Carbonyl-fused heterocyclic derivatives as ubiquitin-specific protease inhibitors

Abstract

The present invention provides carbonyl-fused heterocyclic derivatives as ubiquitin-specific protease inhibitors, and specifically relates to a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof: [Formula 1] TIFF2025531133000108.tif41114

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This invention claims priority to and benefits of Chinese patent application number 202211144812.4 filed with the State Intellectual Property Office of China on September 20, 2022, application number 202310690391.3 filed with the State Intellectual Property Office of China on June 9, 2023, and application number 202311161323.4 filed with the State Intellectual Property Office of China on September 8, 2023, the disclosures of which are incorporated herein by reference in their entireties. [Technical Field]

[0002] The present disclosure belongs to the field of medicinal chemistry and relates to carbonyl-fused heterocyclic derivatives as ubiquitin-specific protease inhibitors, and specifically to a compound represented by formula (I), its isomers, or pharmaceutically acceptable salts thereof: [Background technology]

[0003] USP1 (ubiquitin-specific peptidase 1), an abbreviation for ubiquitin-specific peptidase 1, is a member of the deubiquitinating enzyme family. USP1 forms a USP1-UAF1 complex with its cofactor UAF1 (USP1-associated factor 1) to deubiquitinate two key proteins in the FA and TLS pathways, Ub-FANCD2 and Ub-PCNA, which then activate DNA crosslink repair and promote cancer cell survival. USP1 is highly expressed in a variety of human tumors and is closely associated with tumor development and progression, making it a promising target for tumor therapy.

[0004] Genome-wide targeted knockdown studies based on CRISPR technology have shown that USP1 has synthetic lethal effects on BRCA1 / 2 mutations or other homologous recombination repair deficiencies (HRDs). From the viewpoint of mechanism of action, USP1 and PARP are key regulatory proteins in the DNA crosslink damage and single-strand break repair pathways, respectively, and they complement each other. USP1 complements the ATP-dependent ATPases, facilitating DNA damage repair and avoiding the generation of cytotoxic DNA double-strand breaks. Therefore, USP1 is an important target with great clinical value in the field of DNA damage repair. Summary of the Invention

[0005] The present disclosure provides a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, X 1 and X 2 are each independently C(R 1 ) or N, X 3 is C(R 1 )2, C(=Z), N(R 7 ), S or O; X 4 , X 5 , X 6 and X 7 are each independently C(R 5 ) or N, Each R 1 and R 5 are each independently hydrogen, deuterium, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; and 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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 6-10The aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are optionally substituted independently with one or more substituents; Z is O, S or N(R 8 ) and Or X 2 and X 3 are bonded to each other to jointly form a 5- to 7-membered ring which may be substituted by one or more substituents, or R on two adjacent carbon atoms 5 C, together with the carbon atoms to which they are attached, may be substituted with one or more substituents. 5-7 forming a cycloalkenyl, a 5- to 7-membered heterocycloalkenyl, a phenyl, or a 5- to 6-membered heteroaryl; L is -(C(R 3 R 4 )) m -, -O-, -S-, -N(R 9 )-, -S(O)- or -S(O)-; R 2 is C 3-12 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl or C 5-7 cycloalkenyl, wherein C 3-12 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl and C 5-7 Cycloalkenyl is independently one or more R 2a may be substituted with Each R 3 and R 4 are each independently hydrogen, deuterium, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated alkoxy, C 1-12Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; and 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 alkyl)2, -NHCOC1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 The aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are optionally substituted independently with one or more substituents; Or R 3 and R 4 C, together with the carbon atoms to which they are attached, may be substituted with one or more substituents. 3-6 forming a cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 6 are hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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 6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; and 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC1 -12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are independently one or more R 6a may be substituted with Each R 7 , R 8 or R 9 are each independently hydrogen, -NH2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 1-12 Alkoxy, C 1-12 Deuterated alkoxy, C 3-12 cycloalkyl or 3- to 12-membered heterocyclyl, 1-12 Alkyl, C1-12 Deuterated alkyl, C 1-12 Alkoxy, C 1-12 Deuterated alkoxy, C 3-12 The cycloalkyl or 3- to 12-membered heterocyclyl may be optionally substituted by one or more substituents, Each R 2a and R 6a are each independently hydrogen, deuterium, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; and 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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 The aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are optionally substituted independently with one or more substituents; m is selected from 1, 2 or 3; The condition is X 1 When is N, X 3 is not NH.)

[0006] In some embodiments of the present disclosure, X 1 and X 2 At least one of C(R 1 ) is selected.

[0007] In some embodiments of the present disclosure, X 3 is C(=O), N(R 7 ), S or O.

[0008] In some embodiments of the present disclosure, X 2 is C(R1 ) and X 1 is selected from N, and X 3 is C(=O), N(R 7 ), S or O.

[0009] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 1 is selected from N, and X 3 is N(R 7 ) is selected.

[0010] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 1 is selected from N, and X 3 is selected from S.

[0011] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 1 is selected from N, and X 3 is selected from O.

[0012] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 1 is selected from N, and X 3 is C(R 1 )2 is selected.

[0013] In some embodiments of the present disclosure, X 2 is selected from N, and X 1 is C(R 1 ) and X 3 is C(=O), N(R 7 ), S or O.

[0014] In some embodiments of the present disclosure, X 2 is selected from N, and X 1 is C(R 1) and X 3 is N(R 7 ) is selected.

[0015] In some embodiments of the present disclosure, X 2 is selected from N, and X 1 is C(R 1 ) and X 3 is selected from S.

[0016] In some embodiments of the present disclosure, X 2 is selected from N, and X 1 is C(R 1 ) and X 3 is selected from O.

[0017] In some embodiments of the present disclosure, X 2 is selected from N, and X 1 is C(R 1 ) and X 3 is C(R 1 )2 is selected.

[0018] In some embodiments of the present disclosure, X 1 is C(R 1 ) and X 2 is C(R 1 ) and X 3 is C(=O), N(R 7 ), S or O.

[0019] In some embodiments of the present disclosure, X 1 is C(R 1 ) and X 2 is C(R 1 ) and X 3 is C(R 1 )2 is selected.

[0020] In some embodiments of the present disclosure, X 1 is C(R 1 ) and X 2 is C(R 1) and X 3 is N(R 7 ) is selected.

[0021] In some embodiments of the present disclosure, X 1 is C(R 1 ) and X 2 is C(R 1 ) and X 3 is selected from S.

[0022] In some embodiments of the present disclosure, X 1 is C(R 1 ) and X 2 is C(R 1 ) and X 3 is selected from O. In some further embodiments of the present disclosure, "one or more" as referred to in the present disclosure is selected from 1, 2, 3, 4, 5, or 6.

[0023] In some further embodiments of the present disclosure, "one or more" as referred to in the present disclosure is selected from 1, 2, or 3.

[0024] In some embodiments of the present disclosure, each R 1 and R 5 are each independently hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Archi Le, -N(C 1-12 Alkyl)SO2C1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; and 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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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 The aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may be independently substituted with one or more substituents.

[0025] In some embodiments of the present disclosure, each R 1 and R 5 are each independently hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -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, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl)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- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; and 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, -SO2C 1-6 Alkyl, -NHSO2C 1-6Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl)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 The cycloalkenyl, phenyl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl may be independently substituted with one or more substituents.

[0026] In some embodiments of the present disclosure, each R 1 and R 5 are each independently hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -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, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 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 3-6Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 -membered heteroaryl or 3- to 6-membered heterocyclyl, and 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, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 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 The cycloalkenyl, phenyl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl may be independently substituted with one or more substituents.

[0027] In some embodiments of the present disclosure, each R 1 and R 5 are each independently hydrogen, halogen, -CN, -OH, -NH2, or -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 1-3Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; and 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, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 The cycloalkenyl, phenyl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl may be independently substituted with one or more substituents.

[0028] In some further embodiments of the present disclosure, each R 1 and R 5 are each independently hydrogen, deuterium, halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; and 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 The cycloalkenyl, phenyl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl may be independently substituted with one or more substituents.

[0029] In some further embodiments of the present disclosure, each R 1 and R 5 are each independently hydrogen, deuterium, halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy or C 1-3 deuterated alkoxy; 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Alkoxy or C 1-3 The deuterated alkoxy may be optionally substituted independently with one or more substituents.

[0030] In some further embodiments of the present disclosure, each R 1 and R 5 are independently hydrogen, deuterium, halogen, C 1-3 Alkyl or C 1-3 deuterated alkyl, 1-3 Alkyl or C 1-3 The deuterated alkyl may be independently substituted with one or more substituents.

[0031] In some embodiments of the present disclosure, each R 1 and R 5 are each independently hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, 1-3 Alkyl, C 1-3 Alkoxy, C3-6 The cycloalkyl and 3- to 6-membered heterocyclyl may be independently substituted with one or more substituents.

[0032] In some embodiments of the present disclosure, each R 1 and R 5 are each independently selected from hydrogen, halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl. and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl are independently optionally substituted with one or more substituents.

[0033] In some further embodiments of the present disclosure, each R 1 and R 5 is optionally substituted with one or more groups independently selected from halogen, deuterium, OH, CN, or NH2.

[0034] In some embodiments of the present disclosure, each R 1 and R 5 is optionally substituted with one or more groups independently selected from halogen, OH, CN, or NH2.

[0035] In some embodiments of the present disclosure, each R 1 and R 5 is optionally substituted with 1, 2, or 3 groups independently selected from halogen, OH, CN, or NH2.

[0036] In some embodiments of the present disclosure, each R 1 and R 5 are each independently selected from hydrogen, halogen, —CN, —OH, —NH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl; thyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl may be optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH, CN or NH.

[0037] In some embodiments of the present disclosure, each R 1 and R 5 are each independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl, or azetidinyl, wherein said methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl, or azetidinyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, OH, CN, or NH.

[0038] In some embodiments of the present disclosure, each R 1 are each independently selected from hydrogen, —F, —Cl, —Br, —I, —CN, methyl, ethyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0039] In some embodiments of the present disclosure, each R 1 are each independently selected from hydrogen, —F, methyl, ethyl, or CN.

[0040] In some further embodiments of the present disclosure, each R 1 are each independently selected from hydrogen, -F, methyl, -CD3, ethyl, -CD2CD3, or CN.

[0041] In some embodiments of the present disclosure, each R 1 are each independently selected from hydrogen or —F.

[0042] In some embodiments of the present disclosure, each R 1 are each independently selected from -F.

[0043] In some embodiments of the present disclosure, Z is selected from O or S.

[0044] In some embodiments of the present disclosure, Z is selected from O.

[0045] In some embodiments of the present disclosure, X 2 and X 3 are bonded to each other to jointly form a 5- to 7-membered ring which may be substituted by one or more substituents, and the 5- to 7-membered ring is selected from the group consisting of 5- to 7-membered heterocycloalkenyl, C 5-7 It is selected from cycloalkenyl, phenyl, or 5-6 membered heteroaryl.

[0046] In some embodiments of the present disclosure, X 2 and X 3 are bonded to each other to jointly form a 5- to 7-membered ring which may be substituted with one or more substituents, and X 3 The ring atom at the position indicated is a N atom.

[0047] In some embodiments of the present disclosure, X 2and X 3 are bonded to each other to jointly form a 5- to 7-membered ring which may be substituted with one or more substituents, and X 2 The ring-constituting atom at the position indicated by is a C atom.

[0048] In some embodiments of the present disclosure, X 2 and X 3 are bonded to each other to jointly form a 5- to 7-membered ring which may be substituted with one or more substituents, and X 2 The ring-constituting atom at the position indicated by is a C atom, and X 3 The ring atom at the position indicated is a N atom.

[0049] In some embodiments of the present disclosure, X 2 and X 3 are bonded to each other to jointly form a 5- to 7-membered ring which may be substituted by one or more substituents, and the 5- to 7-membered ring is selected from the group consisting of 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-tetrahydropyridyl, 1,2,3,6 ... tetrahydropyridyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-thiopyranyl, 3,6-dihydro-2H-thiopyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl.

[0050] In some embodiments of the present disclosure, X 2 and X 3are linked to each other to jointly form a 5- to 7-membered ring which may be substituted with one or more substituents, and the 5- to 7-membered ring is selected from 1,2,3,4-tetrahydro-pyridyl, cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 1,2,3,6-tetrahydropyridyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, and pyrimidinyl.

[0051] In some embodiments of the present disclosure, X 2 and X 3 are bonded to each other to jointly form a 5- to 7-membered ring which may be substituted with one or more substituents, and the substituents are selected from the group consisting of halogen, -CN, -OH, -SH, -COOH, NH, -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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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 It is selected from aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl.

[0052] In some embodiments of the present disclosure, X 2 and X 3 are bonded to each other to form a 5- to 7-membered ring which may be substituted with 1, 2 or 3 substituents, and the substituents are selected from halogen, OH, CN or NH2.

[0053] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is N(R 7 ) and X 2 R above 1 and X 3 R above 7 together with the carbon atom and nitrogen atom to which they are attached form a 5- to 7-membered heterocycloalkenyl or a 5-membered heteroaryl which may be substituted with one or more substituents.

[0054] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is C(R 1 )2 and X 2 R above 1 and X 3 The top one R 1 C, together with the carbon atoms to which they are attached, may be substituted with one or more substituents. 5-7 It forms a cycloalkenyl or a 5- to 7-membered heterocycloalkenyl.

[0055] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is C(R 1 )2 and X 2 R above 1 and X 3 The top two R 1 together with the carbon atom to which they are attached form a phenyl or 5- to 6-membered heteroaryl which may be substituted with one or more substituents.

[0056] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is N(R 7 ) and X 2 R above 1 and X 3 R above 7 together with the carbon atom and nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkenyl or a 5-membered heteroaryl which may be substituted with one or more substituents.

[0057] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is N(R 7 ) and X 2 R above 1 and X 3 R above 7 The substituents formed together with the carbon and nitrogen atoms to which they are attached may be one or more of the following substituents: halogen, -CN, -OH, -SH, -COOH, NH, -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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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 It may be substituted with aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl.

[0058] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is N(R 7 ) and X 2 R above 1 and X 3 R above 7 together with the carbon atom and nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkenyl or a 5-membered heteroaryl optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH.

[0059] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is N(R 7 ) and X 2 R above 1 and X 3 R above 7 together with the carbon and nitrogen atoms to which they are attached form 2,3-dihydro-pyrrolyl, 1,2,3,4-tetrahydro-pyridyl, 1,2-dihydro-pyridyl, 1,4-dihydro-pyridyl, pyrrolyl, pyrazolyl or imidazolyl, optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH.

[0060] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is N(R 7 ) and X 2 R above 1 and X 3 R above 7together with the carbon and nitrogen atoms to which they are attached form 1,2,3,4-tetrahydro-pyridyl optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0061] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is C(R 1 )2 and X 2 R above 1 and X 3 The top one R 1 C, together with the carbon atoms to which they are attached, may be substituted with one or more substituents. 5-6 It forms a cycloalkenyl or a 5- to 6-membered heterocycloalkenyl.

[0062] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is C(R 1 )2 and X 2 R above 1 and X 3 The top one R 1 The substituents formed together with the carbon atoms to which they are attached may be one or more of the following substituents: halogen, -CN, -OH, -SH, -COOH, NH, -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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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 It may be substituted with aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl.

[0063] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is C(R 1 )2 and X 2 R above 1 and X 3 The top one R 1 C, together with the carbon atoms to which they are attached, may be substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 5-6 It forms a cycloalkenyl or a 5- to 6-membered heterocycloalkenyl.

