Tricyclic compound and medical uses thereof

Abstract

The present application belongs to the field of medicine, and relates to a tricyclic compound and medical uses thereof, the structure of the compound being represented by formula (I), and specifically relates to a preparation method for the compound, a pharmaceutical composition thereof, and uses thereof in the treatment of diseases.

Description

Tricyclic compounds and their medical uses

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefits of Chinese Patent Application No. 202310745248.X filed with the State Intellectual Property Office of China on June 21, 2023, Chinese Patent Application No. 202311158909.5 filed with the State Intellectual Property Office of China on September 8, 2023, Chinese Patent Application No. 202410316232.1 filed with the State Intellectual Property Office of China on March 19, 2024, and Chinese Patent Application No. 202410761294.3 filed with the State Intellectual Property Office of China on June 13, 2024. The contents disclosed in the above applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to tricyclic compounds, preparation methods thereof, pharmaceutical compositions containing the compounds, and uses thereof in treating diseases. Background Art

[0004] KIF18A is a mitotic kinesin that belongs to the Kinesin-8 family. KIF18A regulates correct chromosome positioning and spindle tension during mitosis. KIF18A deficiency in humans leads to longer spindles and increased chromosome oscillations during the G2 / M phase of the cell cycle. Studies have shown that KIF18A is overexpressed in whole-genome doubling (WGD) tumor cells but is dispensable in normal cells. KIF18A inhibition can induce mitotic arrest in WGD tumor cells without affecting normal cells. Therefore, KIF18A is a promising anti-tumor target.

[0005] Detailed Description of the Invention

[0006] The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0007] in,

[0008] X 1 and Y 1 Connected to form structural units And Y 2 Select N or CR Y2 ;

[0009] Or, X 1 and Y 2 Connected to form structural units And Y 1 Select N or CRY1 ;

[0010] X 1 Select N or CR X1 ;

[0011] X 2 Select N or CR X2 ;

[0012] X 1 With X 2 Connect via a single button;

[0013] Z 1 、Z 2 or Z 3 Each independently selected from N or CR Z1 ;

[0014] Z 4 or Z 5 Each independently selected from N or CR Z2 ;

[0015] Ring A is selected from the group consisting of a Substituted: 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0016] Each R X1 、R X2 、R Y1 、R Y2 、R Z1 or R Z2 Each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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)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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0017] Ring B is selected from optionally substituted by one or more R b Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0018] Each R a or R b Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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)COC1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0019] Ring C is selected from optionally substituted by one or more R c1 Substituted: 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;

[0020] Each R c1 Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0021] Alternatively, two R c1 and R c1 The connected ring atoms together form an optionally substituted ring containing one or more R c2 Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

[0022] Alternatively, two R c1 and R c1 The connected ring atoms together form an optionally substituted ring containing one or more R c2 Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

[0023] Each R c2 Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0024] L 1 Selected from single bond, -O-, -S-, -NR L1 -、C 1-6 Alkylene, deuterated C 1-6 Alkylene, halogenated C 1-6 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)NR L1 -、-C(O)NRL1 -、-NR L1 C(O)-、-NR L1 C(O)O-、-NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, or -C=N(OH)-;

[0025] Each R L1 Each independently selected from H, deuterium, or optionally replaced by one or more R L1a Substituted with the following groups: C 1-6 Alkyl, deuterated C 1- 6-membered alkyl, 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclyl, 6-10-membered aryl, or 5-10-membered heteroaryl;

[0026] Each R L1a Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1- 12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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 1-12Alkyl)2, -NHCOC 1- 12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0027] R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 1a Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl 1-6 Alkylene, 3-12 membered cycloalkenyl C 1-6 Alkylene, 3-12 membered heterocyclic C1-6 alkylene, 6-10 membered aryl C1-6 alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0028] Each R 1a Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, hydroxyl C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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(C1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0029] L 2 Selected from -O-, -S-, -NR L2 -、C 1-6 Alkylene, deuterated C 1-6 Alkylene, halogenated C 1-6 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L2 -、-NR L2 S(O)2-, -S(O)(=NH)-, -NR L2 S(O)(=NH)-, or -C=N(OH)-;

[0030] R L2 Selected from H, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0031] The R X1 、R X2 、R Y1 、R Y2 、R Z1 、R Z2 、R a 、R b 、R c1 、R c2 、R L1 、R L1a 、R 1 、R 1a , or R L2 Optionally substituted with one or more substituents.

[0032] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0033] X 1 and Y 1 Connected to form structural units And Y 2 Select N or CR Y2 ;

[0034] Or, X1 and Y 2 Connected to form structural units And Y 1 Select N or CR Y1 ;

[0035] X 1 Select N or CR X1 ;

[0036] X 2 Select N or CR X2 ;

[0037] X 1 With X 2 Connect via a single button;

[0038] Z 1 、Z 2 or Z 3 Each independently selected from N or CR Z1 ;

[0039] Z 4 or Z 5 Each independently selected from N or CR Z2 ;

[0040] Ring A is selected from the group consisting of a Substituted: 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0041] Each R X1 、R X2 、R Y1 、R Y2 、R Z1 or R Z2 Each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C1-12 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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0042] Ring B is selected from optionally substituted by one or more R b Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0043] Each R a or R b Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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 1-12Alkyl)2, -NHCOC 1- 12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0044] Ring C is selected from optionally substituted by one or more R c1 Substituted: 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;

[0045] Each R c1 Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0046] Alternatively, two R c1 and R c1 The connected ring atoms together form an optionally substituted ring containing one or more R c2Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

[0047] Alternatively, two R c1 and R c1 The connected ring atoms together form an optionally substituted ring containing one or more R c2 Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

[0048] Each R c2 Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0049] L 1 Selected from single bond, -O-, -S-, -NR L1 -、C 1-6 Alkylene, deuterated C 1-6 Alkylene, halogenated C 1-6Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)NR L1 -、-C(O)NR L1 -、-NR L1 C(O)-、-NR L1 C(O)O-、-NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, or -C=N(OH)-;

[0050] Each R L1 Each independently selected from H, deuterium, or optionally replaced by one or more R L1a Substituted with the following groups: C 1-6 Alkyl, deuterated C 1- 6-membered alkyl, 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclyl, 6-10-membered aryl, or 5-10-membered heteroaryl;

[0051] Each R L1a Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1- 12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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(C1-12 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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0052] R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 1a Substituted with the following groups: C 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; each R 1a Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, hydroxyl C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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 1-12Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0053] L 2 Selected from -O-, -S-, -NR L2 -、C 1-6 Alkylene, deuterated C 1-6 Alkylene, halogenated C 1-6 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L2 -、-NR L2 S(O)2-, -S(O)(=NH)-, -NR L2 S(O)(=NH)-, or -C=N(OH)-;

[0054] R L2 Selected from H, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0055] The R X1 、R X2 、R Y1 、R Y2 、R Z1 、R Z2 、R a 、R b 、R c1 、R c2 、R L1 、R L1a 、R 1 、R 1a , or R L2 Optionally substituted with one or more substituents.

[0056] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0057] X 1 and Y 1 Connected to form structural units And Y 2 Select N or CR Y2 ;

[0058] Or, X 1 and Y 2 Connected to form structural units And Y 1 Select N or CRY1 ;

[0059] X 1 Select N or CR X1 ;

[0060] X 2 Select N or CR X2 ;

[0061] X 1 With X 2 Connect via a single button;

[0062] Z 1 、Z 2 or Z 3 Each independently selected from N or CR Z1 ;

[0063] Z 4 or Z 5 Each independently selected from N or CR Z2 ;

[0064] Ring A is selected from the group consisting of a Substituted: 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0065] Each R X1 、R X2 、R Y1 、R Y2 、R Z1 or R Z2 Each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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)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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0066] Ring B is selected from optionally substituted by one or more R b Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0067] Each R a or R b Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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)COC1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0068] Ring C is selected from optionally substituted by one or more R c1 Substituted: 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;

[0069] Each R c1 Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0070] Alternatively, two R c1 together to form optionally one or more R c2 Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

[0071] Alternatively, two Rc1 together to form optionally one or more R c2 Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

[0072] Each R c2 Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0073] L 1 Selected from single bond, -O-, -S-, -NR L1 -、C 1-6 Alkylene, deuterated C 1-6 Alkylene, halogenated C 1-6 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -、-NR L1 C(O)-、-NR L1 C(O)NR L1-, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, or -C=N(OH)-;

[0074] Each R L1 Each independently selected from H, deuterium, or optionally replaced by one or more R L1a Substituted with the following groups: C 1-6 Alkyl, deuterated C 1- 6-membered alkyl, 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclyl, 6-10-membered aryl, or 5-10-membered heteroaryl;

[0075] Each R L1a are each independently selected from oxo, deuterium, halogen, -CN, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1- 12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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- 12Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0076] R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 1a Substituted with the following groups: C 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0077] Each R 1a Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, hydroxyl C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0078] L 2 Selected from -O-, -S-, -NRL2 -、C 1-6 Alkylene, deuterated C 1-6 Alkylene, halogenated C 1-6 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L2 -、-NR L2 S(O)2-, -S(O)(=NH)-, -NR L2 S(O)(=NH)-, or -C=N(OH)-;

[0079] R L2 Selected from H, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0080] The R X1 、R X2 、R Y1 、R Y2 、R Z1 、R Z2 、R a 、R b 、R c1 、R c2 、R L1 、R L1a 、R 1 、R 1a , or R L2 Optionally substituted with one or more substituents.

[0081] In some embodiments, the R X1 、R X2 、R Y1 、R Y2 、R Z1 、R Z2 、R a 、R b 、R c1 、R c2 、R L1 、R L1a 、R 1 、R 1a , or R L2 When optionally substituted with one or more substituents, the "substituent" is selected from a deuterium atom, a hydroxyl group, a thiol group, a halogen group, an amino group, a nitro group, a nitroso group, a cyano group, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, an aldehyde group, an imine group, a C 1-12 Alkyl, halo-C 1-12Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 ester groups, oxo and thio groups, etc., wherein the substituents are optionally substituted by one or more substituents selected from the following: deuterium atoms, oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -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-C1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0082] In some embodiments, the R X1 、R X2 、R Y1 、R Y2 、R Z1 、R Z2 、R a 、R b 、R c1 、R c2 、R L1 、R L1a 、R 1 、R 1a , or R L2 When optionally substituted with one or more substituents, the "substituent" is selected from deuterium atoms, hydroxyl groups, mercapto groups, halogen groups, amino groups, nitro groups, cyano groups, carboxyl groups, aldehyde groups, C 1-3 Alkyl, halo-C 1-3 Alkyl or C3 cycloalkyl.

[0083] In some embodiments, X 1 and Y 1 Connected to form structural units And Y 2 Selected from CR Y2 ; or, X 1 and Y 2 Connected to form structural units And Y 1 Selected from CR Y1 .

[0084] In some embodiments, X 1 and Y 1 Connected to form structural units And Y 2 Selected from CR Y2 ; or, X1 and Y 2 Connected to form structural units And Y 1 Selected from N.

[0085] In some embodiments, X 1 and Y 1 Connected to form structural units And Y 2 Selected from N; or, X 1 and Y 2 Connected to form structural units And Y 1 Selected from CR Y1 .

[0086] In some embodiments, X 1 and Y 1 Connected to form structural units And Y 2 Selected from N; or, X 1 and Y 2 Connected to form structural units And Y 1 Selected from N.

[0087] In some embodiments, X 1 and Y 1 Connected to form structural units And Y 2 Select N or CR Y2 .

[0088] In some embodiments, X 1 and Y 2 Connected to form structural units And Y 1 Select N or CR Y1 .

[0089] In some embodiments, X 1 and Y 1 Connected to form structural units And Y 2 Select N or CR Y2 ;X 1 Selected from CR X1 , X 2 In some embodiments, X 1 and Y 1 Connected to form structural units And Y 2 Select N or CR Y2 .

[0090] In some embodiments, X1 and Y 2 Connected to form structural units And Y 1 Select N or CR Y1 ;X 1 Selected from CR X1 , X 2 In some embodiments, X 1 and Y 2 Connected to form structural units And Y 1 Select N or CR Y1 .

[0091] In some embodiments, X 1 and Y 1 Connected to form structural units And Y 2 Select from N;X 1 Selected from CR X1 , X 2 In some embodiments, X 1 and Y 1 Connected to form structural units And Y 2 Selected from N.

[0092] In some embodiments, X 1 and Y 2 Connected to form structural units And Y 1 Select from N;X 1 Selected from CR X1 , X 2 In some embodiments, X 1 and Y 2 Connected to form structural units And Y 1 Selected from N.

[0093] In some embodiments, X 1 Selected from N.

[0094] In some embodiments, X 1 Selected from CR X1 .

[0095] In some embodiments, X 1 Selected from CH.

[0096] In some embodiments, X 2 Selected from N.

[0097] In some embodiments, X 2 Selected from CR X2.

[0098] In some embodiments, X 2 Selected from CH.

[0099] In some embodiments, X 1 Selected from CR X1 , X 2 Selected from CR X2 .

[0100] In some embodiments, X 1 Selected from CR X1 , X 2 Selected from N.

[0101] In some embodiments, X 1 Selected from CH, X 2 Selected from N.

[0102] In some embodiments, X 1 Selected from N, X 2 Selected from CR X2 .

[0103] In some embodiments, X 1 Selected from N, X 2 Selected from CH.

[0104] In some embodiments, Z 1 、Z 2 and Z 3 CR Z1 .

[0105] In some embodiments, Z 1 、Z 2 and Z 3 All are CH.

[0106] In some embodiments, Z 1 、Z 2 or Z 3 Not N at the same time.

[0107] In some embodiments, Z 1 、Z 2 or Z 3 One or two of them are N.

[0108] In some embodiments, Z 1 and Z 2 N, Z 3 CR Z1 .

[0109] In some embodiments, Z 1 and Z 3 N, Z 2CR Z1 .

[0110] In some embodiments, Z 2 and Z 3 N, Z 1 CR Z1 .

[0111] In some embodiments, Z 1 N, Z 2 and Z 3 CR Z1 .

[0112] In some embodiments, Z 2 N, Z 1 and Z 3 CR Z1 .

[0113] In some embodiments, Z 3 N, Z 1 and Z 2 CR Z1 .

[0114] In some embodiments, Z 4 and Z 5 CR Z2 .

[0115] In some embodiments, Z 4 CH, Z 5 CR Z2 .

[0116] In some embodiments, Z 4 and Z 5 is N.

[0117] In some embodiments, Z 4 or Z 5 Not N at the same time.

[0118] In some embodiments, Z 4 N, Z 5 CR Z2 .

[0119] In some embodiments, Z 5 N, Z 4 CR Z2 .

[0120] In some embodiments, Z 1 、Z 2 and Z 3 CR Z1 , Z 4 and Z 5CR Z2 .

[0121] In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 or Z 5 Not N at the same time.

[0122] In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 or Z 5 At least one of them is N.

[0123] In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 or Z 5 At least two of them are N.

[0124] In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 or Z 5 At least three of them are N.

[0125] In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 or Z 5 There are one, two, three, or four Ns.

[0126] In some embodiments, Z 1 N, Z 2 and Z 3 CR Z1 , Z 4 and Z 5 CR Z2 In some embodiments, Z 2 N, Z 1 and Z 3 CR Z1 , Z 4 and Z 5 CR Z2 In some embodiments, Z 3 N, Z 1 and Z 2 CR Z1 , Z 4 and Z 5 CR Z2In some embodiments, Z 4 N, Z 1 、Z 2 and Z 3 CR Z1 , Z 5 CR Z2 In some embodiments, Z 5 N, Z 1 、Z 2 and Z 3 CR Z1 , Z 4 CR Z2 .

[0127] In some embodiments, Z 1 and Z 2 N, Z 3 CR Z1 , Z 4 and Z 5 CR Z2 In some embodiments, Z 1 and Z 3 N, Z 2 CR Z1 , Z 4 and Z 5 CR Z2 In some embodiments, Z 2 and Z 3 N, Z 1 CR Z1 , Z 4 and Z 5 CR Z2 In some embodiments, Z 1 and Z 4 N, Z 2 and Z 3 CR Z1 , Z 5 CR Z2 In some embodiments, Z 1 and Z 5 N, Z 2 and Z 3 CR Z1 , Z 4 CR Z2 In some embodiments, Z 2 and Z 4 N, Z 1 and Z 3 CR Z1 , Z 5 CR Z2 In some embodiments, Z 2 and Z5 N, Z 1 and Z 3 CR Z1 , Z 4 CR Z2 In some embodiments, Z 3 and Z 4 N, Z 1 and Z 2 CR Z1 , Z 5 CR Z2 In some embodiments, Z 3 and Z 5 N, Z 1 and Z 2 CR Z1 , Z 4 CR Z2 In some embodiments, Z 4 and Z 5 N, Z 1 、Z 2 and Z 3 CR Z1 .

[0128] In some embodiments, Z 1 、Z 2 and Z 4 N, Z 3 CR Z1 , Z 5 CR Z2 In some embodiments, Z 1 、Z 2 and Z 5 N, Z 3 CR Z1 , Z 4 CR Z2 In some embodiments, Z 1 、Z 3 and Z 4 N, Z 2 CR Z1 , Z 5 CR Z2 In some embodiments, Z 1 、Z 3 and Z 5 N, Z 2 CR Z1 , Z 4 CR Z2 In some embodiments, Z 2 、Z 3 and Z 4 N, Z 1 CRZ1 , Z 5 CR Z2 In some embodiments, Z 2 、Z 3 and Z 5 N, Z 1 CR Z1 , Z 4 CR Z2 .

[0129] In some embodiments, Y 2 N, Z 4 and Z 5 For CH.

[0130] In some embodiments, Y 1 N, Z 4 CH, Z 5 is CH or CCH3.

[0131] In some embodiments, Y 2 N, Z 4 CH, Z 5 For CCH3.

[0132] In some embodiments, Y 1 and Z 5 N, Z 4 For CH.

[0133] In some embodiments, Y 1 CH, Z 4 and Z 5 is N.

[0134] In some embodiments, Y 1 N, Z 4 N, Z 5 For CH.

[0135] In some embodiments, Y 1 N, Z 4 CH, Z 5 For CCN.

[0136] In some embodiments, Ring A is selected from the group consisting of a Substituted: 4-12 membered cycloalkenyl or 4-12 membered heterocycloalkenyl.

[0137] In some embodiments, Ring A is selected from the group consisting of a Substituted: 4-10 membered cycloalkenyl or 4-10 membered heterocycloalkenyl.

[0138] In some embodiments, Ring A is selected from the group consisting ofa Substituted: 4-8 membered cycloalkenyl or 4-8 membered heterocycloalkenyl.

[0139] In some embodiments, Ring A is selected from the group consisting of a Substituted: 5-7 membered cycloalkenyl or 5-7 membered heterocycloalkenyl.

[0140] In some embodiments, Ring A is selected from the group consisting of a In some embodiments, the 4-12 membered heterocycloalkenyl is selected from 4-10 membered heterocycloalkenyl, 4-8 membered heterocycloalkenyl or 5-7 membered heterocycloalkenyl. In some embodiments, Ring A is selected from optionally substituted with one or more R a Substituted 6-7 membered heterocycloalkenyl.

[0141] In some embodiments, the "cycloalkenyl" or "heterocycloalkenyl" in Ring A has only one olefinic bond.

[0142] In some embodiments, the 6-10 membered aryl group in Ring A can be selected from phenyl.

[0143] In some embodiments, the 5-10 membered heteroaryl group in Ring A can be selected from 5-6 membered heteroaryl groups.

[0144] In some embodiments, Ring A is selected from the group consisting of a Substituted groups:

[0145] In some embodiments, Ring A is selected from the group consisting of a Substituted groups: In some embodiments, Ring A is selected from the group consisting of a Substituted groups:

[0146] In some embodiments, Ring A is selected from the following groups:

[0147] In some embodiments, Ring A is selected from the following groups:

[0148] In some embodiments, Ring A is selected from the following groups: In some embodiments, Ring A is selected from the following groups: In some embodiments, Ring A is selected from the following groups: In some embodiments, Ring A is selected from the following groups:

[0149] In some embodiments, the "heterocyclyl" disclosed herein is selected from "heterocycloalkyl" or "heterocycloalkenyl".

[0150] In some embodiments, the "heterocyclyl" disclosed herein is selected from "heterocycloalkyl".

[0151] In some embodiments, the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.

[0152] In some embodiments, each R X1 、R X2 、R Y1 、R Y2 、R Z1 or R Z2 Each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -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, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

[0153] In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.

[0154] In some embodiments, each R X1 、R X2 、R Y1 、R Y2 、R Z1 or R Z2 Each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -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, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

[0155] In some embodiments, each R X1 、R X2 、R Y1 、R Y2 、R Z1 or R Z2 Each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group.

[0156] In some embodiments, the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.

[0157] In some embodiments, each R X1 、R X2 、R Y1 、R Y2 、R Z1 or R Z2 Each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -COC 1-4 Alkyl, -OC(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -OC(O)OC 1-4 Alkyl, -SO2C 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -N(C 1-4 Alkyl)SO2C 1-4 Alkyl, -SO2NH2, -SO2NHC 1-4 Alkyl, -SO2N(C 1-4 Alkyl)2, -CONH2, -CONHC 1-4 Alkyl, -CON(C 1-4 Alkyl)2, -NHCOC 1-4 Alkyl, -N(C 1-4 Alkyl)COC 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl.

[0158] In some embodiments, each R X1 、R X2 、R Y1 、R Y2 、R Z1 or R Z2 Each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, 3-6 membered cycloalkyl, or 3-6 membered heterocyclic group.

[0159] In some embodiments, the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.

[0160] In some embodiments, each R X1 、R X2 、R Y1 、R Y2 、R Z1 or R Z2 Each is independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl)amino, cyclopropyl, cyclobutyl, azetidinyl, or oxetanyl.

[0161] In some embodiments, each R X1 、R X2 、R Y1 、R Y2 、R Z1 or R Z2 Each is independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or cyclopropyl.

[0162] In some embodiments, R X1 is selected from H, -F, -Cl, methyl, or methoxy.

[0163] In some embodiments, R X1Selected from H.

[0164] In some embodiments, R X2 is selected from H, -F, -Cl, methyl, or methoxy.

[0165] In some embodiments, R X2 Selected from H.

[0166] In some embodiments, R Y1 is selected from H, -F, -Cl, -CN, methyl, methoxy, trifluoromethyl, or cyclopropyl.

[0167] In some embodiments, R Y1 Selected from H.

[0168] In some embodiments, R Y2 is selected from H, -F, -Cl, -CN, methyl, methoxy, trifluoromethyl, or cyclopropyl.

[0169] In some embodiments, R Z1 is selected from H, -F, -Cl, methyl, or methoxy.

[0170] In some embodiments, R Z1 Selected from H.

[0171] In some embodiments, R Z2 is selected from H, -F, -Cl, -CN, methyl, methoxy, trifluoromethyl, or cyclopropyl.

[0172] In some embodiments, R Z2 is selected from H, -CN, or methyl.

[0173] In some embodiments, R Z2 Selected from H or methyl.

[0174] In some embodiments, Ring B is selected from the group consisting of b Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl.

[0175] In some embodiments, Ring B is selected from the group consisting of b Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocycloalkyl.

[0176] In some embodiments, Ring B is selected from the group consisting of b Substituted: 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl.

[0177] In some embodiments, Ring B is selected from the group consisting ofb Substituted: 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl.

[0178] In some embodiments, Ring B is selected from the group consisting of b Substituted: 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl.

[0179] In some embodiments, Ring B is selected from the group consisting of b Substituted: 6-8 membered cycloalkyl or 6-8 membered heterocycloalkyl.

[0180] In some embodiments, Ring B is selected from the group consisting of b Substituted: 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl.

[0181] In some embodiments, Ring B is selected from the group consisting of b Substituted 3-12 membered heterocycloalkyl.

[0182] In some embodiments, the "3-12 membered" cycloalkyl, "3-12 membered cycloalkyl", "3-12 membered cycloalkenyl", or "3-12 membered heterocycloalkyl" described in Ring B, the "3-12 membered" cycloalkyl group may be independently selected from 3-10 membered, 5-9 membered, or 6-8 membered. In some embodiments, the "3-12 membered" cycloalkyl, "3-12 membered cycloalkyl", "3-12 membered cycloalkenyl", or "3-12 membered heterocycloalkyl" described in Ring B, the "3-12 membered" cycloalkyl group may be independently selected from 4-7 membered.

[0183] In some embodiments, the 3-12 membered cycloalkyl is selected from a 3-10 membered cycloalkyl, a 5-9 membered cycloalkyl, or a 6-8 membered cycloalkyl. In some embodiments, the 3-12 membered cycloalkyl is selected from a 4-7 membered cycloalkyl.

[0184] In some embodiments, the 3-12 membered heterocyclyl is selected from a 3-10 membered heterocyclyl, a 5-9 membered heterocyclyl, or a 6-8 membered heterocyclyl. In some embodiments, the 3-12 membered heterocyclyl is selected from a 4-7 membered heterocyclyl.

[0185] In some embodiments, the 3-12 membered heterocycloalkyl is selected from 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl, or 6-8 membered heterocycloalkyl. In some embodiments, the 3-12 membered heterocycloalkyl is selected from 4-7 membered heterocycloalkyl.

[0186] In some embodiments, the 3-12 membered heterocycloalkenyl is selected from 3-10 membered heterocycloalkenyl, 5-9 membered heterocycloalkenyl, or 6-8 membered heterocycloalkenyl. In some embodiments, the 3-12 membered heterocycloalkenyl is selected from 4-7 membered heterocycloalkenyl.

[0187] In some embodiments, the 6-10 membered aryl groups in Ring B are independently selected from phenyl.

[0188] In some embodiments, the 5-10 membered heteroaryl group in Ring B is independently selected from a 5-6 membered heteroaryl group.

[0189] In some embodiments, Ring B is selected from the group consisting of b Substituted groups include cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl,

[0190] In some embodiments, Ring B is selected from the group consisting of b Substituted groups:

[0191] In some embodiments, Ring B is selected from the group consisting of b Replaced

[0192] In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from

[0193] In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from

[0194] In some embodiments, the structural unit Selected from optionally one or more R b Substituted groups: in The other end of the Y 1 or Y 2 .

[0195] In some embodiments, the structural unit Selected from optionally one or more R b replace in The other end of the Y 1 or Y 2 .

[0196] In some embodiments, the structural unit Selected from

[0197] in The other end of the Y 1 or Y 2 In some embodiments, the structural unit Selected from in The other end of the Y 1 or Y 2 In some embodiments, the structural unit Selected from in The other end of the Y 1 or Y 2 .

[0198] In some embodiments, the structural unit Selected from in The other end of the Y 1 or Y 2 .

[0199] In some embodiments, the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.

[0200] In some embodiments, each R a or R b Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -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 1-6Alkyl)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, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

[0201] In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.

[0202] In some embodiments, each R a or R b Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -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, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

[0203] In some embodiments, each R a or R b are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 In some embodiments, each R a or R b Each independently selected from deuterated C 1-6 alkyl.

[0204] In some embodiments, the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.

[0205] In some embodiments, each R a or R b Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -COC 1-4 Alkyl, -OC(O)C 1- 4-alkyl, -C(O)OC 1-4 Alkyl, -OC(O)OC 1-4 Alkyl, -SO2C 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -N(C 1-4 Alkyl)SO2C 1-4 Alkyl, -SO2NH2, -SO2NHC 1-4 Alkyl, -SO2N(C 1-4 Alkyl)2, -CONH2, -CONHC 1-4Alkyl, -CON(C 1-4 Alkyl)2, -NHCOC 1- 4-alkyl, -N(C 1-4 Alkyl)COC 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl.

[0206] In some embodiments, each R a or R b are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 alkylamino, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl. In some embodiments, each R a or R b Each independently selected from deuterated C 1-4 alkyl.

[0207] In some embodiments, the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.

[0208] In some embodiments, each R a or R b R is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl)amino, cyclopropyl, cyclobutyl, azetidinyl, or oxetanyl. In some embodiments, each R a or R b Each R is independently selected from deuterated methyl. a or R b Each is independently selected from deuterated ethyl.

[0209] In some embodiments, each R a or R bEach is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, -CD3, ethyl, or -CD2CD3.

[0210] In some embodiments, each R a or R b Each R is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or cyclopropyl. a or R b Each is independently selected from -CD3. In some embodiments, each R a or R b Each is independently selected from ethyl or -CD2CD3.

[0211] In some embodiments, each R a Each is independently selected from deuterium, oxo, methyl, -CD3, ethyl, cyclopropyl, or -CD2CD3.

[0212] In some embodiments, each R a Each R is independently selected from deuterium, oxo or methyl. a Each is independently selected from -CD3. In some embodiments, each R a Each is independently selected from ethyl, cyclopropyl, or -CD2CD3.

[0213] In some embodiments, each R b Each is independently selected from oxo, deuterium, -F, -Cl, -OH, -NH2, -CN, or methyl.

[0214] In some embodiments, each R b are each independently selected from -F or -Cl.

[0215] In some embodiments, Ring C is selected from the group consisting of c1 Substituted: 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl.

[0216] In some embodiments, Ring C is selected from the group consisting of c1 Substituted: 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl.

[0217] In some embodiments, Ring C is selected from the group consisting of c1 Substituted: 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl.

[0218] In some embodiments, Ring C is selected from the group consisting of c1 Substituted: 6-8 membered cycloalkyl or 6-8 membered heterocycloalkyl.

[0219] In some embodiments, Ring C is selected from the group consisting of c1 Substituted: 6-10 membered cycloalkyl or 6-10 membered heterocycloalkyl.

[0220] In some embodiments, Ring C is selected from the group consisting of c1 Substituted 3-12 membered heterocycloalkyl. In some embodiments, the 3-12 membered heterocycloalkyl is selected from 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl, or 6-8 membered heterocycloalkyl. In some embodiments, the 3-12 membered heterocycloalkyl is selected from 4-8 membered heterocycloalkyl. In some embodiments, the 3-12 membered heterocycloalkyl is selected from 6-10 membered heterocycloalkyl.

[0221] In some embodiments, the 3-12 membered cycloalkyl, 3-10 membered cycloalkyl, 5-9 membered cycloalkyl or 6-8 membered cycloalkyl is selected from monocyclic cycloalkyl. In some embodiments, the 4-8 membered cycloalkyl is selected from monocyclic cycloalkyl.

[0222] In some embodiments, the 3-12 membered cycloalkyl, 3-10 membered cycloalkyl, 5-9 membered cycloalkyl or 6-8 membered cycloalkyl is selected from a bridged cycloalkyl. In some embodiments, the 4-8 membered cycloalkyl is selected from a bridged cycloalkyl.

[0223] In some embodiments, the 3-12 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl or 6-8 membered heterocycloalkyl is selected from monocyclic heterocycloalkyl. In some embodiments, the 4-8 membered heterocycloalkyl is selected from monocyclic heterocycloalkyl.

[0224] In some embodiments, the 3-12 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl or 6-8 membered heterocycloalkyl is selected from bridged heterocycloalkyl. In some embodiments, the 4-8 membered heterocycloalkyl is selected from bridged heterocycloalkyl.

[0225] In some embodiments, Ring C is selected from the group consisting of c1 Substituted groups:

[0226] In some embodiments, Ring C is selected from the group consisting of c1 Substituted groups: In some embodiments, Ring C is selected from the group consisting of c1 Substituted groups:

[0227] In some embodiments, Ring C is selected from

[0228] In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from

[0229] In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from

[0230] In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from

[0231] In some embodiments, the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.

