _3-6- membered cycloalkenyl, phenyl, 5-6-membered heteroaryl or 3-6-membered heterocyclic group, the -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, _{C 2-3} alkenyl, C 2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -SO ₂ NH ₂ , -CONH ₂ , C _{3-6 cycloalkyl, C 3-6 cycloalkenyl} , phenyl, 5-6-membered heteroaryl and 3-6-membered heterocyclic group are optionally and independently substituted by one or more substituents; or X ³ is selected from C(R ⁵ ), X ⁴ is selected from C(R ⁵ ), and R ⁵ on the two carbon atoms of X ³ and X ⁴ and the carbon atom to which they are connected together form a C 3-6-membered cycloalkenyl group optionally substituted by one or more substituents. Preferably, ^X3 is selected from C( ^R5 ), ^X4 is selected from C( ^R5 ), and ^R5 on the two carbon atoms of ^X3 and X4 and the carbon atom to which they are connected together form a _C5-6 cycloalkenyl, a _5-6 membered heterocycloalkenyl, a phenyl or a 5-6 membered heteroaryl group optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or _NH2 ; or ^X5 is selected from C( ^R5 ), ^X6 is selected from C(R5), and ^R5 on the two carbon atoms of X5 and ^X6 and the carbon atom to which they are connected together form a ^C5-6 cycloalkenyl, a ^5-6 membered heterocycloalkenyl, a phenyl or a 5-6 membered heteroaryl group optionally substituted by one or more substituents ^. Preferably, ^X5 is selected from C( ^R5 ), ^X6 is selected from C( ^R5 ), and ^R5 on the two carbon atoms of ^X5 and ^X6 and the carbon atom to which they are attached together form a _C5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl group which is optionally substituted by 1 _, 2 or ₃ groups selected from halogen, OH, CN or NH2. The compound represented by formula (I) as described in claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein L is selected from -(C(R ³ R ⁴ )) _m -, -O-, -S- or -N(R ⁹ )-; preferably, L is selected from -(C(R ³ R ⁴ )) _m -, -O-, -S- or -NH-. The compound represented by formula (I) as described in claim 6, its isomer or pharmaceutically acceptable salt thereof, wherein each R ³ and R ⁴ are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, _C 2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C Preferably, each _{R 3} and _{R 4} is independently selected from hydrogen _, halogen, _{-CN, -OH, -SH, -COOH, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2 , -NH 2 , -NH 2 , -NH 2 , -NH 2 ,} -NH 2, -NH ₂ , -NH _{2, -NH 2,} -NH 2, -NH ₂ , -NH 2, -NH 2 _, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH ² , -NH 2, -NH 2, -NH ² , -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH ₂ , -NH 2 C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl)SO ₂ C _1-3 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-3 alkyl, -SO ₂ N(C _1-3 alkyl) ₂ , -CONH ₂ , -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C 1-3 alkyl The -OH, _-SH , _-NH2 , -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , C1-3 alkyl, _C2-3 alkenyl, C2-3 _alkynyl , _C1-3 alkoxy, _C1-3 alkylthio, _{-COC1-3 alkyl, -OC(O)C1-3 alkyl, -C(O)OC1-3 alkyl , -OC} (O _{) OC1-3} alkyl _{, -SO2C1-3} alkyl, _-NHSO2C1-3 alkyl, -N( _C1-3 alkyl) _SO2C1-3 alkyl _{, -SO2NH2} , _-SO2NHC1-3 alkyl, _{-SO2N ( C1-3 alkyl} ) ₂ , _{-CONH Preferably} , each of R 3 and R 4 is independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _{1-3 alkoxy, C 1-3 alkylthio , -SO} ² NH ₂ , _{-CONH 2} , _{C 3-6} cycloalkyl _, C _3-6 cycloalkenyl, phenyl, ^5-6 membered heteroaryl and _{3-6 membered} heterocyclic _group . _3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein -OH, _-NH2 , -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl, _C2-3 alkynyl, _{C1-3 alkoxy, C1-3 alkylthio} , _-SO2NH2 , _-CONH2 , _C3-6 cycloalkyl, _C3-6 cycloalkenyl, phenyl, _5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally and independently substituted by