[0064] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is C(R 1 )2 and X 2 R above 1 and X 3 The top one R 1 are the carbons to which they are attached. Together with the atoms form 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-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-thiopyranyl or 3,6-dihydro-2H-thiopyranyl, optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH.

[0065] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is C(R 1 )2 and X 2 R above 1 and X 3 The top one R 1 together with the carbon atoms to which they are attached form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl or 1,2,3,6-tetrahydropyridyl optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH.

[0066] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is C(R 1 )2 and X 2 R above 1 and X 3 The top two R 1 together with the carbon atoms to which they are attached form a phenyl or 5- to 6-membered heteroaryl optionally substituted with one or more substituents, said substituents being halogen, -CN, -OH, -SH, -COOH, NH, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12Alkoxy, 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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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 It is selected from aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl.

[0067] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is C(R 1 )2 and X 2 R above 1 and X 3 The top two R 1 together with the carbon atoms to which they are attached form a phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH.

[0068] In some embodiments of the present disclosure, X 2 is C(R 1 ) and X 3 is C(R 1)2 and X 2 R above 1 and X 3 The top two R 1 together with the carbon atoms to which they are attached form a phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl or pyrimidinyl optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0069] In some embodiments of the present disclosure, X 1 is selected from C(F) and X 2 is selected from CH, and X 3 is selected from NH.

[0070] In some embodiments of the present disclosure, X 1 is selected from C(F) and X 2 is selected from CH, and X 3 is selected from N(NH2).

[0071] In some embodiments of the present disclosure, X 1 is selected from C(F) and X 2 is selected from CH, and X 3 is selected from N(CH3).

[0072] In some embodiments of the present disclosure, X 1 is selected from C(F) and X 2 is selected from CH, and X 3 is selected from N(CH2CH3).

[0073] In some embodiments of the present disclosure, X 1 is selected from C(F) and X 2 is selected from CH, and X 3 teeth, [ka] is selected from.

[0074] In some embodiments of the present disclosure, X1 is selected from C(F) and X 2 is selected from CH, and X 3 is selected from N(CD3).

[0075] In some embodiments of the present disclosure, X 1 is selected from C(F) and X 2 is selected from CH, and X 3 is selected from N(CD2CD3).

[0076] In some embodiments of the present disclosure, X 1 is selected from N, and X 2 is selected from CH, and X 3 is selected from S.

[0077] In some embodiments of the present disclosure, X 1 is selected from C(F) and X 2 is selected from CH, and X 3 is selected from C(=O).

[0078] In some embodiments of the present disclosure, X 1 is selected from CH, and X 2 is selected from CH, and X 3 is selected from S.

[0079] In some embodiments of the present disclosure, X 1 is selected from C(F) and X 2 is selected from CH, and X 3 is selected from S.

[0080] In some embodiments of the present disclosure, X 1 is selected from CH, and X 2 is selected from CH, and X 3 is selected from O.

[0081] In some embodiments of the present disclosure, X 1 is selected from C(F) and X 2 is selected from CH, and X3 is selected from O.

[0082] In some embodiments of the present disclosure, the constitutional unit [ka] teeth, [ka] is.

[0083] In some embodiments of the present disclosure, the constitutional unit [ka] teeth, [ka] is.

[0084] In some embodiments of the present disclosure, X 4 , X 5 , X 6 and X 7 At least two of the C(R 5 ) is selected.

[0085] In some embodiments of the present disclosure, X 4 is C(R 5 ) and X 5 is C(R 5 ) is selected.

[0086] In some embodiments of the present disclosure, X 6 is C(R 5 ) and X 7 is C(R 5 ) is selected.

[0087] In some embodiments of the present disclosure, X 4 is C(R 5) and X 5 is C(R 5 ) and X 6 is C(R 5 ) and X 7 is C(R 5 ) is selected.

[0088] In some embodiments of the present disclosure, X 4 is C(R 5 ) and X 5 is selected from N, and X 6 is C(R 5 ) and X 7 is C(R 5 ) is selected.

[0089] In some embodiments of the present disclosure, X 4 is selected from N, and X 5 is C(R 5 ) and X 6 is C(R 5 ) and X 7 is C(R 5 ) is selected.

[0090] In some embodiments of the present disclosure, X 4 is C(R 5 ) and X 5 is C(R 5 ) and X 6 is selected from N, and X 7 is C(R 5 ) is selected.

[0091] In some embodiments of the present disclosure, X 4 is C(R 5 ) and X 5 is C(R 5 ) and X 6 is C(R 5 ) and X 7 is selected from N.

[0092] In some embodiments of the present disclosure, X4 is selected from N, and X 5 is C(R 5 ) and X 6 is selected from N, and X 7 is C(R 5 ) is selected.

[0093] In some embodiments of the present disclosure, X 4 is C(R 5 ) and X 5 is selected from N, and X 6 is C(R 5 ) and X 7 is selected from N.

[0094] In some further embodiments of the present disclosure, each R 5 are each independently hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 The cycloalkyl or 3- to 6-membered heterocyclyl may be independently substituted with one or more substituents.

[0095] In some embodiments of the present disclosure, each R 5 are each independently selected from hydrogen, —F, —Cl, —Br, —I, —CN, methyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0096] In some further embodiments of the present disclosure, each R 5are each independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, CD3, methoxy, -OCD3, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0097] In some embodiments of the present disclosure, each R 5 are each independently selected from hydrogen or —F.

[0098] In some embodiments of the present disclosure, each R 5 are each independently selected from H.

[0099] In some embodiments of the present disclosure, X 4 is selected from CH, and X 5 is selected from CH.

[0100] In some embodiments of the present disclosure, X 6 is selected from CH, and X 7 is selected from CH.

[0101] In some embodiments of the present disclosure, X 4 is selected from CH, and X 5 is selected from CH, and X 6 is selected from CH, and X 7 is selected from CH.

[0102] In some embodiments of the present disclosure, X 4 is selected from CH, and X 5 is selected from N, and X 6 is selected from CH, and X 7 is selected from CH.

[0103] In some embodiments of the present disclosure, X 4 is selected from CH, and X 5 is selected from CH, and X 6 is selected from CH, and X 7 is selected from C(F).

[0104] In some embodiments of the present disclosure, X 4 is selected from N-H, and X 5 is selected from CH, and X 6 is selected from CH, and X 7 is selected from CH.

[0105] In some embodiments of the present disclosure, X 4 is C(R 5 ) and X 5 is C(R 5 ) and X 4 and X 5 R on two carbon atoms in 5 C, together with the carbon atoms to which they are attached, may be substituted with one or more substituents. 5-6 Cycloal The aryl group forms a 5- or 6-membered heterocycloalkenyl, phenyl, or 5- or 6-membered heteroaryl.

[0106] In some embodiments of the present disclosure, X 4 is C(R 5 ) and X 5 is C(R 5 ) and X 4 and X 5 R on two carbon atoms in 5 C, together with the carbon atoms to which they are attached, may be substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 5-6 It forms a cycloalkenyl, a 5- to 6-membered heterocycloalkenyl, a phenyl, or a 5- to 6-membered heteroaryl.

[0107] In some embodiments of the present disclosure, X 4 is C(R 5 ) and X 5 is C(R 5 ) and X 4 and X 5 R on two carbon atoms in 5are optionally substituted, together with the carbon atoms to which they are attached, by one, two or three groups selected from halogen, OH, CN or NH2, 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-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl, 3,4-dihydro -2H-pyranyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-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, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl.

[0108] In some embodiments of the present disclosure, X 4 is C(R 5 ) and X 5 is C(R 5 ) and X 4 and X 5 R on two carbon atoms in 5 together with the carbon atoms to which they are attached form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, phenyl, pyrrolyl, pyrazolyl, pyridyl or pyrimidinyl optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH.

[0109] In some embodiments of the present disclosure, X 4 is C(R 5 ) and X 5 is C(R 5 ) and X 4 and X 5 R on two carbon atoms in 5 C, together with the carbon atoms to which they are attached, may be substituted with one or more substituents. 5-6It forms a cycloalkenyl, a 5- to 6-membered heterocycloalkenyl, a phenyl, or a 5- to 6-membered heteroaryl.

[0110] In some embodiments of the present disclosure, X 4 is C(R 5 ) and X 5 is C(R 5 ) and X 4 and X 5 R on two carbon atoms in 5 C, together with the carbon atoms to which they are attached, may be substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 5-6 It forms a cycloalkenyl, a 5- to 6-membered heterocycloalkenyl, a phenyl, or a 5- to 6-membered heteroaryl.

[0111] In some embodiments of the present disclosure, X 6 is C(R 5 ) and X 7 is C(R 5 ) and X 6 and X 7 R on two carbon atoms in 5 are optionally substituted, together with the carbon atoms to which they are attached, by one, two or three groups selected from halogen, OH, CN or NH2, such as 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-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-thio forming pyranyl, 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, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl.

[0112] In some embodiments of the present disclosure, X 6 is C(R 5 ) and X 7 is C(R 5 ) and X 6 and X 7 R on two carbon atoms in 5 together with the carbon atoms to which they are attached form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, phenyl, pyrrolyl, pyrazolyl, pyridyl or pyrimidinyl optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH.

[0113] In some embodiments of the present disclosure, L is -(C(R 3 R 4 )) m -, -O-, -S- or -N(R 7 )- is selected from.

[0114] In some embodiments of the present disclosure, each R 7 , R 8 or R 9 are each independently hydrogen, -NH2, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 cycloalkyl or 3- to 12-membered heterocyclyl, 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 The cycloalkyl or 3- to 12-membered heterocyclyl may be optionally substituted with one or more substituents.

[0115] In some embodiments of the present disclosure, each R 7 , R 8 or R 9 are each independently hydrogen, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl,1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl or 3- to 6-membered heterocyclyl may be optionally substituted with one or more substituents.

[0116] In some further embodiments of the present disclosure, each R 7 , R 8 or R 9 are each independently hydrogen, -NH2, C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, 1-6 Deuterated alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-6 The cycloalkyl or 3- to 6-membered heterocyclyl may be optionally substituted with one or more substituents.

[0117] In some embodiments of the present disclosure, each R 7 , R 8 or R 9 are each independently hydrogen, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl or 3- to 6-membered heterocyclyl may be optionally substituted with one or more substituents.

[0118] In some further embodiments of the present disclosure, each R 7 , R 8 or R 9 are each independently hydrogen, -NH2, C 1-3 Deuterated alkyl, C 1-3 Alkyl, C 1-3 Alkoxy, C1-3 Deuterated alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, 1-3 Deuterated alkyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 The cycloalkyl or 3- to 6-membered heterocyclyl may be optionally substituted with one or more substituents.

[0119] In some embodiments of the present disclosure, each R 7 , R 8 or R 9 are each independently hydrogen, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and -NH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl, wherein said -NH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl are independently optionally substituted with one or more substituents.

[0120] In some further embodiments of the present disclosure, each R 7 , R 8 or R 9are each independently selected from hydrogen, -NH2, methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl; and 2, methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl are optionally independently substituted with one or more substituents.

[0121] In some further embodiments of the present disclosure, each R 7 , R 8 or R 9 is optionally substituted with one or more groups independently selected from halogen, deuterium, OH, CN, or NH2.

[0122] In some embodiments of the present disclosure, each R 7 , R 8 or R 9 is optionally substituted with one or more groups independently selected from halogen, OH, CN, or NH2.

[0123] In some embodiments of the present disclosure, each R 7 , R 8 or R 9are each independently selected from hydrogen, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl, wherein said -NH2, methyl, ethyl, isopropyl ... isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl may be optionally substituted by one, two or three groups independently selected from halogen, OH, CN or NH.

[0124] In some further embodiments of the present disclosure, each R 7 , R 8 or R 9 are each independently hydrogen, -NH2, methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidin ... and thiazolidinyl, isoxazolidinyl, and isoxazolidinyl, wherein said -NH2, methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl are optionally substituted by one, two, or three groups independently selected from halogen, OH, CN, or NH2.

[0125] In some embodiments of the present disclosure, each R 7 , R 8 or R 9 are each independently selected from hydrogen, —NH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl, or azetidinyl, wherein said —NH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl, or azetidinyl is optionally substituted by 1, 2, or 3 groups independently selected from halogen, OH, CN, or NH.

[0126] In some further embodiments of the present disclosure, each R 7 , R 8 or R 9are each independently selected from hydrogen, -NH, methyl, -CD, ethyl, -CD, isopropyl, -CH(CD), methoxy, -OCD, ethoxy, -OCD, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl, or azetidinyl, wherein said -NH, methyl, -CD, ethyl, -CD, isopropyl, -CH(CD), methoxy, -OCD, ethoxy, -OCD, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl, or azetidinyl is optionally substituted by one, two, or three groups independently selected from halogen, OH, CN, or NH.

[0127] In some embodiments of the present disclosure, each R 7 , R 8 or R 9 are each independently selected from hydrogen, —NH 2 , methyl, ethyl, or cyclopropyl.

[0128] In some further embodiments of the present disclosure, each R 7 , R 8 or R 9 are each independently selected from hydrogen, -NH2, methyl, ethyl, -CD2CD3, cyclopropyl, or -CD3.

[0129] In some other embodiments of the present disclosure, R 7 is selected from -CD3 or -CD2CD3.

[0130] In some other embodiments of the present disclosure, R 7 is selected from -CD3.

[0131] In some other embodiments of the present disclosure, R 7 is selected from hydrogen or methyl.

[0132] In some other embodiments of the present disclosure, R 7 is selected from methyl.

[0133] In some embodiments of the present disclosure, each R 7 , R 8 or R 9 is selected from hydrogen.

[0134] In some embodiments of the present disclosure, L is -(C(R 3 R 4 )) m -, -O-, -S- or -NH-.

[0135] In some embodiments of the present disclosure, L is —C(R 3 R 4 )- or -C(R 3 R 4 )-C(R 3 R 4 )- is selected from.

[0136] In some embodiments of the present disclosure, each R 3 and R 4 are each independently hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 alkyl)2, -NHCOC 1-12 Alkyl, -N(C1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; and 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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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 The aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may be independently substituted with one or more substituents.

[0137] In some embodiments of the present disclosure, each R 3 and R 4 are each independently hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6Alkenyl, 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, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl)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- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; and 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, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 alkyl)2, -NHCOC1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The cycloalkenyl, phenyl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl may be independently substituted with one or more substituents.

[0138] In some embodiments of the present disclosure, each R 3 and R 4 are each independently hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -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, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 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- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; and 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3Alkenyl, 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, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 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 The cycloalkenyl, phenyl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl may be independently substituted with one or more substituents.

[0139] In some embodiments of the present disclosure, each R 3 and R 4 are each independently hydrogen, halogen, -CN, -OH, -NH2, or -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, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; and 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 The cycloalkenyl, phenyl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl may be independently substituted with one or more substituents.

[0140] In some further embodiments of the present disclosure, each R 3 and R 4 are each independently hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy or C 1-3 deuterated alkoxy; 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy or C 1-3 The deuterated alkoxy may be optionally substituted independently with one or more substituents.

[0141] In some embodiments of the present disclosure, each R 3 and R 4 are each independently hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl or C 1-3 alkoxy, wherein C 1-3 Alkyl and C 1-3 The alkoxy may be optionally substituted independently with one or more substituents.

[0142] In some embodiments of the present disclosure, each R 3 and R 4 are each independently selected from hydrogen, halogen, —CN, —OH, —NH, methyl, ethyl, isopropyl, methoxy, ethoxy, and isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy, and isopropoxy groups may be independently substituted with one or more substituents.