[0232] In some embodiments, each R c1 Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-8 Alkyl, deuterated C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylthio, C 1-8 Alkylamino, di-C 1-8 Alkylamino, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkoxy, halogenated C 1-8 Alkylthio, halo C 1-8 Alkylamino, halogenated di-C 1-8 Alkylamino, -COC 1-8 Alkyl, -OC(O)C 1- 8-alkyl, -C(O)OC 1-8 Alkyl, -OC(O)OC 1-8 Alkyl, -SO2C 1-8 Alkyl, -NHSO2C 1-8 Alkyl, -N(C 1-8 Alkyl)SO2C 1-8 Alkyl, -SO2NH2, -SO2NHC 1-8 Alkyl, -SO2N(C 1-8 Alkyl)2, -CONH2, -CONHC 1-8 Alkyl, -CON(C 1-8Alkyl)2, -NHCOC 1- 8-alkyl, -N(C 1-8 Alkyl)COC 1-8 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;

[0233] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted: 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl or 3-10 membered heterocyclyl;

[0234] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted: 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl or 3-10 membered heterocyclyl.

[0235] In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.

[0236] In some embodiments, each R c1 are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylthio, C 1-8 Alkylamino, di-C 1-8 Alkylamino, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkoxy, halogenated C 1-8 Alkylthio, halo C 1-8 Alkylamino, or halogenated di-C 1-8 Alkylamino;

[0237] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted: 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;

[0238] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted: 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl.

[0239] In some embodiments, each R c1 Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -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, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl;

[0240] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted: 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl;

[0241] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted: 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl.

[0242] In some embodiments, the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.

[0243] In some embodiments, each R c1 are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino;

[0244] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted groups: 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;

[0245] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted: 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl.

[0246] In some embodiments, each R c1 Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -COC 1-4 Alkyl, -OC(O)C 1- 4-alkyl, -C(O)OC 14 Alkyl, -OC(O)OC 1-4 Alkyl, -SO2C 1-4 Alkyl, -NHSO2C 1-4Alkyl, -N(C 1-4 Alkyl)SO2C 1-4 Alkyl, -SO2NH2, -SO2NHC 1-4 Alkyl, -SO2N(C 1-4 Alkyl)2, -CONH2, -CONHC 1-4 Alkyl, -CON(C 1-4 Alkyl)2, -NHCOC 1- 4-alkyl, -N(C 1-4 Alkyl)COC 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 6 membered aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl;

[0247] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted: 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl or 3-6 membered heterocyclyl;

[0248] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted: 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl or 3-6 membered heterocyclyl.

[0249] In some embodiments, the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.

[0250] In some embodiments, each R c1 are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino;

[0251] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted groups: 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;

[0252] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted: 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.

[0253] In some embodiments, each R c1 each independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino;

[0254] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl;

[0255] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl.

[0256] In some embodiments, each R c1 Each is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, methylamino, dimethylamino, trifluoromethyl, trifluoromethoxy;

[0257] Alternatively, two R c1 (and R c1 connected ring atoms) together to form an optionally substituted one or more R c2 Substituted cyclopropyl.

[0258] In some embodiments, each R c2 Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -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, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

[0259] In some embodiments, each R c2 Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -COC 1-4 Alkyl, -OC(O)C 1- 4-alkyl, -C(O)OC 14 Alkyl, -OC(O)OC 1-4 Alkyl, -SO2C1-4 Alkyl, -NHSO2C 1-4 Alkyl, -N(C 1-4 Alkyl)SO2C 1-4 Alkyl, -SO2NH2, -SO2NHC 1-4 Alkyl, -SO2N(C 1-4 Alkyl)2, -CONH2, -CONHC 1-4 Alkyl, -CON(C 1-4 Alkyl)2, -NHCOC 1- 4-alkyl, -N(C 1-4 Alkyl)COC 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl.

[0260] In some embodiments, each R c2 are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0261] In some embodiments, each R c2 Each is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0262] In some embodiments, each R c2 Each is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0263] In some embodiments, L 1 Selected from single bond, -O-, -S-, -NR L1 -、C 1-4 Alkylene, deuterated C 1-4Alkylene, halogenated C 1-4 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -、-NR L1 C(O)-、-NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, or -C=N(OH)-. In some embodiments, L 1 Selected from -OC(O)O-, -OC(O)NR L1 -, or -NR L1 C(O)O-.

[0264] In some embodiments, L 1 Selected from single bond, -O-, -S-, -NR L1 -, methylene, deuterated methylene, ethylene, deuterated ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -、-NR L1 C(O)-、-NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, or -C=N(OH)-. In some embodiments, L 1 Selected from -OC(O)O-, -OC(O)NR L1 -, or -NR L1 C(O)O-.

[0265] In some embodiments, L 1 Selected from single bond, -O-, -S-, -NR L1 -, methylene, ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -、-NR L1 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1S(O)2-、-NR L1 S(O)2NR L1 -, or -S(O)(=NH)-.

[0266] In some embodiments, L 1 Selected from single bond, -O-, -S-, -NR L1 -、-C(O)NR L1 -、-NR L1 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -, or -S(O)(=NH)-.

[0267] In some embodiments, L 1 Selected from -S(O)2NR L1 -. In some embodiments, L 1 Selected from-NR L1 S(O)2-.

[0268] In some embodiments, L 1 Use left-to-right or right-to-left reading order.

[0269] In some embodiments, L 1 Read from left to right.

[0270] In some embodiments, L 1 It is -NHS(O)2-.

[0271] In some embodiments, each R L1 Each independently selected from H, deuterium, or optionally replaced by one or more R L1a Substituted with the following groups: C 1-6 Alkyl, deuterated C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0272] In some embodiments, each R L1 Each independently selected from H, deuterium, or optionally replaced by one or more R L1a Substituted with the following groups: C 1-6 Alkyl, deuterated C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0273] In some embodiments, each R L1Each independently selected from H, deuterium, or optionally replaced by one or more R L1a Substituted with the following groups: C 1-4 Alkyl, deuterated C 1-4 alkyl, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0274] In some embodiments, the 3-10 membered heterocyclyl, 3-8 membered heterocyclyl, or 4-7 membered heterocyclyl are each selected from 3-10 membered heterocycloalkyl, 3-8 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl.

[0275] In some embodiments, each R L1 Each independently selected from H or optionally replaced by one or more R L1a Substituted C 1-4 alkyl.

[0276] In some embodiments, each R L1 Each independently selected from H or optionally replaced by one or more R L1a Substituted groups include methyl, ethyl, n-propyl, or isopropyl.

[0277] In some embodiments, each R L1 are each independently selected from H or methyl.

[0278] In some embodiments, each R L1 are each independently selected from H.

[0279] In some embodiments, each R L1a Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -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)SO2C1-6 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, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

[0280] In some embodiments, each R L1a Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -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, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

[0281] In some embodiments, each R L1aare each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -COC 1-4 Alkyl, -OC(O)C 1- 4-alkyl, -C(O)OC 14 Alkyl, -OC(O)OC 1-4 Alkyl, -SO2C 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -N(C 1-4 Alkyl)SO2C 1-4 Alkyl, -SO2NH2, -SO2NHC 1-4 Alkyl, -SO2N(C 1-4 Alkyl)2, -CONH2, -CONHC 1-4 Alkyl, -CON(C 1-4 Alkyl)2, -NHCOC 1- 4-alkyl, -N(C 1-4 Alkyl)COC 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl.

[0282] In some embodiments, each R L1a are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0283] In some embodiments, each R L1aEach is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0284] In some embodiments, each R L1a Each is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

[0285] In some embodiments, R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 1a Substituted with the following groups: C 1-6 In some embodiments, R 1 Selected from optionally one or more R 1a Substituted groups: 3-10 membered cycloalkyl C 1-4 Alkylene, 3-10 membered cycloalkenyl C 1-4 Alkylene, 3-10 membered heterocyclic group C 1-4 Alkylene, 6-10 membered aryl C 1-4 Alkylene, or 5-10 membered heteroaryl C 1-4 Alkylene.

[0286] In some embodiments, R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 1a Substituted with the following groups: C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, R 1 Selected from optionally one or more R 1a Substituted groups: 3-8 membered cycloalkyl C 1-4 Alkylene, 3-8 membered cycloalkenyl C 1-4 Alkylene, 3-8 membered heterocyclic group C 1-4 Alkylene, phenyl C 1-4 Alkylene, or 5-6 membered heteroaryl C 1-4 Alkylene.

[0287] In some embodiments, R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 1a Substituted with the following groups: C 1-4 In some embodiments, R 1 Selected from optionally one or more R 1a Substituted groups: 3-6 membered cycloalkyl C 1-3 Alkylene, 4-7 membered cycloalkenyl C 1-3 Alkylene, 4-7 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0288] In some embodiments, R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 1a Substituted with the following groups: C 1-4 In some embodiments, R 1 Selected from optionally one or more R 1a Substituted groups: 3-6 membered cycloalkyl C 1-2 Alkylene or 4-7 membered heterocycloalkyl C 1-2 Alkylene.

[0289] In some embodiments, R 1 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 1a In some embodiments, R 1 Selected from optionally one or more R 1a Substituted cyclopropylmethylene, cyclobutylmethylene, azetidinylmethylene, or oxetanylmethylene.

[0290] In some embodiments, R 1 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 1asubstituted with methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thiazinyl, isothiazolidinyl, or thiadiazolidinyl. 1 Selected from optionally one or more R 1a Substituted groups include tetrahydrofuranyl and cyclopropylmethylene.

[0291] In some embodiments, R 1 is selected from methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, tert-butyl, cyclopropyl,

[0292] In some embodiments, R 1 is selected from methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, tert-butyl, cyclopropyl,

[0293] In some embodiments, R 1 Selected from

[0294] In some embodiments, R 1 Selected from methyl, ethyl, isopropyl, cyclopropyl,

[0295] In some embodiments, R 1 Selected from methyl or

[0296] In some embodiments, R 1 Selected from optionally one or more R 1a Substituted C 1-4 alkyl.

[0297] In some embodiments, R 1 Selected from optionally one or more R 1a Substituted ethyl.

[0298] In some embodiments, the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.

[0299] In some embodiments, each R 1a Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -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, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

[0300] In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.

[0301] In some embodiments, each R 1a Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C1-6 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, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

[0302] In some embodiments, the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.

[0303] In some embodiments, each R 1a Each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-4 Alkyl, deuterated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -COC 1-4 Alkyl, -OC(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -OC(O)OC 1-4 Alkyl, -SO2C 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -N(C 1-4 Alkyl)SO2C 1-4 Alkyl, -SO2NH2, -SO2NHC 1-4 Alkyl, -SO2N(C 1-4 Alkyl)2, -CONH2, -CONHC 1-4 Alkyl, -CON(C 1- 4-alkyl)2, -NHCOC 1-4 Alkyl, -N(C 1-4 Alkyl)COC1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl.

[0304] In some embodiments, each R 1a Each independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, deuterated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -OC(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl. In some embodiments, each R 1a are each independently selected from deuterium.

[0305] In some embodiments, the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.

[0306] In some embodiments, each R 1a each independently selected from oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, hydroxymethyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino, -OC(O)C 1-2 Alkyl, -C(O)OC 1-2 Alkyl, -CONHC 1-2 Alkyl, -NHCOC 1-2 In some embodiments, each R 1a are each independently selected from deuterium.

[0307] In some embodiments, each R 1aEach is independently selected from oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, hydroxymethyl, methoxy, trifluoromethyl, trifluoromethoxy, -C(O)OCH3, -C(O)OCH2CH3, or cyclopropyl. 1a are each independently selected from deuterium.

[0308] In some embodiments, each R 1a Each R is independently selected from oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy. 1a are each independently selected from deuterium. In some embodiments, R 1a Selected from hydroxymethyl.

[0309] In other embodiments, R 1a Optionally substituted by one or more substituents selected from the group consisting of oxo, deuterium atom, halogen, hydroxyl, amino, cyano, mercapto, and carboxyl.

[0310] In other embodiments, R 1a Optionally substituted with one or more substituents selected from hydroxy.

[0311] In other embodiments, R 1a is selected from -OH or methyl, said methyl being optionally substituted with one or more hydroxyl groups.

[0312] In some embodiments, R 1a In some embodiments, R 1a Selected from methyl or hydroxymethyl.

[0313] In some embodiments, the structural unit -L 1 -R 1 Selected from or

[0314] In some embodiments, the structural unit -L 1 -R 1 Selected from In some embodiments, the structural unit -L 1 -R 1 Selected from or

[0315] In some embodiments, the structural unit -L1 -R 1 Selected from

[0316] In some embodiments, the structural unit -L 1 -R 1 Selected from or

[0317] In some embodiments, the structural unit -L 1 -R 1 Selected from

[0318] In some embodiments, the structural unit -L 1 -R 1 Selected from In some embodiments, the structural unit -L 1 -R 1 Selected from In some embodiments, the structural unit -L 1 -R 1 Selected from or

[0319] In some embodiments, L 2 Selected from -O-, -S-, -NR L2 -、C 1-4 Alkylene, deuterated C 1-4 Alkylene, halogenated C 1-4 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L2 -, or -NR L2 S(O)2-.

[0320] In some embodiments, L 2 Selected from -O-, -S-, -NR L2 -, methylene, deuterated methylene, ethylene, deuterated ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L2 -, or -NR L2 S(O)2-.

[0321] In some embodiments, L 2 Selected from ethylene, -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-、-S(O)2NR L2 -, or -NR L2 S(O)2-.

[0322] In some embodiments, L 2 Selected from -C(O)NR L2 -, or -NR L2 C(O)-.

[0323] In some embodiments, L 2 Use right-to-left or left-to-right reading order.

[0324] In some embodiments, L 2 Use right-to-left reading order.

[0325] In some embodiments, L 2 It is -NH-C(O)-.

[0326] In some embodiments, R L2 Selected from H, deuterium, C 1-4 Alkyl, deuterated C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0327] In some embodiments, R L2 is selected from H, deuterium, methyl, deuterated methyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0328] In some embodiments, R L2 is selected from H, deuterium or methyl.

[0329] In some embodiments, R L2 Selected from H.

[0330] In some embodiments, the heterocyclic group disclosed herein is selected from heterocycloalkyl. In some embodiments, the heterocyclic group disclosed herein is selected from partially unsaturated heterocyclic groups.

[0331] In some embodiments, the 3-12 membered, 3-10 membered, 3-8 membered, or 4-7 membered heterocyclyl groups disclosed herein are selected from 3-12 membered, 3-10 membered, 3-8 membered, or 4-7 membered heterocycloalkyl groups.

[0332] In some embodiments, the C 1-12 Selected from C 1-10 、C 1-8、C 1-6 、C 1-4 、C 1-3 , or C 1-2 .

[0333] In some embodiments, the C 1-6 Alkyl is selected from C 1-4 Alkyl, C 1-3 Alkyl, or C 1-2 alkyl.

[0334] In some embodiments, the C 1-6 Alkylene is selected from C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 Alkylene.

[0335] In some embodiments, the halogen of the present disclosure is selected from F, Cl, Br, or I.

[0336] In some embodiments, the halo of the present disclosure is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo of the present disclosure is selected from fluoro.

[0337] In some embodiments, the term "one or more" as used herein may refer to an integer from one to ten. For example, "one or more" may refer to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" may refer to one, two, three, four, five, or six; or, "one or more" may refer to one, two, three, or four.

[0338] In some embodiments, the 3-12-membered group of the present disclosure is selected from 3-10-membered, 3-8-membered, 3-6-membered, 4-7-membered, 4-6-membered, 5-8-membered, 5-7-membered, or 5-6-membered.

[0339] In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 or 2 heteroatoms selected from N or O.

[0340] In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 N atom.

[0341] In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 O atom.

[0342] In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 N atom and 1 O atom.

[0343] In some embodiments, the heterocyclic or heteroaryl groups disclosed herein contain one or two heteroatoms selected from N, O, or S.

[0344] In some embodiments, the heterocyclyl or heteroaryl groups disclosed herein contain 1 or 2 N atoms.

[0345] In some embodiments, the heterocyclyl or heteroaryl groups disclosed herein contain 1 N atom and 1 O atom.

[0346] In some embodiments, the heterocyclyl or heteroaryl groups disclosed herein contain 1 N atom and 1 S atom.

[0347] In some embodiments, the heterocyclyl or heterocycloalkyl groups disclosed herein include monocyclic, spirocyclic, fused, or bridged rings. In some embodiments, the heterocyclyl or heterocycloalkyl groups disclosed herein include monocyclic or spirocyclic rings. In some embodiments, the heterocyclyl or heterocycloalkyl groups disclosed herein include monocyclic or bridged rings.

[0348] In some embodiments, in the compounds of formula (I) or pharmaceutically acceptable salts thereof described herein, all hydrogen atoms may be optionally substituted with one or more deuterium atoms.

[0349] The present disclosure relates to compounds of formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-1), formula (III-2), formula (III-3), or pharmaceutically acceptable salts thereof,

[0350] Among them, X 1 、X 2 、Y 1 、Y 2 、Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、L 1 、R 1 、L 2 , Ring A, Ring B and Ring C moieties are as defined in the present disclosure.

[0351] In some embodiments, the ring A is selected from the group consisting of a Substituted 6-7 membered heterocycloalkenyl.

[0352] In some embodiments, the ring A is selected from the group consisting of a Substituted 6-7 membered heterocycloalkenyl, wherein the 6 membered heterocycloalkenyl contains 2 N atoms, and the 7 membered heterocycloalkenyl contains 1 or 2 heteroatoms selected from N or O.

[0353] In some embodiments, the structural unit Selected from n is selected from 0, 1, 2, 3, 4, 5, or 6; m is selected from 0, 1, 2, 3, 4, 5, or 6.

[0354] In some embodiments, the structural unit Selected from

[0355] In some embodiments, n is selected from 0, 1, 2, 3, or 4. In some embodiments, n is selected from 0, 1, or 2.

[0356] In some embodiments, m is selected from 0, 1, 2, 3, or 4. In some embodiments, m is selected from 0, 1, or 2.

[0357] In some embodiments, the structural unit Selected from

[0358] In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

[0359] In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0360] In some embodiments, the compounds of formula (I), (II), (II-1), (II-2), (II-3), (III), (III-1), (III-2), (III-3) or their pharmaceutically acceptable salts disclosed herein do not include the following compounds or their pharmaceutically acceptable salts:

[0361] The present disclosure also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0362] The present disclosure also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0363] In some embodiments, the present disclosure provides compounds having a longer retention time and a shorter retention time in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a whelk-O1 chiral chromatography column. In some embodiments, the chiral chromatography uses n-hexane: dichloromethane: ethanol = 40:40:20 (volume ratio) as the mobile phase. In some embodiments, the chiral chromatography conditions are: chiral HPLC (column: whelk-O1, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 40:40:20; flow rate: 2 mL / min; wavelength: 254 nm). In some embodiments, the retention time of the compound with the longer retention time is about 10-11 minutes, and the retention time of the compound with the shorter retention time is about 7-8 minutes.

[0364] In some embodiments, the present disclosure provides compounds having a longer retention time and a shorter retention time in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatography column of the CHIRALART Cellulose-SB model. In some embodiments, the chiral chromatography uses n-hexane:ethanol = 60:40 (volume ratio) as the mobile phase. In some embodiments, the chiral chromatography conditions are: chiral HPLC (column: CHIRALART Cellulose-SB column, 4.6×250 mm, 5 μm; mobile phase: n-hexane:ethanol = 60:40; flow rate: 1 mL / min; wavelength: 254 nm). In some embodiments, the retention time of the compound with the longer retention time is about 12-13 minutes, and the retention time of the compound with the shorter retention time is about 10-11 minutes.

[0365] In some embodiments, the present disclosure provides compounds having a longer retention time and a shorter retention time in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatography column of the CHIRALART Cellulose SC model. In some embodiments, the chiral chromatography uses n-hexane as mobile phase A and dichloromethane / ethanol = 5 / 1 as mobile phase B. In some embodiments, the chiral chromatography conditions are: chiral HPLC (column: CHIRALART Cellulose SC; mobile phase A: n-hexane, mobile phase B: dichloromethane / ethanol = 5 / 1 (volume ratio); elution gradient: A / B = 55 / 45; flow rate: 1 mL / min; wavelength: 254 nm). In some embodiments, the retention time of the compound with the longer retention time is about 22-23 min, and the retention time of the compound with the shorter retention time is about 19-20 min.

[0366] In some embodiments, the present disclosure provides a structure selected from The compound has a configuration consistent with the compound with a longer or shorter retention time in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatography column of the CHIRALART Amylose-SA model. In some embodiments, the chiral chromatography uses n-hexane:ethanol=50:50 (volume ratio) as the mobile phase. In some embodiments, the chiral chromatography conditions are: chiral HPLC (column: CHIRALART Amylose-SA, 30×250 mm, 5 μm; mobile phase: n-hexane:ethanol=50:50; flow rate: 40 mL / min; wavelength: 254 nm). In some embodiments, the retention time of the compound with the longer retention time is about 9-10 min, and the retention time of the compound with the shorter retention time is about 6-7 min.

[0367] In some embodiments, the present disclosure provides compounds having a longer retention time and a shorter retention time in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatography column of the CHIRALART Cellulose-SC model. In some embodiments, the chiral chromatography uses n-hexane: dichloromethane: ethanol = 60:10:30 as the mobile phase. In some embodiments, the conditions of the chiral chromatography are: chiral HPLC (column: CHIRALART Cellulose-SC, 4.6×250mm, 5μm; mobile phase: n-hexane: dichloromethane: ethanol = 60:10:30 (volume ratio); flow rate: 1mL / min; wavelength: 254nm). In some embodiments, the retention time of the compound with the longer retention time is about 21-22min, and the retention time of the compound with the shorter retention time is about 18-19min.

[0368] In some embodiments, the present disclosure provides compounds having a longer retention time and a shorter retention time in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatographic column of CHIRALARTCellose-SC model. In some embodiments, the chiral chromatography is with n-hexane: dichloromethane: ethanol = 60: 10: 30 (volume ratio) as mobile phase. In some embodiments, the conditions of the chiral chromatography are: chiral HPLC (column: CHIRALARTCellose-SC, 4.6 × 250mm, 5μm; mobile phase: n-hexane: dichloromethane: ethanol = 60: 10: 30; flow rate: 1mL / min; wavelength: 254nm). In some embodiments, the retention time of the compound with a longer retention time is about 10-11min, and the retention time of the compound with a shorter retention time is about 9-10min.

[0369] In some embodiments, the present disclosure provides compounds with longer retention times in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatography column of the CHIRALPAK IK model. In some embodiments, the chiral chromatography uses n-hexane / dichloromethane / ethanol = 50 / 25 / 25 (volume ratio) as the mobile phase. In some embodiments, the chiral chromatography conditions are: the retention time in chiral HPLC (column: CHIRALPAK IK, 4.6×250 mm, 5 μm; mobile phase: n-hexane / dichloromethane / ethanol = 50 / 25 / 25; flow rate: 1 mL / min) is longer. In some embodiments, the retention time of the compound with the longer retention time is about 16 minutes, and the retention time of the compound with the shorter retention time is about 18-19 minutes.

[0370] In some embodiments, the present disclosure provides a structure selected from The compound has a configuration consistent with the compound with a longer or shorter retention time in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatography column of the CHIRALART Amylose-SA model. In some embodiments, the chiral chromatography uses n-hexane:ethanol=50:50 (volume ratio) as the mobile phase. In some embodiments, the chiral chromatography conditions are: chiral HPLC (column: CHIRALART Amylose-SA, 30×250 mm, 5 μm; mobile phase: n-hexane:ethanol=50:50; flow rate: 40 mL / min; wavelength: 254 nm). In some embodiments, the retention time of the compound with the longer retention time is about 9-10 min, and the retention time of the compound with the shorter retention time is about 6-7 min.

[0371] In another aspect, the present disclosure relates to a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0372] In another aspect, the present disclosure relates to a method for treating a disease in a mammal, comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure to a mammal, preferably a human, in need of such treatment.

[0373] In another aspect, the present disclosure relates to use of the compound or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in preparing a medicament for treating a disease.

[0374] In another aspect, the present disclosure relates to use of the compound or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in treating a disease.

[0375] In another aspect, the present disclosure relates to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in treating a disease.

[0376] In some embodiments of the present disclosure, the disease is selected from a KIF18A-related disease.

[0377] In some embodiments of the present disclosure, the disease (eg, a KIF18A-related disease) is selected from cancer (eg, ovarian cancer, breast cancer).

[0378] Technical Effects

[0379] The compounds disclosed herein have high KIF18A inhibitory activity (e.g., KIF18A protein motility activity) and cell proliferation inhibitory activity (e.g., OVCAR3 cells, MDA-MB-468 cells), and exhibit good drugability in in vitro and in vivo metabolic stability, pharmacokinetics, bioavailability, and / or pharmacodynamic studies. For example, in mouse pharmacokinetic studies, the compounds disclosed herein exhibited good pharmacokinetic properties in terms of oral absorption exposure, half-life, and absolute bioavailability. The compounds of the present application can effectively inhibit tumor growth.

[0380] definition

[0381] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0382] 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. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0383] The "substituent" described herein includes all substituents mentioned herein, for example, including the following terms "alkyl", "alkylene", "heteroalkyl", "alkoxy", "alkylamino", "dialkylamino", "alkylthio", "alkenyl", "alkynyl", "cycloalkyl", "cycloalkenyl", "heterocyclyl", "heterocyclylalkyl", "aryl", "heteroaryl" and other related groups, and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include deuterium atoms, hydroxyl, thiol, halogen, amino , nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio , heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester group, etc., which are optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0384] In some embodiments herein, the substituent is selected from a deuterium atom, a hydroxyl group, a sulfhydryl group, a halogen group, an amino group, a nitro group, a nitroso group, a cyano group, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, an aldehyde group, an imine group, a C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 ester groups, oxo and thio groups, etc., wherein the substituents are optionally substituted by one or more substituents selected from the following: deuterium atoms, oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -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)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0385] The term "replacement" or "replaced" means that a specific atom or group can be replaced or replaced by a specified other atom or group. For example, one, two, or three -CH2- in -CH2CH2CH2- can be replaced by O, S, or NH to obtain -O-CH2-CH2-, -O-CH2-, -CH2-O-CH2-, -CH2-O-, -CH2-CH2-O-, -O-, etc.

[0386] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0387] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, “C 1-12 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms or 12 carbon atoms, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, "C 1-3 " means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0388] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0389] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0390] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a covalent bond, it means that the structure is actually AZ.

[0391] When the listed linking groups do not specify their connection direction, the connection direction is arbitrary. For example, in ALZ, the linking group L is -MW-, which means that the structure can be AMWZ or AWMZ.

[0392] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0393] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0394] The term "hydroxy" refers to an -OH group.

[0395] The term "cyano" refers to a -CN group.

[0396] The term "mercapto" refers to a -SH group.

[0397] The term "amino" refers to a -NH2 group.

[0398] The term "nitro" refers to a -NO2 group.

[0399] The term "alkylene" refers to a group of the formula C n H 2n A saturated straight or branched chain divalent hydrocarbon group typically has 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 groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-), butylene (-CH2CH2CH2CH2-, -CH2CH(CH3)CH2- or -CH2CH2CH(CH3)-), and the like. The alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0400] The term "alkyl" refers to a group of the formula C n H 2n+1 The saturated hydrocarbon group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. The alkyl group can be straight or branched and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). The alkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy. Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, and alkylthio groups has the same definition as above.

[0401] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and hydrogen atoms attached thereto) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroalkyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, and typically has 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 "Heteroalkyl" refers to a heteroalkyl group containing from 1 to 6 carbon atoms and from 1 to 3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkyl group (e.g., internal or terminal), including the position at which the heteroalkyl group is attached to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkyl groups include, but are not limited to, alkoxy, alkoxyalkylene, alkylamino, alkylaminoalkylene, dialkylamino, dialkylaminoalkylene, and the like. The heteroalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0402] The term "alkoxy" refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0403] The term "alkylamino" refers to an -NH-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0404] The term "dialkylamino" refers to -N(alkyl)2, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0405] The term "alkylthio" refers to an -S-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0406] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like. The alkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0407] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡CC≡CH), and the like. The alkynyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0408] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocycle, a bridged ring, or a spirocycle. Unless otherwise indicated, the carbocyclic ring is typically a 3-12 ring, a 3 to 10 ring, a 3 to 8 ring, a 4 to 8 ring, a 5 to 8 ring, a 6 to 8 ring, or a 5 to 6 ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc. The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0409] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic ring with at least one double bond that can exist as a monocycle, a bridged ring, or a spirocycle. Unless otherwise indicated, the carbocyclic ring is typically 3 to 12 rings, 3 to 10 rings, 3 to 8 rings, 3 to 6 rings, 4 to 8 rings, 5 to 8 rings, or 5 to 6 rings. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc. The cycloalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)- Alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0410] Term " heterocyclic radical " refers to fully saturated or partially undersaturated (but not fully unsaturated heteroaromatic) and can be with monocycle, bridged ring, and ring or spirocyclic non-aromatic ring.Unless otherwise indicated, the heterocycle is generally 3 to 12 yuan, 3 to 10 yuan, 3 to 8 yuan, 3 to 6 yuan, 4 to 8 yuan, 5 to 8 yuan, 6 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms, preferably heteroatoms are N, O or S) independently selected from sulphur, oxygen, nitrogen, phosphorus, silicon and / or boron.The limiting examples of heterocyclic radical include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N- methylpyrrolidinyl, dihydropyrrolyl, piperidyl, piperazinyl, pyrazolidinyl, 4H- pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc. The heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)- Alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0411] The term "heterocyclenyl" refers to a partially undersaturated (but not completely unsaturated heteroaromatic) non-aromatic ring that can exist with a monocycle, a bridged ring, a ring or a spirocycle. Unless otherwise indicated, the heterocycle is typically 3 to 12 yuan, 3 to 10 yuan, 4 to 8 yuan, 6 to 8 yuan, 4 to 10 yuan, 4 to 12 yuan, 5 to 7 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms, preferably heteroatoms are N, O or S) independently selected from sulphur, oxygen, nitrogen, phosphorus, silicon and / or boron. Non-limiting examples of heterocyclenyl include but are not limited to dihydrofuranyl, dihydropyrrolyl, 2H-pyranyl, dihydrothienyl etc. The heterocycloalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O) -alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0412] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocycle, a bridged ring or a spirocycle. Unless otherwise indicated, the heterocycle is typically a 3 to 12-membered, 3 to 10-membered, 3 to 8-membered, 4 to 8-membered, 5 to 8-membered, 6 to 8-membered, 5 to 6-membered, 3 to 7-membered or 4 to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron (preferably 1 or 2 heteroatoms, preferably N, O or S). Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. The heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O) -alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0413] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0414] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one (e.g., 1, 2, or 3) ring atom selected from N, O, or S, with the remaining ring atoms being C, typically having 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7, or 5 to 6 ring atoms. Preferred heteroaryls have single 4 to 8 rings, especially 5 to 6 rings, or multiple fused rings containing 5 to 14, especially 5 to 10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0415] Unless otherwise specified, the term "deuterated C 1-12 "Alkyl" refers to the above-mentioned "C 1-12 Any number and position of H atoms in the "alkyl" are replaced by deuterium atoms. 1-12 Deuterated alkyl can be C 1-6 Deuterated alkyl or C 1-3 Deuterated alkyl. Examples of deuterated alkyl include, but are not limited to, -CH2D, -CHD2, -CD3, wait.

[0416] The group -L in the present disclosure 1 - Read from left to right or right to left, e.g. group -L 1 - is connected to the left side group and the right side group of the group in the general formula corresponding to the reading order from left to right, for example, when -L 1 When - is -S(O)2NH-, the structure for Or when -L 1 When - is -NHS(O)2-, the structure for

[0417] The group -L in the present disclosure 2 - Reading order from right to left or left to right, e.g. group -L 2 - is connected to the right side group and the left side group of the group in the general formula corresponding to the reading order from right to left, for example, when -L 2 When - is -C(O)NH-, the structure for

[0418] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0419] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0420] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0421] The term "preventing" or "preventing" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0422] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0423] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0424] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0425] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0426] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0427] Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0428] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0429] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included 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 known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0430] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 For example, it should be understood that compounds in which one or more hydrogen atoms in the compounds of formula (I) of the present disclosure are replaced by deuterium atoms are still within the scope of the compounds of formula (I) of the present disclosure.