one ^or more substituents; or, _R3 and R R 3 and ^{R 4} and the carbon atoms to which they are commonly attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, thiacyclobutyl, azacyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or oxolinyl group, which are optionally substituted with one or more substituents; preferably, R ³ and R ⁴ and the carbon atoms to which they are commonly attached form a cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl, or azacyclobutyl group, which are optionally substituted with one or more substituents. The compound represented by formula (I) as described in claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein R ² is selected from C _3-8 cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, 3-8 membered heterocyclic group or C _5-6 cycloalkenyl, and the C _3-8 cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, 3-8 membered heterocyclic group and C _5-6 cycloalkenyl are arbitrarily and independently substituted by one or more R ^2a ; preferably, R ² is selected from C _3-6 cycloalkyl, phenyl, naphthyl, 5-9 membered heteroaryl, 3-6 membered heterocyclic group or C _5-6 cycloalkenyl, and the C _3-6 cycloalkyl, phenyl, naphthyl, 5-9 membered heteroaryl, 3-6 membered heterocyclic group and C The _5-6- membered cycloalkenyl group is optionally and independently substituted by one or more R ^2a ; further preferably, R ² is selected from C _5-6 -cycloalkyl, phenyl, 5-6-membered heteroaryl, 5-6-membered heterocyclic group or C _5-6- cycloalkenyl, and the C _5-6- cycloalkyl, phenyl, 5-6-membered heteroaryl, 5-6-membered heterocyclic group and C _5-6- cycloalkenyl group are optionally and independently substituted by one or more R ^2a . The compound represented by formula (I) as described in claim 8, its isomer or pharmaceutically acceptable salt thereof, wherein R ^2a is selected from halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl _, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _{1-6 alkyl} , -NHSO ₂ C -C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group are optionally and independently substituted with one or more substituents; preferably, R ^2a is selected from halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C 3-8 C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC 1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C 1-3 alkyl, -N(C _1-3 alkyl)SO 2 C _1-3 alkyl, -SO 2 NH 2 , -SO ₂ NHC _1-3 alkyl, -SO ₂ N(C 1-3 alkyl) ₂ , -CONH ₂ , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C 3-6 cycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C ₍ O)OC 1-3 alkyl, -OC(O)OC 1-3 alkyl, -SO ₂ C 1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl)SO 2 C 1-3 alkyl, -SO 2 NH 2 , -SO 2 NHC _1-3 alkyl, -SO ₂ N(C 1-3 alkyl) _{2 3-6} membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, _-NH2 , _-NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl, _{C2-3 alkynyl, C1-3 alkoxy, C1-3 alkylthio ,} -COC1-3 alkyl, -OC(O) _C1-3 alkyl, -C(O _{) OC1-3} alkyl, -OC(O) _OC1-3 alkyl _{, -SO2C1-3} alkyl _{, -NHSO2C1-3} alkyl, -N( _C1-3 alkyl) _SO2C1-3 alkyl _{, -SO2NH2 , -SO2NHC1-3 alkyl, -SO2N(C1-3 alkyl)2 , -CONH2 ,} -CONHC Preferably, R 2a is selected from halogen, -CN, -OH, -NH 2 , ^-NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, _{C 2-3} alkynyl, _{C 1-3 alkoxy, C 1-3 alkylthio} , -SO ₂ NH ₂ , -CONH ₂ , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, _{5-6 membered} heteroaryl _{and 3-6 membered heterocyclic} group _. The -OH, _-NH2 , -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _{C2-3 alkenyl ,} C2-3 alkynyl, _C1-3 alkoxy, _C1-3 alkylthio, _-SO2NH2 , _-CONH2 , _C3-6 cycloalkyl, _C3-6 cycloalkenyl, phenyl, _5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally substituted independently _by one or more substituents. The compound represented by formula (I) as described in claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein ^R6 is selected from hydrogen, halogen, -CN, -OH, -SH, -COOH _{, -NH2} , -NHC1-6alkyl, -N( _C1-6alkyl ) ₂ , _C1-6alkyl , C2-6alkenyl, _{C2-6alkynyl ,} C1-6alkoxy _{, C1-6alkylthio , -COC1-6alkyl} , _-OC (O) _{C1-6alkyl, -C(O)OC1-6alkyl , -OC} (O) _{OC1-6alkyl , -SO2C1-6alkyl , -NHSO2C1-6alkyl} , -N( _C1-6alkyl ) _SO2C1-6alkyl , _-SO2NH2 , _{-SO2NHC1-6alkyl} , _-SO2N ( _C1-6alkyl ) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _{1-6 alkyl} , -NHSO ₂ C Preferably, R ₆ is selected from hydrogen _{, halogen, -CN, -OH , -SH , -COOH ,} -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _3-8 cycloalkyl, C _3-8 cycloalkenyl _, phenyl, _5-10 membered heteroaryl and _3-8 membered heterocyclic group, _and is optionally substituted with one or more R ^6a ; preferably, R ⁶ is selected from hydrogen, halogen, -CN, -OH, _-SH , -COOH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C 3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group. C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _{1-3 alkoxy, C 1-3} alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O) _{OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -NHSO 2 C 1-3 alkyl, -N(C 1-3 alkyl)SO 2 C 1-3 alkyl , -SO 2 NH 2 , -SO 2 NHC 1-3 alkyl} , -SO ₂ N(C _1-3 alkyl) ₂ , -CONH ₂ , -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C _3-6 cycloalkyl, C 2-3 alkyl _3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, _-NH2 , _-NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl, _{C2-3 alkynyl, C1-3 alkoxy, C1-3 alkylthio ,} -COC1-3 alkyl, -OC(O) _C1-3 alkyl, -C(O _{) OC1-3} alkyl, -OC(O) _OC1-3 alkyl _{, -SO2C1-3} alkyl _{, -NHSO2C1-3} alkyl, -N( _C1-3 alkyl) _SO2C1-3 alkyl _{, -SO2NH2 , -SO2NHC1-3 alkyl, -SO2N(C1-3 alkyl)2 , -CONH2 ,} -CONHC Preferably, R is selected from hydrogen, halogen, -CN, -OH, -NH 2 , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, _{C 2-3} alkynyl, C _1-3 alkoxy, _{C 1-3} alkylthio, -SO ₂ NH ₂ , -CONH ₂ , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, _{phenyl ,} ^5-6 membered heteroaryl _{and 3-6 membered} ^heterocyclic group _. R _6a ; -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C _1-3 alkylthio, -SO 2 NH 2 , -CONH ₂ , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein the -OH, -NH 2 , -NHC _1-3 alkyl, -N(C _1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C _1-3 alkylthio, -SO ₂ NH ₂ , -CONH 2 , C 3-6 cycloalkyl, C _3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally and independently substituted by one or more R ^6a . The compound represented by formula (I) as described in claim 10, its isomer or pharmaceutically acceptable salt thereof, wherein R ^6a is selected from halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _1-6 alkyl _, -NHSO ₂ C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C _{1-6 alkyl} , -NHSO ₂ C -C _1-6 alkyl, -N(C _1-6 alkyl)SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group are optionally and independently substituted with one or more substituents; preferably, R ^6a is selected from halogen, -CN, -OH, -SH, -COOH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C 1-3 alkyl, C 3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group. C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC 1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C 1-3 alkyl, -N(C _1-3 alkyl)SO 2 C _1-3 alkyl, -SO 2 NH 2 , -SO ₂ NHC _1-3 alkyl, -SO ₂ N(C 1-3 alkyl) ₂ , -CONH ₂ , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C 3-6 cycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C ₍ O)OC 1-3 alkyl, -OC(O)OC 1-3 alkyl, -SO ₂ C 1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl)SO 2 C 1-3 alkyl, -SO 2 NH 2 , -SO 2 NHC _1-3 alkyl, -SO ₂ N(C 1-3 alkyl) _{2 3-6} membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, _-NH2 , _-NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C2-3 alkenyl, _{C2-3 alkynyl, C1-3 alkoxy, C1-3 alkylthio ,} -COC1-3 alkyl, -OC(O) _C1-3 alkyl, -C(O _{) OC1-3} alkyl, -OC(O) _OC1-3 alkyl _{, -SO2C1-3} alkyl _{, -NHSO2C1-3} alkyl, -N( _C1-3 alkyl) _SO2C1-3 alkyl _{, -SO2NH2 , -SO2NHC1-3 alkyl, -SO2N(C1-3 alkyl)2 , -CONH2 ,} -CONHC Preferably, R 6a is selected from halogen, -CN, -OH, -NH 2 , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, _{C 2-3} alkynyl, _{C 1-3 alkoxy, C 1-3 alkylthio} , -SO ₂ NH ₂ , -CONH ₂ , C _3-6 cycloalkyl, C _3-6 cycloalkenyl _, phenyl, ^5-6 _membered heteroaryl _{and 3-6 membered heterocyclic} group _. The -OH, _-NH2 , -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _{C2-3 alkenyl ,} C2-3 alkynyl, _C1-3 alkoxy, _C1-3 alkylthio, _-SO2NH2 , _-CONH2 , _C3-6 cycloalkyl, _C3-6 cycloalkenyl, phenyl, _5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally substituted independently _by one or more substituents. The compound represented by formula (I) as described in claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein ^R7 and ^R8 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, _-NH2 , _-NHC1-6 alkyl, -N( _C1-6 alkyl) ₂ , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C1-6 alkylthio, -COC1-6 _{alkyl, -OC(O)C1-6 alkyl, -C(O)OC1-6 alkyl, -OC(O)OC1-6 alkyl , -SO2C1-6 alkyl , -NHSO2C1-6 alkyl , -N} ( _{C1-6 alkyl)SO2C1-6 alkyl} , _{-SO2NH2 , -SO2NHC1-6} alkyl, _-SO2 N(C _1-6 alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -NHCOC _1-6 alkyl, -N(C _1-6 alkyl)COC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -COC _1-6 alkyl, -OC(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -OC(O)OC _1-6 alkyl, -SO ₂ C Preferably _{, R 7} and R _{8 are} independently substituted by one _{or more} substituents _; preferably, R 7 and R ₈ are independently selected from hydrogen _, halogen, -CN _{, -OH, -SH, -COOH, -NH 2, -NH 2 , -NH 2 , -NH 2 , -NH} 2, -NH 2, -NH ₂ , -NH _{2 ,} -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, ^-NH 2, -NH ₂ , -NH ² , -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH 2, -NH ₂ , -NH 2 C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkylthio, -COC _1-3 alkyl, -OC(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, -OC(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -NHSO ₂ C _1-3 alkyl, -N(C _1-3 alkyl)SO ₂ C _1-3 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-3 alkyl, -SO ₂ N(C _1-3 alkyl) ₂ , -CONH ₂ , -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHCOC _1-3 alkyl, -N(C _1-3 alkyl)COC _1-3 alkyl, C 1-3 alkyl The -OH, _-SH , _-NH2 , -NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , C1-3 alkyl, _C2-3 alkenyl, C2-3 _alkynyl , _C1-3 alkoxy, _C1-3 alkylthio, _{-COC1-3 alkyl, -OC(O)C1-3 alkyl, -C(O)OC1-3 alkyl , -OC} (O _{) OC1-3} alkyl _{, -SO2C1-3} alkyl, _-NHSO2C1-3 alkyl, -N( _C1-3 alkyl) _SO2C1-3 alkyl _{, -SO2NH2} , _-SO2NHC1-3 alkyl, _{-SO2N ( C1-3 alkyl} ) ₂ , _-CONH Preferably, R 7 and R 8 are independently selected from hydrogen, halogen, -CN, -OH, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, _{C 1-3} alkoxy, C _1-3 alkylthio, -SO ₂ NH ₂ , -CONH ₂ , _{C 3-6} cycloalkyl, C _3-6 cycloalkenyl _{, phenyl , 5-6} membered ^heteroaryl and ^3-6 _membered heterocyclic _group . R 7 and R ₈ together _with the carbon atoms _to which _{they are} commonly _attached form a C _3-6 cycloalkyl, _{a 3-6} membered heterocyclic group or a C _3-6 membered heterocyclic group which is optionally substituted with one or more substituents; preferably, R ⁷ and R ₈ together with the carbon atoms ^to which _{they are} commonly attached form _a C _3-6 cycloalkyl, a 3-6 membered heterocyclic group or _a C _3-6 cycloalkenyl group which is optionally substituted with one or more substituents; preferably, R R ⁷ and R ⁸ and the carbon atom to which they are commonly connected