[0143] In some further embodiments of the present disclosure, each R 3 and R 4 is optionally substituted with one or more groups independently selected from halogen, deuterium, OH, CN, or NH2.

[0144] In some embodiments of the present disclosure, each R 3 and R 4 is optionally substituted with one or more groups independently selected from halogen, OH, CN, or NH2.

[0145] In some embodiments of the present disclosure, each R 3 and R 4 are each independently selected from hydrogen, halogen, —CN, —OH, —NH, methyl, ethyl, isopropyl, methoxy, ethoxy, and isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy, and isopropoxy groups may be substituted with 1, 2, or 3 groups independently selected from halogen, OH, CN, and NH.

[0146] In some embodiments of the present disclosure, each R 3 and R 4 are each independently selected from hydrogen, —F, —Cl, —Br, —I, —CN, methyl, or ethyl.

[0147] In some embodiments of the present disclosure, each R 3 are each independently selected from hydrogen; 4 are each independently selected from hydrogen, —F, —Cl, —Br, —I, —CN, methyl, or ethyl.

[0148] In some embodiments of the present disclosure, each R 3 are each independently selected from hydrogen, —F, —Cl, —Br, —I, —CN, methyl, or ethyl; 4 are each independently selected from hydrogen.

[0149] In some embodiments of the present disclosure, each R3 are each independently selected from hydrogen; 4 are each independently selected from hydrogen, methyl, or ethyl.

[0150] In some embodiments of the present disclosure, each R 3 are each independently selected from hydrogen, methyl, or ethyl; 4 are each independently selected from hydrogen.

[0151] In some embodiments of the present disclosure, each R 3 are each independently selected from methyl; 4 are each independently selected from methyl; or each R 3 are each independently selected from hydrogen; 4 are each independently selected from hydrogen, or each R 3 are each independently selected from hydrogen; 4 are each independently selected from methyl; 3 are each independently selected from methyl; 4 are each independently selected from hydrogen, or each R 3 are each independently selected from hydrogen; 4 are each independently selected from ethyl, or each R 3 are each independently selected from ethyl; 4 are each independently selected from hydrogen.

[0152] In some embodiments of the present disclosure, R 3 and R 4 together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, which may be substituted by one or more substituents.

[0153] In some embodiments of the present disclosure, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl, which may be substituted by one or more substituents.

[0154] In some embodiments of the present disclosure, R 3 and R 4 together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0155] In some embodiments of the present disclosure, R 3 and R 4 The substituents formed together with the carbon atoms to which they are attached may be substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0156] In some embodiments of the present disclosure, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl, oxetanyl or azetidinyl optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0157] In some embodiments of the present disclosure, L is —C(R 3 R 4 )-C(R 3 R 4 )-, and R on two adjacent carbon atoms are selected from 3 and R 3 , R 3 and R 4 , R 4 and R 3 , R 4 and R 4together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl or isoxazolidinyl, which may be substituted by one or more substituents.

[0158] In some embodiments of the present disclosure, L is —C(R 3 R 4 )-C(R 3 R 4 )-, and R on two adjacent carbon atoms are selected from 3 and R 3 , R 3 and R 4 , R 4 and R 3 , R 4 and R 4 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl, which may be substituted by one or more substituents.

[0159] In some embodiments of the present disclosure, L is —C(R 3 R 4 )-C(R 3 R 4 )-, and R on two adjacent carbon atoms are selected from 3 and R 3 , R 3 and R 4 , R 4 and R 3 , R 4 and R 4 However, the substituents formed together with the carbon atoms to which they are attached may be substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0160] In some embodiments of the present disclosure, L is —C(R 3 R 4 )-C(R 3 R 4)-, and R on two adjacent carbon atoms are selected from 3 and R 3 , R 3 and R 4 , R 4 and R 3 , R 4 and R 4 together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0161] In some embodiments of the present disclosure, L is —C(R 3 R 4 )-C(R 3 R 4 )-, and R on two adjacent carbon atoms are selected from 3 and R 3 , R 3 and R 4 , R 4 and R 3 , R 4 and R 4 together with the carbon atom to which they are attached form a cyclobutyl, oxetanyl or azetidinyl optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0162] In some embodiments of the present disclosure, L is -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)-, [ka] [ka] -CH(CH3)CH2-, -CH(F)CH2-, -CH(Cl)CH2-, -CH(Br)CH2-, -CH(I)CH2-, -CH(CN)CH2-, -CH(CF3)CH2-, -CH(OH)CH2-, -CH(NH2)CH2-, [ka] is selected from.

[0163] In some embodiments of the present disclosure, L is -O-, -S-, -NH-, -CH2-, -CH(CH3)-, -CH2CH2-, -C(O)-, [ka] is selected from.

[0164] In some embodiments of the present disclosure, L is -CH2-, -CH(CH3)-, or [ka] is selected from.

[0165] In some embodiments of the present disclosure, L is selected from -CH2-.

[0166] In some embodiments of the present disclosure, L is -C(R 3 R 4 )- or -C(R 3 R 4 )-C(R 3 R 4 )-, each of said carbon atoms may be a chiral carbon atom present in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer.

[0167] In some embodiments of the present disclosure, R 2 is C 3-8 Cycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl or C5-6 cycloalkenyl, wherein C 3-8 Cycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl and C 5-6 Cycloalkenyl is independently one or more R 2a may be substituted with.

[0168] In some embodiments of the present disclosure, R 2 is C 3-6 cycloalkyl, phenyl, naphthyl, 5- to 9-membered heteroaryl, 3- to 6-membered heterocyclyl or C 5-6 cycloalkenyl, wherein C 3-6 Cycloalkyl, phenyl, naphthyl, 5-9 membered Heteroaryl, 3- to 6-membered heterocyclyl and C 5-6 Cycloalkenyl is independently one or more R 2a may be substituted with.

[0169] In some embodiments of the present disclosure, R 2 is C 5-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl or C 5-6 cycloalkenyl, wherein C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 5-6 Cycloalkenyl is independently one or more R 2a may be substituted with.

[0170] In some embodiments of the present disclosure, R 2 is C 5-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl containing 1-3 N atoms, 5-6-membered heterocyclyl containing 1-3 N atoms or C 5-6 cycloalkenyl, wherein C 5-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl containing 1-3 N atoms, 5-6-membered heterocyclyl containing 1-3 N atoms, and C 5-6Cycloalkenyl is independently one or more R 2a may be substituted with.

[0171] In some embodiments of the present disclosure, R 2 is selected from cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclopentenyl or cyclohexenyl; cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclopentenyl, and cyclohexenyl may independently be one or more R 2a may be substituted with.

[0172] In some embodiments of the present disclosure, R 2 is selected from phenyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl, wherein said phenyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolylpyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl are independently selected from one or more R 2a may be substituted with.

[0173] In some embodiments of the present disclosure, R 2is selected from phenyl, pyrazolyl, pyridyl, or pyrimidinyl, wherein said phenyl, pyrazolyl, pyridyl, and pyrimidinyl are independently selected from one or more R 2a may be substituted with.

[0174] In some embodiments of the present disclosure, R 2 is selected from pyrimidinyl, wherein said pyrimidinyl is independently selected from one or more R 2a may be substituted with.

[0175] In some embodiments of the present disclosure, R 2 teeth, [ka] [ka] wherein R is selected from 2 independently represents one or more R 2a may be substituted with.

[0176] In some embodiments of the present disclosure, R 2 teeth, [ka] wherein R is selected from 2 independently represents one or more R 2a may be substituted with.

[0177] In some embodiments of the present disclosure, R 2 teeth, [ka] wherein R is selected from 2 independently represents one or more R 2a may be substituted with.

[0178] In some embodiments of the present disclosure, each R 2a and R 6a are each independently hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; and 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, -SO2C 1-12 Alkyl, -NHSO2C1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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 The aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may be independently substituted with one or more substituents.

[0179] In some embodiments of the present disclosure, each R 2a and R 6a are each independently halogen, -CN, -OH, -SH, -COOH, -NH2, or -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, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 cycloalkenyl, phenyl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; and 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, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl)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 The cycloalkenyl, phenyl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl may be independently substituted with one or more substituents.

[0180] In some embodiments of the present disclosure, each R 2a and R 6a are each independently halogen, -CN, -OH, -SH, -COOH, -NH2, or -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3Alkoxy, 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, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 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- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; and 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, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 The cycloalkenyl, phenyl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl may be independently substituted with one or more substituents.

[0181] In some embodiments of the present disclosure, each R 2a and R 6a are each independently a halogen, -CN, -OH, -NH2, or -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, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; and 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, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 The cycloalkenyl, phenyl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl may be independently substituted with one or more substituents.

[0182] In some further embodiments of the present disclosure, each R 2a and R 6a are each independently halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6cycloalkyl or 3- to 6-membered heterocyclyl, 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 The cycloalkyl or 3- to 6-membered heterocyclyl may be independently substituted with one or more substituents.

[0183] In some embodiments of the present disclosure, each R 2a and R 6a are each independently halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl and 3- to 6-membered heterocyclyl may be independently substituted with one or more substituents.

[0184] In some embodiments of the present disclosure, each R 2a and R 6a are each independently selected from halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, or isoxazolidinyl; wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl are independently optionally substituted with one or more substituents.

[0185] In some embodiments of the present disclosure, each R 2a and R 6a are each independently selected from halogen, —CN, —OH, —NH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl, wherein said methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl are independently optionally substituted with one or more substituents.

[0186] In some further embodiments of the present disclosure, each R 2a and R 6a is optionally substituted with one or more groups independently selected from halogen, deuterium, OH, CN, or NH2.

[0187] In some embodiments of the present disclosure, each R 2a and R 6a is optionally substituted with 1, 2, or 3 groups independently selected from halogen, OH, CN, or NH2.

[0188] In some embodiments of the present disclosure, R 2a is halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, wherein said methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl are optionally substituted with 1, 2, or 3 groups independently selected from halogen, OH, CN, or NH.

[0189] In some embodiments of the present disclosure, R 2ais selected from halogen, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl, wherein said methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy and cyclopropyl are optionally substituted with 1, 2 or 3 groups independently selected from halogen, OH, CN or NH.

[0190] In some embodiments of the present disclosure, R 2a is -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, [ka] is selected from.

[0191] In some embodiments of the present disclosure, R 2a is methyl, isopropyl, methoxy or [ka] is selected from.

[0192] In some embodiments of the present disclosure, R 2a isopropyl, methoxy or [ka] is selected from.

[0193] In some embodiments of the present disclosure, R 2 teeth, [ka] [ka] is selected from.

[0194] In some embodiments of the present disclosure, R 2 teeth, [ka] is selected from.

[0195] In some embodiments of the present disclosure, R 2 teeth, [ka] is selected from.

[0196] In some embodiments of the present disclosure, R 6 are hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -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 1-1 2 alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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, C6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; and 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, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 alkyl)2, -CONH2, -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- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are independently one or more R 6a may be substituted with.

[0197] In some embodiments of the present disclosure, R 6 are hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -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)C1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl)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- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; and 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, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl)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 3-8Cycloalkenyl, phenyl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are independently one or more R 6a may be substituted with.

[0198] In some embodiments of the present disclosure, R 6 are hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -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, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 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 Shik Roalkyl, C 3-6 cycloalkenyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; and 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 1-3Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 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- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently one or more R 6a may be substituted with.

[0199] In some embodiments of the present disclosure, R 6 are hydrogen, halogen, -CN, -OH, -NH2, -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, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; and 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, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6Cycloalkenyl, phenyl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently one or more R 6a may be substituted with.

[0200] In some other embodiments of the present disclosure, R 6 are hydrogen, halogens, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl may independently be one or more R 6a may be substituted with.

[0201] In some embodiments of the present disclosure, R 6 are hydrogen, halogens, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently one or more R 6a may be substituted with.

[0202] In some embodiments of the present disclosure, R 6 is C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, 3-6Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently one or more R 6a may be substituted with.

[0203] In some embodiments of the present disclosure, R 6 is C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing 1 to 3 N atoms, or 5- to 6-membered heterocyclyl containing 1 to 3 N atoms, 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing 1 to 3 N atoms, and 5- to 6-membered heterocyclyl containing 1 to 3 N atoms may independently be one or more R 6a may be substituted with.

[0204] In some embodiments of the present disclosure, R 6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl may independently be one or more R 6a may be substituted with.

[0205] In some embodiments of the present disclosure, R 6 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl, wherein said phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl are independently selected from one or more R 6a may be substituted with.

[0206] In some embodiments of the present disclosure, R 6 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, or pyrimidinyl, wherein said phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, and pyrimidinyl are independently selected from one or more R 6a may be substituted with.

[0207] In some embodiments of the present disclosure, R 6 is selected from pyrazolyl or imidazolyl, wherein said pyrazolyl and imidazolyl are independently selected from one or more R 6a may be substituted with.

[0208] In some embodiments of the present disclosure, R 6 teeth, [ka] [ka] wherein R is selected from 6 independently represents one or more R 6a may be substituted with.

[0209] In some embodiments of the present disclosure, R 6 teeth, [ka] wherein R is selected from 6 independently represents one or more R 6a may be substituted with.

[0210] In some embodiments of the present disclosure, R 6 teeth, [ka] wherein R is selected from 6 independently represents one or more R 6a may be substituted with.

[0211] In some embodiments of the present disclosure, R 6a is selected from halogen, —CN, —OH, —NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl, wherein said methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl are optionally substituted with 1, 2, or 3 groups independently selected from halogen, OH, CN, or NH2.

[0212] In some embodiments of the present disclosure, R 6a is selected from halogen, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, or oxetanyl, wherein said methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, and oxetanyl are optionally substituted with 1, 2, or 3 groups independently selected from halogen, OH, CN, or NH.

[0213] In some other embodiments of the present disclosure, R 6ais selected from halogen, methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropoxy, cyclopropyl, or oxetanyl, wherein said methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropoxy, cyclopropyl, or oxetanyl are optionally substituted by 1, 2, or 3 groups independently selected from F, Cl, Br, I, OH, CN, or NH2.

[0214] In some embodiments of the present disclosure, R 6a is -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, [ka] is selected from.

[0215] In some other embodiments of the present disclosure, R 6a -F, -Cl, -Br, -I, Methyl, -CD3, isopropyl, methoxy, -OCD3, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2CF3, -CF2CF3, [ka] is selected from.

[0216] In some embodiments of the present disclosure, R 6a is methyl, isopropyl, difluoromethyl, trifluoromethyl, [ka] is selected from.

[0217] In some other embodiments of the present disclosure, R 6a is methyl, -CD3, isopropyl, difluoromethyl, trifluoromethyl, [ka] is selected from.

[0218] In some other embodiments of the present disclosure, R 6a is methyl, isopropyl, difluoromethyl, trifluoromethyl, [ka] is selected from.

[0219] In some other embodiments of the present disclosure, R 6a is selected from methyl, isopropyl or trifluoromethyl.

[0220] In some other embodiments of the present disclosure, R 6a is methyl, isopropyl, trifluoromethyl or [ka] is selected from.

[0221] In some embodiments of the present disclosure, R 6 teeth, [ka] [ka] [ka] is selected from.

[0222] In some other embodiments of the present disclosure, R 6 teeth, [ka] [ka] is selected from.

[0223] In some embodiments of the present disclosure, R 6 teeth, [ka] is selected from.

[0224] In some other embodiments of the present disclosure, R 6 teeth, [ka] is selected from.

[0225] In some embodiments of the present disclosure, R 6 teeth, [ka] is selected from.

[0226] In some other embodiments of the present disclosure, R 6 teeth, [ka] is selected from.