[0431] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0432] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0433] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

[0434] The compounds of the present disclosure may have one or more atropisomers. Unless otherwise specified, atropisomers refer to optically active isomers resulting from the obstruction of free rotation between single bonds. The compounds of the present disclosure containing a chiral axis can be isolated in racemic form. When the energy barrier for free rotation between single bonds of the compounds of the present disclosure containing a chiral axis is sufficiently high, the atropisomers can be isolated in optically pure form.

[0435] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0436] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0437] In all administration methods of the compound of formula (I) described herein, the daily dosage is 0.001 to 2000 mg / kg body weight. The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.

[0438] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0439] The compounds of formula (II-2) or formula (III-2) disclosed herein can be prepared by those skilled in the art of organic synthesis via route 1 or route 2, wherein X 1 、X 2 、Y 1 、Y 2 、Z 4 、Z 5 、R 1 , Ring A, Ring B and Ring C moieties are as defined in the present disclosure.

[0440] Route 1

[0441] Route 2

[0442] Each product obtained by the reaction in the above-mentioned route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. The starting materials can be synthesized by themselves or purchased from commercial institutions (such as, but not limited to, Adrich or Sigma). These raw materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in this disclosure can be obtained as single isomers or mixtures of isomers using synthetic methods.

[0443] This disclosure uses the following abbreviations:

[0444] NMP stands for N-methylpyrrolidone; DIPEA stands for diisopropylethylamine; DIEA stands for diisopropylethylamine; Xant-Phos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium; EA stands for ethyl acetate; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; t-BuXPhos stands for (methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II); DCM stands for dichloromethane; MeOH stands for methanol; Me stands for methyl; Et stands for ethyl; DMSO stands for dimethyl sulfoxide; HATU stands for 2-(7-azabenzotriazole)-N,N,N',N' -tetramethyluronium hexafluorophosphate; THF stands for tetrahydrofuran; DEAD stands for diethyl azodicarboxylate; Boc stands for tert-butyloxycarbonyl; EDCI stands for 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; DMAP stands for 4-dimethylaminopyridine; NBS stands for N-bromosuccinimide; PMB stands for p-methoxybenzyl; LiHMDS stands for lithium bis(trimethylsilyl)amide; DAST stands for diethylaminosulfur trifluoride; Boc2O stands for di-tert-butyl dicarbonate; BAST stands for bis(2-methoxyethyl)aminosulfur trifluoride; 9-BBN stands for lithium 9-borabicyclo[3.3.1]nonane hydride; TFA stands for trifluoroacetic acid; THP stands for tetrahydropyran; TEMPO stands for 2,2,6,6-tetramethylpiperidinium oxide; and DCE stands for 1,2-dichloroethane.

[0445] Commercially available compounds were referred to by their supplier catalog names.

[0446] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of the present disclosure. The present disclosure has been described in detail herein and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications will be made to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0447] All reagents used in this disclosure were commercially available and used without further purification. Example

[0448] Preparation Example A-6

[0449] Step A:

[0450] Compound A-1 (2.5 g) and 6-azaspiro[2.5]octane hydrochloride (2.1 g) were added to a 100 mL single-necked flask in sequence. After dissolving with DMSO (30 mL), potassium carbonate (5.2 g) was added and stirred in an oil bath at 140°C for 20 h. After the reaction was completed, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with n-hexane (100 mL). The aqueous phase was adjusted to pH 6 with 3N aqueous hydrochloric acid, filtered, and the filter cake was dried to obtain compound A-2 (2.9 g). MS (ESI-, [MH]) - )m / z:356.16. 1 H NMR (500MHz, DMSO-d6) δ17.07(s,1H),8.06(d,1H),7.75(dd,1H),7.69(d,1H),3.10(t,4H),1.55(s,4H),0.41(s,4H).

[0451] Step B:

[0452] Compound A-2 (1 g) and potassium carbonate (0.774 g) were added to a 100 mL single-necked flask in sequence. After dissolving with DMF (20 mL), iodomethane (0.795 g) was added and the mixture was stirred at room temperature for 15 h. After the reaction, 50 mL of water was added to the reaction solution, extracted with EA (100 mL), washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 10 / 1) to obtain compound A-3 (0.916 g). MS (ESI+, [M+H] + )m / z:371.99.

[0453] Step C:

[0454] Compound A-3 (0.916 g), 2-hydroxy-1-sulfonamide (0.556 g), allylpalladium(II) chloride dimer (0.044 g), t-BuXPhos (0.105 g), and potassium carbonate (0.682 g) were added to a 250 mL single-necked flask in sequence. The mixture was dissolved in dioxane (20 mL) and heated at 100°C under nitrogen for 4 h. After the reaction, 50 mL of water was added to the reaction solution, and the mixture was extracted with EA (100 mL), washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 1 / 1) to obtain compound A-4 (0.525 g). MS (ESI+, [M+H] + )m / z:369.14. 1H NMR(500MHz,DMSO-d6)δ10.00(s,1H),7.59(d,1H),6.91(d,1H),6.77(dd,1H),4.91(t,1H),3.76 (s,3H),3.75–3.71(m,2H),3.31–3.29(m,2H),2.99–2.94(m,4H),1.48–1.43(m,4H),0.32(s,4H).

[0455] Step D:

[0456] Compound A-4 (0.525 g), methanol (16 mL), lithium hydroxide monohydrate (0.269 g) and distilled water (4 mL) were added to a 50 mL single-necked flask in sequence and heated at 60°C for 36 h. After the reaction, the solvent was evaporated under reduced pressure, distilled water (20 mL) was added, and the mixture was stirred in an ice bath. 1N dilute hydrochloric acid (9 mL) was then added dropwise to adjust the pH of the system to about 2-3. Stirring was continued in an ice bath for 10 min and then allowed to stand. Filtered with suction, the filter cake was dried to obtain compound A-5 (0.413 g). MS (ESI+, [M+H] + )m / z:355.10. 1 H NMR(500MHz,DMSO-d6)δ16.89(s,1H),10.26(s,1H),7.96(d,1H),7.35(d,1H),7.17(dd,1H),5 .05–4.80(m,1H),3.79–3.72(m,2H),3.36(t,2H),3.01(t,4H),1.68–1.44(m,4H),0.43(s,4H).

[0457] Step E:

[0458] Compound A-5 (0.413 g), ammonium chloride (0.623 g), and HATU (0.886 g) were added sequentially to a 100 mL single-necked flask. Dissolved in DMF (15 mL), DIPEA (1.506 g) was added, and the mixture was stirred at room temperature for 1 h. After the reaction, 200 mL of water was added to the reaction solution, and the mixture was extracted with EA (300 mL). The mixture was washed with saturated sodium bicarbonate solution (100 mL × 2) and saturated brine (100 mL × 2), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain compound A-6 (0.224 g). MS (ESI+, [M+H] + )m / z:354.41. 1H NMR(500MHz,DMSO-d6)δ9.96(s,1H),8.59(d,1H),7.74(d,1H),7.45(d,1H),7.06(d,1H),6.93(d d,1H),4.91(t,1H),3.77–3.71(m,2H),3.31–3.28(m,2H),2.90(t,4H),1.51(t,4H),0.35(s,4H).

[0459] Preparation Example B-2

[0460] Step A:

[0461] Under nitrogen protection at -78°C, a solution of B-1 (2.6 g) in DCM (100 mL) was added to DAST (3.58 g). The reaction solution was stirred at -78°C under nitrogen protection for 2 hours, then returned to room temperature and stirred overnight. After the reaction was completed, the reaction solution was poured into ice water (100 mL), and the mixture was adjusted to pH 8-9 with saturated sodium bicarbonate aqueous solution, extracted with DCM (80 ml × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 20 / 1) to obtain compound B-2 (2.0 g). 1 H NMR(500MHz,Chloroform-d)δ5.16–4.83(m,1H),4.13(d,1H),3.75(s,3H),3.31-2.19(m,1H),2.80–2.62(m,1H), 2.21–1.96(m,2H),1.97–1.78(m,1H),1.51–1.43(m,9H).

[0462] Preparation Example C-5

[0463] Step A:

[0464] C-1 (10 g) and THF (100 mL) were added sequentially to a reaction flask under N2 protection. The mixture was stirred in an ice bath, and Boc2O (21 g) was added dropwise, followed by a 1M solution of vinylmagnesium bromide in tetrahydrofuran (101 mL). The ice bath was removed, and the reaction was stirred at room temperature for 20 h. After the reaction was completed, 1N dilute hydrochloric acid (160 mL) was added to the reaction flask under ice bath, and stirring was continued for 20 min. Extraction was performed with EA (200 mL), and the mixture was washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated brine (50 mL × 2), respectively, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: PE / EA = 10 / 1) to yield C-2 (7.1 g). 1H NMR (500MHz, DMSO-d6) δ7.82(dd,1H),5.77(ddd,1H),5.21–5.15(m,2H),5.02–4.97(m,2H),2.95(dd,1H),2.40–2.36(m,1H),1.48(s,9H).

[0465] Step B:

[0466] To a 250 mL single-necked flask, add C-2 (3 g), acetic acid (35 mL), and zinc powder (4.4 g) in sequence. Heat to 70°C under nitrogen for 4 h. After the reaction, filter with suction, dilute the filtrate with ethyl acetate (300 mL), add distilled water (600 mL), and add solid sodium bicarbonate while stirring to adjust the pH to approximately 7-8. Separate the liquids, take the organic phase, wash it with saturated sodium bicarbonate solution (100 mL x 2) and saturated brine (100 mL x 2), and dry it over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (eluent: PE / EA = 10 / 1) to obtain C-3 (2 g). 1 H NMR(500MHz,DMSO-d6)δ5.78(ddd,1H),5.20–5.16(m,1H),5.07–5.02(m,1H),4.98–4.85(m,1H),4.0 0–3.94(m,1H),3.33–3.27(m,1H),2.80(dd,1H),2.48–2.41(m,2H),2.25–2.19(m,1H),1.42(s,9H).

[0467] Step C:

[0468] In a 250 mL single-necked flask, C-3 (1.59 g) was dissolved in DCM (24 mL) and stirred under ice bath. BAST (2.21 mL) and ethanol (0.08 mL) were added. The temperature was then gradually returned to room temperature and stirred for 16 h. After the reaction was completed, EA (100 mL) was used for extraction, and the mixture was washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated brine (50 mL × 2), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EA = 20 / 1) to obtain C-4 (0.89 g). 1H NMR(500MHz,DMSO-d6)δ5.88–5.77(m,1H),5.16–5.10(m,1H),5.00–4.94(m,1H),4.91–4.83(m ,1H),4.04–3.97(m,1H),3.01–2.93(m,1H),2.20–2.09(m,2H),2.01–1.82(m,2H),1.40(s,9H).

[0469] Step D:

[0470] In a 250 mL two-necked flask, dissolve C-4 (0.86 g) in THF (35 mL) under nitrogen and stir under an ice bath. Add a 0.5 M solution of 9-BBN in tetrahydrofuran (20.8 mL), remove the ice bath, and stir at room temperature for 2.5 h. Add distilled water (40 mL) dropwise, followed by sodium perborate tetrahydrate (5.35 g), and stir at room temperature for 16 h. After the reaction is complete, filter and dilute the filtrate with EA (100 mL), wash with saturated sodium bicarbonate solution (50 mL x 2) and saturated brine (50 mL x 2), respectively, and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to dryness. The resulting crude product is purified by silica gel column chromatography (eluent: PE / EA = 10 / 1) to yield C-5 (0.9 g). 1 H NMR(500MHz,DMSO-d6)δ4.48–4.42(m,1H),4.39(t,1H),4.05–3.98(m,1H),3.41–3.34(m,2H ),2.98–2.88(m,1H),2.04–1.93(m,3H),1.88–1.70(m,2H),1.66–1.59(m,1H),1.40(s,9H).

[0471] Preparation Example D-4

[0472] Step A:

[0473] Referring to step A of Preparation Example A-6, 3-azaspiro[bicyclo[3.2.1]octane-8,1'-cyclopropane] hydrochloride was used instead of 6-azaspiro[2.5]octane hydrochloride to prepare compound D-1 (2.2 g). MS (ESI+, [M+H] + )m / z:384.15.

[0474] Step B:

[0475] Referring to step B of Preparation Example A-6, Compound D-1 was substituted for Compound A-2 to prepare Compound D-2 (1.5 g). MS (ESI+, [M+H] + )m / z:398.18.

[0476] Step C:

[0477] Referring to step C of Preparation Example A-6, methylsulfonamide was used instead of 2-hydroxy-1-sulfonamide to prepare compound D-3 (0.54 g). MS (ESI+, [M+H] + )m / z:365.27.

[0478] Step D:

[0479] Compound D-3 (450 mg), methanol (5 mL), and aqueous ammonia (5 mL) were added sequentially to a 30 mL microwave tube and heated at 90°C for 5 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and then 30 mL of water was added. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent DCM / MeOH = 30 / 1) to obtain compound D-4 (147 mg). MS (ESI+, [M+H] + )m / z:350.25. 1 H NMR(500MHz,DMSO-d6)δ9.87(s,1H),8.31(s,1H),7.53(d,1H),7.49(s,1H),7.05(d,1H),6.91(dd,1H),3. 02(s,3H),3.01–2.86(m,4H),1.93–1.74(m,4H),1.48–1.38(m,2H),0.66–0.56(m,2H),0.44–0.32(m,2H).

[0480] Preparation Example E-4

[0481] Step A:

[0482] Referring to step A of Preparation Example A-6, (1R, 5S)-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane] hydrochloride was used instead of 6-azaspiro[2.5]octane hydrochloride to prepare compound E-1 (7.2 g). MS (ESI+, [M+H] + )m / z:384.15.

[0483] Step B:

[0484] Referring to step B of Preparation Example A-6, Compound E-1 was substituted for Compound A-2 to prepare Compound E-2 (5.5 g). MS (ESI+, [M+H] + )m / z:398.18.

[0485] Step C:

[0486] Referring to step C of Preparation Example A-6, methylsulfonamide was used instead of 2-hydroxy-1-sulfonamide to prepare compound E-3 (0.97 g). MS (ESI+, [M+H] + )m / z:365.27.

[0487] Step D:

[0488] Referring to step D of Preparation Example D-4, E-3 was substituted for D-3 to prepare compound E-4 (0.28 g). MS (ESI+, [M+H] + )m / z:350.25. 1 H NMR(500MHz,DMSO-d6)δ13.79(s,1H),9.78(s,1H),7.59–7.32(m,2H),6.84(d,1H),6.81–6.66(m,1H),3.88(t,2H ),3.01(s,3H),2.29–2.15(m,2H),1.94(d,2H),1.92–1.75(m,2H),0.89(dd,2H),0.56(dd,2H),0.13–0.07(m,2H).

[0489] Example 1

[0490] Step A:

[0491] Compound 1-1 (1.2 g), DMSO (10 mL), 2-piperidinemethanol (0.713 g), and DIPEA (3.24 mL) were added sequentially to a 50 mL single-necked flask and heated to 120°C for 2 h under nitrogen. After the reaction, distilled water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 ml × 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 4 / 1) to obtain compound 1-2 (600 mg). MS (ESI+, [M+H] + )m / z:288.88. 1 H NMR(500MHz,DMSO-d6)δ7.79(d,1H),7.02(dd,1H),4.60(t,1H),4.19–4.10(m,1H),3.78(d,1H) ,3.63-3.57(m,2H),3.10-3.05(m,1H),1.81-1.77(m,1H),1.67–1.54(m,4H),1.51-1.45(m,1H).

[0492] Step B:

[0493] Compound 1-2 (600 mg), tert-butanol (10 mL), and potassium tert-butoxide (815 mg) were added sequentially to a 100 mL single-necked flask. Under N2 protection, the mixture was heated to 80°C for 2 h. After the reaction, the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and distilled water (20 mL) and ethyl acetate (20 mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 9 / 1) to obtain compound 1-3 (400 mg). MS (ESI+, [M+H] + )m / z:268.87. 1 H NMR(500MHz,DMSO-d6)δ7.54(d,1H),6.82(d,1H),4.56–4.51(m,1H),4.33(dd,1H),3.95(dd,1H),3. 30–3.23(m,1H),2.60-2.54(m,1H),1.81(d,1H),1.71(t,2H),1.49–1.35(m,2H),1.22–1.11(m,1H).

[0494] Step C:

[0495] To a 50 mL single-necked flask, compound A-6 (0.050 g), Pd2(dba)3 (5.18 mg), Xant-Phos (8.21 mg), compound 1-3 (0.038 g) dissolved in dioxane (6 mL), and cesium carbonate (0.138 g) were added sequentially. Under N2 protection, the mixture was heated to 100°C and reacted for 12 h. After completion of the reaction, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain compound 1 (20 mg). 1 H NMR(500MHz,DMSO-d6)δ11.82(s,1H),10.17(s,1H),7.97(d,1H),7.86(d,1H),7.67(d,1H) ,7.22(d,1H),7.07(dd,1H),4.92(s,1H),4.57(d,1H),4.34(dd,1H),4.01(dd,1H),3.75(t, 2H),3.35(t,2H),3.30–3.25(m,1H),2.98–2.89(m,4H),2.60–2.54(m,1H),1.83(d,1H),1.7 1(t,2H),1.57(s,4H),1.49–1.38(m,2H),1.27-1.24(m,1H),0.37(s,4H).HRMS(ESI+,[M+H] + )m / z:542.2445.

[0496] Example 2

[0497] Step A:

[0498] Compound 2-1 (1.37 g), N-tert-butyloxycarbonyl-2-piperidin-2-ylethanol (1.50 g), THF (50 mL), and triphenylphosphine (2.06 g) were added sequentially to a 250 mL three-necked flask. A solution of DEAD (1.37 g) in THF (5 mL) was slowly added dropwise under N2 protection while cooling on ice. After addition, the mixture was stirred at room temperature for 15 h. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 20 / 1) to give compound 2-2 (2.72 g). MS (ESI+, [M+H] + )m / z:385.94. 1 H NMR(500MHz,DMSO-d6)δ8.44(d,1H),7.99(d,1H),4.31(s,1H),4.17(d,1H),4.12–4.01(m,1H),3.83(d ,1H),2.80(d,1H),2.13-2.09(m,1H),1.93-1.90(m,1H),1.62–1.50(m,5H),1.36(s,9H),1.29–1.24(m, 1H).

[0499] Step B:

[0500] Compound 2-2 (2.20 g), ethyl acetate (20 mL) and HCl in ethyl acetate solution (4 M, 12 mL) were added to a 100 mL single-necked bottle in sequence, and the mixture was stirred at room temperature for 1.5 h. The reaction solution was concentrated to obtain compound 2-3 (1.7 g). MS (ESI+, [M+H] + )m / z:285.94.

[0501] Step C:

[0502] Compound 2-3 (1.7 g), NMP (50 mL) and DIEA (1.8 g) were added to a 100 mL single-necked bottle in sequence and heated to 50°C for 12 h. After the reaction, 100 mL of distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA=10 / 1) to obtain compound 2-4 (330 mg). MS (ESI+, [M+H] + )m / z:250.02. 1H NMR(500MHz,DMSO-d6)δ8.02(d,1H),7.13(d,1H),4.33-4.30(m,1H),4.26-4.21(m,1H),3.92-3.89(m,1H),3.4 3-3.40(m,1H),3.06-3.01(m,1H),2.16-2.12(m,1H),1.96-1.91(m,1H),1.88–1.79(m,1H),1.65–1.51(m,5H).

[0503] Step D:

[0504] Compound 2-4 (320 mg), methanol (20 mL), ammonium chloride (687 mg), distilled water (5 mL) and iron powder (720 mg) were added to a 100 mL single-necked bottle in sequence and heated to 70°C for 3 h. After the reaction was completed, the mixture was filtered and the filter cake was washed with 100 mL of ethyl acetate. The organic phase was concentrated to obtain compound 2-5 (270 mg). MS (ESI+, [M+H] + )m / z:220.04. 1 H NMR(500MHz,DMSO-d6)δ7.42(d,1H),6.14(d,1H),5.36(s,2H),4.10(dd,2H),3.62-3.59(m,1H) ,3.23-3.20(m,1H),3.00-2.97(m,1H),1.97–1.89(m,1H),1.86–1.72(m,2H),1.58–1.44(m,5H).

[0505] Step E:

[0506] Compound 2-5 (220 mg), compound A-2 (135 mg), 1,2-dichloroethane (15 mL), EDCI (240 mg) and DMAP (150 mg) were added to a 50 mL single-necked bottle in sequence and heated to 70°C for 5 h. After the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (PE:EA=10:1) to obtain compound 2-6 (150 mg). MS (ESI+, [M+H] + )m / z:559.18. 1H NMR(500MHz,DMSO-d6)δ11.41(s,1H),7.96(d,1H),7.81(d,1H),7.68–7.64(m,2H),7.64–7.61(m,1H),4.42–4.28(m,2H),3.51-3.48(m,1H), 3.35-3.31(m,1H),3.27-3.23(m,1H),2.99(t,4H),2.03-2.00(m,1H), 1.98–1.90(m,1H),1.79–1.71(m,1H),1.69–1.48(m,9H),0.34(s,4H).

[0507] Step F:

[0508] To a 50 mL single-necked flask, compound 2-6 (120 mg), 2-hydroxy-1-sulfonamide (50 mg), dioxane (10 mL), potassium carbonate (55.2 mg), allylpalladium(II) chloride dimer (4.93 mg), and t-BuXPhos (8.48 mg) were added sequentially. Under N2 protection, the mixture was heated to 100°C for 4 h. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 2 (40 mg). 1 H NMR(500MHz,DMSO-d6)δ11.51(s,1H),7.99(d,1H),7.90(d,1H),7.80(d,1H),7.18(d,1H),7.03(dd,1H),4.42–4.28(m,2H),3.76(t,2H),3.49-3 .44(m,1H),3.34(t,3H),3.30–3.26(m,3H),2.95(t,4H),2.10–1.90(m,2 H),1.78–1.72(m,1H),1.70–1.45(m,9H),0.35(s,4H).HRMS(ESI+,[M+H] + )m / z:556.2595.

[0509] Example 3

[0510] Step A:

[0511] Compound 3-1 (1 g), acetonitrile (20 mL), and NBS (3.34 g) were added sequentially to a 100 mL single-necked flask and stirred at room temperature under nitrogen for 18 hours. After completion of the reaction, 50 mL of distilled water was added to the reaction solution, followed by extraction with EA (100 mL), washing with saturated brine (50 mL x 2), and drying over anhydrous sodium sulfate. The product was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 20 / 1) to afford compound 3-2 (0.8 g). 1 H NMR (500MHz, DMSO-d6) δ10.00(s,1H),7.45(s,1H),2.24(s,3H).

[0512] Step B:

[0513] Compound 3-2 (0.2 g), N-tert-butyloxycarbonyl-2-piperidin-2-ylethanol (0.189 g), triphenylphosphine (0.236 g), and THF (10 mL) were added sequentially to a 100 mL two-necked flask and stirred in an ice bath under nitrogen. DEAD (0.157 g) dissolved in THF (2 mL) was then added dropwise, and the mixture was gradually returned to room temperature and stirred for 16 h. After the reaction, 50 mL of distilled water was added to the reaction solution, which was then extracted with EA (100 mL). The solution was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 10 / 1) to obtain compound 3-3 (0.279 g). 1 H NMR(500MHz,DMSO-d6)δ7.61(s,1H),4.42–4.32(m,1H),3.98–3.90(m,1H),3.86–3.78(m,2H),2.89–2.72(m,1H),2.2 9(s,3H),2.17–2.10(m,1H),2.00–1.93(m,1H),1.67–1.61(m,1H),1.61–1.51(m,4H),1.37(s,9H),1.29–1.23(m,1H).

[0514] Step C:

[0515] Compound 3-3 (0.262 g), ethyl acetate (6 mL), and 4 M hydrogen chloride in dioxane solution (0.7 mL) were added to a 100 mL single-necked flask in sequence and stirred at room temperature for 18 hours. After the reaction, the mixture was filtered and the filter cake was dried to obtain compound 3-4 (0.178 g). 1H NMR(500MHz,DMSO-d6)δ9.12(s,1H),8.99(s,1H),7.64(s,1H),4.05(t,2H),3.31–3.26(m,1H),3.26–3.21(m,1H),2.94– 2.82(m,1H),2.33(s,3H),2.29–2.21(m,1H),2.05–1.94(m,2H),1.81–1.70(m,2H),1.68–1.58(m,1H),1.55–1.42(m,2H).

[0516] Step D:

[0517] Compound 3-4 (0.14 g), NMP (2 mL), and DIPEA (0.175 g) were added sequentially to a 10 mL microwave tube, placed in a microwave reactor, and heated to 150°C at 100 W for 40 minutes. After the reaction, 50 mL of distilled water was added to the reaction solution, which was then extracted with EA (100 mL). The solution was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 20 / 1) to obtain compound 3-5 (0.098 g). MS (ESI+, [M+H] + )m / z:296.90. 1 H NMR (500 MHz, DMSO-d6) δ 6.81 (s, 1H), 4.16 (dd, 2H), 3.70–3.60 (m, 1H), 3.38–3.33 (m, 1H), 3.11–3.01 (m, 1H), 2.08 (s, 3H), 2.04–1.97 (m, 1H), 1.91–1.83 (m, 1H), 1.81–1.72 (m, 1H), 1.62–1.44 (m, 5H). Step E:

[0518] To a 50 mL single-necked flask, compound A-6 (0.062 g), compound 3-5 (0.089 g), Pd2(dba)3 (0.007 g), Xant-Phos (0.010 g), and cesium carbonate (0.194 g) were added in sequence, dissolved in dioxane (6 mL), and heated at 100°C under nitrogen for 12 h. After the reaction, 50 mL of distilled water was added to the reaction solution, and the mixture was extracted with EA (100 mL), washed with saturated brine (50 mL x 2), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 1 / 1) to obtain compound 3 (0.042 g). 1H NMR(500MHz,DMSO-d6)δ12.76(s,1H),10.16(s,1H),8.05(d,1H),7.58(s,1H) ,7.25(d,1H),7.11(dd,1H),4.93(t,1H),4.20–4.11(m,2H),3.85–3.79(m,1H ),3.78–3.74(m,2H),3.36–3.32(m,3H),3.12–3.06(m,1H),2.95(t,4H),2.14 (s,3H),2.04–1.99(m,1H),1.93–1.43(m,11H),0.36(s,4H).HRMS(ESI+,[M+H] + )m / z:570.2756.

[0519] Step F:

[0520] Compound 3 (134 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 64:30:6; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 3_A (63 mg, retention time 13.363 minutes) and compound 3_B (67 mg, retention time 15.056 minutes).

[0521] Compound 3_A: 1 H NMR(500MHz,DMSO-d6)δ12.76(s,1H),10.16(s,1H),8.05(d,1H),7.58(s,1H) ,7.25(d,1H),7.11(dd,1H),4.93(t,1H),4.21–4.11(m,2H),3.85–3.79(m,1H ),3.79–3.72(m,2H),3.37–3.33(m,3H),3.12–3.06(m,1H),2.95(t,4H),2.13 (s,3H),2.04–1.98(m,1H),1.94–1.40(m,11H),0.36(s,4H).HRMS(ESI+,[M+H] + )m / z:570.2757.

[0522] Compound 3_B: 1H NMR(500MHz,DMSO-d6)δ12.76(s,1H),10.16(s,1H),8.05(d,1H),7.58(s,1H),7.25(d,1H),7 .11(dd,1H),5.03–4.86(m,1H),4.21–4.11(m,2H),3.85–3.79(m,1H),3.79–3.73(m,2H),3.37 –3.33(m,3H),3.12–3.06(m,1H),2.95(t,4H),2.13(s,3H),2.04–1.98(m,1H),1.93–1.43(m,11H),0.36(s,4H).HRMS(ESI+,[M+H] + )m / z:570.2762.

[0523] Example 4

[0524] Step A:

[0525] Compound 4-1 (1 g) was added to a 50 mL two-necked flask and dissolved in DCM (15 mL). After cooling in an ice bath, urea peroxide (1.1 g) was added in batches. Stirring in an ice bath was continued for 15 min, and trifluoroacetic anhydride (2.01 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 15 h. After the reaction was complete, 30 mL of water was added, and the pH of the aqueous phase was adjusted to approximately 9 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed sequentially with 10% sodium sulfite solution (30 mL) and saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 1 / 1) to obtain compound 4-2 (0.77 g). 1 H NMR(500MHz,DMSO-d6)δ9.11(s,1H),8.07(s,1H),2.50(s,3H).

[0526] Step B:

[0527] Compound 4-2 (0.76 g), bis-(4-methoxybenzyl)-amine (1.5 g), potassium carbonate (1.11 g), and acetonitrile (25 mL) were added sequentially to a 50 mL single-necked bottle and heated under reflux at 80°C with stirring for 16 h. After the reaction was complete, the mixture was filtered through celite and the filter cake was washed with EA (30 mL). The filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA = 3 / 1) to give compound 4-3 (1.34 g). MS (ESI+, [M+H] + )m / z:410.17. 1H NMR (500MHz, DMSO-d6) δ8.84(s,1H),7.25–7.21(m,4H),7.03(s,1H),6.89–6.85(m,4H),4.67(s,4H),3.71(s,6H),2.42(s,3H).

[0528] Step C:

[0529] Compound 4-3 (1.3 g), toluene (12 mL), and DIPEA (13 mL) were added to a 100 mL single-necked flask. After cooling in an ice bath, phosphorus oxychloride (5.5 mL) was added and the mixture was heated at 70°C with stirring for 20 min. After the reaction was completed, most of the solvent was removed by rotary evaporation under reduced pressure, and distilled water (30 mL) was added. The pH of the aqueous phase was adjusted to approximately 9-10 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 5 / 1) to obtain compound 4-4 (0.64 g). 1 H NMR (500MHz, DMSO-d6) δ7.21–7.16(m,4H),6.92–6.88(m,4H),6.71(s,1H),4.70(s,4H),3.73(s,6H),2.22(s,3H).

[0530] Step D:

[0531] Compound 4-4 (0.57 g), methyl 2-piperidinate (0.76 g), NMP (8 mL), and DIPEA (0.34 g) were added sequentially to a 30 mL microwave tube and heated at 140°C for 2 h. After the reaction was complete, 50 mL of water was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 6.5 / 1) to obtain compound 4-5 (0.26 g). MS (ESI+, [M+H] + )m / z:535.29. 1 H NMR(500MHz,DMSO-d6)δ7.12–7.08(m,4H),6.90–6.86(m,4H),6.13(s,1H),4 .73–4.48(m,5H),3.75–3.70(m,7H),3.44(s,3H),3.39–3.33(m,1H),2.20(s, 3H),1.78–1.70(m,1H),1.67–1.54(m,2H),1.54–1.42(m,1H),1.35–1.22(m,2H).

[0532] Step E:

[0533] Compound 4-5 (2.78 g) was added to a 100 mL single-necked flask, dissolved in ethanol (20 mL), and heated at 80°C with stirring. Stannous chloride dihydrate (3 g) was added, and heating and stirring at 80°C were continued for 5 h. After the reaction was completed, 80 mL of water was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 5 / 1) to obtain compound 4-6 (0.76 g). MS (ESI+, [M+H] + )m / z:472.89.

[0534] Step F:

[0535] Compound 4-6 (0.75 g) was added to a 100 mL single-necked flask, dissolved in DMF (5 mL), and then cooled in an ice bath. 60% sodium hydride (0.13 g) was added, stirred at room temperature for 5 min, and then iodomethane (0.15 mL) was added and stirred at room temperature for 2 h. After the reaction was completed, 50 mL of water was added and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 5 / 1) to obtain compound 4-7 (0.59 g). MS (ESI+, [M+H] + )m / z:487.25.