together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, which is optionally substituted with one or more substituents; further preferably, R 7 and R 8 together with the carbon atom to which they are commonly connected form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, thiacyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, which is optionally substituted with one or more substituents; further preferably, R ⁷ and R ⁸ and the carbon atoms to which they are commonly attached together form a cyclopropyl, cyclobutyl, oxacyclobutyl, azacyclobutyl, pyrrolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl group which may be optionally substituted with one or more substituents. The compound represented by formula (I) as described in claim 1, its isomer or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (I-1), , wherein X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , R ² , R ³ , R ⁴ and R ⁶ are as defined in the compound of formula (I) as described in claim 1; or the compound of formula (I) as described in claim 1, its isomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (I-2), , wherein X ⁴ is selected from CH or N; X ¹ , X ² , R ² , L and R ⁶ are as defined in the compound of formula (I) as described in claim 1; or the compound of formula (I) as described in claim 1, its isomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (I-3), , wherein X ⁴ is selected from CH or N; X ¹ , R ² , L and R ⁶ are as defined in the compound of formula (I) as described in claim 1; or the compound of formula (I) as described in claim 1, its isomer or a pharmaceutically acceptable salt thereof, selected from the compound of formula (I-4), , wherein, X ⁴ is selected from CH or N; X ¹ , R ² , R ³ , R ⁴ and R ⁶ are as defined in the compound of formula (I) described in claim 1; the carbon atom to which R ³ and R ⁴ are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or a form enriched in one mirror image isomer; or the compound of formula (I) described in claim 1, its isomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (I-5), , wherein, X ⁴ is selected from CH or N; Y ¹ , Y ² and Y ³ are independently selected from CH or N; X ¹ , R ³ , R ⁴ , R ⁶ and R ^2a are as defined in the compound of formula (I) described in claim 1; the carbon atom to which R ³ and R ⁴ are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or a form enriched in one mirror image isomer; or the compound of formula (I) described in claim 1, its isomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (I-6), , wherein, X ⁴ is selected from CH or N; Y ¹ , Y ² and Y ³ are as defined in the compound of formula (I-5); X ¹ , R ³ , R ⁴ , R ^2a and R ^6a are as defined in the compound of formula (I) described in claim 1; the carbon atom to which R ³ and R ⁴ are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or a form enriched in one mirror image isomer; or the compound of formula (I) described in claim 1, its isomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (I-7), , wherein, X ⁴ is selected from CH or N; Y ¹ , Y ² and Y ³ are defined as the compound represented by formula (I-5); X ¹ , R ³ , R ⁴ , R ^2a and R ^6a are defined as the compound represented by formula (I) described in claim 1; the carbon atom to which R ³ and R ⁴ are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or in a form enriched in one mirror image isomer. A compound of the following formula, an isomer thereof or a pharmaceutically acceptable salt thereof, . A pharmaceutical composition comprising a therapeutically or preventively effective amount of the compound described in any one of claims 1 to 14, its isomers or pharmaceutically acceptable salts thereof. A use of a compound according to any one of claims 1 to 14, an isomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease associated with the inhibition of ubiquitin-specific protease 1 (USP1).