[0227] In some embodiments of the present disclosure, R 6 teeth, [ka] is selected from.

[0228] In some embodiments of the present disclosure, the "hetero" is independently selected from oxygen, sulfur, and nitrogen heteroatoms, where the nitrogen atoms are optionally quaternized or oxidized to N(O), and the sulfur atoms are optionally oxidized to S(O) or S(O).

[0229] In some embodiments of the present disclosure, the "hetero" is independently selected from oxygen, sulfur, and nitrogen heteroatoms, and the sulfur heteroatom may be oxidized to S(O) or S(O).

[0230] In some embodiments of the present disclosure, m is selected from 1.

[0231] In some embodiments of the present disclosure, in the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof, the compound represented by formula (I) is selected from compounds represented by formula (I-1). [ka] In the formula, X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , R 2 , R 3 , R 4 and R 6 is as defined for compounds of formula (I), R 3 , R 4 The carbon atom to which is attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer.

[0232] In some embodiments of the present disclosure, in the compound represented by formula (I), its isomer, or its pharmaceutically acceptable salt, the compound represented by formula (I) is selected from compounds represented by formula (I-2). [ka] During the ceremony, X 5 is selected from CH or N, X 1 , X 3 , R 2 , R 3 , R 4 and R 6 is as defined for compounds of formula (I), R 3 , R 4 The carbon atom to which is attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer.

[0233] In some embodiments of the present disclosure, in the compound represented by formula (I), its isomer, or its pharmaceutically acceptable salt, the compound represented by formula (I) is selected from compounds represented by formula (I-3). [ka] During the ceremony, X 5 is selected from CH or N, X 3 , R 2 , R 3 , R 4 and R 6 is as defined for compounds of formula (I), R 3 , R 4 The carbon atom to which is attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer.

[0234] In some embodiments of the present disclosure, in the compound represented by formula (I), its isomer, or its pharmaceutically acceptable salt, the compound represented by formula (I) is selected from the compounds represented by formula (I-4). [ka] During the ceremony, X 5 is selected from CH or N, R 2 , R 3 , R 4 and R 6 is as defined for compounds of formula (I), R 3 , R 4 The carbon atom to which is attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer.

[0235] In some embodiments of the present disclosure, in the compound represented by formula (I), its isomer, or its pharmaceutically acceptable salt, the compound represented by formula (I) is selected from the compounds represented by formula (I-5). [ka] During the ceremony, X 5 is selected from CH or N, Y 1 , Y 2 and Y 3 are each independently selected from CH or N; X 3 , R 3 , R 4 , R 6 and R 2a is as defined for compounds of formula (I), R 3 , R 4 The carbon atom to which is attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer.

[0236] In some embodiments of the present disclosure, Y 1 is selected from N.

[0237] In some embodiments of the present disclosure, Y 1 and Y 3 are both selected from N.

[0238] In some embodiments of the present disclosure, Y 1 is selected from N, Y 2 and Y 3 are both selected from CH.

[0239] In some embodiments of the present disclosure, Y 1 and Y 3 are both selected from N, and Y 2 is selected from CH.

[0240] In some embodiments of the present disclosure, in the compound represented by formula (I), its isomer, or a pharmaceutically acceptable salt thereof, the compound represented by formula (I) is selected from the compounds represented by formula (I-6). [ka] During the ceremony, X 5 is selected from CH or N, Y 1 , Y 2 and Y 3 is as defined for the compound of formula (I-5), X 3 , R 2a , R 3 , R 4 and R 6a is as defined for compounds of formula (I), R 3 , R 4 The carbon atom to which is attached may be in the form of a single (R) or (S) enantiomer, or It may be a chiral carbon atom that is present in a form enriched in one enantiomer.

[0241] In some embodiments of the present disclosure, in the compound represented by formula (I), its isomer, or its pharmaceutically acceptable salt, the compound represented by formula (I) is selected from the compounds represented by formula (I-7). [ka] During the ceremony, X 5 is selected from CH or N, Y 1 , Y 2 and Y 3 is as defined for the compound of formula (I-5), X 3 , R 2a , R 3 , R 4 and R 6a is as defined for compounds of formula (I), R 3 , R 4 The carbon atom to which is attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer.

[0242] Further embodiments of the present disclosure are any combination of the above variables.

[0243] In another aspect, the present disclosure further provides a compound represented by the formula: [ka] [ka] [ka]

[0244] In another aspect, the present disclosure further provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound described herein, its isomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient. .

[0245] In another aspect, the present disclosure further provides use of a compound according to the present disclosure, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for treating or preventing a disease associated with the inhibition of ubiquitin-specific protease 1 (USP1).

[0246] In another aspect, the present disclosure further provides a method for treating or preventing a disease associated with the inhibition of ubiquitin-specific protease 1 (USP1), comprising administering to a mammal (preferably a human) in need of said treatment or prevention a therapeutically or prophylactically effective amount of a compound described herein, an isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0247] In another aspect, the present disclosure further provides use of a compound according to the present disclosure, an isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating or preventing a disease associated with the inhibition of ubiquitin-specific protease 1 (USP1).

[0248] In another aspect, the present disclosure further provides a compound according to the present disclosure, an isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating or preventing a disease associated with the inhibition of ubiquitin-specific protease 1 (USP1).

[0249] In another aspect, in some embodiments of the present disclosure, the disease associated with inhibition of ubiquitin-specific protease 1 (USP1) is selected from tumors or cancers (eg, breast cancer). [Effects of the Invention]

[0250] The compounds of the present disclosure are inhibitors of ubiquitin-specific protease 1 (USP1) with novel structures and exhibit favorable inhibitory effects on ubiquitin-specific protease 1 (USP1) signal transduction. The compounds of the present disclosure exhibit favorable in vivo and in vitro inhibitory effects, including, but not limited to, favorable in vitro inhibitory effects on enzyme activity and cellular activity, favorable liver microsome stability, favorable pharmacokinetic properties, and favorable in vivo efficacy, and may be developed as new USP1 inhibitors. DETAILED DESCRIPTION OF THE INVENTION

[0251] Related Definitions Unless otherwise specified, the following terms and phrases used herein are defined as follows: A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition and should be understood according to its ordinary meaning. Trade names used herein are intended to refer to the corresponding commercial product or its active ingredient.

[0252] As used herein, the term "pharmaceutically acceptable" means that the compounds, materials, compositions and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0253] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, prepared from a compound having certain substituents found in this disclosure and a relatively non-toxic acid or base. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or in a suitable inert solvent. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent. Certain compounds of the present disclosure contain both basic and acidic functional groups and, therefore, can be converted into either base or acid addition salts.

[0254] The pharmaceutically acceptable salts of the present disclosure can be synthesized from a parent compound that contains an acid or base group by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base form of the compound with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0255] The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomer- or diastereomer-enriched mixtures, all of which are within the scope of the present disclosure. Substituents such as alkyl groups may also have additional asymmetric carbon atoms. All such isomers and mixtures thereof are within the scope of the present disclosure.

[0256] Solid wedge bonds unless otherwise noted [ka] and wedge-shaped dashed bond [ka] indicates the absolute configuration of the stereocenter, and a straight solid bond [ka] and straight dashed bond [ka] indicates the relative configuration of the stereocenters.

[0257] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are within the scope of the present disclosure. 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 prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via recombination of some bonding electrons.

[0258] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) or C-14( 14 As another example, hydrogen can be replaced with deuterium to form a deuterated drug, where the bond between deuterium and carbon is stronger than the normal hydrogen-carbon bond, and deuterated drugs have the potential to reduce toxic side effects, improve drug stability, enhance efficacy, and extend the biological half-life of drugs compared to non-deuterated drugs. All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0259] The terms "may" or "optionally" mean that the described event or condition may occur, but does not necessarily have to occur, and include both the occurrence of said event or condition and the absence of said event or condition.

[0260] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable, and the substituent may include variants of deuterium and hydrogen. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Substitution with oxo does not occur in aromatic groups. The term "optionally substituted" means that the group may or may not be substituted, and unless otherwise specified, the type and number of substituents can be any based on chemical feasibility.

[0261] The term "substituents" as used herein includes all substituents described in the context of the present specification, such as the term "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- to 6-membered heterocycloalkyl", "C 6-10Some non-limiting examples of the "substituents" include deuterium atoms, hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide groups, sulfoxide groups, sulfone groups, sulfonamide, carboxy, carboxaldehyde, imino, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, haloalkenyl, cycloalkenyl, and halocycloalkenyl. , alkynyl, haloalkynyl, cycloalkynyl, halocycloalkynyl, heteroalkyl, haloheteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocycloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl , acyloxy, urethane groups, amide groups, ureido, epoxy groups, ester groups, oxo and thio groups, and the groups include deuterium atoms, oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH, -C(O)NH-alkyl, -C(O)N(alkyl), -NHC(O)-alkyl, -C(O)-alkyl, - and optionally substituted with one or more substituents selected from S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocycloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0262] In some embodiments of the present specification, the substituent is a deuterium atom, hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide group, sulfoxide group, sulfone group, sulfonamide, carboxyl, aldehyde, imide group, C 1-12 Alkyl, Halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cyclo Alkyl, C 2-12 Alkenyl, Halo-C 2-12 Alkenyl, 3- to 12-membered cycloalkenyl, halo-3- to 12-membered cycloalkenyl, C 2-12 Alkynyl, Halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6- to 10-membered aryl, 6- to 10-membered aryloxy, 6- to 10-membered arylthio, 6- to 10-membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 Alkylthio, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, 5- to 10-membered heteroarylthio, 5- to 10-membered heteroarylalkylene, 5- to 10-membered heteroarylalkoxy, 5- to 10-membered heteroarylalkylthio, 3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyloxy, 3- to 12-membered heterocyclylthio, 3- to 12-membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclylC 1-12 Alkoxy, 3-12 membered heterocyclylC 1-12 Alkylthio, C 1-12 Achill, C 1-12 Acyloxy, carbamate group, C 1-12 Amide, ureido, epoxy group, C 2-12 ester groups, oxo and thio, and the substituents are selected from deuterium atoms, oxo, hydroxyl, amino, nitro, halogen, cyano, C1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, DiC 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated diC 1-12 Alkylamino, carboxy, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -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)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)N(C 1-12 alkyl) 2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkylC 1-12 Alkylene, 3- to 12-membered cycloalkyloxy, 3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclylC 1-12 Alkylene, 3- to 12-membered heterocycloxy, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkylC 1-12 alkylene, 3- to 12-membered heterocycloalkyloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylC alkylene, 5- to 10-membered heteroaryloxy, 6- to 10-membered aryl, 6- to 10-membered arylC 1-12 It may be substituted with one or more substituents selected from alkylene or 6- to 10-membered aryloxy.

[0263] When any variable (e.g., R) occurs more than one time in a compound composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0 to 2 R, then said group may optionally be substituted with up to 2 R, and each occurrence of R is an independent option. Furthermore, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0264] When one variable is selected from a single bond, it means that the two groups attached thereto are directly linked; for example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0265] When the listed linking group does not specify the direction of connection, the direction of connection is arbitrary, for example: [ka] In the case where the linking group L is -MW-, -MW- connects ring A and ring B in the same direction as the reading order from left to right, so that [ka] and by joining ring A and ring B in the opposite left-to-right reading order, [ka] Combinations of the above linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0266] Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of the group can be bonded to other groups via a chemical bond. If the bonding form of the chemical bond is a non-fixed position and an H atom is present at the linkable site, when chemically bonded, the number of H atoms at the site decreases according to the number of bonded chemical bonds, resulting in a group with a corresponding valence. The chemical bond connecting the site to another group is represented by a straight solid line bond. [ka] , straight dashed bond [ka] , or wavy line [ka] For example, the straight solid bond of -OCH3 represents that the group is connected to another group via the oxygen atom of the group, [ka] The straight broken bond represents a bond between the nitrogen atoms of the group and another group, [ka] The wavy line indicates that the phenyl group is linked to another group via the carbon atoms at positions 1 and 2 of the phenyl group. [ka] represents that any linkable site of the piperidinyl group can be linked to another group via one chemical bond, and at least [ka] Even if an H atom is shown on the -N-, [ka] teeth, [ka] When the group is linked to one chemical bond, the number of hydrogen atoms at that site is reduced by one to form a corresponding monovalent piperidinyl group.

[0267] 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 of 1 to 12 carbon atoms. 1-12 Alkyl is C 1-6 Alkyl or C 1-3 Unless otherwise specified, the term "C 1-6 "Alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 Alkyl is C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6 and C5 alkyl, etc., and can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). 1-6 Examples of 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.

[0268] Unless otherwise specified, the term "C 1-12 "Deuterated alkyl" is the same as "C 1-12 It means that any number and positions of H atoms in the "alkyl" are replaced with deuterium atoms. 1-12 Deuterated alkyls are C1-6 Deuterated alkyl or C 1-3 It may be a deuterated alkyl. Examples of deuterated alkyls include -CH2D, -CHD2, [ka] [ka] These include, but are not limited to:

[0269] Unless otherwise specified, the term "C 1-12 The term "alkylene" by itself or as part of another substituent refers to a straight or branched chain divalent hydrocarbon radical of 1 to 12 carbon atoms, including those containing 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 group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH- or -CHCH(CH)-), butylene (-CHCHCHCHCH-, -CHCH(CH)CH- or -CHCHCH(CH)-), and the like. The alkylene group may be optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocycloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0270] Unless otherwise specified, the term "C 1-12 "Alkoxy" refers to an alkyl group containing 1 to 12 carbon atoms attached to the remainder of the molecule through an oxygen atom. 1-12 Alkoxy is C 1-6Alkoxy or C 1-3 Unless otherwise specified, the term "C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom. 1-6 Alkoxy is C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6 and C5 alkoxy, etc. 1-6 Examples of 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), pentyloxy (n-pentyloxy, isopentyloxy, and neopentyloxy), hexyloxy, and the like.

[0271] Unless otherwise specified, the term "C 1-12 "Alkylthio" refers to an alkyl group containing 1 to 12 carbon atoms attached to the remainder of the molecule through a sulfur atom. 1-12 Alkylthio is C 1-6 Alkylthio or C 1-3 Unless otherwise specified, the term "C 1-6 "Alkylthio" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through a sulfur atom. 1-6 Alkylthio is C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6 and C5 alkylthio, etc. 1-6Examples of 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.

[0272] Unless otherwise noted, "C 2-12 "Alkenyl" is intended to represent a straight or branched hydrocarbon group of 2 to 12 carbon atoms containing at least one carbon-carbon double bond, which may be located in any position within the group. 2-12 Al Kenyl is C 2-6 Alkenyl, C 2-3 Alkenyl or C 2-3 The C may be alkenyl. 2-4 Alkenyl is C 2-3 , C4, C3 and C2 alkenyl, etc., 2-4 Alkenyl can be monovalent, divalent or polyvalent. 2-4 Examples of alkenyl include, but are not limited to, vinyl, propenyl, butenyl, 1,3-butadiene, and the like. 2-3 "Alkenyl" is intended to represent a straight or branched hydrocarbon group of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located in any position within the group. 2-3 Alkenyl includes C3 and C2 alkenyl, 2-3 Alkenyl can be monovalent, divalent or polyvalent. 2-3 Examples of alkenyl include, but are not limited to, vinyl, propenyl, and the like.

[0273] Unless otherwise noted, "C 2-12 The term "alkynyl" is intended to represent a straight or branched hydrocarbon group of 2 to 12 carbon atoms containing at least one carbon-carbon triple bond, which may be located in any position within the group.2-12 Alkynyl is C 2-6 , C 2-3 C includes C, C, and C alkynyl, and can be monovalent, divalent, or polyvalent. 2-3 Examples of alkynyl include, but are not limited to, ethynyl, propynyl, and the like.