[0536] Step G:

[0537] Compound 4-7 (0.59 g), DCM (6 mL), anisole (0.43 mL) and trifluoroacetic acid (6 mL) were added to a 100 mL single-necked bottle in sequence and heated at 60°C with stirring for 16 h. After the reaction was completed, most of the solvent was removed by rotary evaporation under reduced pressure, 50 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 1 / 1) to obtain compound 4-8 (0.22 g). MS (ESI+, [M+H] + )m / z:247.05. 1H NMR(500MHz,DMSO-d6)δ5.74(s,1H),5.43(s,2H),4.20–4.11(m,1H),3.42–3.36(m,1H),3.16(s,3H),2.5 5–2.51(m,1H),2.18(s,3H),1.95–1.87(m,1H),1.81–1.74(m,1H),1.65–1.58(m,1H),1.46–1.32(m,3H).

[0538] Step H:

[0539] In a 50 mL single-necked bottle, compound 4-8 (217 mg), HATU (670 mg), DCM (10 mL), and DIPEA (0.31 mL) were added in sequence. After stirring evenly, compound A-2 (346 mg) was added and stirred at room temperature for 12 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent PE / EA = 10 / 1) to obtain compound 4-9 (467 mg). MS (ESI+, [M+H] + )m / z:586.22.

[0540] Step I:

[0541] Compound 4-9 (460 mg), 2-hydroxy-1-sulfonamide (151 mg), dioxane (10 mL), potassium carbonate (277 mg), allylpalladium (II) chloride dimer (14.44 mg), and t-BuXPhos (34.1 mg) were added sequentially to a 50 mL single-necked bottle. Under N2 protection, the mixture was heated to 100°C and reacted for 2 h. After completion of the reaction, the mixture was filtered with celite, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH = 40 / 1) to obtain compound 4 (250 mg). MS (ESI+, [M+H] + )m / z:583.27.

[0542] Step J:

[0543] Compound 4 (250 mg) was separated by preparative HPLC (separation conditions: column: whelk-O1, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 40:40:20; flow rate: 2 mL / min; wavelength: 254 nm) to give compound 4_A (110 mg, retention time 7.199 minutes) and compound 4_B (100 mg, retention time 10.291 minutes).

[0544] Compound 4_A: 1H NMR(500MHz,DMSO-d6)δ13.14(s,1H),10.19(s,1H),8.08(d,1H),7.60(s ,1H),7.27(d,1H),7.13(dd,1H),4.93(t,1H),4.36–4.26(m,1H),3.76(t, 2H),3.62(dd,1H),3.35(t,2H),3.26(s,3H),3.01–2.92(m,4H),2.75–2.6 7(m,1H),2.38(s,3H),1.98–1.65(m,5H),1.55–1.22(m,5H),0.37(s,4H). HRMS(ESI+,[M+H] + )m / z:583.2708.

[0545] Compound 4_B: 1 H NMR(500MHz,DMSO-d6)δ13.14(s,1H),10.18(s,1H),8.08(d,1H),7.60(s,1H),7.27(d,1H),7.13(dd,1H),4.93(s,1H),4.37–4.27(m,1H),3.76( t,2H),3.62(dd,1H),3.35(t,2H),3.26(s,3H),2.97(s,4H),2.76–2.67 (m,1H),2.38(s,3H),2.00–1.65(m,6H),1.63–1.35(m,4H),0.37(s,4H). HRMS(ESI+,[M+H] + )m / z:583.2712.

[0546] Example 5

[0547] Step A:

[0548] Compound 5-1 (2 g), p-toluenesulfonic acid hydrate (0.44 g), 2,5-hexanedione (1.62 mL), and toluene (25 mL) were added sequentially to a 100 mL single-necked flask and heated with stirring at 120°C under N2 protection for 16 h. After the reaction was complete, heating was stopped and most of the solvent was removed by rotary evaporation under reduced pressure. 40 mL of water was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 50 / 1) to obtain compound 5-2 (1.4 g). MS (ESI+, [M+H] + )m / z:251.96. 1H NMR (500MHz, DMSO-d6) δ8.89(d,1H),7.85(d,1H),5.87(s,2H),1.93(s,6H).

[0549] Step B:

[0550] Compound 5-2 (1 g) and methyl 2-piperidinate (3 g) were added to a 25 mL single-necked flask and heated at 90°C with stirring for 2.5 h. After the reaction was complete, heating was stopped and 40 mL of distilled water was added. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed sequentially with 1N dilute hydrochloric acid solution (30 mL) and saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 10 / 1) to obtain compound 5-3 (1.17 g). MS (ESI+, [M+H] + )m / z:359.12. 1 H NMR(500MHz,DMSO-d6)δ8.48(d,1H),6.95(d,1H),5.82–5.77(m,2H),4.97–4.91(m,1H),3.66(s,3H),3.39–3.33(m,1H), 3.17–3.10(m,1H),2.10–2.03(m,1H),1.95(s,3H),1.86(s,3H),1.86–1.81(m,1H),1.70–1.58(m,2H),1.53–1.33(m,2H).

[0551] Step C:

[0552] Compound 5-3 (1.7 g), ethanol (20 mL), saturated aqueous ammonium chloride solution (10 mL), and iron powder (1.32 g) were added to a 100 mL single-necked flask in sequence and heated at 80°C for 8 h under N2 protection. After the reaction was complete, heating was stopped, the filtrate was filtered through diatomaceous earth, and suction was applied. 40 mL of distilled water was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 5 / 1) to obtain compound 5-4 (1 g). MS (ESI+, [M+H] + )m / z:297.24. 1H NMR(500MHz,DMSO-d6)δ9.26(s,1H),7.87(d,1H),6.47(d,1H),5.86(s,2H),4.59–4.52(m,1H),4.06–3.98(m,1H),2.8 0–2.71(m,1H),2.05–1.99(m,1H),1.92(s,3H),1.91(s,3H),1.89–1.84(m,1H),1.69–1.63(m,1H),1.59–1.38(m,3H).

[0553] Step D:

[0554] Compound 5-4 (1 g) was added to a 100 mL single-necked flask, dissolved in DMF (5 mL), and then cooled in an ice bath. 60% sodium hydride (0.2 g) was added, and the mixture was stirred at room temperature for 5 min. After that, iodomethane (0.25 mL) was added and stirred at room temperature for 2 h. After the reaction was completed, 50 mL of water was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 5 / 1) to obtain compound 5-5 (0.95 g). MS (ESI+, [M+H] + )m / z:311.04.

[0555] Step E:

[0556] Compound 5-5 (0.95 g), ethanol (20 mL), hydroxylamine hydrochloride (4.48 g), water (10 mL), and triethylamine (1.34 mL) were added sequentially to a 100 mL microwave vial and heated with stirring at 140°C for 6 h. After the reaction was complete, 50 mL of water was added and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 1 / 1) to give compound 5-6 (0.34 g). MS (ESI+, [M+H] + )m / z:233.03. 1 H NMR(500MHz,DMSO-d6)δ7.51(d,1H),6.24(t,1H),5.59(s,2H),4.23–4.15(m,1H),3.47–3.38(m,1H),3.1 9(s,3H),2.60–2.52(m,1H),1.96–1.87(m,1H),1.80–1.70(m,1H),1.67–1.58(m,1H),1.49–1.33(m,3H).

[0557] Step F:

[0558] To a 50 mL two-necked flask, compound A-2 (0.68 g), THF (10 mL), N-methylmorpholine (0.31 mL), and isobutyl chloroformate (0.31 mL) were added sequentially. After stirring at room temperature for 0.5 h, compound 5-6 (0.22 g) was added. Under N2 protection, a THF solution of LiHMDS (1 M, 2.4 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 12 h. After the reaction was complete, 10 mL of saturated ammonium chloride solution was added, followed by 30 mL of water. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE / EA = 10 / 1) to obtain compound 5-7 (0.33 g). MS (ESI+, [M+H] + )m / z:572.19. 1 H NMR(500MHz,DMSO-d6)δ11.90(s,1H),7.92(d,1H),7.74(s,1H),7.73–7.66(m,2H),7.44(d,1H),4.40–4.30(m,1H),3.80–3.72( m,1H),3.10(s,3H),3.04–2.95(m,4H),2.81–2.73(m,1H),1.91–1.80(m,2H),1.64–1.46(m,4H),1.38–1.32(m,4H),0.28(s,4H).

[0559] Step G:

[0560] Referring to step 1 of Example 4, compound 5-7 was substituted for compound 4-9 to synthesize compound 5 (200 mg). MS (ESI+, [M+H] + )m / z:569.34.

[0561] Step H:

[0562] Compound 5 (200 mg) was separated by preparative HPLC (separation conditions: column: REFLECT I-Cellulose C, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 70:15:15; flow rate: 1 mL / min; wavelength: 250 nm) to give compound 5_A (70 mg, retention time: 13.266 minutes) and compound 5_B (70 mg, retention time: 16.903 minutes).

[0563] Compound 5_A: 1H NMR(500MHz,DMSO-d6)δ12.08(s,1H),10.21(s,1H),8.00(d,1H),7.91(d,1H ),7.53(d,1H),7.25(d,1H),7.11(dd,1H),4.95(s,1H),4.41–4.32(m,1H),3 .82–3.67(m,3H),3.37(t,2H),3.11(s,3H),3.00–2.89(m,4H),2.82–2.73(m ,1H),1.91–1.76(m,2H),1.63–1.44(m,4H),1.42–1.32(m,4H),0.29(s,4H). HRMS (ESI+, [M+H] + )m / z:569.2550.

[0564] Compound 5_B: 1 H NMR(500MHz,DMSO-d6)δ12.08(s,1H),10.22(s,1H),8.00(d,1H),7.91(d,1H ),7.53(d,1H),7.25(d,1H),7.11(dd,1H),4.95(s,1H),4.42–4.30(m,1H),3 .85–3.71(m,3H),3.37(t,2H),3.10(s,3H),3.01–2.89(m,4H),2.82–2.73(m ,1H),1.91–1.77(m,2H),1.62–1.43(m,4H),1.40–1.32(m,4H),0.28(s,4H). HRMS (ESI+, [M+H] + )m / z:569.2550.

[0565] Example 6

[0566] Step A:

[0567] Compound 6-1 (3 g) and concentrated sulfuric acid (8.6 mL) were added to a 100 mL single-necked flask in sequence and stirred in an ice bath. Nitric acid (1.4 mL) was added dropwise. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was poured into 500 mL of ice water, and ethyl acetate (250) mL and water (250) mL were added. The organic phase was separated, washed with saturated brine (250 mL × 2), and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 10 / 1) to obtain compound 6-2 (0.843 g). MS (ESI-, [MH] - )m / z:232.98. 1H NMR(500MHz,DMSO-d6)δ11.15(br s,1H),7.74(s,1H),2.44(s,3H).

[0568] Step B:

[0569] Referring to step B of Example 3, compound 6-3 was synthesized by replacing compound 3-2 with compound 6-2. 1 H NMR(500MHz,DMSO-d6)δ7.87(s,1H),4.34–4.26(m,1H),4.18–4.08(m,1H),4.01–3.95(m,1H),3.88–3.78(m,1H),2.9 0–2.69(m,1H),2.51(s,3H),2.16–2.07(m,1H),1.98–1.90(m,1H),1.63–1.50(m,5H),1.36(s,9H),1.29–1.23(m,1H).

[0570] Step C:

[0571] Compound 6-3 (0.98 g), DCM (50 mL), and trifluoroacetic acid (1.69 mL) were added sequentially to a 250 mL single-necked flask and stirred at room temperature for 5 h. After the reaction, 50 mL of water was added, and the mixture was extracted with DCM (100 mL). The mixture was washed with saturated sodium carbonate solution (50 mL × 2) and saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give compound 6-4 (0.716 g). MS (ESI+, [M+H] + )m / z:344.02.

[0572] Step D:

[0573] Referring to step D of Example 3, compound 6-4 was substituted for compound 3-4 to synthesize compound 6-5. MS (ESI+, [M+H] + )m / z:264.07. 1 H NMR(500MHz,DMSO-d6)δ6.96(s,1H),4.30–4.23(m,1H),4.23–4.15(m,1H),4.00–3.92(m,1H),3.45–3.38(m,1H),3.09–3 .00(m,1H),2.33(s,3H),2.17–2.07(m,1H),2.00–1.90(m,1H),1.87–1.78(m,1H),1.66–1.58(m,2H),1.58–1.48(m,3H).

[0574] Step E:

[0575] Compound 6-5 (0.42 g), methanol (16 mL), distilled water (4 mL), iron powder (0.738 g), and ammonium chloride (0.707 g) were added sequentially to a 100 mL single-necked flask and heated to 70°C for 3 h. After the reaction, ethyl acetate (100) mL was added and filtered. The filtrate was washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated brine (50 mL × 2) in sequence and dried over anhydrous sodium sulfate. The product was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain compound 6-6 (0.337 g). MS (ESI+, [M+H] + )m / z:234.08. 1 H NMR (500 MHz, DMSO-d6) δ 5.98 (s, 1H), 5.25 (s, 2H), 4.09–4.00 (m, 2H), 3.69–3.60 (m, 1H), 3.30–3.21 (m, 1H), 3.04–2.95 (m, 1H), 2.07 (s, 3H), 1.93–1.80 (m, 2H), 1.79–1.70 (m, 1H), 1.59–1.42 (m, 5H). Step F:

[0576] Referring to step E of Example 2, compound 6-6 was substituted for compound 2-6 to synthesize compound 6-7. MS (ESI+, [M+H] + )m / z:573.2.

[0577] Step G:

[0578] Referring to step F of Example 2, compound 6 was synthesized by replacing compound 2-7 with compound 6-7. MS (ESI+, [M+H] + )m / z:570.33.

[0579] Step H:

[0580] Compound 6 was separated by high-pressure preparative separation (Cellulose-SC column, n-hexane:ethanol:dichloromethane = 8:1:1) to give compound 6_A (retention time 4.053 minutes) and compound 6_B (retention time 4.602 minutes).

[0581] Compound 6_A: 1H NMR(500MHz,DMSO-d6)δ11.43(s,1H),10.15(s,1H),8.00–7.79(m,2H),7.1 8(d,1H),7.04(dd,1H),4.93(t,1H),4.35-4.31(m,1H),4.24-4.21(m,1H),3 .76(q,2H),3.49-3.44(m,1H),3.35(t,4H),2.95(t,4H),2.28(s,3H),1.99- 1.95(m,2H),1.74(s,1H),1.68–1.44(m,9H),0.35(s,4H).HRMS(ESI+,[M+H] + )m / z:570.2754.

[0582] Compound 6_B: 1 H NMR(500MHz,DMSO-d6)δ11.42(s,1H),10.14(s,1H),8.08–7.77(m,2H),7.18(s,1H),7.04(d,1H),4.93(t,1H),4.34(dd,1H),4.24(s,1H),3.75(q ,2H),3.52–3.46(m,1H),3.38(s,4H),2.95(t,4H),2.28(s,3H),2.01–1. 94(m,2H),1.74(s,1H),1.68–1.44(m,9H),0.35(s,4H).HRMS(ESI+,[M+H] + )m / z:570.2759.

[0583] Example 7

[0584] Step A:

[0585] Compound 7-1 (0.3 g), N-tert-butyloxycarbonyl-2-piperidin-2-ylethanol (0.430 g), triphenylphosphine (0.533 g), and THF (15 mL) were added sequentially to a 100 mL two-necked flask and stirred in an ice bath under nitrogen. A solution of DEAD (0.408 g) in THF (5 mL) was added dropwise, and the mixture was gradually returned to room temperature and stirred for 16 h. After the reaction, 50 mL of distilled water was added to the reaction solution, and the mixture was extracted with EA (100 mL). The mixture was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EA = 10 / 1) to obtain compound 7-2 (0.587 g). 1H NMR(500MHz,DMSO-d6)δ7.65–7.56(m,1H),7.53(d,1H),4.40–4.34(m,1H),4.09–4.05(m,1H),4.03–3.98(m,1H),3 .90–3.80(m,1H),2.86–2.69(m,1H),2.20–2.13(m,1H),1.91–1.82(m,1H),1.60–1.50(m,5H),1.29–1.23(m,10H).

[0586] Step B:

[0587] Compound 7-2 (0.435 g), ethyl acetate (30 mL), and 4 M hydrogen chloride dioxane solution (4.85 mL) were added to a 250 mL single-necked flask in sequence and stirred at room temperature for 16 hours. After the reaction was completed, the mixture was filtered and the filter cake was dried to obtain compound 7-3 (0.306 g). MS (ESI+, [M+H] + )m / z:303.28. 1 H NMR(500MHz,DMSO-d6)δ9.15(s,1H),9.03(s,1H),7.69(dd,1H),7.58(d,1H),4.33–4.22(m,2H),3.25–3.13(m,2H),2.91–2. 80(m,1H),2.23–2.14(m,1H),2.04–1.97(m,1H),1.96–1.88(m,1H),1.78–1.68(m,2H),1.68–1.58(m,1H),1.53–1.40(m,2H).

[0588] Step C:

[0589] Compound 7-3 (0.335 g), NMP (10 mL), and DIPEA (0.319 g) were added sequentially to a 35 mL microwave tube and placed in a microwave reactor. The mixture was heated to 120°C at 100 W for 30 minutes. After the reaction, 50 mL of distilled water was added, followed by extraction with EA (100 mL). The mixture was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EA = 20 / 1) to obtain compound 7-4 (0.25 g). MS (ESI+, [M+H] + )m / z:283.28. 1H NMR(500MHz,DMSO-d6)δ7.03(d,1H),6.86(d,1H),4.20–4.14(m,2H),3.69–3.63(m,1H),3.41–3.36(m,1H),3.1 2–3.05(m,1H),2.09–2.02(m,1H),1.93–1.86(m,1H),1.80–1.73(m,1H),1.62–1.54(m,3H),1.53–1.44(m,2H).

[0590] Step D:

[0591] Compound 7-4 (0.236 g), compound A-6 (0.23 g), Pd2(dba)3 (0.024 g), Xant-Phos (0.038 g), cesium carbonate (0.636 g), and dioxane (18 mL) were added sequentially to a 100 mL single-necked flask. The mixture was heated at 100°C for 16 h under nitrogen protection. After the reaction, the crude filter cake was filtered and purified by silica gel column chromatography (eluent: PE / EA = 1 / 1) to obtain compound 7 (0.233 g). MS (ESI+, [M+H] + )m / z:556.54.

[0592] Step E:

[0593] Compound 7 (233 mg) was separated by preparative HPLC (separation conditions column: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 64:30:6; flow rate: 1 mL / min; wavelength: 254 nm) to obtain compound 7_A (110 mg, retention time 21.231 minutes) and compound 7_B (108 mg, retention time 23.644 minutes).

[0594] Compound 7_A: 1H NMR(500MHz,DMSO-d6)δ12.86(s,1H),10.16(s,1H),8.06(d,J=8.6Hz,1H),7.63(d,J=8.2Hz,1H),7 .26(d,J=2.1Hz,1H),7.14(d,J=8.3Hz,1H),7.11(dd,J=8.6,2.2Hz,1H),5.01–4.86(m,1H),4.22–4. 17(m,1H),4.15–4.10(m,1H),3.84–3.79(m,1H),3.78–3.73(m,2H),3.38–3.32(m,3H),3.16–3.10( m,1H),2.96(t,J=5.3Hz,4H),2.09–2.03(m,1H),2.00–1.41(m,11H),0.37(s,4H).HRMS(ESI+,[M+H] + )m / z:556.2604.

[0595] Compound 7_B: 1 H NMR(500MHz,DMSO-d6)δ12.86(s,1H),10.16(s,1H),8.06(d,J=8.6Hz,1H),7.63(d,J=8.3Hz,1H),7 .26(d,J=2.2Hz,1H),7.14(d,J=8.3Hz,1H),7.11(dd,J=8.6,2.2Hz,1H),4.98–4.87(m,1H),4.22–4. 17(m,1H),4.16–4.10(m,1H),3.84–3.79(m,1H),3.78–3.73(m,2H),3.39–3.32(m,3H),3.17–3.10( m,1H),2.96(t,J=5.3Hz,4H),2.09–2.03(m,1H),1.98–1.41(m,11H),0.37(s,4H).HRMS(ESI+,[M+H] + )m / z:556.2596.

[0596] Example 8

[0597] Step A:

[0598] Referring to step A of Example 2, compound 8-1 was substituted for N-tert-butyloxycarbonyl-2-piperidin-2-ylethanol to obtain compound 8-2. MS (ESI+, [M+H] + )m / z:388.27.

[0599] Step B:

[0600] Referring to step B of Example 2, compound 8-2 was substituted for compound 2-2 to prepare compound 8-3. MS (ESI+, [M+H] + )m / z:288.32.

[0601] Step C:

[0602] Referring to step C of Example 2, compound 8-4 was prepared by replacing compound 2-3 with compound 8-3. 1 H NMR(500MHz,DMSO-d6)δ8.06(d,1H),7.21(d,1H),4.36-4.31(m,1H),4.25-4.21(m,1H),3.87–3.80(m,2H),3 .74-3.71(m,1H),3.66–3.58(m,2H),3.35–3.32(m,1H),3.31–3.25(m,1H),2.03–1.95(m,2H).MS(ESI+,[M+H] + )m / z:252.25.

[0603] Step D:

[0604] Referring to step D of Example 2, compound 8-4 was substituted for compound 2-4 to prepare compound 8-5. MS (ESI+, [M+H] + )m / z:222.35.

[0605] Step E:

[0606] Referring to step E of Example 2, compound 8-6 was prepared by replacing compound 2-5 with compound 8-5. 1 H NMR(500MHz,DMSO-d6)δ11.47(s,1H),8.02(d,1H),7.85(d,1H),7.69–7.59(m,3H),4.34-4.31(m,2H),3 .83–3.65(m,3H),3.51–3.38(m,4H),2.99(t,4H),1.99(q,2H),1.53(s,4H),0.34(s,4H).MS(ESI+,[M+H] + )m / z:561.40.

[0607] Step F:

[0608] Referring to step F of Example 2, compound 8 was prepared by replacing compound 2-6 with compound 8-6. 1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),10.16(s,1H),8.05(d,1H),7.91(d,1H),7.84(d,1H),7.20(d,1H),7.04(dd,1H),4.93(t,1H),4.40-4.36(m ,1H),4.30-4.27(m,1H),3.80–3.67(m,5H),3.49–3.40(m,4H),3.35(t,2 H),2.96(t,4H),2.00(q,2H),1.56(s,4H),0.36(s,4H).HRMS(ESI+,[M+H] + )m / z:558.2391.

[0609] Example 9

[0610] Step A:

[0611] To a 100 mL single-necked flask, compound 3-2 (0.6 g), tert-butyl 3-(2-hydroxyethyl)morpholine-4-carboxylate (1.04 g), toluene (15 mL), and cyanomethylenetri-n-butylphosphine (1.35 g) were added sequentially. The mixture was heated under reflux at 100°C with stirring for 15 h under N2 protection. After the reaction, the reaction solution was evaporated under reduced pressure, 30 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent PE / EA = 10 / 1) to obtain compound 9-1 (0.77 g). 1 H NMR(500MHz, CDCl3)δ7.26(s,1H),4.30–4.20(m,1H),4.06–3.98(m,1H),3.96–3.83(m,3H),3.82–3.73( m,1H),3.62(dd,1H),3.53–3.42(m,1H),3.25–3.09(m,1H),2.31(s,3H),2.29–2.17(m,2H),1.45(s,9H).

[0612] Step B:

[0613] Referring to step C of Example 3, compound 9-2 (495 mg) was prepared by replacing compound 3-3 with compound 9-1. 1H NMR(500MHz,DMSO-d6)δ9.54(s,2H),7.65(s,1H),4.10–4.04(m,3H),3.90(dt,1H),3.75–3.69(m,1H),3.61–3.5 4(m,1H),3.53–3.46(m,1H),3.23(dt,1H),3.16–3.06(m,1H),2.33(s,3H),2.20–2.12(m,1H),2.07–2.00(m,1H).

[0614] Step C:

[0615] Referring to step D of Example 3, compound 9-2 was used instead of compound 3-4 to prepare compound 9-3 (350 mg). MS (ESI+, [M+H] + )m / z:299.25.

[0616] Step D:

[0617] Referring to step E of Example 3, compound 9 (200 mg) was prepared by replacing compound 3-5 with compound 9-3. MS (ESI+, [M+H] + )m / z:572.54.

[0618] Step E:

[0619] Compound 9 (200 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose SC, 30×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 65:30:5; flow rate: 40 mL / min; wavelength: 254 nm) to give Compound 9_A (47 mg, retention time: 14.028 minutes) and Compound 9_B (76 mg, retention time: 15.817 minutes). Compound 9_A: 1H NMR(500MHz,DMSO-d6)δ12.91(s,1H),10.16(s,1H),8.06(d,1H),7.64(s,1H),7.26(d,1H),7 .12(dd,1H),5.09–4.70(m,1H),4.25–4.18(m,1H),4.09–4.02(m,1H),3.84(dt,1H),3.80–3.7 1(m,4H),3.68–3.62(m,1H),3.50–3.42(m,1H),3.36–3.34(m,2H),3.31–3.27(m,2H),3.01–2 .88(m,4H),2.16(s,3H),1.88(q,2H),1.85–1.32(m,4H),0.41–0.34(m,4H).HRMS(ESI+,[M+H] + )m / z:572.2546.

[0620] Compound 9_B: 1 H NMR(500MHz,DMSO-d6)δ12.91(s,1H),10.16(s,1H),8.06(d,1H),7.64(s,1H),7.26(d,1H),7 .12(dd,1H),5.21–4.71(m,1H),4.25–4.18(m,1H),4.09–4.02(m,1H),3.84(dt,1H),3.79–3.7 1(m,4H),3.68–3.62(m,1H),3.49–3.43(m,1H),3.36–3.33(m,2H),3.31–3.26(m,2H),3.01–2 .88(m,4H),2.16(s,3H),1.88(q,2H),1.84–1.34(m,4H),0.41–0.33(m,4H).HRMS(ESI+,[M+H] + )m / z:572.2553.

[0621] Example 10

[0622] Step A:

[0623] Referring to step A of Example 1, 3-hydroxymethylmorpholine was substituted for 2-piperidinemethanol to synthesize compound 10-1. MS (ESI+, [M+H] + )m / z:291.24. 1H NMR(500MHz,DMSO-d6)δ7.82(d,1H),7.09(d,1H),4.75(t,1H),4.02–3.97(m,1H),3.99–3.80(m,1 H),3.89–3.84(m,1H),3.85–3.68(m,1H),3.65–3.59(m,2H),3.58–3.48(m,2H),3.31–3.25(m,1H).

[0624] Step B:

[0625] Referring to step B of Example 1, compound 10-1 was substituted for compound 1-2 to obtain compound 10-2. MS (ESI+, [M+H] + )m / z:271.25. 1 H NMR(500MHz,DMSO-d6)δ7.58(d,1H),6.90(d,1H),4.48–4.30(m,1H),4.25–4.1 5(m,1H),4.00–3.85(m,3H),3.56–3.43(m,2H),3.16(t,1H),2.95–2.75(m,1H).

[0626] Step C:

[0627] Referring to step C of Example 1, compound 10 was obtained by replacing compound 1-3 with compound 10-2. 1 H NMR(500MHz,DMSO-d6)δ11.86(s,1H),10.18(s,1H),7.97(d,1H),7.92(d,1H),7.70(d,1H ),7.23(d,1H),7.15–7.02(m,1H),4.92(t,1H),4.48–4.32(m,1H),4.27–4.20(m,1H),4.06 –3.90(m,1H),3.75(q,2H),3.57–3.43(m,2H),3.35(t,2H),3.30–3.15(m,1H),2.99–2.85 (m,4H),2.84–2.70(m,1H),1.34(d,2H),1.31–1.21(m,4H),0.37(s,4H).HRMS(ESI+,[M+H] + )m / z:544.2242.

[0628] Example 11

[0629] Step A:

[0630] With reference to step 1 of Example 4, compound 11 was obtained by replacing 2-hydroxy-1-sulfonamide with ethylsulfonamide. 1 H NMR(500MHz,DMSO-d6)δ13.12(s,1H),10.22(s,1H),8.07(d,1H),7.60(s,1H ),7.28(d,1H),7.25–7.02(m,1H),4.31(d,1H),3.62(d,1H),3.26(s,4H),3. 21(q,2H),2.97(s,4H),2.72(t,1H),2.38(s,3H),1.98(d,2H),1.83(s,2H), 1.68(d,1H),1.46(q,3H),1.30–1.15(m,4H),0.37(s,4H).HRMS(ESI+,[M+H] + )m / z:567.2750.

[0631] Example 12

[0632] Step A:

[0633] With reference to step 1 of Example 4, compound 12 was obtained by replacing 2-hydroxy-1-sulfonamide with methanesulfonamide. 1 H NMR(500MHz,DMSO-d6)δ13.14(s,1H),10.23(s,1H),8.09(d,1H),7.60(s,1H),7.26(d,1H),7.18–7.06(m,1H),4.31(d,1H),3.26(s,2H) ,3.11(s,4H),2.98(s,4H),2.73(d,1H),2.38(s,3H),1.99(s,2H),1.57–1.41(m,3H),1.37–1.12(m,6H),0.37(s,4H).HRMS(ESI+,[M+H] + )m / z:553.2599.

[0634] Step B:

[0635] Compound 12 (200 mg) was separated by preparative HPLC (separation conditions: column: (R,R)-Whelk O 1, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 40:45:15; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 12_A (80 mg, retention time 7.319 minutes) and compound 12_B (80 mg, retention time 10.588 minutes).

[0636] Compound 12_A:1 H NMR(500MHz,DMSO-d6)δ13.14(s,1H),10.23(s,1H),8.09(d,1H),7.60(s,1H), 7.26(d,1H),7.13(dd,1H),4.31(d,1H),3.66–3.26(m,2H),3.20–3.05(m,4H),2 .97(s,4H),2.78–2.65(m,1H),2.38(s,3H),1.98(d,2H),1.68(d,2H),1.57–1. 41(m,3H),1.29–1.21(m,2H),0.90–0.80(m,2H),0.37(s,4H).HRMS(ESI+,[M+H] + )m / z:553.2602.

[0637] Compound 12_B: 1 H NMR(500MHz,DMSO-d6)δ13.14(s,1H),10.23(s,1H),8.09(d,1H),7.60(s,1H), 7.26(d,1H),7.13(dd,1H),4.31(d,1H),3.66–3.26(m,2H),3.20–3.05(m,4H),2 .98(s,4H),2.77–2.67(m,1H),2.38(s,3H),1.98(d,2H),1.68(d,2H),1.57–1. 41(m,3H),1.28–1.21(m,2H),0.91–0.79(m,2H),0.37(s,4H).HRMS(ESI+,[M+H] + )m / z:553.2603.

[0638] Example 13

[0639] Step A:

[0640] Referring to step D of Example 4, ethyl morpholine-3-carboxylate was used instead of methyl 2-piperidinate to prepare compound 13-1 (650 mg). MS (ESI+, [M+H] + )m / z:551.35. 1H NMR (500MHz, DMSO-d6) δ7.13–7.08(m,4H),6.90–6.86(m,4H),6.18(s,1H),4.66–4.53(m,4H),4.11–4.06(m,1H),4.03(q, 1H),4.01–3.95(m,1H),3.93–3.85(m,1H),3.79(dd,1H),3.75–3.68(m,8H),3.55–3.45(m,2H),2.21(s,3H),1.05(t,3H).

[0641] Step B:

[0642] Referring to step E of Example 4, compound 13-1 was used instead of compound 4-5 to prepare compound 13-2 (480 mg). MS (ESI+, [M+H] + )m / z:475.57.

[0643] Step C:

[0644] Referring to step F of Example 4, compound 13-2 was used instead of compound 4-6 to prepare compound 13-3 (331 mg). MS (ESI+, [M+H] + )m / z:489.29.