[0274] Unless otherwise stated, the term "halogen," by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom.

[0275] Unless otherwise noted, C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 and the range of n to n+m is also included, for example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 For the same reason, n- to n+m-membered rings means that the number of ring-constituting atoms is n to n+m, and for example, a 3- to 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 the range of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring.

[0276] Unless otherwise specified, the term "ring" refers to a substituted or unsubstituted cycloalkyl, heterocyclyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. So-called rings include monocyclic, bicyclic, spirocyclic, fused, or bridged rings. The number of ring-constituting atoms is usually defined as the number of ring members; for example, a "5- to 7-membered ring" means that 5 to 7 atoms are arranged in a ring. Unless otherwise specified, the ring may contain 1 to 3 heteroatoms. Thus, "5- to 7-membered ring" includes, for example, phenyl, pyridine, and piperidinyl, and the term "ring" also includes ring systems containing at least one ring, each of which independently satisfies the above definition.

[0277] Unless otherwise noted, "C 3-12 "Cycloalkyl" refers to a monocyclic or bicyclic saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, 3-12 Cycloalkyl is C 3-8 , C 3-6 and C 5-6 C includes cycloalkyl and the like and can be monovalent, divalent, or polyvalent. 3-12 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0278] Unless otherwise specified, the term "C 3-12 "Cycloalkenyl" by itself or in combination with other terms When taken in combination, each of the C groups represents a partially unsaturated cyclic hydrocarbon group having 3 to 12 ring atoms and containing at least one carbon-carbon double bond, and the C group may be monovalent, divalent, or polyvalent. 3-12 Cycloalkenyl is C 3-6 Cycloalkenyl, C 5-6 Includes cycloalkenyl, etc. 3-6 Examples of cycloalkenyl include: [ka] These include, but are not limited to:

[0279] Unless otherwise noted, the term "5- to 7-membered heterocycloalkenyl," by itself or in combination with other terms, refers to a partially unsaturated cyclic group of 5 to 7 ring atoms, each containing at least one carbon-carbon double bond, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, N, or Se, and the remainder are carbon atoms, in which the nitrogen atom is optionally quaternized, and in which the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p (wherein p is 1 or 2). This includes monocyclic and bicyclic rings, where bicyclic rings include spiro rings, fused rings, and bridged rings, and any rings in the bicyclic ring are non-aromatic. It can be monovalent, divalent, or polyvalent. Furthermore, for the "5- to 7-membered heterocycloalkenyl," a heteroatom may occupy the position at which the heterocycloalkenyl is attached to the remainder of the molecule. The 5- to 7-membered heterocycloalkenyl includes 5- to 6-membered heterocycloalkenyl. Examples of 5- to 6-membered heterocycloalkenyl include: [ka] These include, but are not limited to:

[0280] Unless otherwise specified, the term "3- to 6-membered heterocycloalkyl," by itself or in combination with other terms, refers to a saturated cyclic group of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, with the nitrogen atom optionally being quaternized, and the nitrogen and sulfur heteroatoms optionally being oxidized (i.e., NO and S(O)). pand p is 1 or 2). These are monocyclic. Furthermore, for the "3- to 6-membered heterocycloalkyl," a heteroatom may occupy the position at which the heterocycloalkyl is attached to the remainder of the molecule. The 3- to 6-membered heterocycloalkyl includes 3-, 4-, 5-, and 6-membered heterocycloalkyls. Examples of 3- to 6-membered heterocycloalkyls include oxacyclopropyl, thiocyclopropyl, aziridyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl), tetrahydrothiophene-1,1-dioxid-3-yl, tetrahydrothiophene-1,1-dioxid-2-yl, tetrahydrofuranyl (including tetrahydrofuran-2-yl). and the like.

[0281] Unless otherwise specified, the term "C 6-10 "Aryl" refers to a cyclic hydrocarbon group having a conjugated π-electron system of 6 to 10 carbon atoms, which may be monocyclic, fused bicyclic, or fused tricyclic, in which each ring is aromatic. It may be monovalent, divalent, or polyvalent. 6-10 Aryl is C9, C 10 and C6 aryl. 6-10 Examples of aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0282] Unless otherwise indicated, the term "5-10-membered heteroaryl" refers to a cyclic group having a conjugated π-electron system of 5 to 10 ring atoms, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, N, or Se, and the remainder are carbon atoms. The ring may be monocyclic, fused bicyclic, or fused tricyclic, in which each ring is aromatic. The ring may be monovalent, divalent, or polyvalent. The nitrogen atom may be optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). pand p is 1 or 2). It can be monovalent, divalent, or polyvalent. The 5-10 membered heteroaryl may be bonded to the rest of the molecule via a heteroatom or carbon atom. The 5-10 membered heteroaryl includes 5-8 membered, 5-7 membered, 5-6 membered, 5-membered, and 6-membered heteroaryl, etc. Examples of the 5- to 10-membered heteroaryl include 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 (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl). and the like), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxaline (including 2-quinoxaline and 5-quinoxaline, etc.), or quinolinyl (including 3-quinolinyl and 6-quinolinyl, etc.).

[0283] The term "3- to 12-membered heterocyclyl" 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 specified, the heterocyclyl is typically a 3- to 12-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Non-limiting examples of heterocyclyl include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, and the like. The heterocyclyl may be oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH, -C(O)NH-alkyl, -C(O)N(alkyl), -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)-alkyl, -S(O)NH, -S(O)NH-alkyl, -S(O)N(alkyl), cycloalkyl, cycloalkyl. The 3- to 12-membered heterocycloalkyl may be substituted with one or more groups selected from the group consisting of oxy, heterocyclyl, heterocycloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, and aryloxy. The 3- to 12-membered heterocycloalkyl includes 3- to 8-membered, 3- to 6-membered, 4- to 5-membered, 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl. Examples of "3- to 12-membered heterocycloalkyl" and "3- to 6-membered heterocycloalkyl" include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl), tetrahydrofuranyl (including tetrahydrofuran-2-yl), tetrahydropyranyl, piperidinyl (1-piperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5 ... Examples of alkyl groups include, but are not limited to, 1-piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), 2-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, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or dioxepanyl.

[0284] The term "treatment" means administering a compound or formulation according to the present disclosure to improve or eliminate a disease or one or more symptoms associated with said disease, and includes the following: (i) To inhibit the disease or condition, i.e., to arrest its progression. (ii) alleviating the disease or condition, i.e., reducing or eliminating the disease or condition;

[0285] The term "prevention" means administering a compound or formulation according to the present disclosure to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or condition in a mammal, particularly where such mammal is susceptible to the condition but has not yet been diagnosed as suffering from it.

[0286] The term "therapeutically or prophylactically effective amount" refers to an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays a particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically or prophylactically effective amount" varies depending on the compound, the condition and its severity, the method of administration, and the age of the mammal being treated, but can generally be determined by one of ordinary skill in the art based on their own knowledge and the present disclosure.

[0287] Therapeutic or prophylactic doses of compounds of the present disclosure can be determined based, for example, on the specific therapeutic or prophylactic application, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition is not fixed and depends on various factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, compounds of the present disclosure can be provided for parenteral administration in an aqueous physiological buffer containing about 0.1 to 10% w / v of the compound. Some typical dose ranges are about 1 to about 1 g / kg body weight / day. In some embodiments, the dose ranges from about 0.01 mg / kg to about 100 mg / kg body weight / day. Dosages will depend on variables such as the type and progression of the disease or condition, the patient's general health, the relative biological potency of the selected compound, the excipient formulation, and its route of administration. Effective doses can be obtained by extrapolation of dose-response curves derived from in vitro or animal model test systems.

[0288] The terms "comprise" or "comprise" and their English variants, such as comprises or comprising, are to be understood in an open and non-exclusive sense, i.e., "including but not limited to."

[0289] A "pharmaceutical composition" refers to a composition containing one or more compounds described in the present disclosure, their isomers, or pharmaceutically acceptable salts thereof, as well as other ingredients such as physiologically / pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and promote absorption of the active ingredient(s) to exert biological activity.

[0290] Pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with a suitable pharmaceutically acceptable excipient.

[0291] The pharmaceutical compositions of the present disclosure can be manufactured by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, lyophilizing or other methods well known in the art.

[0292] The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments exemplified below, embodiments formed in combination with other chemical synthetic methods, and equivalent alternative embodiments known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0293] The chemical reactions in specific embodiments of the present disclosure are carried out in suitable solvents, which must be suitable for the chemical transformations of the present disclosure and the necessary reagents and materials. In some cases, those skilled in the art may need to modify or select synthetic steps or reaction schemes based on existing embodiments to obtain compounds of the present disclosure.

[0294] The raw materials or intermediates used in the embodiments of the present disclosure can be obtained commercially or prepared by conventional methods. One important consideration in designing a synthetic route in the art is the selection of a suitable protecting group for a reactive functional group (e.g., an amino group in the present disclosure). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed.), Hoboken, New Jersey: John Wiley & Sons, Inc.

[0295] In some embodiments, some of the compounds of the present disclosure can be prepared by one skilled in the art of organic synthesis with reference to the following schemes. [ka] where: X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , L, R 2 and R 6 is as described above for the compound of formula (I), Y is selected from halogen, —OH, methylsulfonyloxy, benzenesulfonyloxy, or p-toluenesulfonyloxy.

[0296] In some embodiments of the present invention, Y is selected from -Cl, -Br, -I, -OH, methylsulfonyloxy, or p-toluenesulfonyloxy.

[0297] In some embodiments of the present invention, Y is selected from -Cl.

[0298] In some embodiments, some of the compounds of the present disclosure can be prepared by one skilled in the art of organic synthesis with reference to the following schemes. [ka] where: X 1 , X 2 , X 4 , X 5 , X 6 , X 7 , L, R 2 , R 6 and R 7 is as described above for compounds of formula (I), and X is selected from halogen.

[0299] In some embodiments of the present invention, X is selected from -Cl, -Br, -I.

[0300] In some embodiments of the present invention, X is selected from -I.

[0301] Furthermore, the present disclosure is further illustrated by reference to examples, which are not intended to limit the scope of the present disclosure. All reagents used in this disclosure are commercially available and can be used without further purification. [Example]

[0302] [Mode for Carrying Out the Invention] The present disclosure will be described in detail below with reference to examples, but this does not mean any adverse limitations on the present disclosure. In this specification, the present disclosure is described in detail and specific embodiments thereof are also disclosed. It will be apparent to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0303] Example 1 [ka]

[0304] Step 1: Preparation of Intermediate 1-2 1-1 (1 g), tert-butyl carbamate (0.612 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (0.192 g), tris(dibenzylideneacetone)dipalladium (0.218 g), cesium carbonate (3.10 g), and 1,4-dioxane (20 mL) were sequentially placed in a 100 mL one-neck flask, and the mixture was stirred under nitrogen protection. The reaction was carried out for 6 hours at 85° C. The solvent was evaporated from the reaction mixture under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography to obtain intermediate 1-2 (0.8 g). 1H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.99 (dd, J = 10.9, 2.2 Hz, 1H), 1.49 (s, 9H). MS (ESI, [M+H] + ) m / z: 247.20.

[0305] Step 2: Preparation of Intermediate 1-3 At -78°C, a 2.5M solution of n-butyllithium in tetrahydrofuran (3.99 mL) was slowly added dropwise to a solution of intermediate 1-2 (0.8 g) and N,N,N',N'-tetramethylethylenediamine (1.13 g) in tetrahydrofuran (10 mL). The mixture was then warmed to -20°C and stirred for 1.5 hours. The temperature was then lowered to -78°C, and a solution of iodine (2.47 g) in tetrahydrofuran (5 mL) was slowly added. The mixture was then warmed to room temperature and reacted for 3 hours. The reaction was quenched by adding saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography to give intermediate 1-3 (0.7 g). 1 H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.16 (s, 1H), 1.47 (s, 9H). MS (ESI, [M+H] + ) m / z: 373.03.

[0306] Step 3: Preparation of Intermediates 1-4 Intermediate 1-3 (0.70 g), Intermediate A-1 (0.528 g), tris(dibenzylideneacetone)dipalladium (0.172 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (0.13 g), cesium carbonate (1.84 g), and 1,4-dioxane (15 mL) were sequentially added to a 50 mL one-neck flask, and the mixture was reacted under nitrogen protection at 100° C. for 12 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain Intermediate 1-4 (0.4 g). 1 H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 7.96 (s, 1H), 7.92 (d, J = 1.3 Hz, 1H), 7.75-7.70 (m, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.17 (s, 2H), 3.77 (s, 3H). MS (ESI, [M+H] + ) m / z: 426.24.

[0307] Step 4: Preparation of Compound 1 Intermediate 1-4 (0.4 g), Intermediate B-1 (0.365 g), potassium phosphate (0.399 g), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.179 g), tris(dibenzylideneacetone)dipalladium (0.172 g), 1,4-dioxane (20 mL), and water (1 mL) were sequentially added to a 35 mL microwave tube and heated to 130 °C in a microwave oven under nitrogen protection for 2 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give compound 1 (0.33 g). 1H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.66 (s, 1H), 8.26 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.73-7.69 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 5.18 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 1.71- 1.65 (m, 1H), 1.09-1.04 (m, 1H), 0.97-0.93 (m, 1H), 0.92-0.87 (m, 1H), 0.82-0.77 (m, 1H). HRMS (ESI) m / z [M + H] + : 540.1774.

[0308] Example 2 [ka] Preparation of Compound 2: A solution of potassium hydroxide (0.042 g, 0.741 mmol) in water (1 mL) was added dropwise to a solution of compound 1 (0.1 g), tetrabutylammonium bromide (0.006 g), and 2,4-dinitrophenylhydroxylamine (0.148 g) in dichloromethane (5 mL), and the mixture was allowed to react at 40°C for 2 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give compound 2 (0.03 g). 1 H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.35 (d, J = 1.1 Hz, 1H), 7.92 (d, J = 1.3 Hz, 1H), 7.73-7.69 (m, 2H), 7.44-7.40 (m, 2H), 5.66 (s, 2H), 5.23 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 1.69-1.64 (m, 1H), 1.10-1.05 (m, 1H), 0.99-0.94 (m, 1H), 0.92-0.87 (m, 1H), 0.84-0.78 (m, 1H). HRMS (ESI) m / z [M + H] + : 555.1886.

[0309] Example 3 [ka] Preparation of Compound 3: At 0°C, 60% sodium hydride (0.006 g) was added to a solution of compound 1 (0.060 g) in N,N-dimethylformamide (3 mL) and the mixture was allowed to react at 0°C for 30 minutes. Iodomethane (0.024 g) was added to the reaction mixture, which was then warmed to room temperature and allowed to react for 40 minutes. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography to give compound 3 (0.048 g). 1 H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.47 (s, 1H), 7.92 (s, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 5.22 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.50 (s, 3H), 1.71-1.61 (m, 1H), 1.35-1.21 (m, 2H), 1.05-0.98 (m, 2H). HRMS (ESI) m / z [M + H] + : 554.1935.

[0310] Example 4 [ka]

[0311] Step 1: Preparation of Intermediate 2-4 Intermediate 1-3 (0.3 g), Intermediate A-2 (0.251 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (0.093 g), tris(dibenzylideneacetone)dipalladium (0.074 g), cesium carbonate (0.787 g), and 1,4-dioxane (15 mL) were sequentially placed in a 50 mL single-neck flask, and the mixture was reacted under nitrogen protection at 100° C. for 12 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give Intermediate 2-4 (0.125 g). 1 H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H),7.57 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 5.18 (s, 2H), 4.50-4.42 (m, 1H), 1.39 (d, J = 6.5 Hz, 6H). MS (ESI, [M+H] + ) m / z: 454.21.