[0645] Step D:

[0646] Referring to step G of Example 4, compound 13-3 was used instead of compound 4-7 to prepare compound 13-4 (160 mg). MS (ESI+, [M+H] + )m / z:249.10.

[0647] Step E:

[0648] Referring to step H of Example 4, compound 13-4 was substituted for compound 4-8 to prepare compound 13-5 (226 mg). MS (ESI+, [M+H] + )m / z:588.26.

[0649] Step F:

[0650] Referring to step 1 of Example 4, compound 13-5 was substituted for compound 4-9 to prepare compound 13 (150 mg). MS (ESI+, [M+H] + )m / z:585.36.

[0651] Step G:

[0652] Compound 13 (150 mg) was separated by preparative HPLC (separation conditions: column: (R,R)-whelk-O1, 30×250 mm, 10 μm; mobile phase: n-hexane: dichloromethane: ethanol = 50:25:25; flow rate: 2 mL / min; wavelength: 254 nm) to give compound 13_A (38 mg, retention time: 12.000 minutes) and compound 13_B (25 mg, retention time: 14.500 minutes).

[0653] Compound 13_A: 1 H NMR(500MHz,DMSO-d6)δ13.29(s,1H),10.17(s,1H),8.07(d,1H),7.68(s,1H),7.27(d,1 H),7.13(dd,1H),4.95(s,1H),4.20(dd,1H),3.99(dd,1H),3.89(d,1H),3.76(t,2H),3. 68–3.62(m,1H),3.63–3.57(m,1H),3.54(t,1H),3.35(t,2H),3.27(s,3H),3.01–2.92(m ,4H),2.90–2.81(m,1H),2.40(s,3H),2.02–1.43(m,4H),0.37(s,4H).HRMS(ESI+,[M+H] + )m / z:585.2502.

[0654] Compound 13_B: 1 H NMR(500MHz,DMSO-d6)δ13.29(s,1H),10.19(s,1H),8.08(d,1H),7.68(s,1H),7.27(d,1 H),7.13(dd,1H),4.93(s,1H),4.20(dd,1H),3.99(dd,1H),3.89(d,1H),3.76(t,2H),3. 68–3.62(m,1H),3.63–3.58(m,1H),3.54(t,1H),3.35(t,2H),3.27(s,3H),3.02–2.91(m ,4H),2.91–2.81(m,1H),2.40(s,3H),2.08–1.43(m,4H),0.37(s,4H).HRMS(ESI+,[M+H] + )m / z:585.2502.

[0655] Example 14

[0656] Step A:

[0657] Compound B-2 (7.98 g), compound 14-1 (6.0 g) and THF (120 mL) were added to a 250 mL three-necked flask in sequence. Under N2 protection, LiHMDS (1 M, 60 mL) was slowly added dropwise in an ice bath. The reaction was stirred at room temperature for 3 h. After the reaction was completed, 200 mL of saturated ammonium chloride solution was added and extracted with EA (3×100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE:EA=20:1) to obtain compound 14-2 (6.2 g). 1 H NMR(500MHz,DMSO-d6)δ9.81(s,1H),7.85(s,1H),7.73(d,1H),5.00(s,1H),4.12–3.87(m, 1H),3.33(s,1H),2.65(s,1H),2.44(s,1H),2.12–1.89(m,2H),1.41(s,9H).MS(ESI-,[MH] - )m / z:496.13.

[0658] Step B:

[0659] Compound 14-2 (6.1 g) and dichloromethane (120 mL) were added to a 500 mL three-necked flask in sequence, and trifluoroacetic acid (19.14 mL) was slowly added under ice bath. The reaction was stirred at room temperature for 3.0 h. After the reaction was completed, 200 mL of saturated sodium bicarbonate solution was added and extracted with DCM (3×100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-3 (4.8 g). 1 H NMR(500MHz,DMSO-d6)δ8.34(d,1H),7.73(d,1H),3.65-3.62(m,1H),3.33(d,1H),3.07-3.03(m,1H),2 .77-2.73(m,1H),2.33–2.18(m,1H),2.06-2.01(m,1H),1.92(t,1H),1.88–1.74(m,1H).MS(ESI-,[MH] - )m / z:396.09.

[0660] Step C:

[0661] Compound 14-3 (4.7 g), NMP (40 mL), and DIEA (4.2 mL) were added sequentially to a 100 mL microwave reaction vial, placed in a microwave reactor, and heated to 100°C at 100 W for 150 minutes. After the reaction, 300 mL of water was added to the reaction solution, and the mixture was extracted with EA (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 4:1) to obtain compound 14-4 (3.6 g). 1 H NMR(500MHz,DMSO-d6)δ10.82(s,1H),6.94(d,1H),6.88(d,1H),4.55-4.51(m,1H),4.18-4.12(m ,1H),2.85–2.73(m,1H),2.42-2.38(m,1H),2.15-2.11(m,2H),2.04–1.85(m,1H).MS(ESI-,[MH] - )m / z:316.18.

[0662] Step D:

[0663] Compound 14-4 (3.0 g) and DMF (20 mL) were added to a 100 mL single-necked flask in sequence, and NaH (450 mg) was added under ice bath. After stirring for 5 min, iodomethane (1.6 g) was added and the mixture was reacted at room temperature for 20 min. After the reaction, 200 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with EA (3×100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was slurried with 20 mL of petroleum ether and filtered to obtain compound 14-5 (2.5 g). 1 H NMR(500MHz,DMSO-d6)δ7.25(d,1H),6.99(d,1H),4.63–4.47(m,1H),4.31–4.17(m,1H),3.24(s,3 H),2.82-2.79(m,1H),2.48–2.38(m,1H),2.22–2.06(m,2H),2.05–1.86(m,1H).HRMS(ESI+,[M+H] + )m / z:332.0200.

[0664] Step E:

[0665] Referring to step C of Example 1, compound 14-5 was substituted for compound 1-3 to prepare compound 14. MS (ESI+, [M+H] + )m / z:605.24.

[0666] Step F:

[0667] Compound 14 was subjected to chiral preparative separation (separation conditions: CHIRALART Cellulose-SB column; mobile phase: n-hexane:ethanol = 60:40) to give compound 14_A (retention time: 3.811 minutes) and compound 14_B (retention time: 4.129 minutes).

[0668] Compound 14_A: 1 H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.20(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7.28(d,1H),7.13(dd,1H),4.94(s,1H),4.68(d,1H ),4.21(dd,1H),3.75(d,2H),3.36(t,2H),3.27(s,3H),3.03–2.86(m,5 H),2.43-2.39(m,1H),2.23–1.31(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:605.2364.

[0669] Compound 14_B: 1 H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.20(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7.28(d,1H),7.13(dd,1H),4.94(s,1H),4.68(d,1H ),4.21(dd,1H),3.75(d,2H),3.36(t,2H),3.27(s,3H),3.03–2.86(m,5 H),2.43-2.39(m,1H),2.23–1.31(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:605.2365.

[0670] Example 15

[0671] Step A:

[0672] Compound 14-5 (1.0 g), 1,4-dioxane (20 mL), benzophenone imine (655 mg), cesium carbonate (2.45 g), Xant-phos (348 mg), and Pd2(dba)3 (276 mg) were added sequentially to a 100 mL single-necked flask. The mixture was reacted at 100°C under N2 protection for 4.5 h. After the reaction, 100 mL of EA was added to the reaction solution, which was filtered with suction. The filtrate was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 9:1) to obtain compound 15-1 (760 mg). 1 H NMR(500MHz,DMSO-d6)δ7.70–7.64(m,2H),7.59–7.52(m,1H),7.47(dd,2H),7.34(dd,3H),7.24(d,1H),7.14(dd,2H),6.34(d,1H),4.1 9-4.14(m,1H),4.03(dd,1H),3.19(s,3H),2.56-2.52(m,1H),2.31-2.28(m,1H),1.98–1.78(m,2H),1.54-1.51(m,1H).MS(ESI+,[M+H] + )m / z:433.28.

[0673] Step B:

[0674] Compound 15-1 (700 mg), ethyl acetate (12 mL), and a dioxane solution of HCl (4 M, 6 mL) were added sequentially to a 100 mL single-necked bottle and reacted at room temperature for 5.0 h. After the reaction, the reaction solution was poured into 100 mL of saturated sodium bicarbonate solution and extracted with EA (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain compound 15-2 (410 mg). MS (ESI+, [M+H] + )m / z:269.03.

[0675] Step C:

[0676] Referring to step E of Example 2, compound 15-3 was prepared by replacing compound 2-5 with compound 15-2. 1H NMR(500MHz,DMSO-d6)δ13.24(s,1H),7.92–7.79(m,2H),7.77–7.70(m,2H),7.43(d,1H),4.68(d,1H),4.28–4.16(m, 1H),3.27(s,3H),3.03(t,4H),2.90-2.86(m,1H),2.45–2.39(m,1H),2.25–1.48(m,7H),0.39(s,4H).MS(ESI+,[M+H] + )m / z:608.29.

[0677] Step D:

[0678] With reference to step F of Example 2, compound 15 was prepared by replacing compound 2-6 with compound 15-3 and replacing 2-hydroxy-1-sulfonamide with ethylsulfonamide. 1 H NMR(500MHz,DMSO-d6)δ13.22(s,1H),8.04(d,1H),7.74(d,1H),7.41(d,1H),7.23(d,1H),7.08(m,1H),4.68-4.64(m,1H),4.20(dd,1H),3 .27(s,3H),3.16(q,2H),2.97(t,4H),2.90-2.86(m,1H),2.42-2.38(m,1H),2.20–1.62(m,7H),1.20(t,3H),0.39(s,4H).HRMS(ESI+,[M+H] + )m / z:589.2418.

[0679] Step E:

[0680] Compound 15 was subjected to chiral preparative separation (separation conditions: CHIRALART Cellulose-SB column, 4.6×250 mm, 5 μm; mobile phase: n-hexane:ethanol = 60:40; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 15_A (retention time: 10.472 min) and compound 15_B (retention time: 12.454 min).

[0681] Compound 15_A: 1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.25(s,1H),8.08(d,1H),7.74(d,1H ),7.42(d,1H),7.28(d,1H),7.25–7.04(m,1H),4.68(d,1H),4.29–4.11(m,1H ),3.27(s,3H),3.22(q,2H),3.10–2.85(m,4H),2.99–2.81(m,1H),2.23–2.00 (m,3H),1.95–1.50(m,4H),1.29–1.12(m,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:589.2418.

[0682] Compound 15_B: 1 H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.25(s,1H),8.08(d,1H),7.74(d,1H ),7.42(d,1H),7.28(d,1H),7.25–7.04(m,1H),4.68(d,1H),4.29–4.11(m,1H ),3.27(s,3H),3.22(q,2H),3.10–2.85(m,4H),2.99–2.81(m,1H),2.23–2.00 (m,3H),1.95–1.50(m,4H),1.29–1.12(m,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:589.2423.

[0683] Example 16

[0684] Step A:

[0685] Referring to step D of Example 15, compound 16 was obtained by replacing ethylsulfonamide with methylsulfonamide. 1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.26(d,1H),7.13(dd,1H),4.72–4.64(m,1H),4.23–4 .17(m,1H),3.27(s,3H),3.11(s,3H),3.04–2.95(m,4H),2.93–2.87(m,1 H),2.46–2.40(m,1H),2.20–1.49(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:575.2258.

[0686] Step B:

[0687] Compound 16 (210 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose SC; mobile phase A: n-hexane, mobile phase B: dichloromethane / ethanol = 5 / 1; elution gradient: A / B = 55 / 45; flow rate: 1 mL / min; wavelength: 254 nm) to give compounds 16_A (100 mg, retention time: 19.782 min) and 16_B (100 mg, retention time: 22.455 min).

[0688] Compound 16_A: 1 H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.22(s,1H),8.08(d,1H),7.73(d, 1H),7.40(d,1H),7.25(d,1H),7.14-7.10(m,1H),4.69-4.62(m,1H),4.23 -4.16(m,1H),3.26(s,3H),3.10(s,3H),3.01-2.95(m,4H),2.92-2.85(m, 1H),2.46-2.36(m,1H),2.17-1.45(m,7H),0.37(s,4H).HRMS(ESI+,[M+H] + )m / z:575.2269.

[0689] Compound 16_B: 1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d, 1H),7.42(d,1H),7.26(d,1H),7.15-7.12(m,1H),4.72-4.64(m,1H),4.26 -4.17(m,1H),3.27(s,3H),3.12(s,3H),3.03-2.95(m,4H),2.94-2.86(m, 1H),2.47-2.39(m,1H),2.21-1.47(m,7H),0.38(s,4H).HRMS(ESI+,[M+H] + )m / z:575.2268.

[0690] Example 17

[0691] Step A:

[0692] To a 100 mL single-necked flask, compound 14-4 (350 mg), potassium carbonate (304 mg), acetonitrile (15 mL), and 4-methoxybenzyl chloride (224 mg) were added sequentially and heated under reflux at 80°C with stirring for 3 h. After the reaction was complete, the mixture was filtered, the filter cake was washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent PE / EA = 20 / 1) to obtain compound 17-1 (420 mg). 1 H NMR(500MHz,DMSO-d6)δ7.21–7.16(m,2H),7.10(d,1H),6.91–6.86(m,3H),5.14–5.00(m,2H),4.60–4.52(m,1H ),4.46–4.38(m,1H),3.71(s,3H),2.91–2.82(m,1H),2.55–2.51(m,1H),2.42–2.11(m,2H),2.10–1.88(m,1H).

[0693] Step B:

[0694] Referring to step E of Example 3, compound 17-1 was substituted for compound 3-5 to obtain compound 17-2 (240 mg). MS (ESI+, [M+H] + )m / z:711.45. 1H NMR(500MHz,DMSO-d6)δ13.21(s,1H),10.19(s,1H),8.06(d,1H),7.65–7.60(m,1H),7. 33(d,1H),7.27(d,1H),7.23(d,1H),7.21(s,1H),7.12(dd,1H),6.90–6.87(m,2H),5.15 –5.05(m,2H),4.93(s,1H),4.73–4.63(m,1H),4.36(dd,1H),3.75(t,2H),3.71(s,3H),3 .35(t,2H),2.99–2.90(m,5H),2.39–1.94(m,4H),1.91–1.42(m,4H),0.47–0.34(m,4H).

[0695] Step C:

[0696] In a 100 mL single-necked flask, compound 17-2 (240 mg) was dissolved in anisole (10 mL), and aluminum chloride (675 mg) was added. The mixture was stirred at room temperature for 24 h. After the reaction was complete, the mixture was evaporated under reduced pressure, 40 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH = 30 / 1) to obtain compound 17 (16 mg). 1 H NMR(500MHz,DMSO-d6)δ13.17(s,1H),10.71(s,1H),10.18(s,1H),8.07(d,1H),7.65(d ,1H),7.27(d,1H),7.13(dd,1H),7.10(d,1H),4.93(t,1H),4.75–4.65(m,1H),4.17–4. 09(m,1H),3.80–3.72(m,2H),3.35(t,2H),3.03–2.93(m,4H),2.92–2.82(m,1H),2.46– 2.35(m,1H),2.21–2.05(m,3H),1.95–1.49(m,4H),0.46–0.35(m,4H).HRMS(ESI+,[M+H] + )m / z:591.2216.

[0697] Example 18

[0698] Step A:

[0699] Referring to step A of Example 2, compound 18-1 was prepared by replacing N-tert-butyloxycarbonyl-2-piperidin-2-ylethanol with compound C-5. 1 H NMR(500MHz,DMSO-d6)δ8.44(d,1H),7.99(d,1H),4.55(s,1H),4.19(d,1H),4.11–3.97 (m,2H),2.99(t,1H),2.15–1.95(m,5H),1.38(s,9H),1.28–1.12(m,1H).MS(ESI+,[M+H] + )m / z:422.09.

[0700] Step B:

[0701] Referring to step B of Example 2, compound 18-2 was prepared by replacing compound 2-2 with compound 18-1. 1 H NMR(500MHz,DMSO-d6)δ8.45(d,1H),8.00(d,1H),4.26(t,2H),3.07–2.97(m,1H),2.85–2.76(m,1H),2.56-2.51(m,1H),2 .07-2.03(m,1H),1.92-1.90(m,1H),1.84(q,2H),1.70-1.68(m,1H),1.49-1.42(m,1H),1.29–1.13(m,1H).MS(ESI+,[M+H] + )m / z:322.07.

[0702] Step C:

[0703] Referring to step C of Example 2, compound 18-2 was substituted for compound 2-3 to prepare compound 18-3. HRMS (ESI+, [M+H] + )m / z:286.1004.

[0704] Step D:

[0705] Referring to step D of Example 2, compound 18-3 was substituted for compound 2-4 to prepare compound 18-4. MS (ESI+, [M+H] + )m / z:256.14.

[0706] Step E:

[0707] Referring to step E of Example 2, compound 18-4 was substituted for compound 2-5 to prepare compound 18-5. MS (ESI+, [M+H] + )m / z:595.28.

[0708] Step F:

[0709] Referring to step F of Example 2, compound 18 was prepared by replacing compound 2-6 with compound 18-5. 1 H NMR(500MHz,DMSO-d6)δ11.56(s,1H),8.10(d,1H),7.86(dd,2H),7.13(s,1H),6.98(d,1H),4.50–4.34(m,2H),3.82(d,1H),3. 75(t,2H),3.51(d,1H),3.29(t,3H),3.20(t,1H),2.96(d,4H),2.40–1.81(m,7H),1.55(s,4H),0.35(s,4H).HRMS(ESI+,[M+H] + )m / z:592.2417.

[0710] Step G:

[0711] Compound 18 was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane:dichloromethane:ethanol = 64:30:6; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 18_A (retention time: 2.762 min) and compound 18_B (retention time: 3.108 min).

[0712] Compound 18_A: 1 H NMR(500MHz,DMSO-d6)δ11.56(s,1H),8.10(d,1H),7.86(dd,2H),7.13(s,1H),6.98(d,1H),4.50–4.34(m,2H),3.82(d,1H),3. 75(t,2H),3.51(d,1H),3.29(t,3H),3.20(t,1H),2.96(d,4H),2.40–1.81(m,7H),1.55(s,4H),0.35(s,4H).HRMS(ESI+,[M+H] + )m / z:592.2417.

[0713] Compound 18_B: 1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),8.10(d,1H),7.86(dd,2H),7.13(s,1H),6.98(d,1H),4.50–4.34(m,2H),3.82(d,1H),3. 75(t,2H),3.51(d,1H),3.29(t,3H),3.20(t,1H),2.96(d,4H),2.40–1.81(m,7H),1.55(s,4H),0.35(s,4H).HRMS(ESI+,[M+H] + )m / z:592.2419.

[0714] Example 19

[0715] Step A:

[0716] Compound 7-1 (0.45 g), compound C-5 (0.715 g), triphenylphosphine (0.8 g), and THF (20 mL) were added sequentially to a 250 mL two-necked flask. Stirring was performed under nitrogen in an ice bath. A solution of DEAD (0.612 g) in THF (5 mL) was added dropwise, and the mixture was gradually returned to room temperature and stirred for 18 h. After the reaction, 50 mL of distilled water was added, followed by extraction with EA (100 mL). The mixture was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EA = 20 / 1) to yield compound 19-1 (0.894 g). 1 H NMR(500MHz,DMSO-d6)δ7.69–7.56(m,1H),7.53(d,1H),4.72–4.48(m,1H),4.11–3 .99(m,3H),3.06–2.90(m,1H),2.16–1.98(m,4H),1.96–1.76(m,2H),1.26(s,9H).

[0717] Step B:

[0718] Compound 19-1 (0.864 g), DCM (30 mL), and TFA (1.5 mL) were added to a 250 mL single-necked flask in sequence and stirred at room temperature for 16 hours. After the reaction, 50 mL of distilled water was added, and the mixture was extracted with EA (100 mL). The mixture was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: MeOH / DCM = 50 / 1) to obtain compound 19-2 (0.656 g). MS (ESI+, [M+H]+ )m / z:339.20. 1 H NMR(500MHz,DMSO-d6)δ7.67(dd,1H),7.54(d,1H),4.25–4.17(m,2H),3.04–2.96(m,1H),2.79–2.71(m,1H),2. 57–2.52(m,1H),2.28–2.01(m,2H),1.95–1.88(m,1H),1.87–1.78(m,2H),1.77–1.63(m,1H),1.57–1.42(m,1H).

[0719] Step C:

[0720] Compound 19-2 (0.44 g), NMP (10 mL), and DIPEA (0.335 g) were added sequentially to a 35 mL microwave tube and placed in a microwave reactor. The mixture was heated to 120°C at 100 W for 90 minutes. After the reaction, 50 mL of distilled water was added, followed by extraction with EA (100 mL). The mixture was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography (eluent: PE / EA = 20 / 1) to afford compound 19-3 (0.25 g). 1 H NMR(500MHz, DMSO-d6)δ7.11(d,1H),6.99(d,1H),4.28–4.20(m,2H),3.93–3.84(m,1H),3.57–3.52(m,1H),3.15–3.08(m,1H),2.21–1.92(m,6H).

[0721] Step D:

[0722] To a 50 mL single-necked flask, compound A-6 (0.231 g), compound 19-3 (0.209 g), Pd2(dba)3 (0.024 g), Xant-Phos (0.038 g), cesium carbonate (0.640 g), and dioxane (20 mL) were added in sequence. Under nitrogen protection, the mixture was heated at 100°C for 8 h. After the reaction, 50 mL of distilled water was added, and the mixture was extracted with EA (100 mL). The mixture was washed with saturated brine (50 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE / EA = 1 / 1) to obtain compound 19 (0.210 g). MS (ESI+, [M+H] + )m / z:592.15.

[0723] Step E:

[0724] Compound 19 (150 mg) was separated by preparative HPLC (separation conditions: whelk-O1, 20×250 mm, 5 μm; mobile phase: n-hexane:(dichloromethane-ethanol) = 66:34 (6:1); flow rate: 22 mL / min; wavelength: 254 nm) to give compound 19_A (68 mg, retention time 25.02 minutes) and compound 19_B (68 mg, retention time 27.13 minutes).

[0725] Compound 19_A: 1 H NMR(500MHz,DMSO-d6)δ12.81(s,1H),10.17(s,1H),8.06(d,1H),7.76(d,1H) ,7.26(d,1H),7.22(d,1H),7.11(dd,1H),4.93(t,1H),4.26–4.17(m,2H),4.0 4–3.98(m,1H),3.79–3.72(m,2H),3.54–3.47(m,1H),3.35(t,2H),3.22–3.15 (m,1H),3.04–2.89(m,4H),2.31–1.55(m,10H),0.38(s,4H).HRMS(ESI+,[M+H] + )m / z:592.2421.

[0726] Compound 19_B: 1 H NMR(500MHz,DMSO-d6)δ12.81(s,1H),10.17(s,1H),8.06(d,1H),7.76(d,1H), 7.26(d,1H),7.22(d,1H),7.11(dd,1H),4.99–4.87(m,1H),4.25–4.16(m,2H),4 .04–3.98(m,1H),3.79–3.73(m,2H),3.54–3.47(m,1H),3.35(t,2H),3.22–3.1 5(m,1H),3.04–2.91(m,4H),2.31–1.58(m,10H),0.38(s,4H).HRMS(ESI+,[M+H] + )m / z:592.2421.

[0727] Example 20

[0728] Step A:

[0729] Compound 14-5 (2.09 g) was subjected to preparative HPLC (separation conditions: column: CHIRALART Amylose-SA, 30×250 mm, 5 μm; mobile phase: n-hexane: ethanol = 50:50; flow rate: 40 mL / min; wavelength: 254 nm) to give compound 20-1A (0.97 g, retention time of 6.313 minutes) and compound 20-1B (0.97 g, retention time of 9.344 minutes).

[0730] Compound 20_1A: 1 H NMR(500MHz,DMSO-d6)δ7.25(d,1H),6.99(d,1H),4.58–4.51(m,1H),4.31–4.22(m,1H), 3.24(s,3H),2.86–2.78(m,1H),2.49–2.40(m,1H),2.23–2.05(m,2H),2.04–1.87(m,1H).

[0731] Compound 20_1B: 1 H NMR(500MHz,DMSO-d6)δ7.25(d,1H),6.99(d,1H),4.60–4.52(m,1H),4.30–4.21(m,1H), 3.24(s,3H),2.87–2.77(m,1H),2.48–2.40(m,1H),2.22–2.06(m,2H),2.03–1.88(m,1H).

[0732] Step B:

[0733] Compound D-4 (60 mg), compound 20-1A (68.4 mg), Pd2(dba)3 (15.7 mg), Xant-Phos (20 mg), cesium carbonate (168 mg), and dioxane (8 mL) were added sequentially. The mixture was heated at 100°C under nitrogen for 4 h. After completion of the reaction, 30 mL of distilled water was added to the reaction solution, and the mixture was extracted with EA (20 mL × 3), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 1 / 1) to obtain compound 20-A (68 mg). 1H NMR(500MHz,DMSO-d6)δ10.96(s,1H),10.08(s,1H),7.84–7.78(m,2H),7.41(d,1H),7 .25(d,1H),7.06(dd,1H),4.70–4.60(m,1H),4.23–4.14(m,1H),3.27(s,3H),3.08(s,3 H),3.05–2.98(m,4H),2.87–2.76(m,1H),2.45–2.35(m,1H),2.19–1.92(m,5H),1.87–1 .76(m,2H),1.52–1.40(m,2H),0.69–0.59(m,2H),0.46–0.32(m,2H).HRMS(ESI+,[M+H] + )m / z:601.2424.

[0734] Referring to the preparation method of compound 20_A, compound 20-1B was used instead of compound 20-1A to prepare compound 20_B (80 mg). 1 H NMR(500MHz,DMSO-d6)δ10.96(s,1H),10.08(s,1H),7.86–7.76(m,2H),7.41(d,1H),7 .25(d,1H),7.06(dd,1H),4.75–4.60(m,1H),4.23–4.15(m,1H),3.27(s,3H),3.08(s,3 H),3.06–2.95(m,4H),2.86–2.78(m,1H),2.47–2.34(m,1H),2.21–1.98(m,5H),1.88–1 .76(m,2H),1.55–1.41(m,2H),0.70–0.60(m,2H),0.48–0.34(m,2H).HRMS(ESI+,[M+H] + )m / z:601.2430.

[0735] Example 21

[0736] Step A:

[0737] Referring to step D of Example 14, deuterated iodomethane-D3 was used to replace iodomethane to prepare compound 21-1. 1H NMR(500MHz,DMSO-d6)δ7.24(d,1H),6.99(d,1H),4.57–4.51(m,1H),4.28–4.22(m ,1H),2.86–2.79(m,1H),2.48–2.41(m,1H),2.21–2.07(m,2H),2.02–1.88(m,1H).

[0738] Step B:

[0739] Compound 21-1 (0.26 g) was separated by preparative HPLC (separation conditions: column: CHIRALART Amylose-SA (30*250 mm, 5 um); mobile phase: ethanol: n-hexane = 60:40; flow rate: 40 mL / min; wavelength: 254 nm) to give compound 21-2A (0.129 g, retention time of 6.20 minutes) and compound 21-2B (0.126 g, retention time of 9.10 minutes).

[0740] Compound 21-2A: 1 H NMR(500MHz,DMSO-d6)δ7.24(d,1H),6.99(d,1H),4.58–4.51(m,1H),4.28–4.21(m,1H),2. 86–2.79(m,1H),2.48–2.41(m,1H),2.21–2.07(m,2H),2.02–1.88(m,1H).HRMS(ESI+,[M+H] + )m / z:335.0388.

[0741] Compound 21-2B: 1 H NMR(500MHz,DMSO-d6)δ7.24(d,1H),6.99(d,1H),4.58–4.51(m,1H),4.28–4.21(m,1H),2. 86–2.79(m,1H),2.48–2.41(m,1H),2.21–2.07(m,2H),2.02–1.88(m,1H).HRMS(ESI+,[M+H] + )m / z:335.0380.

[0742] Step C:

[0743] Referring to step E of Example 14, compound 21-2A was substituted for compound 14-5 to prepare compound 21-A. 1H NMR(500 MHz,DMSO-d6)δ13.20(s,1H),10.19(s,1H),8.08(d,1H),7.74(d,1H),7.41(d ,1H),7.28(d,1H),7.13(dd,1H),5.04–4.83(m,1H),4.73–4.63(m,1H),4.25–4 .15(m,1H),3.80–3.73(m,2H),3.37–3.34(m,2H),3.06–2.94(m,4H),2.93–2.8 7(m,1H),2.47–2.39(m,1H),2.31–1.33(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:608.2556.

[0744] Referring to the preparation method of compound 21_A, compound 21-2B was used to replace compound 21-2A to prepare compound 21_B. 1 H NMR(500MHz,DMSO-d6)δ13.19(s,1H),10.19(s,1H),8.08(d,1H),7.74(d,1H),7 .41(d,1H),7.28(d,1H),7.13(dd,1H),5.06–4.83(m,1H),4.71–4.64(m,1H),4.2 4–4.17(m,1H),3.79–3.72(m,2H),3.38–3.34(m,2H),3.06–2.94(m,4H),2.93–2 .87(m,1H),2.46–2.39(m,1H),2.34–1.30(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:608.2560.

[0745] Example 22

[0746] Referring to the preparation method of compound 20_A, compound E-4 was used instead of compound D-4 to prepare compound 22_A (84 mg). 1HNMR(500MHz,DMSO-d6)δ11.58(s,1H),10.10(s,1H),7.90(d,1H),7.74(d,1H),7 .41(d,1H),7.08(d,1H),6.97(dd,1H),4.64(s,1H),4.32–4.05(m,1H),3.84–3.7 3(m,2H),3.27(s,3H),3.17(d,1H),3.08(s,3H),2.97–2.75(m,1H),2.48(d,2H), 2.23–1.85(m,7H),0.99(t,2H),0.60(t,2H),0.21–0.06(m,2H).HRMS(ESI+,[M+H] + )m / z:601.2420.

[0747] Referring to the preparation method of compound 20_B, compound E-4 was used instead of compound D-4 to prepare compound 22_B (85 mg). 1 HNMR(500MHz,DMSO-d6)δ11.58(s,1H),10.10(s,1H),7.90(d,1H),7.74(d,1H),7. 41(d,1H),7.08(d,1H),6.97(dd,1H),4.74–4.59(m,1H),4.32–4.05(m,1H),3.87–3 .72(m,2H),3.27(s,3H),3.08(s,3H),2.95–2.71(m,1H),2.53(d,1H),2.48(d,2H) ,2.26–1.85(m,7H),0.99(t,2H),0.60(t,2H),0.21–0.06(m,2H).HRMS(ESI+,[M+H] + )m / z:601.2421.

[0748] Example 23

[0749] Step A:

[0750] Referring to step E of Preparation Example A-6, Compound A-2 was substituted for Compound A-5 to obtain Compound 23-1. MS (ESI+, [M+H] + )m / z: 357.10. 1 H NMR (500MHz, DMSO-d6) δ8.44(s,1H),7.58(s,1H),7.50–7.43(m,3H),2.97–2.92(m,4H),1.54–1.45(m,4H),0.33(s,4H).

[0751] Step B:

[0752] Compound 23-1 (0.4 g), methanesulfonamide (0.128 g), cuprous iodide (0.011 g), N'-(2,6-dimethylphenyl)-N-(pyridin-2-ylmethyl)oxamide (0.016 g), and cesium carbonate (0.915 g) were added to a 100 mL single-necked flask in sequence. The mixture was dissolved in tert-butanol (10 mL) and heated at 100°C under nitrogen for 6 h. After the reaction, the solvent was evaporated under reduced pressure. 50 mL of water was added to the reaction solution, and the mixture was extracted with EA (100 mL). The mixture was washed with saturated brine (50 mL x 2) and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH = 20:1) to obtain compound 23-2 (0.363 g). MS (ESI+, [M+H]) + )m / z:324.12. 1 H NMR(500MHz,DMSO-d6)δ10.00(s,1H),8.61(d,1H),7.75(d,1H),7.45(d,1H),7.05(d ,1H),6.94(dd,1H),3.05(s,3H),2.93–2.89(m,4H),1.56–1.46(m,4H),0.35(s,4H).