[0312] Step 2: Preparation of Compound 4 Intermediate 2-4 (0.10 g, 0.220 mmol), Intermediate B-1 (0.085 g), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.042 g), potassium phosphate (0.140 g), tris(dibenzylideneacetone)dipalladium (0.040 g), 1,4-dioxane (5 mL), and water (0.25 mL) were sequentially added to a 25 mL single-neck flask and reacted at 100 °C for 1 hour under nitrogen protection. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give compound 4 (0.068 g). 1 H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.66 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 5.19 (s, 2H), 4.47-4.41 (m, 1H), 3.80 (s, 3H), 1.71- 1.65 (m, 1H), 1.38 (d, J = 6.5 Hz, 6H), 1.11-1.05 (m, 1H), 0.97-0.93 (m, 1H), 0.91-0.85 (m, 1H), 0.83-0.76 (m, 1H). HRMS (ESI) m / z [M + H] + : 568.2097.

[0313] Example 5 [ka] Step 1: Preparation of intermediate 3-4 Intermediate 1-3 (0.40 g), Intermediate A-3 (0.34 g), tris(dibenzylideneacetone)dipalladium (0.10 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (0.074 mg), cesium carbonate (1.05 g), and 1,4-dioxane (15 mL) were sequentially placed in a 50 mL single-neck flask, and the mixture was reacted under nitrogen protection at 100° C. for 12 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give Intermediate 3-4 (0.21 g). 1 H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.23 ​​(d, J = 1.3 Hz, 1H), 8.07-8.02 (m, 1H), 7.95 (s, 1H), 7.85 (dd, J = 8.3, 2.3 Hz, 1H), 5.76-5.68 (m, 1H), 5.20 (s, 2H), 1.44 (d, J = 6.7 Hz, 6H). MS (ESI, [M+H]+ ) m / z: 455.22. Step 2: Preparation of Compound 6 Intermediate 3-4 (0.2 g), Intermediate B-1 (0.171 g), potassium phosphate (0.187 g), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.084 g), tris(dibenzylideneacetone)dipalladium (0.081 g), 1,4-dioxane (20 mL), and water (1 mL) were sequentially added to a 35 mL microwave tube and heated to 130 °C in a microwave oven under nitrogen protection for 2 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give compound 6 (0.15 g). 1 H NMR (500 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.66 (s, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.26 (d, J = 1.3 Hz, 1H), 8.23 ​​(d, J = 1.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.85 (dd, J = 8.3, 2.3 Hz, 1H), 5.74-5.67 (m, 1H), 5.22 (s, 2H), 3.79 (s, 3H), 1.71-1.65 (m, 1H), 1.43 (d, J = 6.7 Hz, 6H), 1.09-1.05 (m, 1H), 0.97-0.93 (m, 1H), 0.89-0.85 (m, 1H), 0.81-0.77 (m, 1H). HRMS (ESI) m / z [M + H] + : 569.2043.

[0314] Example 6 [ka] Preparation of Compound 6: Intermediate 3-4 (0.050 g), Intermediate B-2 (0.055 g), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.021 g), potassium phosphate (0.070 g), tris(dibenzylideneacetone)dipalladium (0.020 g), 1,4-dioxane (2.5 mL), and water (0.125 mL) were sequentially added to a 25 mL one-neck flask, and the mixture was reacted at 100°C for 1 hour under nitrogen protection. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography to obtain Compound 6 (0.035 g). 1 H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.66-8.62 (m, 1H), 8.32-8.28 (m, 1H), 8.24-8.21 (m, 1H), 8.02 (d, J = 5 Hz, 1H), 7.87-7.82 (m, 1H), 7.36(s, 1H), 5.73-5.65 (m, 1H), 5.23 (s, 2H), 4.38-4.29 (m, 1H), 1.81 (s, 3H), 1.42 (d, J = 5 Hz, 6H), 1.25 (d, J = 5 Hz, 6H). HRMS (ESI) m / z [M + H] + : 543.2245.

[0315] Example 7 [ka] Preparation of Compound 7: At 0°C, 60% sodium hydride (0.005 g) was added to a solution of compound 6 (0.050 g) in N,N-dimethylformamide (1 mL), and the mixture was reacted at 0°C for 30 minutes. Iodomethane (0.019 g) was added to the reaction mixture, and the mixture was warmed to room temperature and reacted for 1 hour. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. The resulting crude product was purified by silica gel column chromatography to give compound 7 (0.035 g). 1 H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 1.2 Hz, 1H), 8.24-8.22 (m, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.86 (dd, J = 8.3, 2.3 Hz, 1H), 5.73-5.67 (m, 1H), 5.27 (s, 2H), 3.79 (s, 3H), 3.50 (s, 3H), 1.69- 1.64 (m, 1H), 1.43 (d, J = 6.7 Hz, 6H), 1.10-1.05 (m, 1H), 0.98-0.93 (m, 1H), 0.90-0.85 (m, 1H), 0.81-0.76 (m, 1H). HRMS (ESI) m / z [M + H] + : 583.2206.

[0316] Example 8 [ka] Preparation of Compound 8: At 0°C, 60% sodium hydride (0.007 g) was added to a solution of compound 6 (0.080 g) in N,N-dimethylformamide (2 mL), and the mixture was reacted at 0°C for 30 minutes. Iodoethane (0.033 g) was added to the reaction solution, which was then warmed to room temperature and reacted for 2 hours. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give compound 7 (0.04 g). 1 H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.54 (d, J = 1.2 Hz, 1H), 8.23 ​​(d, J = 1.3 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 8.3, 2.3 Hz, 1H), 5.73-5.67 (m, 1H), 5.26 (s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 1.71-1.65 (m, 1H), 1.43 (d, J = 6.7 Hz, 6H), 1.34 (t, J = 7.2 Hz, 3H), 1.10-1.05 (m, 1H), 0.97-0.93 (m, 1H), 0.91-0.87 (m, 1H), 0.81-0.77 (m, 1H). HRMS (ESI) m / z [M + H] + : 597.2357.

[0317] Example 9 [ka]

[0318] Step 1: Preparation of intermediate 4-4 Intermediate 1-3 (0.3 g), Intermediate A-4 (0.226 g), cesium carbonate (0.787 g), tris(dibenzylideneacetone)dipalladium (0.074 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (0.056 g), and 1,4-dioxane (15 mL) were sequentially added to a 50 mL one-neck flask, and the mixture was reacted under nitrogen protection at 100° C. for 12 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain Intermediate 4-4 (0.086 g). 1 H NMR (500 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.96 (s, 1H), 7.60-7.54 (m, 2H), 7.47 (d, J = 8.2 Hz, 2H), 6.75 (s, 1H), 5.19 (s, 2H), 2.33 (s, 3H). MS (ESI, [M+H] + ) m / z: 426.18.

[0319] Step 2: Preparation of Compound 9 Intermediate 4-4 (0.050 g), Intermediate B-1 (0.091 g), tris(dibenzylideneacetone)dipalladium (0.054 g), potassium phosphate (0.075 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.050 g), 1,4-dioxane (3 mL), and water (0.15 mL) were sequentially added to an 8 mL microwave tube, and the reaction was carried out under nitrogen protection by microwave heating to 130 °C for 2 hours. The solvent was evaporated from the reaction solution under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography to obtain compound 9 (0.040 g). 1 H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.66 (s, 1H), 8.26 (d, J = 1.3 Hz, 1H), 7.60-7.54 (m, 2H), 7.46 (d, J = 8.3 Hz, 2H), 6.75 (s, 1H), 5.20 (s, 2H), 3.80 (s, 3H), 2.32 (s, 3H), 1.72-1.62 (m, 1 H), 0.99-0.81 (m, 4H). HRMS (ESI) m / z [M + H] + : 540.1767.

[0320] Example 10 [ka] Preparation of Compound 10: Intermediate 3-4 (0.050 g), Intermediate B-3 (0.036 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.021 g), potassium phosphate (0.070 g), tris(dibenzylideneacetone)dipalladium (0.020 g), 1,4-dioxane (3 mL), and water (0.15 mL) were sequentially added to an 8 mL microwave tube and heated to 130 °C under nitrogen protection for 2 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give compound 10 (0.011 g). 1 H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.66 - 8.56 (m, 2H), 8.29-8.19 (m, 2H), 8.03 (d, J = 8.2 Hz, 1H), 7.89-7.79 (m, 1H), 7.68-7.58 (m, 1H), 7.34-7.24 (m, 1H), 5.75-5.650 (m, 1H), 5.21 (s, 2H), 2.89-2.79 (m, 1H), 1.43 (d, J = 6.7 Hz, 6H), 1.03 (d, J = 6.6 Hz, 6H). HRMS (ESI) m / z [M + H] + : 540.2148.

[0321] Example 11 [ka]

[0322] Step 1: Preparation of intermediate 11-2 Intermediate 11-1 (0.40 g), N,N-dimethylformamide (8 mL), Intermediate A-5 (0.72 g), and potassium carbonate (0.82 g) were sequentially added to a 50 mL one-neck flask, and the mixture was heated to 40° C. and reacted for 3 hours. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and suction filtered. The solvent was evaporated under reduced pressure, and the residue was purified using a silica gel column to obtain Intermediate 11-2 (0.65 g). 1 H NMR (500 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.17 (s, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 6.88 (s, 2H), 5.12 (s, 2H), 4.46 (hept, J = 6.6 Hz, 1H), 1.39 (d, J = 6.6 Hz, 6H). MS (ESI, [M+H] + ) m / z: 435.17.

[0323] Step 2: Preparation of intermediate 11-3 Intermediate 11-2 (0.20 g), N,N-dimethylformamide (12 mL), iodine (1.23 g), cuprous iodide (8.77 mg), and isoamyl nitrite (0.27 g) were sequentially added to a 30 mL microwave tube and reacted for 1 hour by microwave heating at 120 °C. The reaction mixture was poured into saturated sodium sulfite solution (100 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and suction filtered. The solvent was evaporated under reduced pressure, and the residue was purified using a silica gel column to obtain intermediate 11-3 (0.2 g). 1 H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.17 (s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 5.17 (s, 2H), 4.46 (dt, J = 13.2, 6.6 Hz, 1H), 1.40 (d, J = 6.6 Hz, 6H). MS (ESI, [M+H] + ) m / z:546.03.

[0324] Step 3: Preparation of Compound 11 Intermediate 11-3 (0.15 g), Intermediate B-1 (0.11 g), 1,4-dioxane (2 mL), water (0.2 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.026 g), potassium phosphate (0.18 g), and tris(dibenzylideneacetone)dipalladium (0.025 g) were sequentially added to a 10 mL single-neck flask. Under nitrogen protection, the mixture was heated to 100 °C for 3 h. The reaction mixture was cooled to room temperature and poured into water (100 mL). The resulting solution was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and suction filtered. The solvent was evaporated under reduced pressure. The residue was purified using a silica gel column to obtain Compound 11 (65 mg). 1 H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.69 (s, 1H), 8.17 (s, 1H), 7.52 (dd, J = 23.5, 8.2 Hz, 4H), 5.24 (s, 2H), 4.43 (dt, J = 13.3, 6.6 Hz, 1H), 3.86 (s, 3H), 1.81 - 1.73 (m, 1H), 1.39 (d, J = 6.7 Hz, 6H), 1.06 - 1.02 (m, 2H), 0.86 - 0.79 (m, 2H). HRMS (ESI) m / z [M + H] + : 568.1749.

[0325] Example 12 [ka]

[0326] Step 1: Preparation of intermediate 12-2 Intermediate 12-1 (1.0 g), tetrahydrofuran (20 mL), and aqueous ammonia (1 mL) were added to a 100 mL single-neck flask in an ice bath, and the mixture was allowed to warm to room temperature and react for 2 hours. The reaction mixture was concentrated, and 50 mL of water was added. The mixture was stirred vigorously for 10 minutes, filtered with suction, and the filter cake was washed with 10 mL of water and dried to give Intermediate 12-2 (1.5 g). 1 H NMR (500 MHz, DMSO-d6) δ 8.81 (dd, J = 4.2, 1.6 Hz, 1H), 8.50 (d, J = 18.9 Hz, 2H), 8.05 (dd, J = 8.4, 1.5 Hz, 1H), 7.85 (dd, J = 8.5, 4.2 Hz, 1H). MS (ESI, [M+H] + ) m / z: 181.06.

[0327] Step 2: Preparation of intermediate 12-3 Intermediate 12-2 (1.0 g), ethanol (10 mL), and trifluoroacetic acid (0.43 mL) were added to a 100 mL single-neck flask in an ice bath, and platinum oxide (0.38 g) was added under nitrogen protection. After replacing the atmosphere with hydrogen, the hydrogenation reaction was carried out overnight. The reaction solution was suction filtered through a diatomaceous earth pad, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography to give Intermediate 12-3 (0.51 g). 1 H NMR (500 MHz, DMSO-d6) δ 7.00 (s, 1H), 3.26 - 3.16 (m, 2H), 2.60 (t, J = 6.4 Hz, 2H), 1.87 - 1.77 (m, 2H). MS (ESI, [M+H] + ) m / z: 185.11.

[0328] Step 3: Preparation of intermediate 12-4 In an ice bath, intermediate 12-3 (100 mg), tetrahydrofuran (5 mL), and triphosgene (96 mg) were sequentially added to a 10 mL reaction bottle, allowed to warm to room temperature, and stirred for 1 hour. Imidazole (737 mg) was added, and the mixture was stirred at room temperature for 5 minutes, then heated to 70 °C and allowed to react for 1.5 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was separated. The organic phase was concentrated, and the resulting crude product was purified by silica gel column chromatography to obtain intermediate 12-4 (85 mg). 1 H NMR (500 MHz, DMSO-d6) δ 7.65 (s, 1H), 3.73 (t, J = 5.7 Hz, 2H), 2.79 (t, J = 6.1 Hz, 2H), 2.16 - 2.07 (m, 2H). MS (ESI, [M+H] + ) m / z: 211.11.

[0329] Step 4: Preparation of Intermediate 12-5 Intermediate 12-4 (50 mg, 0.237 mmol), Intermediate A-6 (78 mg), potassium carbonate (98 mg, 0.712 mmol), and N,N-dimethylformamide (2 mL The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into saturated sodium chloride solution (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phase was concentrated, and the resulting crude product was purified by silica gel column chromatography to obtain intermediate 12-5 (67 mg). 1 H NMR (500 MHz, DMSO-d6) δ 7.95 - 7.91 (m, 1H), 7.74 - 7.69 (m, 2H), 7.49 - 7.45 (m, 2H), 5.08 (s, 2H), 3.84 - 3.80 (m, 2H), 3.76 (s, 3H), 2.84 (t, J = 6.0 Hz, 2H), 2.21 - 2.11 (m, 2H). MS (ESI, [M+H] + ) m / z: 449.26.