[0753] Step C:

[0754] Compound 21-1 (0.160 g), compound 23-2 (0.154 g), Pd2(dba)3 (0.022 g), Xant-Phos (0.028 g), and cesium carbonate (0.467 g) were added to a 100 mL single-necked bottle in sequence, dissolved in dioxane (10 mL), and heated to 100°C under N2 protection for 6 h. After the reaction, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain compound 23 (135 mg). MS (ESI+, [M+H] + )m / z:578.42.

[0755] Step D:

[0756] Compound 23 (135 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane:dichloromethane:ethanol = 60:10:30; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 23_A (61 mg, retention time: 18.704 min) and compound 23_B (62 mg, retention time: 21.194 min).

[0757] Compound 23_A: 1 H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.26(d,1H),7.13(dd,1H),4.71–4.63(m,1H), 4.24–4.18(m,1H),3.12(s,3H),3.04–2.95(m,4H),2.94–2.88(m,1H),2.46–2.40(m,1H),2.21–1.59(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:578.2465.

[0758] Compound 23_B: 1 H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.26(d,1H),7.13(dd,1H),4.73–4.64(m,1H), 4.24–4.16(m,1H),3.12(s,3H),3.03–2.95(m,4H),2.94–2.88(m,1H),2.45–2.39(m,1H),2.19–1.60(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:578.2452.

[0759] Example 24

[0760] Step A:

[0761] Referring to step C of Preparation Example A-6, compound D-2 was substituted for compound A-3 to prepare compound 24-1 (410 mg). MS (ESI+, [M+H] + )m / z:395.16.

[0762] Step B:

[0763] Referring to step D of Preparation Example A-6, Compound 24-1 was substituted for Compound A-4 to prepare Compound 24-2 (160 mg). MS (ESI-, [MH] - )m / z:379.14.

[0764] Step C:

[0765] Referring to step E of Preparation Example A-6, Compound 24-2 was substituted for Compound A-5 to prepare Compound 24-3 (110 mg). MS (ESI-, [MH] - )m / z:378.16.

[0766] Step D:

[0767] Referring to step E of Example 14, compound 24-3 was substituted for compound A-6 to prepare compound 24 (120 mg). MS (ESI+, [M+H] + )m / z:631.24.

[0768] Step E:

[0769] Compound 24 (120 mg) was subjected to chiral HPLC separation (model: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane / dichloromethane / ethanol = 40 / 30 / 30; flow rate: 1 mL / min) to give compound 24_A (45 mg, retention time: 5.982 min) and compound 24_B (45 mg, retention time: 6.642 min).

[0770] Compound 24_A: 1 H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.05(s,1H),7.86–7.75(m,2H),7.41(d,1H),7 .32–7.24(m,1H),7.05(d,1H),4.66(d,1H),4.25–4.14(m,1H),3.79–3.72(m,2H),3.27 (s,3H),3.07–2.95(m,4H),2.85–2.77(m,1H),2.43–2.35(m,1H),2.22–1.76(m,8H),1 .47(s,2H),1.24–1.23(m,2H),0.68–0.60(m,2H),0.44–0.34(m,2H).HRMS(ESI+,[M+H] + )m / z:631.2532.

[0771] Compound 24_B: 1H NMR(500MHz,DMSO-d6)δ10.98(s,1H),10.05(s,1H),7.85–7.75(m,2H),7.41(d,1H),7 .29–7.24(m,1H),7.05(d,1H),4.66(d,1H),4.22–4.16(m,1H),3.79–3.71(m,2H),3.27 (s,3H),3.06–2.93(m,4H),2.89–2.80(m,1H),2.46–2.39(m,1H),2.19–1.82(m,8H),1 .47(s,2H),1.24–1.21(m,2H),0.67–0.62(m,2H),0.44–0.34(m,2H).HRMS(ESI+,[M+H] + )m / z:631.2529.

[0772] Example 25

[0773] Step A:

[0774] Referring to step A of Example 14, compound 25-1 was substituted for compound 14-1 to prepare compound 25-2. MS (ESI-, [MH] - )m / z:354.31.

[0775] Step B:

[0776] Compound 25-2 (7.12 g), DCM (60 mL), and a solution of sodium hydroxide (6.41 g) in water (50 mL) were added to a 250 mL single-necked flask. After stirring, benzyltrimethylammonium tribromide (25 g) was added and the mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the mixture was separated, and the aqueous phase was extracted with DCM (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA = 4 / 1) to obtain compound 25-3 (7.94 g). 1 H NMR(500MHz,DMSO-d6)δ9.89(s,1H),7.70(s,1H),5.08–4.82(m,1H),4.18–3.94(m,1H),3.30–3 .14(m,1H),2.77–2.68(m,1H),2.47–2.30(m,1H),2.18(s,3H),2.10–1.88(m,2H),1.41(s,9H).

[0777] Step C:

[0778] Referring to step B of Example 14, compound 25-3 was substituted for compound 14-2 to prepare compound 25-4. MS (ESI+, [M+H] + ) m / z: 412.08.

[0779] Step D:

[0780] Referring to step C of Example 14, compound 25-5 was prepared by replacing compound 14-3 with compound 25-4. 1 H NMR(500MHz,DMSO-d6)δ10.33(s,1H),6.83(s,1H),4.55–4.47(m,1H),4.15–4.0 8(m,1H),2.84–2.75(m,1H),2.47–2.36(m,1H),2.17(s,3H),2.16–1.86(m,3H).

[0781] Step E:

[0782] Referring to step D of Example 14, compound 25-6 was prepared by replacing compound 14-4 with compound 25-5. 1 H NMR(500MHz,DMSO-d6)δ6.99(s,1H),4.34–4.24(m,1H),3.97–3.91(m,1H),3.29(s,3H), 2.88–2.80(m,1H),2.43–2.37(m,1H),2.36(s,3H),2.24–2.14(m,1H),2.14–1.91(m,2H).

[0783] Step F:

[0784] Referring to step C of Example 1, compound 25-6 was substituted for compound 1-3 to prepare compound 25. MS (ESI+, [M+H] + )m / z:619.41.

[0785] Step G:

[0786] Compound 25 was subjected to chiral preparative separation (separation conditions: column: CHIRALARTCellose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane:dichloromethane:ethanol = 60:10:30; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 25_A (retention time: 9.40 minutes) and compound 25_B (retention time: 10.8 minutes).

[0787] Compound 25_A: 1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.20(s,1H),8.07(d,1H),7.69(s,1H),7.27 (d,1H),7.14(dd,1H),4.93(s,1H),4.49–4.37(m,1H),3.91(dd,1H),3.82–3.71(m,2 H),3.36(t,2H),3.31(s,3H),3.03–2.88(m,5H),2.41(s,3H),2.40–2.34(m,1H),2.1 9–2.10(m,2H),2.10–2.03(m,1H),2.03–1.38(m,4H),0.39(s,4H).HRMS(ESI+,[M+H] + )m / z:619.2523.

[0788] Compound 25_B: 1 H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.20(s,1H),8.07(d,1H),7.69(s,1H),7.27 (d,1H),7.14(dd,1H),4.93(s,1H),4.49–4.39(m,1H),3.91(dd,1H),3.82–3.71(m,2 H),3.36(t,2H),3.31(s,3H),3.03–2.88(m,5H),2.41(s,3H),2.40–2.34(m,1H),2.1 9–2.10(m,2H),2.09–2.00(m,1H),1.98–1.40(m,4H),0.39(s,4H).HRMS(ESI+,[M+H] + )m / z:619.2524.

[0789] Example 26

[0790] Step A:

[0791] Compound 25-5 (0.5 g) and DMF (8 mL) were added to a 100 mL single-necked flask. NaH (0.07 g) was added under ice-cooling, and after stirring for 5 min, deuterated iodomethane-d3 (0.26 g) was added. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, 50 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with EA (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was slurried with 20 mL of petroleum ether and filtered to obtain compound 26-1 (0.24 g). 1H NMR(500MHz,DMSO-d6)δ6.99(s,1H),4.33–4.26(m,1H),3.98–3.92(m,1H),2.89–2 .80(m,1H),2.43–2.37(m,1H),2.35(s,3H),2.22–2.15(m,1H),2.10–1.91(m,2H).

[0792] Step B:

[0793] Compound 23-2 (155 mg), Pd2(dba)3 (43.9 mg), Xant-Phos (55.5 mg), compound 26-1 (176 mg) dissolved in dioxane (8 mL), and cesium carbonate (390 mg) were added sequentially to a 50 mL single-necked bottle. Under N2 protection, the mixture was heated to 100°C and reacted for 4 h. After completion of the reaction, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain compound 26 (250 mg). MS (ESI+, [M+H] + )m / z:592.34.

[0794] Step C:

[0795] Compound 26 was subjected to chiral preparative separation (separation conditions: column: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 70:15:15; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 26_A (retention time: 8.27 minutes) and compound 26_B (retention time: 9.43 minutes).

[0796] Compound 26_A: 1 H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.14(dd,1H),4.48–4.39(m,1H),3.91(dd,1H),3.12( s,3H),3.02–2.88(m,5H),2.41(s,3H),2.40–2.35(m,1H),2.17–2.10(m, 2H),2.09–2.01(m,1H),1.99–1.35(m,4H),0.39(s,4H).HRMS(ESI+,[M+H] + )m / z:592.2611.

[0797] Compound 26_B: 1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.14(dd,1H),4.47–4.39(m,1H),3.91(dd,1H),3.12( s,3H),3.03–2.87(m,5H),2.41(s,3H),2.40–2.34(m,1H),2.18–2.10(m, 2H),2.09–2.02(m,1H),1.99–1.33(m,4H),0.39(s,4H).HRMS(ESI+,[M+H] + )m / z:592.2612.

[0798] Example 27

[0799] Step A:

[0800] Referring to step F of Example 25, compound 23-2 was substituted for compound A-6 to obtain compound 27 (300 mg). MS (ESI+, [M+H] + )m / z:589.23.

[0801] Step B:

[0802] Compound 27 (300 mg) was separated by chiral HPLC (model: (R,R) Whelk-O1, 4.6×250 mm, 5 μm; mobile phase: dichloromethane / ethanol = 1 / 1; flow rate: 1 mL / min) to give compound 27_A (90 mg, retention time: 8.329 min) and compound 27_B (90 mg, retention time: 8.987 min).

[0803] Compound 27_A: 1 H NMR(500MHz,DMSO-d6)δ13.19(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.16–7.12(m,1H),4.43(d,1H),4.08–3.98 (m,1H),3.31(s,3H),3.12(s,3H),3.01–2.89(m,4H),2.41(s,4H),2.18–1.67(m,7H),1.20–1.15(m,1H),0.39(s,4H).HRMS(ESI+,[M+H] + )m / z:589.2424.

[0804] Compound 27_B:1 H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.17–7.11(m,1H),4.43(d,1H),3.94–3.87 (m,1H),3.30(s,3H),3.12(s,3H),3.02–2.94(m,4H),2.41(s,4H),2.20–1.53(m,7H),1.27–1.22(m,1H),0.39(s,4H).HRMS(ESI+,[M+H] + )m / z:589.2412.

[0805] Example 28

[0806] Step A:

[0807] Referring to step F of Example 25, compound D-4 was used instead of compound A-6 to prepare compound 28 (220 mg). MS (ESI+, [M+H] + )m / z:615.34.

[0808] Step B:

[0809] Compound 28 was subjected to chiral preparative separation (separation conditions: REFLECT I-Amylose A column, 4.6×250 mm, 5 μm; mobile phase: n-hexane:ethanol = 70:30; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 28_A (retention time: 12.807 min) and compound 28_B (retention time: 15.227 min).

[0810] Compound 28_A: 1 H NMR(500MHz,DMSO-d6)δ10.98(s,1H),10.09(s,1H),7.82(d,1H),7.75(s,1H), 7.25(d,1H),7.07(dd,1H),4.40(d,1H),3.95–3.85(m,1H),3.30(s,3H),3.08(s ,3H),3.01(d,4H),2.84(t,1H),2.41(s,3H),2.36(s,1H),2.19–1.93(m,5H),1. 82(s,2H),1.47(s,2H),0.74–0.58(m,2H),0.49–0.30(m,2H).HRMS(ESI+,[M+H] + )m / z:615.2578.

[0811] Compound 28_B: 1 H NMR(500MHz,DMSO-d6)δ10.98(s,1H),10.09(s,1H),7.82(d,1H),7.75(s,1H), 7.25(d,1H),7.07(dd,1H),4.40(d,1H),3.95–3.85(m,1H),3.30(s,3H),3.08(s ,3H),3.01(d,4H),2.84(t,1H),2.41(s,3H),2.36(s,1H),2.17–1.95(m,5H),1. 82(s,2H),1.47(s,2H),0.74–0.58(m,2H),0.44–0.33(m,2H).HRMS(ESI+,[M+H] + )m / z:615.2575.

[0812] Example 29

[0813] Step A:

[0814] Referring to step C of Preparation Example A-6, compound E-2 was substituted for compound A-3 to prepare compound 29-1. MS (ESI+, [M+H] + )m / z:395.17.

[0815] Step B:

[0816] Referring to step D of Preparation Example D-4, compound 29-1 was substituted for compound D-3 to prepare compound 29-2. MS (ESI+, [M+H] + )m / z:380.18.

[0817] Step C:

[0818] Referring to the preparation method of compound 20_A, compound 29-2 was used instead of compound D-4 to prepare compound 29_A (45 mg). 1HNMR(500MHz,DMSO-d6)δ11.59(s,1H),10.06(s,1H),7.89(d,1H),7.74(d,1H),7.41(d,1H),7.10( d,1H),6.97(dd,1H),4.92(s,1H),4.65(d,1H),4.25–4.06(m,1H),3.84–3.65(m,4H),3.27(s,3H), 2.97–2.75(m,1H),2.53(d,2H),2.49–2.34(m,2H),2.15(d,1H),2.10–1.99(m,3H),1.91(d,2H),1. 18(t,1H),1.05–0.95(m,2H),0.90–0.79(m,1H),0.60(t,2H),0.25–0.10(m,2H).HRMS(ESI+,[M+H] + )m / z:631.2533.

[0819] Referring to the preparation method of compound 20_B, compound 29-2 was used instead of compound D-4 to prepare compound 29_B (43 mg). 1 HNMR(500MHz,DMSO-d6)δ11.59(s,1H),10.06(s,1H),7.89(d,1H),7.74(d,1H),7.41(d,1H),7.10(d ,1H),6.97(dd,1H),4.92(s,1H),4.65(d,1H),4.25–4.06(m,1H),3.84–3.65(m,4H),3.27(s,3H),2. 97–2.75(m,1H),2.57–2.51(m,2H),2.49–2.36(m,2H),2.16(d,1H),2.13–2.00(m,3H),1.91(d,2H), 1.23(s,1H),1.05–0.95(m,2H),0.90–0.79(m,1H),0.60(t,2H),0.25–0.10(m,2H).HRMS(ESI+,[M+H] + )m / z:631.2519.

[0820] Example 30

[0821] Step A:

[0822] Compound 29-2 (200 mg), Pd2(dba)3 (48.3 mg), Xant-Phos (61 mg), compound 25-6 (219 mg) dissolved in dioxane (8 mL), and cesium carbonate (429 mg) were added sequentially to a 50 mL single-necked bottle. Under N2 protection, the mixture was heated to 100°C and reacted for 5 h. After completion of the reaction, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain compound 30 (200 mg). MS (ESI+, [M+H] + )m / z:645.42.

[0823] Step B:

[0824] Compound 30 was separated by chiral preparative separation (separation conditions: column: (R,R) Whelk-O1, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 40:30:30; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 30_A (retention time: 8.84 minutes) and compound 30_B (retention time: 9.68 minutes).

[0825] Compound 30_A: 1 H NMR(500MHz,DMSO-d6)δ11.63(s,1H),10.07(s,1H),7.89(d,1H),7.68(s,1H),7.10( d,1H),6.98(dd,1H),4.91(t,1H),4.44–4.35(m,1H),3.88–3.81(m,1H),3.78–3.71(m ,4H),3.30(s,3H),2.89–2.79(m,1H),2.58–2.51(m,2H),2.48–2.35(m,5H),2.20–1. 85(m,8H),1.02–0.93(m,2H),0.63–0.56(m,2H),0.17–0.08(m,2H).HRMS(ESI+,[M+H] + )m / z:645.2678.

[0826] Compound 30_B: 1H NMR(500MHz,DMSO-d6)δ11.63(s,1H),10.07(s,1H),7.89(d,1H),7.68(s,1H),7.10( d,1H),6.98(dd,1H),4.92(t,1H),4.48–4.35(m,1H),3.90–3.81(m,1H),3.79–3.64(m ,4H),3.30(s,3H),2.90–2.80(m,1H),2.58–2.51(m,2H),2.48–2.35(m,5H),2.20–1. 87(m,8H),1.02–0.94(m,2H),0.63–0.55(m,2H),0.18–0.08(m,2H).HRMS(ESI+,[M+H] + )m / z:645.2673.

[0827] Example 31

[0828] Step A:

[0829] Referring to step C of Example 23, compound 29-2 was substituted for compound 23-2 to prepare compound 31 (170 mg). MS (ESI+, [M+H] + )m / z:634.26.

[0830] Step B:

[0831] Compound 31 (170 mg) was subjected to chiral HPLC separation (model: CHIRALPAK IK, 4.6×250 mm, 5 μm; mobile phase: n-hexane / dichloromethane / ethanol = 50 / 25 / 25; flow rate: 1 mL / min) to give compound 31_A (60 mg, retention time: 8.894 min) and compound 31_B (60 mg, retention time: 10.344 min).

[0832] Compound 31_A: 1H NMR(500MHz,DMSO-d6)δ11.59(s,1H),10.06(s,1H),7.88(d,1H),7.74(d,1H),7.40(d,1H),7.09(s, 1H),6.99–6.94(m,1H),4.96–4.88(m,1H),4.65(d,1H),4.21–4.12(m,1H),3.82–3.69(m,4H),3.34–3 .32(m,1H),3.31–3.29(m,1H),2.88–2.78(m,1H),2.56–2.51(m,1H),2.47–2.44(m,1H),2.20–1.87( m,7H),1.32–1.28(m,1H),1.02–0.95(m,2H),0.63–0.55(m,2H),0.18–0.08(m,2H).HRMS(ESI+,[M+H] + )m / z:634.2697.

[0833] Compound 31_B: 1 H NMR(500MHz,DMSO-d6)δ11.59(s,1H),10.06(s,1H),7.89(d,1H),7.74(d,1H),7.40(d,1H),7.1 0(d,1H),7.00–6.92(m,1H),4.97–4.87(m,1H),4.65(d,1H),4.20–4.12(m,1H),3.81–3.70(m,4H ),3.34–3.32(m,1H),3.31–3.29(m,1H),2.89–2.75(m,1H),2.58–2.52(m,1H),2.48–2.41(m,1H) ,2.25–1.81(m,7H),1.29–1.26(m,1H),1.03–0.95(m,2H),0.63–0.55(m,2H),0.18–0.10(m,2H). HRMS(ESI+,[M+H] + )m / z:634.2704.

[0834] Example 32

[0835] Step A:

[0836] Referring to the preparation method of compound 20-A, compound 21-1 was used instead of compound 20-1A to prepare compound 32 (45 mg). 1HNMR(500MHz,DMSO-d6)δ10.96(s,1H),10.08(s,1H),7.81(t,2H),7.41(d,1H ),7.25(d,1H),7.06(dd,1H),4.66(d,1H),4.25–4.14(m,1H),3.08(s,3H),3. 05–2.94(m,4H),2.95–2.75(m,1H),2.46–2.32(m,1H),2.22–1.88(m,5H),1.8 3(d,2H),1.47(s,2H),0.79–0.58(m,2H),0.55–0.26(m,2H).HRMS(ESI+,[M+H] + )m / z:604.2609.

[0837] Example 33

[0838] Step A:

[0839] Referring to step C of Example 23, compound 23-2 was replaced with compound E-4 to prepare compound 33. HRMS (ESI+, [M+H] + )m / z:604.2597.

[0840] Step B:

[0841] Compound 33 (105 mg) was separated by preparative HPLC (separation conditions: column: CHIRALPAK IK, 5 μm, 21.2*250 mm; mobile phase: n-hexane: dichloromethane: ethanol = 60:20:20; flow rate: 20 mL / min; wavelength: 254 nm) to give compound 33_A (45 mg, retention time 13.5 minutes) and compound 33_B (45 mg, retention time 16.1 minutes).

[0842] Compound 33_A: 1H NMR(500MHz,DMSO-d6)δ11.58(s,1H),10.10(s,1H),7.89(d,1H),7.74(d,1H),7.40( d,1H),7.08(d,1H),6.97(dd,1H),4.71–4.59(m,1H),4.21–4.12(m,1H),3.83–3.73(m ,2H),3.08(s,3H),2.87–2.77(m,1H),2.56–2.51(m,1H),2.49–2.43(m,2H),2.20–1. 89(m,7H),1.02–0.96(m,2H),0.65–0.55(m,2H),0.19–0.09(m,2H).HRMS(ESI+,[M+H] + )m / z:604.2601.

[0843] Compound 33_B: 1 H NMR(500MHz,DMSO-d6)δ11.58(s,1H),10.10(s,1H),7.89(d,1H),7.74(d,1H),7.41( d,1H),7.08(d,1H),6.97(dd,1H),4.71–4.60(m,1H),4.22–4.10(m,1H),3.82–3.72(m ,2H),3.08(s,3H),2.87–2.79(m,1H),2.56–2.52(m,1H),2.49–2.42(m,2H),2.20–1. 89(m,7H),1.03–0.96(m,2H),0.64–0.56(m,2H),0.19–0.09(m,2H).HRMS(ESI+,[M+H] + )m / z:604.2596.

[0844] Example 34

[0845] Step A:

[0846] To a 100 mL single-necked flask, bis-(4-methoxybenzyl)amine (3.5 g), DCM (30 mL), and DIPEA (2.46 mL) were added sequentially. Compound 34-1 (2.66 g) was added under ice-cooling conditions and the mixture was allowed to react at room temperature for 1 h. After completion of the reaction, 40 mL of water was added and the mixture was extracted with DCM (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 2.5 / 1) to afford compound 34-2 (4 g). 1H NMR (500MHz, DMSO-d6) δ7.17–7.12(m,4H),6.88–6.84(m,4H),4.28(s,2H),4.25(s,4H),4.15(q,2H),3.73(s,6H),1.21(t,3H).

[0847] Step B:

[0848] To a 100 mL single-necked flask, compound 34-2 (4 g), DMF (20 mL), and iodomethane (4.18 g) were added sequentially. 60% sodium hydride (1 g) was added under ice-cooling conditions, and the mixture was allowed to react at room temperature for 12 h. After completion of the reaction, 80 mL of water was added, and the mixture was extracted with EA (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to afford compound 34-3 (3 g). 1 H NMR (500MHz, DMSO-d6) δ7.08–7.03(m,4H),6.81–6.77(m,4H),4.26(s,4H),4.20(q,2H),3.70(s,6H),1.62(s,6H),1.24(t,3H).

[0849] Step C:

[0850] To a 100 mL single-necked flask, 34-3 (3 g), trifluoroacetic acid (20 mL), and anisole (2.42 g) were added sequentially and stirred at room temperature for 3 h. After the reaction, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to give compound 34-4 (1.3 g). 1 H NMR (500MHz, DMSO-d6) δ7.03(s,2H),4.14(q,2H),1.50(s,6H),1.20(t,3H).

[0851] Step D:

[0852] To a 100 mL single-necked flask, compound 23-1 (900 mg), compound 34-4 (641 mg), cesium carbonate (2.06 g), N1-(2,6-dimethylphenyl)-N2-(pyridin-2-ylmethyl)oxamide (72 mg), cuprous iodide (48 mg), and tert-butanol (25 mL) were added in sequence. Under N2 protection, the mixture was heated to 100°C and reacted for 5 h. After the reaction, 60 mL of water was added and the mixture was extracted with DCM (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH = 150 / 1) to obtain compound 34-5 (708 mg). MS (ESI+, [M+H]+ )m / z:424.28.

[0853] Step E:

[0854] Compound 34-5 (350 mg) and THF (10 mL) were added to a 50 mL two-necked flask. Under N2 protection and an ice bath, 2 M sodium borohydride solution (0.85 mL) was added dropwise. After the reaction was completed, 5 mL of methanol and 1 mL of 2 N hydrochloric acid solution were added to quench the reaction. The product was purified by silica gel column chromatography (eluent: DCM / MeOH = 50 / 1) to obtain compound 34-6 (310 mg). MS (ESI+, [M+H] + )m / z:382.26.

[0855] Step F:

[0856] Referring to the preparation method of compound 20_A, compound 34-6 was used instead of compound D-4 to prepare compound 34_A. 1 H NMR(500MHz,DMSO-d6)δ13.25(s,1H),9.97(s,1H),8.05(d,1H),7.74(d,1H),7.45–7.39(m,2H),7.18(dd,1H),5.11(s,1H),4.72–4.64(m,1H) ,4.21(dd,1H),3.55(s,2H),3.27(s,3H),3.01–2.86(m,5H),2.47–2.38 (m,1H),2.19–1.52(m,7H),1.25(s,6H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:633.2681.

[0857] Referring to the preparation method of compound 20_B, compound 34-6 was used instead of compound D-4 to prepare compound 34_B. 1 H NMR(500MHz,DMSO-d6)δ13.26(s,1H),9.97(s,1H),8.05(d,1H),7.74(d,1H),7.46–7.37(m,2H),7.18(dd,1H),5.11(s,1H),4.72–4.64(m,1H) ,4.21(dd,1H),3.55(s,2H),3.27(s,3H),3.01–2.86(m,5H),2.47–2.38 (m,1H),2.21–1.46(m,7H),1.25(s,6H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:633.2685.

[0858] Example 35

[0859] Step A:

[0860] Referring to step B of Example 34, 1,2-dibromoethane was used instead of iodomethane to prepare compound 35-1. MS (ESI+, [M+H] + )m / z:434.21.

[0861] Step B:

[0862] Referring to step C of Example 34, compound 35-2 was prepared by replacing 34-3 with 35-1. MS (ESI+, [M+H] + ) m / z: 194.12. Step C:

[0863] Referring to step D of Example 34, compound 35-3 was prepared by replacing 34-4 with 35-2. MS (ESI+, [M+H] + )m / z:422.29.

[0864] Step D:

[0865] Referring to step E of Example 34, compound 35-4 was prepared by substituting 35-3 for 34-5. 1 H NMR(500MHz,DMSO-d6)δ9.90(s,1H),8.66(d,1H),7.73(d,1H),7.44(d,1H),7.12(d,1H),6.95(dd,1H),4 .94(t,1H),3.74(d,2H),2.88(t,4H),1.52(t,4H),1.09(q,2H),0.95(q,2H),0.35(s,4H).MS(ESI+,[M+H] + )m / z:380.24.

[0866] Step E:

[0867] Referring to the preparation method of compound 20_A, compound 35-4 was used instead of compound D-4 to prepare compound 35_A (67 mg). 1HNMR(500MHz,DMSO-d6)δ13.26(s,1H),10.12(s,1H),8.06(d,1H),7.75(d,1H),7.42(d,1H),7.34(d,1H),7.19 -7.05(m,1H),4.96(t,1H),4.67(s,1H),4.27–4.17(m,1H),3.75(d,2H),3.28(s,3H),3.05–2.85(m,6H),2.43 (d,1H),2.20–1.97(m,3H),1.75(s,3H),1.25–1.08(m,2H),1.05–0.94(m,2H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:631.2518.

[0868] Referring to the preparation method of compound 20_B, compound 35-4 was used instead of compound D-4 to prepare compound 35_B (57 mg). 1 H NMR(500MHz,DMSO-d6)δ13.26(s,1H),10.12(s,1H),8.06(d,1H),7.75(d,1H),7.42(d,1H),7.34(d, 1H),7.22–7.02(m,1H),4.97(s,1H),4.68(d,1H),4.35–4.20(m,1H),3.75(s,2H),3.27(s,3H),3.06–2.74(m,5 H),2.48–2.39(m,1H),2.22–1.38(m,7H),1.25–1.07(m,2H),1.02–0.93(m,2H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:631.2512.

[0869] Example 36

[0870] Referring to step C of Example 1, compound 36-A was prepared by replacing compound 1-3 with compound 21-2A and replacing compound A-6 with compound 24-3. 1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.05(s,1H),7.81(d,1H),7.79(d,1H),7.41(d,1H),7.2 6(d,1H),7.05(dd,1H),4.94(t,1H),4.69–4.62(m,1H),4.18(dd,,1H),3.76(q,2H),3.35–3.32 (m,2H),3.05–2.97(m,4H),2.86–2.77(m,1H),2.45–2.35(m,1H),2.20–2.02(m,4H),1.99–1.87 (m,1H),1.86–1.74(m,2H),1.47(s,2H),0.67–0.59(m,2H),0.43–0.33(m,2H).HRMS(ESI+,[M+H] + )m / z:634.2703.

[0871] Referring to the preparation method of compound 36_A, 21-2B was used instead of 21-2A to prepare compound 36_B. 1 H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.05(s,1H),7.81(d,1H),7.79(d,1H),7.41(d,1H),7.2 6(d,1H),7.05(dd,1H),4.94(t,1H),4.69–4.62(m,1H),4.19(dd,1H),3.76(q,2H),3.35–3.32( m,2H),3.07–2.98(m,4H),2.86–2.77(m,1H),2.45–2.35(m,1H),2.22–2.03(m,4H),1.99–1.88( m,1H),1.86–1.74(m,2H),1.47(s,2H),0.68–0.57(m,2H),0.43–0.34(m,2H).HRMS(ESI+,[M+H] + )m / z:634.2715.

[0872] Example 37

[0873] Step A:

[0874] Compound 34-2 (3.500 g), DMF (20 mL), iodomethane (1.340 g), and potassium carbonate (1.78 g) were added sequentially to a 100 mL single-necked flask and stirred at room temperature for 12 h. After the reaction, 80 mL of water was added and extracted with EA (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give compound 37-1 (3 g). 1 H NMR (500MHz, DMSO-d6) δ7.08–7.03(m,4H),6.81–6.77(m,4H),4.33–4.11(m,7H),3.72(s,6H),1.46(d,3H),1.20(t,3H).

[0875] Step B:

[0876] Compound 37-1 (2.300 g), trifluoroacetic acid (20 mL), and anisole (1.92 g) were added sequentially to a 100 mL single-necked flask and stirred at room temperature for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to afford compound 37-2 (0.9 g). 1 HNMR(500MHz,DMSO-d6)δ7.12(s,2H),4.14(q,2H),3.97(q,1H),1.45(d,3H),1.21(t,3H).

[0877] Step C:

[0878] Referring to step B of Example 23, compound 37-2 was substituted for methanesulfonamide to prepare compound 37-3. MS (ESI+, [M+H] + )m / z:410.25. 1 H NMR(500MHz,DMSO-d6)δ10.41(s,1H),8.57(d,1H),7.74(d,1H),7.46(d,1H),7.09(d,1H),6.95(dd,1H) ,4.22(q,1H),4.10–4.02(m,2H),2.90(t,4H),1.56–1.48(m,4H),1.45(d,3H),1.14(t,3H),0.35(s,4H).

[0879] Step D:

[0880] Compound 37-3 (0.330 g) and THF (30 mL) were added to a 50 mL two-necked flask to dissolve the mixture. 2 M lithium borohydride solution (0.80 mL) was added dropwise under nitrogen protection in an ice bath, and the mixture was transferred to room temperature and stirred for 16 h. After the reaction, 5 mL of methanol was added to quench the reaction mixture. 30 mL of distilled water was added, and the mixture was extracted with EA (2 × 20 mL), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain compound 37-4 (0.180 g). MS (ESI+, [M+H] + )m / z:368.32. 1 H NMR(500MHz,DMSO-d6)δ9.98(s,1H),8.57(d,1H),7.72(d,1H),7.44(d,1H),7.08(d,1H),6.95(dd,1H),4.99(br s,1H),3.83(dd,1H),3.45(dd,1H),3.24–3.18(m,1H),2.95–2.87(m,4H),1.57–1.46(m,4H),1.27(d,3H),0.35(s,4H).

[0881] Step E:

[0882] Referring to the preparation method of compound 20_A, compound 37-4 was substituted for compound D-4 to prepare compound 37-5. MS (ESI+, [M+H] + )m / z:619.50.

[0883] Referring to the preparation method of compound 20_B, compound 37-4 was substituted for compound D-4 to prepare compound 37-6. MS (ESI+, [M+H] + )m / z:619.37.

[0884] Step F:

[0885] Compound 37-5 (155 mg) was separated by preparative HPLC (separation conditions: column: CHIRALPAK IG, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 60:30:10; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 37_A (41 mg, retention time 8.381 minutes) and compound 37_B (56 mg, retention time 10.409 minutes).

[0886] Compound 37-6 (160 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose SB, 5 μm, 30*250 mm; mobile phase: ethanol: dichloromethane = 1:5 (phase A), n-hexane (phase B), 35A65B isocratic elution; flow rate: 40 mL / min; wavelength: 254 nm) to give compound 37_C (49 mg, retention time of 10.8 minutes) and compound 37_D (70 mg, retention time of 13.2 minutes).

[0887] Compound 37_A: 1 H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d,1 H),7.30(d,1H),7.15(dd,1H),5.16–4.86(m,1H),4.73–4.62(m,1H),4.25–4.14(m,1H), 3.93–3.76(m,1H),3.56–3.42(m,1H),3.30–3.25(m,4H),3.09–2.93(m,4H),2.93–2.87( m,1H),2.46–2.39(m,1H),2.21–1.50(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:619.2519.

[0888] Compound 37_B: 1 H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d,1 H),7.30(d,1H),7.15(dd,1H),5.16–4.87(m,1H),4.74–4.59(m,1H),4.26–4.15(m,1H), 3.87–3.80(m,1H),3.55–3.45(m,1H),3.30–3.25(m,4H),3.11–2.94(m,4H),2.93–2.87( m,1H),2.46–2.39(m,1H),2.24–1.50(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:619.2512.

[0889] Compound 37_C: 1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d, 1H),7.30(d,1H),7.15(dd,1H),5.01(t,1H),4.72–4.64(m,1H),4.24–4.18(m,1H),3.8 7–3.81(m,1H),3.52–3.45(m,1H),3.29–3.25(m,4H),3.03–2.93(m,4H),2.93–2.87(m, 1H),2.46–2.39(m,1H),2.18–1.54(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:619.2502.

[0890] Compound 37_D: 1 H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d, 1H),7.30(d,1H),7.15(dd,1H),5.01(t,1H),4.71–4.64(m,1H),4.23–4.18(m,1H),3.8 7–3.81(m,1H),3.52–3.45(m,1H),3.30–3.25(m,4H),3.03–2.93(m,4H),2.93–2.87(m, 1H),2.47–2.40(m,1H),2.23–1.50(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:619.2487.

[0891] Example 38

[0892] Step A:

[0893] Referring to step B of Example 23, methanesulfonamide was replaced with isopropylsulfonamide to obtain compound 38-1. MS (ESI+, [M+H] + )m / z:352.22.

[0894] Step B:

[0895] Referring to step E of Example 14, compound 38-1 was used instead of compound A-6 to obtain compound 38. MS (ESI+, [M+H] + )m / z:603.31

[0896] Step C:

[0897] Compound 38 was subjected to chiral preparative separation (column: REFLECT Cellulose B, 4.6×250 mm, 5 μm; mobile phase: n-hexane:dichloromethane:ethanol = 70:15:15; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 38_A (retention time: 8.997 min) and compound 38_B (retention time: 10.442 min).

[0898] Compound 38_A: 1 H NMR (500MHz, DMSO) δ13.18 (s, 1H), 10.18 (s, 1H), 8.07 (d, J = 8.6Hz, 1H), 7.74 (d, J=8.4Hz,1H),7.42(d,J=8.5Hz,1H),7.31(d,J=2.3Hz,1H),7.16(dd,J=8.7, 2.1Hz,1H),4.72–4.64(m,1H),4.24–4.17(m,1H),3.42–3.31(m,1H),3.27(s, 3H),3.00–2.94(m,4H),2.95–2.86(m,1H),2.47–2.37(m,1H),2.19–2.00(m, 3H),1.87–1.49(m,4H),1.27(d,J=6.8Hz,6H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:603.2556.

[0899] Compound 38_B:. 1 H NMR (500MHz, DMSO) δ13.18(s,1H),10.18(s,1H),8.07(d,J=8.6Hz,1H),7.74(d,J=8.5Hz,1H),7. 42(d,J=8.5Hz,1H),7.31(d,J=2.2Hz,1H),7.16(dd,J=8.6,2.2Hz,1H),4.74–4.62(m,1H),4.24– 4.17(m,1H),3.42–3.32(m,1H),3.27(s,3H),3.01–2.94(m,4H),2.94–2.86(m,1H),2.47–2.36(m ,1H),2.20–2.00(m,3H),1.93–1.48(m,4H),1.27(d,J=6.8Hz,6H),0.40(s,4H).HRMS(ESI+,[M+H] +)m / z:603.2554.

[0900] Example 39

[0901] Step A:

[0902] Referring to step B of Example 23, cyclopropylsulfonamide was used instead of methanesulfonamide to obtain compound 39-1. MS (ESI+, [M+H] + )m / z:350.21.

[0903] Step B:

[0904] Referring to step E of Example 14, compound 39-1 was substituted for compound A-6 to obtain compound 39. MS (ESI+, [M+H] + )m / z:601.40.

[0905] Step C:

[0906] Compound 39 was subjected to chiral preparative separation (separation conditions: column: CHIRALART Cellulose-SB, 4.6×250 mm, S-5 μm deuterated 103#; mobile phase: n-hexane:ethanol = 60:40; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 39_A (retention time: 8.72 minutes) and compound 39_B (retention time: 9.96 minutes).

[0907] Compound 39_A: 1 H NMR(500MHz,DMSO-d6)δ13.23(s,1H),10.22(s,1H),8.09(d,1H),7.75(d,1H),7.42(d, 1H),7.32(d,1H),7.16(dd,1H),4.71–4.63(m,1H),4.21(dd,1H),3.28(s,3H),3.03–2. 95(m,4H),2.95–2.87(m,1H),2.81–2.74(m,1H),2.47–2.39(m,1H),2.20–2.10(m,2H), 2.09–2.01(m,1H),1.99–1.47(m,4H),1.04–0.98(m,4H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:601.2418.

[0908] Compound 39_B: 1H NMR(500MHz,DMSO-d6)δ13.23(s,1H),10.22(s,1H),8.09(d,1H),7.75(d,1H),7.42(d, 1H),7.32(d,1H),7.16(dd,1H),4.71–4.63(m,1H),4.21(dd,1H),3.28(s,3H),3.03–2. 95(m,4H),2.94–2.87(m,1H),2.80–2.74(m,1H),2.47–2.39(m,1H),2.18–2.09(m,2H), 2.08–2.00(m,1H),1.99–1.47(m,4H),1.05–0.97(m,4H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:601.2412.

[0909] Example 40

[0910] Step A:

[0911] To a 250 mL single-necked flask, compound 40-1 (4.4 g), dichloromethane (100 mL), triphenylphosphine (26.2 g), and iodine (6.8 g) were added sequentially and stirred at 50°C under nitrogen for 16 h. After the reaction, 200 mL of saturated aqueous sodium sulfite solution was added, and the mixture was extracted with dichloromethane (3 × 150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under reduced pressure and purified by silica gel column chromatography (PE / EA = 95 / 5) to give compound 40-2 (6.9 g). 1 H NMR (500MHz, CDCl3) δ4.78–4.41(m,2H),4.24–4.18(m,1H),4.11–3.83(m,2H),2.42–2.23(m,2H).

[0912] Step B:

[0913] To a 250 mL single-necked flask, compound 40-2 (2 g), acetonitrile (60 mL), thioacetic acid (1.2 g), potassium carbonate (2.8 g), and 18-crown-6 (113 mg) were added sequentially and reacted at 85°C under nitrogen for 12 h. After completion of the reaction, the solvent was evaporated under reduced pressure, 100 mL of water was added, and extraction was performed with diethyl ether (3 × 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to dryness to obtain compound 40-3 (1.4 g), which was directly used in the subsequent reaction.

[0914] Step C:

[0915] To a 100 mL single-necked flask, compound 40-3 (1 g), acetonitrile (30 mL), N-chlorosuccinimide (3.7 g), and dilute hydrochloric acid (2 mol / L, 6 mL) were added sequentially. The mixture was stirred at 25°C for 2 h under nitrogen. After the reaction, 70 mL of water was added and the mixture was extracted with diethyl ether (3 × 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under reduced pressure and purified by silica gel column chromatography (PE / EA = 95 / 5) to afford compound 40-4 (820 mg). 1 H NMR (500MHz, CDCl3) δ3.61–3.56(m,2H),3.49–3.31(m,2H),2.98–2.87(m,1H),1.90–1.85(m,2H).

[0916] Step D:

[0917] Compound 40-4 (500 mg) and ammonia-dioxane solution (0.4 mol / L, 5 mL) were added sequentially to a 100 mL single-necked flask and stirred at 25°C for 4 h. After the reaction, the solvent was evaporated under reduced pressure and dried under vacuum at 60°C for 6 h to obtain compound 40-5 (470 mg), which was directly used in the subsequent reaction. 1 H NMR (500MHz, DMSO) δ7.36 (s, 2H), 3.84–3.60 (m, 4H), 3.25–3.07 (m, 1H), 2.05–1.90 (m, 2H).

[0918] Step E:

[0919] Referring to step B of Example 23, compound 40-5 was substituted for methanesulfonamide to prepare compound 40-6 (120 mg). MS (ESI-, [MH] - )m / z:378.16.

[0920] Step F:

[0921] Referring to the preparation method of compound 20_A, compound 40-6 was substituted for compound D-4 to prepare compound 40-7 (110 mg). MS (ESI+, [M+H] + )m / z:631.33.

[0922] Referring to the preparation method of compound 20_B, compound 40-6 was substituted for compound D-4 to prepare compound 40-8 (110 mg). MS (ESI+, [M+H] + )m / z:631.12.

[0923] Step G:

[0924] Compound 40-7 (110 mg) was separated by chiral HPLC (model: CHIRALART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: n-hexane / dichloromethane / ethanol = 65 / 17.5 / 17.5; flow rate: 40 mL / min) to give compound 40_A (30 mg, retention time: 13.2 min) and compound 40_B (30 mg, retention time: 15.5 min).

[0925] Compound 40-8 (100 mg) was separated by chiral HPLC (model: CHIRALART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: n-hexane / dichloromethane / ethanol = 65 / 17.5 / 17.5; flow rate: 40 mL / min) to give compound 40_C (30 mg, retention time: 14.1 min) and compound 40_D (30 mg, retention time: 16.0 min).

[0926] Compound 40_A: 1 H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.38(s,1H),8.08(d,1H),7.74(d,1H), 7.42(d,1H),7.28(d,1H),7.19–7.12(m,1H),4.68(d,1H),4.26–4.17(m,1H),4 .07–3.98(m,2H),3.90–3.77(m,2H),3.69–3.60(m,1H),3.27(s,3H),3.06–2.8 7(m,5H),2.47–2.38(m,1H),2.20–1.52(m,9H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:631.2501.

[0927] Compound 40_B: 1 H NMR(500MHz,DMSO-d6)δ13.17(s,1H),10.36(s,1H),8.09(d,1H),7.74(d,1H), 7.42(d,1H),7.30(d,1H),7.20–7.14(m,1H),4.67(d,1H),4.26–4.18(m,1H),4 .10–3.98(m,2H),3.90–3.80(m,2H),3.68–3.61(m,1H),3.27(s,3H),3.05–2.8 7(m,5H),2.46–2.35(m,1H),2.20–1.52(m,9H),0.40(s,4H).HRMS(ESI+,[M+H]+ )m / z:631.2502.

[0928] Compound 40_C: 1 H NMR(500MHz,DMSO-d6)δ13.17(s,1H),10.36(s,1H),8.08(d,1H),7.74(d,1H), 7.42(d,1H),7.29(d,1H),7.21–7.12(m,1H),4.68(d,1H),4.25–4.18(m,1H),4 .09–3.98(m,2H),3.89–3.78(m,2H),3.70–3.59(m,1H),3.27(s,3H),3.06–2.8 2(m,5H),2.47–2.36(m,1H),2.24–1.53(m,9H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:631.2531.

[0929] Compound 40_D: 1 H NMR(500MHz,DMSO-d6)δ13.17(s,1H),10.36(s,1H),8.09(d,1H),7.74(d,1H), 7.42(d,1H),7.30(d,1H),7.19–7.14(m,1H),4.68(d,1H),4.26–4.17(m,1H),4 .11–3.98(m,2H),3.93–3.78(m,2H),3.70–3.60(m,1H),3.27(s,3H),3.04–2.8 7(m,5H),2.47–2.36(m,1H),2.24–1.55(m,9H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:631.2530.

[0930] Example 41

[0931] Step A:

[0932] Referring to step D of Example 34, compound 41-1 was substituted for compound 34-4 to prepare compound 41-2. MS (ESI+, [M+H] + )m / z:464.27.

[0933] Step B:

[0934] Referring to the preparation method of compound 20_A, compound 41-2 was used instead of compound D-4 to prepare compound 41-3A. MS (ESI+, [M+H]+ )m / z:715.32.

[0935] Referring to the preparation method of compound 20_B, compound 41-2 was used instead of compound D-4 to prepare compound 41-3B. MS (ESI+, [M+H] + )m / z:715.38.

[0936] Step C:

[0937] To a 100 mL single-necked flask were added compound 41-3A (170 mg), ethanol (12 mL) and p-toluenesulfonic acid (9 mg) in sequence, and the reaction solution was reacted at 60°C under nitrogen for 3 h. After the reaction, the reaction solution was poured into 50 mL of water and extracted with EA (3×50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM:MeOH=50:1) to give compound 41_A (105 mg). 1 H NMR(500MHz,DMSO-d6)δ13.24(s,1H),10.10(s,1H),8.06(d,1H),7.75(d,1 H),7.42(d,1H),7.30(d,1H),7.20–7.04(m,1H),5.46(s,1H),4.67(s,1H),4 .39–4.22(m,1H),3.42(s,2H),3.27(s,3H),3.07–2.78(m,4H),2.48–2.40( m,1H),2.21–1.46(m,8H),0.78–0.60(m,4H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:631.2525.

[0938] Referring to the preparation method of compound 41_A, compound 41-3B was used instead of compound 41-3A to prepare compound 41_B. 1 H NMR(500MHz,DMSO-d6)δ13.24(s,1H),10.10(s,1H),8.06(d,1H),7.75(d ,1H),7.42(d,1H),7.30(d,1H),7.20–7.04(m,1H),5.47(s,1H),4.67(s,1 H),4.27–4.17(m,1H),3.42(s,2H),3.27(s,3H),3.03–2.92(m,4H),2.43( d,1H),2.20–1.46(m,8H),0.72–0.60(m,4H),0.40(s,4H).MS(ESI+,[M+H] +)m / z:631.2530.

[0939] Example 42

[0940] Step A:

[0941] To a 100 mL single-necked flask, methylamine hydrochloride (0.573 g) and potassium carbonate (1.174 g) were added sequentially and dissolved in methanol (15 mL). Compound 42-1 (0.750 g) was then added and stirred at room temperature for 0.5 h. Sodium borohydride (0.139 g) was then added under an ice bath. The mixture was gradually returned to room temperature and stirred overnight for 18 h. The reaction was quenched with 10 mL of saturated ammonium chloride solution. 50 mL of water was added to the reaction mixture, extracted with DCM (100 mL), washed with saturated brine (50 mL x 2), and dried over anhydrous sodium sulfate. The residue was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH = 20:1) to afford compound 42-2 (0.611 g). 1 H NMR (500MHz, DMSO-d6) δ7.80(d,1H),7.71(d,1H),3.63(s,2H),2.37(br s,1H),2.29(s,3H).

[0942] Step B:

[0943] Compound 42-2 (0.611 g), 1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid (0.614 g), HATU (1.162 g), and DIPEA (0.564 g) were added to a 100 mL single-necked bottle in sequence, dissolved in DCM (15 mL), and heated at 30°C for 18 h. After completion, 50 mL of water was added to the reaction solution, extracted with EA (100 mL), washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. The solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA = 10:1) to obtain compound 42-3 (0.709 g). HRMS (ESI+, [M+H] + )m / z:526.0147.

[0944] Step C:

[0945] Compound 42-3 (0.507 g) and dichloromethane (20 mL) were added sequentially to a 100 mL single-necked flask. Trifluoroacetic acid (1.1 mL) was slowly added under ice-cooling and the reaction was stirred at room temperature for 18 h. After the reaction was completed, 100 mL of saturated sodium bicarbonate solution was added and extracted with DCM (3 × 100 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH = 20:1) to obtain compound 42-4 (0.380 g). MS (ESI+, [M+H] + )m / z:425.82.

[0946] Step D:

[0947] To a 100 mL single-necked flask, compound 42-4 (0.438 g), NMP (8 mL), and DIPEA (0.199 g) were added sequentially and heated at 120°C for 6 h. After completion, the reaction mixture was added with 100 mL of water, extracted with EA (50 x 2 mL), washed with saturated brine (50 mL x 2), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA = 2:1) to afford compound 42-5 (0.208 g). 1 H NMR(500MHz,DMSO-d6)δ7.52(d,1H),7.04(d,1H),4.65(d,1H),4.46–4.41(m,1H),4.31(d,1 H),3.86–3.80(m,1H),3.50–3.42(m,1H),2.94(s,3H),2.59–2.47(m,1H),2.29–2.13(m,3H).

[0948] Step E:

[0949] Referring to step C of Example 1, compound 42-5 was substituted for compound 1-3 to prepare compound 42. MS (ESI+, [M+H] + )m / z:619.33.

[0950] Step F:

[0951] Compound 42 (110 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Amylose-SA, 4.6×250 mm, 5 μm; mobile phase: n-hexane:dichloromethane:ethanol = 60:20:20; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 42_A (43 mg, retention time 7.102 minutes) and compound 42_B (45 mg, retention time 8.575 minutes).

[0952] Compound 42_A: 1 H NMR(500MHz,DMSO-d6)δ13.16(s,1H),10.20(s,1H),8.06(d,1H),7.75(d,1H),7.65(d,1H), 7.27(d,1H),7.13(dd,1H),4.97–4.90(m,1H),4.54(d,1H),4.40(d,1H),4.27–4.21(m,1H), 3.94–3.87(m,1H),3.78–3.74(m,2H),3.51–3.45(m,1H),3.37–3.34(m,2H),3.01–2.93(m,7 H),2.59–2.45(m,1H),2.34–2.17(m,3H),1.99–1.37(m,4H),0.38(s,4H).HRMS(ESI+,[M+H] + )m / z:619.2521.

[0953] Compound 42_B: 1 H NMR(500MHz,DMSO-d6)δ13.16(s,1H),10.20(s,1H),8.06(d,1H),7.75(d,1H),7.65(d,1H), 7.27(d,1H),7.13(dd,1H),5.00–4.88(m,1H),4.54(d,1H),4.40(d,1H),4.27–4.21(m,1H), 3.94–3.87(m,1H),3.79–3.73(m,2H),3.51–3.45(m,1H),3.37–3.34(m,2H),3.01–2.93(m,7 H),2.59–2.45(m,1H),2.34–2.17(m,3H),2.02–1.36(m,4H),0.38(s,4H).HRMS(ESI+,[M+H] + )m / z:619.2520.

[0954] Example 43

[0955] Referring to the preparation method of compound 34_B, compound 21-2B was used to replace compound 20-1B to prepare compound 43. 1H NMR(500MHz,DMSO-d6)δ13.25(s,1H),9.97(s,1H),8.05(d,1H),7.74(d,1H),7. 43–7.40(m,2H),7.18(dd,1H),5.11(s,1H),4.72–4.64(m,1H),4.23–4.14(m,1H ),3.55(s,2H),3.00–2.93(m,4H),2.93–2.86(m,1H),2.47–2.39(m,1H),2.18–2 .02(m,3H),2.01–1.50(m,4H),1.27–1.23(m,6H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:636.2862.

[0956] Example 44

[0957] Step A:

[0958] Referring to step E of Preparation Example A-6, Compound E-1 was substituted for Compound A-5 to prepare Compound 44-1 (600 mg). MS (ESI+, [M+H] + )m / z:383.05.

[0959] Step B:

[0960] Compound 44-1 (300 mg), cyclopropylsulfonamide (143 mg), cuprous iodide (15 mg), N1-(2,6-dimethylphenyl)-N2-(pyridin-2-ylmethyl)oxamide (11 mg), cesium carbonate (640 mg), and isopropanol (5 mL) were added sequentially to a 50 mL single-necked bottle and reacted at 100°C for 8 h under nitrogen. After completion of the reaction, the reaction system was filtered, and the filtrate was evaporated to dryness under reduced pressure. Compound 44-2 (220 mg) was purified by silica gel column chromatography (DCM / MeOH = 95 / 5). MS (ESI-, [MH] - )m / z:374.16.

[0961] Step C:

[0962] Referring to the preparation method of compound 20_A, compound 44-2 was used instead of compound D-4 to prepare compound 44_A (70 mg). 1H NMR(500MHz,DMSO-d6)δ11.57(s,1H),10.06(s,1H),7.87(d,1H),7.73(d,1H),7.40( d,1H),7.11(d,1H),7.03–6.96(m,1H),4.63(d,1H),4.21–4.12(m,1H),3.81–3.70(m ,2H),3.25(s,3H),2.85–2.69(m,2H),2.56–2.51(m,1H),2.46–2.42(m,1H),2.21–1. 82(m,8H),1.02–0.93(m,6H),0.61–0.55(m,2H),0.18–0.08(m,2H).HRMS(ESI+,[M+H] + )m / z:627.2572.

[0963] Referring to the preparation method of compound 20_B, compound 44-2 was used instead of compound D-4 to prepare compound 44-B (70 mg). 1 H NMR(500MHz,DMSO-d6)δ11.57(s,1H),10.06(s,1H),7.87(d,1H),7.73(d,1H),7.40( d,1H),7.11(d,1H),7.03–6.96(m,1H),4.64(d,1H),4.21–4.12(m,1H),3.84–3.72(m ,2H),3.25(s,3H),2.86–2.70(m,2H),2.56–2.52(m,1H),2.48–2.44(m,1H),2.24–1. 81(m,8H),1.07–0.92(m,6H),0.65–0.55(m,2H),0.17–0.10(m,2H).HRMS(ESI+,[M+H] + )m / z:627.2581.

[0964] Example 45

[0965] Step A:

[0966] Referring to step A of Example 14, compound 45-1 was substituted for compound 14-1 to obtain compound 45-2. MS (ESI-, [MH] - )m / z:402.23.

[0967] Step B:

[0968] Referring to step B of Example 14, compound 45-2 was substituted for compound 14-2 to obtain compound 45-3. MS (ESI-, [MH] - )m / z:302.09.

[0969] Step C:

[0970] Referring to step C of Example 14, compound 45-3 was substituted for compound 14-3 to obtain compound 45-4. MS (ESI-, [MH] - )m / z:281.99.

[0971] Step D:

[0972] Referring to step D of Example 14, compound 45-4 was used instead of compound 14-4 to obtain compound 45-5. 1 H NMR(500MHz,DMSO-d6)δ7.83(dd,1H),7.71(d,1H),7.30(d,1H),4.11–4.04(m,1H),4.01–3.96( m,1H),3.36(s,3H),3.03–2.94(m,1H),2.49–2.41(m,1H),2.25–2.17(m,1H),2.17–2.02(m,2H).

[0973] Step E:

[0974] Compound 45-5 (610 mg), THF (5 mL), methanol (5 mL) and 10% dry palladium / carbon (109 mg) were added to a 100 mL two-necked flask in sequence and stirred at room temperature for 3 h under a H2 atmosphere. After the reaction was completed, the mixture was filtered through celite, washed with methanol, and the filtrate was concentrated to dryness to obtain compound 45-6 (500 mg). MS (ESI+, [M+H] + )m / z:268.29.

[0975] Step F:

[0976] Referring to step H of Example 4, compound 45-6 was used instead of compound 4-8 to obtain compound 45-7. 1H NMR(500MHz,DMSO- d6)δ11.26(s,1H),7.69(d,1H),7.47(d,1H),7.45(d,1H),7.38(dd,1H),7.34(dd,1H),7.12(d,1H),3.87–3.78(m,2H),3.30(s,3H ),3.06–3.00(m,4H),2.98–2.91(m,1H),2.44–2.36(m,1H),2.26–2.18(m,1H),2.18–1.91(m,2H),1.54–1.46(m,4H),0.32(s,4H).

[0977] Step G:

[0978] Referring to step 1 of Example 4, compound 45-7 was substituted for compound 4-9 to obtain compound 45. MS (ESI+, [M+H] + )m / z:604.41.

[0979] Step H:

[0980] Compound 45 was subjected to chiral preparative separation (separation conditions: column: CHIRALPAK IK, 4.6×250 mm, 5 μm; mobile phase: n-hexane:dichloromethane:ethanol = 60:20:20; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 45_A (retention time: 10.9 minutes) and compound 45_B (retention time: 12.08 minutes).

[0981] Compound 45_A: 1 H NMR(500MHz,DMSO-d6)δ11.62(s,1H),10.08(s,1H),7.83(d,1H),7.50(d,1H),7.32(dd, 1H),7.16(d,1H),7.13(d,1H),7.03(dd,1H),4.95(s,1H),3.88–3.81(m,2H),3.79–3.73( m,2H),3.34–3.33(m,2H),3.30(s,3H),3.00–2.96(m,4H),2.96–2.91(m,1H),2.44–2.35( m,1H),2.27–2.18(m,1H),2.17–1.93(m,2H),1.54(s,4H),0.35(s,4H).HRMS(ESI+,[M+H] + )m / z:604.2385.

[0982] Compound 45_B: 1H NMR(500MHz,DMSO-d6)δ11.62(s,1H),10.08(s,1H),7.83(d,1H),7.50(d,1H),7.32(dd, 1H),7.16(d,1H),7.13(d,1H),7.03(dd,1H),4.95(s,1H),3.87–3.81(m,2H),3.79–3.72( m,2H),3.34–3.33(m,2H),3.30(s,3H),3.00–2.96(m,4H),2.96–2.90(m,1H),2.43–2.34( m,1H),2.26–2.17(m,1H),2.15–1.92(m,2H),1.55(s,4H),0.35(s,4H).HRMS(ESI+,[M+H] + )m / z:604.2404.

[0983] Example 46

[0984] Step A:

[0985] To a 100 mL two-necked flask, compound C-5 (4.76 g), DCM (30 mL), water (15 mL), iodophenyldiacetic acid (11.56 g), and TEMPO (0.28 g) were added sequentially and stirred at room temperature for 12 h. After the reaction, 60 mL of water was added, and the pH of the aqueous phase was adjusted to approximately 9-10 by adding saturated sodium bicarbonate solution. The mixture was extracted with DCM (2 × 40 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 46-1 (4.4 g). 1 H NMR(500MHz,DMSO-d6)δ12.28(s,1H),4.75–4.65(m,1H),4.09–3.96(m,1H),3.00– 2.89(m,1H),2.57–2.51(m,1H),2.47–2.39(m,1H),2.15–1.77(m,4H),1.40(s,9H).

[0986] Step B:

[0987] Compound 46-1 (4.4 g) and potassium carbonate (4.35 g) were added sequentially to a 100 mL single-necked flask. After dissolving in DMF (20 mL), iodomethane (5.59 g) was added and the mixture was stirred at room temperature for 12 h. After completion of the reaction, 70 mL of water was added to the reaction mixture, and the mixture was extracted with EA (3 × 25 mL), washed with saturated brine (2 × 50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give compound 46-2 (4.23 g). 1H NMR(500MHz,DMSO-d6)δ4.79–4.69(m,1H),4.07–3.98(m,1H),3.59(s,3H),3.02–2 .91(m,1H),2.65–2.53(m,2H),2.17–1.97(m,3H),1.94–1.76(m,1H),1.39(s,9H).

[0988] Step C:

[0989] Referring to step A of Example 14, compound 46-2 was substituted for compound B-2 to obtain compound 46-3. MS (ESI-, [MH] - )m / z:510.07.

[0990] Step D:

[0991] Referring to step B of Example 14, compound 46-3 was substituted for compound 14-2 to obtain compound 46-4. MS (ESI-, [MH] - )m / z:409.99.

[0992] Step E:

[0993] Referring to step C of Example 14, compound 46-4 was substituted for compound 14-3 to obtain compound 46-5. MS (ESI-, [MH] - )m / z:330.02.

[0994] Step F:

[0995] Referring to step D of Example 14, compound 46-6 was obtained by replacing compound 14-4 with compound 46-5. 1 H NMR(500MHz,DMSO-d6)δ7.63(d,1H),7.33(d,1H),3.82–3.59(m,2H),3.18(s,3 H),3.06–2.96(m,1H),2.83–2.59(m,1H),2.37–2.24(m,1H),2.22–1.85(m,4H).

[0996] Step G:

[0997] Referring to step C of Example 1, compound 46 was obtained by replacing compound 1-3 with compound 46-6. 1H NMR(500MHz,DMSO-d6)δ13.37(s,1H),10.21(s,1H),8.09(d,1H),8.03(d,1H) ,7.75(d,1H),7.28(d,1H),7.14(dd,1H),4.94(s,1H),3.87–3.54(m,4H),3.3 6(t,2H),3.20(s,3H),3.16–3.08(m,1H),3.02–2.94(m,4H),2.85–2.62(m,1H ),2.34–2.05(m,4H),2.02–1.37(m,5H),0.42–0.35(m,4H).HRMS(ESI+,[M+H] + )m / z:619.2513.

[0998] Example 47

[0999] Step A:

[1000] Referring to step G of Example 45, methylsulfonamide was used instead of 2-hydroxy-1-sulfonamide to obtain compound 47. MS (ESI+, [M+H] + )m / z:574.35.

[1001] Step B:

[1002] Compound 47 was subjected to chiral preparative separation (separation conditions: column: CHIRALPAK IK, 4.6×250 mm, 5 μm; mobile phase: n-hexane:dichloromethane:ethanol = 70:15:15; flow rate: 1 mL / min; wavelength: 254 nm) to give compound 47_A (retention time: 23.0 minutes) and compound 47_B (retention time: 26.1 minutes).

[1003] Compound 47_A: 1 H NMR(500MHz,DMSO-d6)δ11.64(s,1H),10.11(s,1H),7.85(d,1H),7.50(d,1H),7. 32(dd,1H),7.15(d,1H),7.13(d,1H),7.04(dd,1H),3.88–3.80(m,2H),3.30(s,3 H),3.09(s,3H),3.00–2.96(m,4H),2.96–2.91(m,1H),2.43–2.35(m,1H),2.27–2 .17(m,1H),2.17–1.99(m,2H),1.59–1.48(m,4H),0.35(s,4H).HRMS(ESI+,[M+H] +)m / z:574.2291.