[0330] Step 5: Preparation of Compound 12 Intermediate 12-5 (50.0 mg), Intermediate B-3 (92 mg), tris(dibenzylideneacetone)dipalladium (51.0 mg), potassium phosphate (70.9 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (47.8 mg), 1,4-dioxane (2 mL), and water (0.04 mL) were sequentially added to a 10 mL microwave tube, and the mixture was heated to 130 °C in a microwave oven under nitrogen protection for 2 hours. The reaction mixture was concentrated, and the resulting crude product was purified by silica gel column chromatography to give compound 12 (25 mg). 1 H NMR (500 MHz, DMSO-d6) δ 8.63 - 8.53 (m, 1H), 7.91 (d, J = 9.6 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.34 - 7.24 (m, 1H), 5.12 (s, 2H), 3.88 (t, J = 5.6 Hz, 2H), 3.75 (s, 3H), 3.62 - 3.52 (m, 1H), 2.92 (t, J = 6.0 Hz, 2H), 2.28 - 2.18 (m, 2H), 1.16 (d, J = 6.7 Hz, 6H). HRMS (ESI) m / z [M + H] + : 534.2234.

[0331] Example 13 [ka] Intermediate 12-5 (50.0 mg), Intermediate B-1 (43.2 mg), tris(dibenzylideneacetone)dipalladium (51.0 mg, 0.056 mmol), potassium phosphate (70.9 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (47.8 mg), 1,4-dioxane (3 mL), and water (0.15 mL) were sequentially added to a 10 mL microwave tube, and the mixture was heated in a microwave oven at 130 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated, and the resulting crude product was purified by silica gel column chromatography to give compound 13 (60 mg). 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.92 (s, 1H), 7.70 - 7.64 (m, 2H), 7.52 - 7.46 (m, 2H), 5.11 (s, 2H), 3.89 - 3.86 (m, 2H), 3.83 (s, 3H), 3.75 (s, 3H) , 2.91 (t, J = 6.0 Hz, 2H), 2.27 - 2.17 (m, 2H), 1.7 - 1.6 (m, 1H), 1.07 - 0.97 (m, 2H), 0.84 (s, 2H). HRMS (ESI) m / z [M + H] + : 563.2130.

[0332] Example 14 [ka] Intermediate 12-5 (50.0 mg), Intermediate B-2 (55.7 mg), tris(dibenzylideneacetone)dipalladium (51.0 mg), potassium phosphate (70.9 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (47.8 mg), 1,4-dioxane (3 mL), and water (0.15 mL) were sequentially added to a 10 mL microwave tube, and the mixture was heated in a microwave oven at 130 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated, and the resulting crude product was purified by silica gel column chromatography to give compound 14 (34 mg). 1 H NMR (500 MHz, DMSO-d6) δ 7.92 (d, J = 1.3 Hz, 1H), 7.76 - 7.65 (m, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.33 (s, 1H), 5.26 - 5.16 (m, 1H), 5.12 (s, 2H), 3.88 (t, J = 5.6 Hz, 2H), 3.75 (s, 3H), 2.90 (t, J = 6.0 Hz, 2H), 2.27 - 2.17 (m, 2H), 2.12 (s, 3H), 1.33 (d, J = 6.6 Hz, 6H). HRMS (ESI) m / z [M + H] + : 537.2339.

[0333] Example 15 [ka] Sodium hydride (11.12 mg) was added to a solution of compound 9 (100 mg) in N,N-dimethylformamide (1 mL) at 0°C. After the addition was complete, the mixture was allowed to react for 30 minutes while maintaining the temperature at 0°C. Deuterated iodomethane (28.2 mg) was added to the reaction solution, and the mixture was allowed to react at 0°C. After the reaction was complete, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated brine, dried, and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to obtain 77 mg of compound 15. HRMS (ESI) m / z [M + H] + : 557.1737. 1 H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.47 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 6.75 (s, 1H) ), 5.24 (s, 2H), 3.80 (s, 3H), 2.31 (s, 3H), 1.69 - 1.62 (m, 1H), 1.11-1.04 (m, 1H), 0.99-0.93 (m, 1H), 0.93-0.86 (m, 1H), 0.84-0.77 (m, 1H).

[0334] Example 16 [ka] Sodium hydride (8.46 mg, 60% dispersion in mineral oil) was added to a solution of compound 4 (80 mg) in N,N-dimethylformamide (1 mL) at 0°C. After the addition was complete, the mixture was allowed to react for 30 minutes while maintaining the temperature at 0°C. Deuterated iodomethane (21.45 mg) was added to the reaction solution, and the mixture was allowed to warm to room temperature. After the reaction was complete, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated brine, dried, and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to obtain 45 mg of compound 16. HRMS (ESI) m / z [M + H] + : 585.2446. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.47 (s, 1H), 8.17 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 5.23 (s, 2H), 4.46-4.38 (m, 1H), 3.80 (s, 3H), 1.71-1.62 (m, 1H), 1.39 (d, J = 6.5 Hz, 6H), 1.11-1.05 (m, 1H), 0.98-0.94 (m, 1H), 0.92-0.86 (m, 1H), 0.83-0.76 (m, 1H).

[0335] Example 17 [ka]

[0336] Step 1: Synthesis of intermediate 17-1 (4-Bromophenyl)hydrazine (24.07 g) and hexafluoroisopropanol (300 mL) were mixed, and ethyl 2,4-dioxovalerate (18.5 g) was added in an ice bath. The mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=90:10) to obtain 27.8 g of intermediate 17-1. MS (ESI): m / z = 309.08 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.79-7.74 (m, 2H), 7.59-7.53 (m, 2H), 6.77 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.34 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0337] Step 2: Synthesis of intermediate 17-2 Intermediate 17-1 (10 g), methanol (40 mL), water (20 mL), and lithium hydroxide hydrate (6.79 g) were mixed and stirred at room temperature for 12 hours. The reaction mixture was concentrated to remove methanol, and the residue was diluted with ethyl acetate (50 mL). The pH was adjusted to 6 with saturated aqueous citric acid solution, and the organic phase was directly concentrated to obtain 8.9 g of Intermediate 17-2. MS (ESI): m / z = 281.18 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ 12.81 (br, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 6.72 (s, 1H), 2.34 (s, 3H).

[0338] Step 3: Synthesis of intermediate 17-3 Intermediate 17-2 (6 g) and dichloromethane (60 mL) were mixed, and the reaction mixture was cooled to 0°C. N,O-dimethylhydroxylamine hydrochloride (2.29 g), 4-methylmorpholine (2.38 g), and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (4.50 g) were added thereto, and the mixture was allowed to warm to room temperature and react for 3 hours with stirring. The reaction mixture was adjusted to pH 5-6 with 1 M dilute hydrochloric acid and extracted with dichloromethane (100 mL). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain 6.4 g of Intermediate 17-3. MS (ESI): m / z= 324.05 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.75 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 6.66 (s, 1H), 3.73 (s, 3H), 3.34 (s, 3H), 2.36 (s, 3H).

[0339] Step 4: Synthesis of intermediate 17-4 At 0°C under nitrogen atmosphere, 3M methylmagnesium bromide (7.77 ml) was slowly added dropwise to a solution of intermediate 17-3 (6.3 g, 19.43 mmol) in tetrahydrofuran (50 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 5.4 g of intermediate 17-4. MS (ESI): m / z= 279.08 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 7.77 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 6.72 (s, 1H), 2.49 (s, 3H), 2.35 (s, 3H) ).

[0340] Step 5: Synthesis of intermediate 17-5 Intermediate 17-4 (1.6 g) and 1,2-dichloroethane (40 mL) were mixed and cooled to 0 °C. N,N-diethyl-1,1,1-trifluoro-14-sulfonamide (7.39 g) and triethylamine trihydrofluoride (4.62 g) were added dropwise. After the addition was complete, the mixture was heated to 70 °C and stirred for 12 hours. The reaction mixture was poured into water (20 mL), the pH was adjusted to 7-8 with saturated sodium bicarbonate, and ethyl acetate (100 mL) was added for extraction. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain 0.72 g of Intermediate 17-5. MS (ESI): m / z= 301.04 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.76- 7.71 (m, 2H), 7.55-7.51 (m, 2H), 6.53 (s, 1H), 2.34 (s, 3H), 1.99 (t, J = 18.8 Hz, 3H).

[0341] Step 6: Synthesis of intermediate 17-6 Intermediate 17-5 (1.5 g), zinc powder (39.1 mg), 1,1'-bis(diphenylphosphino)ferrocene (276 mg), tris(dibenzylideneacetone)palladium (228 mg), zinc cyanide (360 mg), and N,N-dimethylacetamide (10 mL) were mixed and reacted at 150 °C for 12 hours under a nitrogen atmosphere. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain 800 mg of intermediate 17-6. MS (ESI): m / z= 248.22 [M+H] + .

[0342] Step 7: Synthesis of intermediate 17-7 Intermediate 17-6 (770 mg) and tetrahydrofuran (5 mL) were mixed, and 2.5 M lithium aluminum hydride (2.49 mL) was added in an ice bath. After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography to give 720 mg of intermediate 17-7. MS (ESI): m / z= 252.25 [M+H] + .

[0343] Step 8: Synthesis of intermediate 17-8 Intermediate 17-7 (300 mg), tris(dibenzylideneacetone)dipalladium (109 mg), cesium carbonate (1167 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (138 mg), tert-butyl (6-chloro-5-fluoro-4-iodopyridin-3-yl)carbamate (445 mg), and 1,4-dioxane (5 mL) were mixed and reacted under a nitrogen atmosphere at 100 ° C. for 12 hours. The reaction solution was concentrated as is, and the resulting crude product was separated and purified by silica gel column chromatography to obtain 300 mg of intermediate 17-8. MS (ESI): m / z= 422.22 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.56-7.52 (m, 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.50 (s, 1H), 5.17 (s, 2H), 2.31 (s, 3H), 1.97 (t, J = 18.8 Hz, 3H).

[0344] Step 9: Synthesis of intermediate 17-9 Intermediate 17-8 (300 mg), potassium phosphate (453 mg), (4-cyclopropyl-6-methoxypyrimidin-5-yl)borate (276 mg), tris(dibenzylideneacetone)dipalladium (65.1 mg), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (67.8 mg), 1,4-dioxane (5 mL), and water (0.25 mL) were mixed and reacted under a nitrogen atmosphere at 100°C for 1 hour. The reaction solution was concentrated as is, and the resulting crude product was separated and purified by silica gel column chromatography to obtain 70 mg of intermediate 17-9. MS (ESI): m / z= 536.22 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 7.52 (d, J = 6.4 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 6.50 (s, 1H), 5.18 (s, 2H), 3.80 (s, 3H), 2.30 (s, 3H), 1.97 (t, J = 18.8 Hz, 3H), 1.66 (td, J = 8.1, 4.0 Hz, 1H), 1.06 (ddd, J = 7.5, 4.7, 2.5 Hz, 1H), 0.99-0.92 (m, 1H), 0.92-0.84 (m, 1H), 0.84-0.76 (m, 1H).

[0345] Step 10: Synthesis of Compound 17 At 0°C, sodium hydride (11 mg) was slowly added to a stirred solution of intermediate 17-9 (100 mg) in N,N-dimethylformamide (3 mL). After the addition was complete, the mixture was allowed to react for 30 minutes at 0°C. Deuterated iodomethane (28 mg) was added to the reaction mixture, which was then warmed to room temperature and reacted for 1 hour. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated brine, dried, and concentrated. The resulting crude product was purified by silica gel column chromatography to give 42 mg of compound 17. HRMS (ESI) m / z [M + H] + : 553.2368. 1 H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.47 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.50 (s, 1H), 5.27-5.19 (m, 2H), 3.80 (s, 3H), 2.30 (d, J = 8.9 Hz, 3H), 1.97 (t, J = 18.8 Hz, 3H), 1.65 (td, J = 8.0, 4.1 Hz, 1H), 1.11-1.04 (m, 1H), 0.99-0.93 (m, 1H), 0.92-0.86 (m, 1H), 0.83-0.77 (m, 1H).

[0346] Test Example 1: In vitro cell proliferation inhibitory activity 1.1 Measurement of MDA-MB-436 cell proliferation inhibitory activity MDA-MB-436 cells in good growth condition were collected and collected in a centrifuge tube. The cell density was adjusted to 10 4 The solution was adjusted to a concentration of 1000 nM / mL and inoculated into a 96-well plate (100 μL / well). After overnight incubation in a cell culture incubator, compounds were added using a nanoliter pipettor to final concentrations of 1000 nM to 0.457 nM. Duplicate wells were also set up, including control wells. After 7 days of incubation in the cell culture incubator, detection reagent CCK-8 (manufacturer: Dojindo Chemical Industries, 10 μL / well) was added and the cells were incubated in the cell culture incubator for 2 hours. The absorbance values ​​at 450 nm were measured using an Envision microplate reader. A four-parameter analysis was performed, and a dose-response curve was fitted to determine the IC. 50 was calculated. The experimental results are shown in Table 1. A is 0 nM <IC 50 ≦50nM, B is 50nM <IC 50 ≤100nM, C is 100nM <IC 50 ≦1000nM, D is 1000nM <IC 50 of represent. [Table 1]

[0347] Test Example 2: In vitro enzyme inhibitory activity 2.1 Measurement of USP1 / UAF1 enzyme inhibitory activity 10 μl of USP1 / UAF1 protein solution (10 nM concentration) was added to each detection well. Using a nanoliter pipettor, each compound dissolved in DMSO was added to the detection wells to a final concentration of 1000 nM to 0.24 nM. Duplicate wells were used, as well as control wells. After incubating the system at room temperature for 30 minutes, 10 μl of Ub-rhodamine (300 nM concentration) was added to each detection well. After incubation at room temperature for 90 minutes, the plate was read using a PerkinElmer Envision multifunction microplate reader (Ex. 490 nm / Em. 520 nm). IC was calculated using a four-parameter fitting. 50 was calculated. The experimental results are shown in Table 2. A is 0 nM <IC 50 ≦50nM, B is 50nM <IC 50 ≤100nM, C is 100nM <IC 50 ≦1000nM, D is 1000nM <IC 50 Represents. [Table 2] The compounds of the present disclosure have good USP1 / UAF1 enzyme inhibitory activity.

[0348] Test Example 3: In vitro CYP450 enzyme inhibitory activity The human liver microsome incubation system was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.2 mg / ml), CYP450-specific substrate, test compound, and NADPH+MgCl2 solution, and incubating at 37°C and 300 rpm for 0.5 hours. A positive control group and a negative control group were also set up. The positive control group used a specific inhibitor instead of the test compound in the above system, and the negative control group used a solvent instead of the test compound in the above system. After incubation, an acetonitrile solution containing an internal standard was added to the sample to prepare a supernatant by protein precipitation, which was then diluted and used to measure the metabolites of the specific substrate by LC / MS / MS. The inhibition rate was calculated using the formula (1-(test group / negative control group)) × 100%. The compounds of the present disclosure inhibited the CYP450 activity. It has low in vitro inhibitory effect on P450 enzymes.

[0349] Test Example 4: Pharmacokinetics in mice ICR mice weighing 18 to 22 g were acclimated for 3 to 5 days and then randomly divided into groups (9 mice per group), and a test compound solution was intragastrically administered at a dose of 10 mg / kg. Blood samples were collected at 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours, and plasma samples for testing were prepared from the collected blood via the orbit. 30 μL of the test plasma sample and the standard curve sample were aspirated and added to an acetonitrile solution containing an internal standard substance, and the supernatant was obtained by protein precipitation, diluted, and used for LC / MS / MS measurement. A non-compartmental model was used for fitting. The compounds of the present disclosure have good pharmacokinetic properties.

Claims

1. A compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof. 【Chemical 1】 (In the formula, X1 and X2 are each independently selected from C(R1) or N; X3 is selected from C(R1)2, C(=Z), N(R7), S or O; X4, X5, X6 and X7 are each independently selected from C(R5) or N; Each R1 and R5 independently represents hydrogen, deuterium, halogen, —CN, —OH, —SH, —COOH, —NH2, —NHC1-12 alkyl, —N(C1-12 alkyl)2, C1-12 alkyl, C1-12 deuterated alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 deuterated alkoxy, C1-12 alkylthio, —COC1-12 alkyl, —OC(O)C1-12 alkyl, —C(O)OC1-12 alkyl, —OC(O)OC1-12 alkyl, —SO2C1- 12 alkyl, -NHSO2C1-12 alkyl, -N(C1-12 alkyl)SO2C1-12 alkyl, -SO2NH2, -SON2NHC1-12 alkyl, -SON2N(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- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl wherein said —OH, —SH, —NH2, —NHC1-12 alkyl, —N(C1-12 alkyl)2, C1-12 alkyl, C1-12 deuterated alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 deuterated alkoxy, C1-12 alkylthio, —COC1-12 alkyl, —OC(O)C1-12 alkyl, —C(O)OC1-12 alkyl, —OC(O)OC1-12 alkyl, —SO2C1-12 alkyl, —NHSO2C1-12 alkyl, —N(C1- -12 alkyl)SO2C1-12 alkyl, -SON2NH2, -SONHC1-12 alkyl, -SON2N(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- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are optionally independently substituted by one or more substituents, Z is selected from O, S or N(R8); or X2 and X3 are bonded together to form a 5- to 7-membered ring which may be substituted with one or more substituents; or R5 on two adjacent carbon atoms, together with the carbon atom to which they are attached, form a C5-7 cycloalkenyl, a 5- to 7-membered heterocycloalkenyl, a phenyl or a 5- to 6-membered heteroaryl optionally substituted by one or more substituents; L is selected from —(C(R3R4))m-, —O—, —S—, —N(R9)—, —S(O)—, or —S(O)2-; R2 is selected from C3-12 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or C5-7 cycloalkenyl, wherein said C3-12 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, and C5-7 cycloalkenyl are optionally independently substituted with one or more R2a; Each R3 and R4 independently represents hydrogen, deuterium, halogen, —CN, —OH, —SH, —COOH, —NH2, —NHC1-12 alkyl, —N(C1-12 alkyl)2, C1-12 alkyl, C1-12 deuterated alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 deuterated alkoxy, C1-12 alkylthio, —COC1-12 alkyl, —OC(O)C1-12 alkyl, —C(O)OC1-12 alkyl, —OC(O)OC1-12 alkyl, —SO2C1- 12 alkyl, -NHSO2C1-12 alkyl, -N(C1-12 alkyl)SO2C1-12 alkyl, -SO2NH2, -SON2NHC1-12 alkyl, -SON2N(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- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl wherein said —OH, —SH, —NH2, —NHC1-12 alkyl, —N(C1-12 alkyl)2, C1-12 alkyl, C1-12 deuterated alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 deuterated alkoxy, C1-12 alkylthio, —COC1-12 alkyl, —OC(O)C1-12 alkyl, —C(O)OC1-12 alkyl, —OC(O)OC1-12 alkyl, —SO2C1-12 alkyl, —NHSO2C1-12 alkyl, —N(C1- -12 alkyl)SO2C1-12 alkyl, -SON2NH2, -SONHC1-12 alkyl, -SON2N(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- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are optionally independently substituted by one or more substituents, or R3 and R4 together with the carbon atom to which they are attached form a C3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl optionally substituted by one or more substituents; R6 is hydrogen, halogen, —CN, —OH, —SH, —COOH, —NH2, —NHC1-12 alkyl, —N(C1-12 alkyl)2, C1-12 alkyl, C1-12 deuterated alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 deuterated alkoxy, C1-12 alkylthio, —COC1-12 alkyl, —OC(O)C1-12 alkyl, —C(O)OC1-12 alkyl, —OC(O)OC1-12 alkyl, —SO2C1-12 alkyl, —NHSO2 selected from C alkyl, —N(C alkyl)SO C alkyl, —SONH, —SONHC alkyl, —SON(C alkyl) —CONH, —CONHC alkyl, —CON(C alkyl) —NHCOC alkyl, —N(C alkyl)COC alkyl, C cycloalkyl, C cycloalkenyl, C aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; The —OH, —SH, —NH2, —NHC1-12 alkyl, —N(C1-12 alkyl)2, C1-12 alkyl, C1-12 deuterated alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 deuterated alkoxy, C1-12 alkylthio, —COC1-12 alkyl, —OC(O)C1-12 alkyl, —C(O)OC1-12 alkyl, —OC(O)OC1-12 alkyl, —SO2C1-12 alkyl, —NHSO2C1-12 alkyl, —N(C1-12 alkynyl), alkyl)SO2C1-12 alkyl, —SO2NH2, —SON2NHC1-12 alkyl, —SON(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- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are optionally independently substituted by one or more R6a; each R7, R8 or R9 is independently selected from hydrogen, —NH2, C1-12 alkyl, C1-12 deuterated alkyl, C1-12 alkoxy, C1-12 deuterated alkoxy, C3-12 cycloalkyl or 3-12 membered heterocyclyl, wherein said —NH2, C1-12 alkyl, C1-12 deuterated alkyl, C1-12 alkoxy, C1-12 deuterated alkoxy, C3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted by one or more substituents; Each R2a and R6a independently represents hydrogen, deuterium, halogen, —CN, —OH, —SH, —COOH, —NH2, —NHC1-12 alkyl, —N(C1-12 alkyl)2, C1-12 alkyl, C1-12 deuterated alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 deuterated alkoxy, C1-12 alkylthio, —COC1-12 alkyl, —OC(O)C1-12 alkyl, —C(O)OC1-12 alkyl, —OC(O)OC1-12 alkyl, —SO2C1 -12 alkyl, -NHSO2C1-12 alkyl, -N(C1-12 alkyl)SO2C1-12 alkyl, -SO2NH2, -SONHC1-12 alkyl, -SON2N(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- to 10-membered heteroaryl or 3- to 12-membered heterocyclo and said —OH, —SH, —NH2, —NHC1-12 alkyl, —N(C1-12 alkyl)2, C1-12 alkyl, C1-12 deuterated alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 deuterated alkoxy, C1-12 alkylthio, —COC1-12 alkyl, —OC(O)C1-12 alkyl, —C(O)OC1-12 alkyl, —OC(O)OC1-12 alkyl, —SO2C1-12 alkyl, —NHSO2C1-12 alkyl, —N(C1- -12 alkyl)SO2C1-12 alkyl, -SON2NH2, -SONHC1-12 alkyl, -SON2N(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- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are optionally independently substituted by one or more substituents, m is selected from 1, 2, or 3, with the proviso that when X1 is N, X3 is not NH.

2. At least one of X1 and X2 is selected from C(R1), and X3 is selected from C=O, N(R7), S or O, preferably X2 is selected from C(R1), X1 is selected from N and X3 is selected from C=O, N(R7), S or O, or X2 is selected from N, X1 is selected from C(R1), and X3 is selected from C=O, N(R7), S or O, or X1 is selected from C(R1), X2 is selected from C(R1), and X3 is selected from C ═O, N(R7), S or O, more preferably X2 is selected from C(R1), X1 is selected from N and X3 is selected from N(R7), or X2 is selected from N, X1 is selected from C(R1) and X3 is selected from N(R7), or X1 is selected from C(R1), X2 is selected from C(R1) and X3 is selected from N(R7). The compound of formula (I) according to claim 1, its isomer or a pharmaceutically acceptable salt thereof.

3. X2 and X3 are bonded together to form a 5- to 7-membered ring which may be substituted with one or more substituents, and the 5- to 7-membered ring is selected from a 5- to 7-membered heterocycloalkenyl, a C5-7 cycloalkenyl, a phenyl, or a 5- to 6-membered heteroaryl; preferably, X2 and X3 are bonded together to form a 5- to 7-membered ring which may be substituted with one or more substituents, and the ring atom at the position represented by X3 is a N atom; more preferably, X2 and X3 are The compound represented by formula (I), its isomer or pharmaceutically acceptable salt thereof according to claim 1, wherein X2 and X3 are bonded to each other to form a 5- to 7-membered ring which may be substituted with one or more substituents, and the ring atom at the position represented by X2 is a C atom; most preferably, X2 and X3 are bonded to each other to form a 5- to 7-membered ring which may be substituted with one or more substituents, and the ring atom at the position represented by X2 is a C atom, and the ring atom at the position represented by X3 is a N atom.

4. A compound represented by formula (I) according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein at least two of X4, X5, X6 and X7 are selected from C(R5), preferably X4 is selected from C(R5) and X5 is selected from C(R5), or preferably X6 is selected from C(R5) and X7 is selected from C(R5).

5. each R1 and R5 is independently selected from hydrogen, deuterium, halogen, —CN, —OH, —NH2, —NHC1-3 alkyl, —N(C1-3 alkyl)2, C1-3 alkyl, C1-3 deuterated alkyl, C1-3 alkoxy or C1-3 deuterated alkoxy, wherein said C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 alkoxy or C1-3 deuterated alkoxy is optionally and independently substituted by one or more substituents, preferably each R1 and R5 is optionally and independently substituted by one or more groups selected from halogen, deuterium, OH, CN or NH2, preferably each R1 is independently selected from hydrogen, —F, methyl, —CD3, ethyl, —CD2CD3 or CN; Or preferably, each R5 is independently selected from hydrogen or -F, a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 2 or 4.

6. The compound represented by formula (I) according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein L is selected from -(C(R3R4))m-, -O-, -S- or -N(R9)-, preferably L is selected from -(C(R3R4))m-, -O-, -S- or -NH-.

7. each R3 and R4 is 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- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; -6 cycloalkenyl, phenyl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are optionally independently substituted with one or more substituents, preferably each R3 and R4 is independently selected from hydrogen, halogen, —CN, —OH, —NH2, C1-3 alkyl, C1-3 deuterated alkyl, C1-3 alkoxy or C1-3 deuterated alkoxy, wherein said C1-3 alkyl, C1-3 deuterated alkyl, C1-3 alkoxy or C1-3 deuterated alkoxy are optionally independently substituted with one or more substituents, preferably each R3 and R4 is independently optionally substituted with one or more groups selected from halogen, deuterium, OH, CN or NH2; or R3 and R4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, which may be substituted by one or more substituents, preferably R3 and R4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl, which may be substituted by one or more substituents.

8. R2 is selected from C3-8 cycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or C5-6 cycloalkenyl, wherein said C3-8 cycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, and C5-6 cycloalkenyl are optionally independently substituted with one or more R2a, preferably R2 is selected from C3-6 cycloalkyl, phenyl, naphthyl, 5- to 9-membered heteroaryl, 3- to 6-membered heterocyclyl, or C5-6 cycloalkenyl, wherein said C3-6 cycloalkyl, phenyl, naphthyl, 5- to 9-membered heteroaryl, 3- to 6-membered heterocyclyl, and C5-6 cycloalkenyl are independently substituted with one or more R2a. The compound represented by formula (I) according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein the 5- to 9-membered heteroaryl, the 3- to 6-membered heterocyclyl and the C5-6 cycloalkenyl are optionally independently substituted with one or more R2a, and more preferably R2 is selected from C5-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl or C5-6 cycloalkenyl, and the C5-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl and C5-6 cycloalkenyl are optionally independently substituted with one or more R2a.

9. R6 is selected from hydrogen, halogen, —CN, —OH, —NH2, C1-3 alkyl, C1-3 deuterated alkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein said C1-3 alkyl, C1-3 deuterated alkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl is A compound represented by formula (I) according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein terocycyl may be independently substituted with one or more R6a, preferably R6 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl or pyrimidinyl, and the phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl and pyrimidinyl may be independently substituted with one or more R6a.

10. Each R2a and R6a is independently selected from halogen, -CN, -OH, -NH2, C1-3 alkyl, C1-3 deuterated alkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C3-6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein said C1-3 alkyl, C1-3 deuterated alkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C3-6 cycloalkyl or 3- to 6-membered heterocyclyl is independently optionally substituted by one or more substituents, preferably each R2a and R6a is independently selected from halo. R2a and R6a are each independently selected from the group consisting of aryl, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, each of which is optionally substituted with one or more substituents, and preferably each of R2a and R6a is optionally substituted with one or more groups independently selected from halogen, deuterium, OH, CN, or NH2; Or, R2a is -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 【Chemistry 2】 is selected from Or, R6a is -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 【Chemistry 3】 10. The compound of formula (I) according to claim 8 or 9, an isomer thereof or a pharmaceutically acceptable salt thereof, selected from:

11. The compound of formula (I) according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein each R7, R8 or R9 is independently selected from hydrogen, -NH2, C1-3 deuterated alkyl, C1-3 alkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C3-6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein said -NH2, C1-3 deuterated alkyl, C1-3 alkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C3-6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted by one or more groups, preferably each R7, R8 or R9 is independently substituted by one or more groups selected from halogen, deuterium, OH, CN or NH2, preferably each R7, R8 or R9 is independently selected from hydrogen, -NH2, methyl, ethyl, -CD2CD3, cyclopropyl or -CD3.

12. A compound represented by formula (I) according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof, selected from compounds represented by formula (I-1): 【Chemistry 4】 wherein X1, X3, X4, X5, X6, X7, R2, R3, R4 and R6 are as defined for the compounds of formula (I); The carbon atom to which R3 and R4 are attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer. or a compound represented by formula (I) according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof, selected from compounds represented by formula (I-2): 【Chemistry 5】 (In the formula, X5 is selected from CH or N; X1, X3, R2, R3, R4 and R6 are as defined for compounds of formula (I); The carbon atom to which R3 and R4 are attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer. or a compound represented by formula (I) according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof, selected from compounds represented by formula (I-3): 【Chemistry 6】 (In the formula, X5 is selected from CH or N; X3, R2, R3, R4 and R6 are as defined for compounds of formula (I); The carbon atom to which R3 and R4 are attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer. or a compound represented by formula (I) according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof, selected from compounds represented by formula (I-4): 【Chemistry 7】 (In the formula, X5 is selected from CH or N; R2, R3, R4 and R6 are as defined for compounds of formula (I); The carbon atom to which R3 and R4 are attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer. or a compound represented by formula (I) according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof, selected from compounds represented by formula (I-5): 【Chemistry 8】 (In the formula, X5 is selected from CH or N; Y1, Y2, and Y3 are each independently selected from CH or N; X, R, R, R and R are as defined for compounds of formula (I); The carbon atom to which R3 and R4 are attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer. or a compound represented by formula (I) according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof, selected from compounds represented by formula (I-6): 【Chemistry 9】 (In the formula, X5 is selected from CH or N; Y1, Y2 and Y3 are as defined for the compound of formula (I-5), X3, R2a, R3, R4 and R6a are as defined for compounds of formula (I); The carbon atom to which R3 and R4 are attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer. Or, a compound represented by formula (I) according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof, selected from compounds represented by formula (I-7). 【Chemistry 10】 (In the formula, X5 is selected from CH or N; Y1, Y2 and Y3 are as defined for the compound of formula (I-5), X3, R2a, R3, R4 and R6a are as defined for compounds of formula (I); The carbon atom to which R3 and R4 are attached may be a chiral carbon atom, existing in the form of a single (R) or (S) enantiomer, or enriched in one enantiomer.

13. A compound of the following formula, an isomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】

14. A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of the compound according to any one of claims 1 to 13, its isomer or a pharmaceutically acceptable salt thereof.

15. Use of the compound according to any one of claims 1 to 13, its isomer, or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for treating or preventing a disease associated with the inhibition of ubiquitin-specific protease 1 (USP1).

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