[1004] Compound 47_B: 1 H NMR(500MHz,DMSO-d6)δ11.64(s,1H),10.11(s,1H),7.85(d,1H),7.50(d,1H),7. 32(dd,1H),7.15(d,1H),7.13(d,1H),7.04(dd,1H),3.87–3.80(m,2H),3.30(s,3 H),3.09(s,3H),3.00–2.96(m,4H),2.96–2.91(m,1H),2.44–2.35(m,1H),2.27–2 .17(m,1H),2.16–1.99(m,2H),1.59–1.48(m,4H),0.35(s,4H).HRMS(ESI+,[M+H] + )m / z:574.2301.

[1005] Example 48

[1006] Step A:

[1007] To a 100 mL single-necked flask, compound 48-1 (1.700 g), DIPEA (1.971 g), and DCM (20 mL) were added sequentially. Methanesulfonic anhydride (2.125 g) was then added to the system under an ice bath. The mixture was gradually warmed to room temperature and stirred overnight for 18 hours. After the reaction, 50 mL of water was added to the reaction solution, and the mixture was extracted with DCM (100 mL). The mixture was washed with saturated brine (50 mL x 2) and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM) to obtain compound 48-2 (1.520 g). 1 H NMR (500MHz, DMSO-d6) δ7.22–7.16(m,2H),6.55(d,1H),6.50(dd,1H),4.04(d,2H),3.78(s,3H),3.75(s,3H),2.81(s,3H).

[1008] Step B:

[1009] Under nitrogen at -78°C, a 2.5M solution of n-butyllithium (12.02 mL) was added dropwise to a 250 mL two-necked flask containing compound 48-2 (3.58 g) and THF (60 mL). After 15 minutes, acetone (16.39 mL) was added dropwise, and the system was then transferred to 0°C for 2 hours. The reaction was quenched with 20 mL of saturated ammonium chloride solution, extracted with EA (200 mL), washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated brine (50 mL × 2), respectively, and dried over anhydrous sodium sulfate. The residue was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 2 / 1) to obtain compound 48-3 (0.788 g). 1 H NMR(500MHz,DMSO-d6)δ7.20(d,1H),7.06(t,1H),6.55(d,1H),6.50(dd,1H), 4.74(s,1H),4.04(d,2H),3.78(s,3H),3.75(s,3H),3.07(s,2H),1.27(s,6H).

[1010] Step C:

[1011] Compound 48-3 (0.380 g), DCM (10 mL), and TFA (0.714 g) were added sequentially to a 100 mL single-necked flask and stirred at room temperature for 2 h. After completion of the reaction, DCM (20 mL) was added to dilute the reaction mixture, filtered, and the filtrate was concentrated under reduced pressure. Dichloromethane (15 mL) and n-hexane (15 mL) were added to the residue, and the mixture was stirred at room temperature for 1 h. The filter cake was collected by filtration to yield compound 48-4 (0.141 g). 1 HNMR(500MHz,DMSO-d6)δ6.71(s,2H),4.77(s,1H),3.15(s,2H),1.29(s,6H).

[1012] Step D:

[1013] Referring to step B of Example 23, compound 48-4 was substituted for methanesulfonamide to prepare compound 48-5. MS (ESI+, [M+H] + )m / z:382.23. 1 H NMR(500MHz,DMSO-d6)δ9.95(s,1H),8.60(d,1H),7.74(d,1H),7.45(d,1H),7.06(d,1H),6.93(d d,1H),4.84(s,1H),3.22(s,2H),2.95–2.87(m,4H),1.57–1.47(m,4H),1.30(s,6H),0.35(s,4H).

[1014] Step E:

[1015] Referring to step E of Example 14, compound 48-5 was substituted for compound A-6 to prepare compound 48. MS (ESI+, [M+H] + )m / z:633.43.

[1016] Step F:

[1017] Compound 48 (168 mg) was separated by preparative HPLC (separation conditions: column: CHIRALPAK IK, 5 μm, 21.2*250 mm; mobile phase: n-hexane: dichloromethane: ethanol = 40:10:30; flow rate: 20 mL / min; wavelength: 254 nm) to give compound 48_A (77 mg, retention time 12.5 minutes) and compound 48_B (60 mg, retention time 14.6 minutes).

[1018] Compound 48_A: 1 H NMR(500MHz,DMSO-d6)δ13.19(s,1H),10.18(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.27(d,1H),7.12(dd,1H),4.86(s,1H),4.72–4.65 (m,1H),4.23–4.13(m,1H),3.30–3.24(m,5H),3.05–2.94(m,4H),2.94– 2.87(m,1H),2.46–2.39(m,1H),2.21–1.52(m,7H),1.31(s,6H),0.39(s, 4H).HRMS(ESI+,[M+H] + )m / z:633.2683.

[1019] Compound 48_B: 1 H NMR(500MHz,DMSO-d6)δ13.19(s,1H),10.18(s,1H),8.09(d,1H),7.74(d,1H) ,7.42(d,1H),7.27(d,1H),7.12(dd,1H),4.86(s,1H),4.72–4.64(m,1H),4.2 4–4.17(m,1H),3.29–3.25(m,5H),3.06–2.94(m,4H),2.93–2.87(m,1H),2.46 –2.40(m,1H),2.19–1.50(m,7H),1.31(s,6H),0.39(s,4H).HRMS(ESI+,[M+H] +)m / z:633.2677.

[1020] Example 49

[1021] Step A:

[1022] Referring to step A of Preparation Example A-6, 8-azabicyclo[3.2.1]octane hydrochloride was used instead of 6-azaspiro[2.5]octane hydrochloride to obtain compound 49-1. MS (ESI+, [M+H] + )m / z:357.98.

[1023] Step B:

[1024] Referring to step E of Preparation Example A-6, compound 49-1 was substituted for compound A-5 to obtain compound 49-2. MS (ESI+, [M+H] + )m / z:356.99.

[1025] Step C:

[1026] Referring to step C of Preparation Example D-4, compound 49-2 was substituted for compound D-2 to obtain compound 49-3. MS (ESI+, [M+H] + )m / z:324.01.

[1027] Step D:

[1028] Referring to the preparation method of compound 20_A, compound 49-3 was used instead of compound D-4 to prepare compound 49_A. 1 H NMR(500MHz,DMSO-d6)δ11.57(s,1H),10.09(s,1H),7.88(d,1H),7.73(d,1H),7.41 (d,1H),7.06(d,1H),6.95(dd,1H),4.60–4.51(m,1H),4.23–4.16(m,1H),3.77–3.6 6(m,2H),3.27(s,3H),3.08(s,3H),2.87–2.79(m,1H),2.44–2.35(m,1H),2.21–2.0 4(m,4H),2.03–1.92(m,3H),1.78–1.64(m,3H),1.58–1.45(m,3H).HRMS(ESI+,[M+H] + )m / z:575.2268.

[1029] Referring to the preparation method of compound 20_B, compound 49-3 was used instead of compound D-4 to prepare compound 49_B. 1H NMR(500MHz,DMSO-d6)δ11.57(s,1H),10.09(s,1H),7.87(d,1H),7.73(d,1H),7.41 (d,1H),7.06(d,1H),6.95(dd,1H),4.60–4.51(m,1H),4.22–4.15(m,1H),3.77–3.6 7(m,2H),3.27(s,3H),3.08(s,3H),2.87–2.78(m,1H),2.44–2.35(m,1H),2.20–2.0 3(m,4H),2.01–1.89(m,3H),1.78–1.63(m,3H),1.57–1.44(m,3H).HRMS(ESI+,[M+H] + )m / z:575.2254.

[1030] Example 50

[1031] Step A:

[1032] Referring to step E of Example 42, compound 23-2 was substituted for compound A-6 to prepare compound 50. MS (ESI+, [M+H] + )m / z:589.34.

[1033] Step B:

[1034] Compound 50 was subjected to chiral preparative separation (separation conditions: CHIRALART Cellulose-SB column; 30×250 mm, 5 μm; mobile phase: n-hexane:ethanol = 68:32; flow rate: 40 mL / min; wavelength: 254 nm) to give compound 50_A (retention time: 9.102 min) and compound 50_B (retention time: 13.454 min).

[1035] Compound 50_A: 1 H NMR(500MHz,DMSO-d6)δ13.17(s,1H),10.27(s,1H),8.08(d,1H),7.89–7.54(m,2H),7.43–7.03(m,2H),4.54(d,1H),4.41(d,1H),4.24(d,1 H),4.02(t,1H),3.90(d,1H),3.47(s,1H),3.12(s,3H),2.97(s,6H),2.25(d,3H),1.99(s,2H),1.72(s,3H),0.38(s,4H).HRMS(ESI+,[M+H] + )m / z:589.2402.

[1036] Compound 50_B: 1 H NMR(500MHz,DMSO-d6)δ13.16(s,1H),10.25(s,1H),8.08(d,1H),7.76(d,1H),7.65 (d,1H),7.25(d,1H),7.13(dd,1H),4.54(d,1H),4.40(d,1H),4.35–4.05(m,1H),4.0 3–3.97(m,1H),3.95–3.86(m,1H),3.65–3.45(m,1H),3.12(s,3H),3.10–2.84(m,6H ),2.38–2.13(m,3H),1.99(s,1H),1.97–1.22(m,4H),0.38(s,4H).HRMS(ESI+,[M+H] + )m / z:589.2411.

[1037] Example 51

[1038] Step A:

[1039] Referring to step A of Preparation Example A-6, (1R, 5S)-3-azabicyclo[3.2.1]octane hydrochloride was substituted for 6-azaspiro[2.5]octane hydrochloride to prepare compound 51-1 (1.9 g). MS (ESI+, [M+H] + )m / z:358.12.

[1040] Step B:

[1041] Referring to step B of Preparation Example A-6, Compound 51-1 was substituted for Compound A-2 to prepare Compound 52-2 (1.8 g). MS (ESI+, [M+H] + )m / z:372.16.

[1042] Step C:

[1043] Referring to step C of Preparation Example A-6, compound 51-2 was substituted for compound A-3, and methylsulfonamide was substituted for 2-hydroxy-1-sulfonamide to prepare compound 51-3 (0.75 g). MS (ESI+, [M+H] + )m / z:339.27.

[1044] Step D:

[1045] Referring to step D of Preparation Example D-4, compound 51-3 was substituted for compound D-3 to prepare compound 51-4 (0.47 g). MS (ESI+, [M+H]+ )m / z:324.28.

[1046] Step E:

[1047] Referring to the preparation method of compound 20_A, compound 51-4 was used instead of compound D-4 to prepare compound 51-A. 1 H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.78(dd,2H),7.41(d,1 H),7.19(d,1H),7.02(dd,1H),4.65(d,1H),4.26–4.10(m,1H),3.27(s,3H), 3.08(s,3H),2.98(d,2H),2.88–2.75(m,3H),2.44–2.35(m,1H),2.26(s,2H) ,2.20–2.03(m,2H),2.02–1.91(m,3H),1.67–1.46(m,4H).HRMS(ESI+,[M+H] + )m / z:575.2263.

[1048] Referring to the preparation method of compound 20_B, compound 51-4 was used instead of compound D-4 to prepare compound 51-B. 1 H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.85–7.60(m,2H),7. 41(d,1H),7.19(d,1H),7.02(dd,1H),4.65(d,1H),4.23–4.15(m,1H),3.27 (s,3H),3.08(s,3H),2.98(d,2H),2.81(q,3H),2.38(d,1H),2.26(s,2H), 2.20–2.05(m,2H),2.05–1.80(m,3H),1.65–1.48(m,4H).HRMS(ESI+,[M+H] + )m / z:575.2268.

[1049] Example 52

[1050] Step A:

[1051] Compound 52-1 (2 g), compound B-2 (2.2 g), trimethylaluminum (2 mol / L toluene solution, 5 mL), and toluene (50 mL) were added sequentially to a 250 mL single-necked flask and heated under reflux at 120°C for 2 h under nitrogen. After the reaction, 150 mL of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 90 / 10) to obtain compound 52-2 (1.5 g). MS (ESI+, [M+H] + )m / z:498.97.

[1052] Step B:

[1053] Compound 52-2 (1.5 g) and dichloromethane (30 mL) were added to a 100 mL three-necked flask in sequence. Trifluoroacetic acid (19.14 mL) was slowly added under ice bath and stirred at room temperature for 3 h. After the reaction, 100 mL of saturated sodium bicarbonate solution was added and extracted with DCM (3×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 52-3 (1.2 g). MS (ESI+, [M+H] + )m / z:398.92

[1054] Step C:

[1055] Compound 52-3 (1.2 g), NMP (10 mL), and DIEA (1 mL) were added sequentially to a 100 mL single-necked flask and heated to 120°C for 8 h. After the reaction, 100 mL of water was added to the reaction solution, and the mixture was extracted with EA (3×50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE / EA=4 / 1) to obtain compound 52-4 (820 mg). MS (ESI+, [M+H] + )m / z:318.99.

[1056] Step D:

[1057] Compound 52-4 (820 mg) and DMF (10 mL) were added sequentially to a 100 mL single-necked flask. NaH (125 mg) was added under ice bath, stirred for 5 min, and then iodomethane (480 mg) was added. The mixture was reacted at room temperature for 1 h. After the reaction, 100 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with EA (3 × 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, slurried with 20 mL of petroleum ether, and filtered to obtain compound 52-5 (310 mg). MS (ESI+, [M+H] + )m / z:333.01.

[1058] Step E:

[1059] Referring to step C of Example 23, compound 52-5 was substituted for compound 21-1 to prepare compound 52 (180 mg). MS (ESI+, [M+H] + )m / z:576.21.

[1060] Step F:

[1061] Compound 52 (180 mg) was subjected to chiral HPLC separation (model: (R,R) Whelk-O1, 4.6×250 mm, 5 μm; mobile phase: n-hexane / dichloromethane / ethanol = 45 / 40 / 15; flow rate: 1 mL / min) to give Compound 52_A (60 mg, retention time: 8.889 min) and Compound 52_B (60 mg, retention time: 10.070 min).

[1062] Compound 52_A: 1 H NMR(500MHz,DMSO-d6)δ13.47(s,1H),10.27(s,1H),8.55(s,1H),8.10(d,1H),7.28(d,1H),7.21–7.12(m,1H),4.70–4.61(m,1H),4 .45–4.36(m,1H),3.33(s,3H),3.13(s,3H),3.04–2.88(m,5H),2.49–2.42(m,1H),2.37–1.59(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:576.2209.

[1063] Compound 52_B: 1 H NMR(500MHz,DMSO-d6)δ13.47(s,1H),10.27(s,1H),8.55(s,1H),8.10(d,1H),7.28(d,1H),7.18–7.13(m,1H),4.70–4.61(m,1H),4 .44–4.38(m,1H),3.33(s,3H),3.13(s,3H),3.05–2.90(m,5H),2.49–2.42(m,1H),2.35–1.64(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m / z:576.2210.

[1064] Example 53

[1065] To a 50 mL single-necked flask, compound 51-4 (300 mg), compound 21-2A (342 mg), Pd2(dba)3 (85 mg), Xant-Phos (107 mg), cesium carbonate (907 mg), and dioxane (15 mL) were added sequentially and dissolved. Under nitrogen, the mixture was heated at 100°C for 4 h. After completion of the reaction, 30 mL of distilled water was added to the reaction solution, and the mixture was extracted with EA (20 mL × 3), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 1 / 1) to obtain compound 53-A (254 mg). 1 H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.89–7.70(m,2H),7.4 1(d,1H),7.19(d,1H),7.10–6.91(m,1H),4.65(d,1H),4.28–4.05(m,1H),3 .08(s,3H),2.98(d,2H),2.89–2.71(m,3H),2.49–2.32(m,1H),2.26(s,2H) ,2.19–2.04(m,2H),1.98–1.79(m,3H),1.64–1.51(m,4H).HRMS(ESI+,[M+H] + )m / z:578.2458.

[1066] Referring to the preparation method of compound 53_A, compound 21-2B was used instead of compound 21-2A to prepare compound 53_B. 1 H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.87–7.69(m,2H),7.41(d,1H),7.19(d,1H),7.12–6.95(m,1H),4.65(d,1H),4.29–4. 15(m,1H),3.08(s,3H),2.98(d,2H),2.89–2.65(m,3H),2.40(s,1H),2.26(s,2H),2.20–1.87(m,5H),1.67–1.49(m,4H).HRMS(ESI+,[M+H] + )m / z:578.2470.

[1067] Example 54

[1068] Step A:

[1069] Referring to step C of Example 49, 2-hydroxy-1-sulfonamide was used instead of methylsulfonamide to obtain compound 54-1. MS (ESI+, [M+H] + )m / z:354.05

[1070] Step B:

[1071] Referring to the preparation method of Example 43, Compound 54 was prepared by replacing Compound 34-6 with Compound 54-1. 1 H NMR(500MHz,DMSO-d6)δ11.58(s,1H),10.05(s,1H),7.87(d,1H),7.73(d,1H),7.4 1(d,1H),7.07(d,1H),6.95(dd,1H),4.92(s,1H),4.60–4.51(m,1H),4.25–4.13(m ,1H),3.74(t,2H),3.72–3.66(m,2H),3.30(s,1H),2.90–2.79(m,1H),2.44–2.34( m,1H),2.25–1.82(m,8H),1.78–1.64(m,3H),1.59–1.44(m,3H).HRMS(ESI+,[M+H] + )m / z:608.2554.

[1072] Example 55

[1073] Step A:

[1074] Referring to step E of Preparation Example A-6, Compound 51-1 was substituted for Compound A-5 to prepare Compound 55-1. MS (ESI+, [M+H] + )m / z:357.00.

[1075] Step B:

[1076] Referring to step C of Preparation Example A-6, Compound 55-1 was substituted for Compound A-3 to prepare Compound 55-2. MS (ESI-, [MH] - )m / z:354.07.

[1077] Step C:

[1078] Referring to step B of Example 54, compound 55 was prepared by replacing compound 54-1 with compound 55-2. 1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.04(s,1H),7.91–7.59(m,2H),7.41(d,1H) ,7.20(d,1H),7.02(dd,1H),5.09–4.77(m,1H),4.72–4.54(m,1H),4.24–4.09(m,1H ),3.80–3.71(m,2H),3.33–3.30(m,2H),3.02–2.94(m,2H),2.87–2.75(m,3H),2.43 –2.36(m,1H),2.26(s,2H),2.18–1.90(m,5H),1.63–1.50(m,4H).HRMS(ESI+,[M+H] + )m / z:608.2543.

[1079] Example 56

[1080] Step A:

[1081] Referring to step D of Example 14, compound 56-1 was prepared by replacing iodomethane with iodoethane. 1 H NMR(500MHz,DMSO-d6)δ7.32(d,1H),6.98(d,1H),4.55–4.51(m,1H),4.25–4.22(m,1H),3.95–3.8 4(m,2H),2.84–2.79(m,1H),2.47–2.40(m,1H),2.20–2.07(m,2H),2.03–1.89(m,1H),1.10(t,3H).

[1082] Step B:

[1083] To a 100 mL single-necked flask, compound 56-1 (0.214 g), compound 51-4 (0.200 g), Pd2(dba)3 (0.028 g), Xant-Phos (0.036 g), and cesium carbonate (0.604 g) were added in sequence, dissolved in dioxane (10 mL), and heated to 100°C under N2 protection for 6 h. After completion of the reaction, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain compound 56 (265 mg). 1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.80–7.77(m,2H),7.47(d ,1H),7.19(d,1H),7.02(dd,1H),4.65–4.62(m,1H),4.18–4.15(m,1H),4.04–3 .86(m,2H),3.08(s,3H),2.98(d,2H),2.85–2.77(m,3H),2.41–2.36(m,1H),2. 26(s,2H),2.13–1.90(m,5H),1.64–1.51(m,4H),1.14(t,3H).HRMS(ESI+,[M+H] + )m / z:589.2385.

[1084] Example 57

[1085] To a 100 mL single-necked flask, compound 56-1 (0.198 g), compound E-4 (0.200 g), Pd2(dba)3 (0.026 g), Xant-Phos (0.033 g), and cesium carbonate (0.559 g) were added in sequence, dissolved in dioxane (10 mL), and heated to 100°C under N2 protection for 6 h. After completion of the reaction, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain compound 57 (223 mg). 1 H NMR(500MHz,DMSO-d6)δ11.59(s,1H),10.10(s,1H),7.90(d,1H),7.75(d,1H),7.47(d,1H),7 .08(d,1H),6.97(dd,1H),4.66–4.62(m,1H),4.16–4.13(m,1H),3.97–3.86(m,2H),3.79–3.7 7(m,2H),3.08(s,3H),2.85–2.80(m,1H),2.55–2.52(m,1H),2.47–2.43(m,2H),2.16–1.88(m ,7H),1.14(t,3H),1.00–0.98(m,2H),0.62–0.59(m,2H),0.15–0.12(m,2H).HRMS(ESI+,[M+H] + )m / z:615.2542.

[1086] Example 58

[1087] Step A:

[1088] Referring to step D of Example 14, iodomethane was replaced with d5-deuterated iodoethane to prepare compound 58-1. MS (ESI+, [M+H] + )m / z:351.07.

[1089] Step B:

[1090] Referring to step C of Example 55, compound 58 was prepared by replacing compound 21-2B with compound 58-1. 1 H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.04(s,1H),7.79(d,1H),7.77(d,1H),7.47(d, 1H),7.20(d,1H),7.02(dd,1H),4.93(s,1H),4.68–4.60(m,1H),4.19–4.13(m,1H),3.7 8–3.69(m,2H),3.33(s,1H),3.01–2.93(m,2H),2.86–2.75(m,3H),2.43–2.35(m,1H),2 .26(s,2H),2.18–2.04(m,2H),2.04–1.89(m,4H),1.64–1.48(m,4H).HRMS(ESI+,[M+H] + )m / z:624.2824.

[1091] Example 59

[1092] Referring to the preparation method of Example 29_A, compound 59 was prepared by replacing compound 20-1A with compound 58-1. 1 H NMR(500MHz,DMSO-d6)δ11.60(s,1H),10.06(s,1H),7.89(d,1H),7.74(d,1H),7.47(d,1H),7. 10(d,1H),6.97(dd,1H),4.92(t,1H),4.69–4.58(m,1H),4.21–4.11(m,1H),3.81–3.70(m,4H), 3.34–3.30(m,2H),2.89–2.75(m,1H),2.54–2.42(m,2H),2.20–2.07(m,2H),2.06–1.97(m,4H) ,1.94–1.85(m,2H),1.05–0.95(m,2H),0.63–0.54(m,2H),0.18–0.10(m,2H).HRMS(ESI+,[M+H] + )m / z:650.2970.

[1093] Example 60

[1094] Referring to step B of Example 56, compound 60 was prepared by replacing compound 56-1 with compound 58-1. 1 H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.79(dd,2H),7.47(d,1H),7.19(d,1H),7.02(dd,1H),4.64(d,1H),4.23–4.13(m,1 H),3.08(s,3H),2.98(d,2H),2.88–2.74(m,3H),2.45–2.34(s,1H),2.26(s,2H),2.20–1.85(m,5H),1.67–1.48(m,4H).HRMS(ESI+,[M+H] + )m / z:594.2713.

[1095] Example 61

[1096] Referring to the preparation method of Example 57, Compound 61 was prepared by replacing Compound 56-1 with Compound 58-1. 1 H NMR(500MHz,DMSO-d6)δ11.59(s,1H),10.10(s,1H),7.90(d,1H),7.75(d,1H),7.4 7(d,1H),7.08(d,1H),6.97(dd,1H),4.64(d,1H),4.15(dd,1H),3.86–3.70(m,2H) ,3.08(s,3H),2.87–2.76(m,1H),2.56–2.52(m,1H),2.49–2.40(m,2H),2.26–1.81 (m,7H),1.07–0.95(m,2H),0.68–0.53(m,2H),0.25–0.08(m,2H).HRMS(ESI+,[M+H] + )m / z:620.2866.

[1097] Example 62

[1098] Step A:

[1099] To a 100 mL single-necked flask, compound 14-4 (0.5 g), cyclopropylboronic acid (0.15 g), pyridine (0.13 g), sodium carbonate (0.37 g), copper acetate (0.31 g), and DCE (30 mL) were added sequentially and heated to 60°C for 4 h. After completion of the reaction, the mixture was filtered through celite, and the filtrate was washed sequentially with saturated aqueous sodium bicarbonate (20 mL), 2N aqueous hydrochloric acid (20 mL), and saturated brine (30 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA = 1 / 3) to obtain compound 62-1 (420 mg). 1 H NMR(500MHz,DMSO-d6)δ7.46(d,1H),7.04(d,1H),4.49–4.39(m,1H),4.19–4.10(m,1H),2.85–2.76(m,1H),2.7 5–2.67(m,1H),2.45–2.37(m,1H),2.19–1.87(m,3H),1.14–1.03(m,2H),0.69–0.60(m,1H),0.58–0.47(m,1H).

[1100] Step B:

[1101] Referring to the preparation method of compound 53_A, compound 62-1 was used to replace compound 21-2A to prepare compound 62. 1 H NMR(500MHz,DMSO-d6)δ10.88(s,1H),10.07(s,1H),7.89–7.72(m,2H),7.63(d,1H),7.19 (d,1H),7.13–6.92(m,1H),4.53(d,1H),4.15–4.01(m,1H),3.08(s,3H),2.98(d,2H),2.8 9–2.79(m,2H),2.79–2.60(m,2H),2.42–2.33(m,1H),2.26(s,2H),2.19–2.05(m,2H),2.0 7–1.88(m,5H),1.67–1.45(m,2H),1.25–1.02(m,2H),0.66–0.56(m,2H).HRMS(ESI+,[M+H] + )m / z:601.2405.

[1102] Example 63

[1103] Referring to step C of Example 55, compound 63 was prepared by replacing compound 21-2B with compound 62-1. 1H NMR(500MHz,DMSO-d6)δ10.89(s,1H),10.04(s,1H),7.83(d,1H),7.78(d,1H),7.63(d,1 H),7.21(d,1H),7.12–6.94(m,1H),4.93(s,1H),4.53(d,1H),4.15–4.04(m,1H),3.85–3 .69(m,2H),2.97(d,2H),2.88–2.66(m,4H),2.37(s,1H),2.26(s,2H),2.17–1.87(m,5H) ,1.69–1.41(m,4H),1.25(d,2H),1.20–1.01(m,2H),0.66–0.56(m,2H).HRMS(ESI+,[M+H] + )m / z:631.2485.

[1104] Example 64

[1105] Referring to the preparation method of compound 61, compound 64 was prepared by replacing compound 58-1 with compound 62-1. 1 H NMR(500MHz,DMSO-d6)δ11.63(s,1H),10.10(s,1H),7.91(d,1H),7.78(d,1H),7.62(d,1H),7. 08(d,1H),6.97(dd,1H),4.62–4.50(m,1H),4.09–4.02(m,1H),3.82–3.73(m,2H),3.08(s,3H), 2.85–2.76(m,1H),2.75–2.70(m,1H),2.57–2.38(m,3H),2.18–1.89(m,7H),1.17–1.07(m,2H) ,1.02–0.95(m,2H),0.69–0.63(m,1H),0.63–0.52(m,3H),0.19–0.10(m,2H).HRMS(ESI+,[M+H] + )m / z:627.2548.

[1106] Example 65

[1107] Referring to the preparation method of compound 64, compound 29-2 was used to replace compound E-4 to prepare compound 65. 1H NMR(500MHz,DMSO-d6)δ11.63(s,1H),10.06(s,1H),7.90(d,1H),7.77(d,1H),7.62(d,1H),7. 10(d,1H),6.97(dd,1H),4.92(t,1H),4.62–4.49(m,1H),4.10–4.02(m,1H),3.81–3.70(m,4H), 3.34–3.29(m,2H),2.86–2.76(m,1H),2.75–2.70(m,1H),2.57–2.36(m,3H),2.19–1.88(m,7H) ,1.15–1.06(m,2H),1.03–0.95(m,2H),0.70–0.52(m,4H),0.19–0.05(m,2H).HRMS(ESI+,[M+H] + )m / z:657.2664.

[1108] Example 66

[1109] Step A:

[1110] Compound 66-1 (2 g) and methanol (30 mL) were added to a 100 mL single-necked flask in sequence. Under nitrogen protection, the mixture was cooled in an ice bath and then NBS (6.57 g) was added. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the solvent was evaporated under reduced pressure and the mixture was purified by silica gel column chromatography (PE / EA = 90 / 10) to obtain compound 66-2 (2.3 g). MS (ESI-, [MH] - )m / z:273.75.

[1111] Step B:

[1112] Referring to step A of Example 14, compound 66-2 was substituted for compound 14-1 to prepare compound 66-3. MS (ESI-, [MH] - )m / z:520.98.

[1113] Step C:

[1114] Referring to step B of Example 14, compound 66-3 was substituted for compound 14-2 to prepare compound 66-4. MS (ESI-, [MH] - )m / z:420.88.

[1115] Step D:

[1116] Referring to step C of Example 14, compound 66-4 was substituted for compound 14-3 to prepare compound 66-5. MS (ESI-, [MH] -)m / z:340.95.

[1117] Step E:

[1118] Referring to step D of Example 14, compound 66-5 was substituted for compound 14-4 to prepare compound 66-6 (120 mg). MS (ESI+, [M+H] + )m / z:357.01.

[1119] Step F:

[1120] Referring to the preparation method of compound 53_A, compound 66-6 was substituted for compound 21-2A to prepare compound 66 (30 mg). MS (ESI+, [M+H] + )m / z:600.21.

[1121] Example 67

[1122] Referring to step A of Example 33, compound 67 was prepared by replacing compound 21-1 with compound 66-6.

[1123] 1 H NMR(500MHz,DMSO-d6)δ11.90(s,1H),10.15(s,1H),7.96–7.86(m,2H),7.09(d,1H),7.03–6.96(m, 1H),4.55(d,1H),4.28–4.21(m,1H),3.82–3.72(m,2H),3.55(s,3H),3.09(s,3H),2.96–2.87(m,1H),2.48– 2.36(m,3H),2.22–1.88(m,7H),1.05–0.96(m,2H),0.64–0.53(m,2H),0.18–0.09(m,2H).HRMS(ESI+,[M+H] + )m / z:626.2342.

[1124] Experimental Example 1 KIF18A protein motor activity inhibition experiment

[1125] KIF18A (1-374) protein (manufacturer: Cytoskeleton Inc) was diluted to 50 nM using a buffer containing tubulin (manufacturer: Cytoskeleton Inc) and paclitaxel, and 3 μL was added to the detection wells per well. Different compounds dissolved in DMSO were added to the detection wells using a nanoliter pipette to make the final concentration of the compound 1000 nM-0.244 nM. Two replicate wells were used, and a control was set up at the same time. The above system was incubated for 15 minutes. ATP (187.5 nM) was added to the detection wells at 2 μL per well, reacted at room temperature for 15 minutes, and then ADP-Glo ​​reagent (manufacturer: Promega) was added to the detection wells at 5 μL per well and incubated at room temperature for 40 minutes. Kinase Detection reagent (manufacturer: Promega) was then added at 10 μL per well and incubated at room temperature for 40 minutes. Luminescence module detection was performed using an Envision multifunctional microplate reader, and four-parameter fitting was used to calculate IC 50 .

[1126] The experimental results are shown in Table 1.

[1127] Table 1

[1128] Note: A stands for IC 50 ≤150nM; B means 150nM<IC 50 ≤500nM.

[1129] Test Example 2 Cell proliferation inhibition experiment

[1130] 2.1 Determination of OVCAR3 cell proliferation inhibitory activity

[1131] Take OVCAR3 cells that are in good growth state, collect them into a centrifuge tube, and adjust the cell density to 4×10 4 Cells were inoculated with 100 μL / well of the sample into a 96-well plate and cultured overnight in a cell culture incubator. Compounds were added using a nanoliter pipette to a final concentration of 2000 nM to 0.91 nM in duplicate wells, with a control set. After 7 days of culture in the cell culture incubator, the detection reagent CCK-8 (Beijing Tongren Chemical, 10 μL / well) was added. After 2 hours of incubation in the cell culture incubator, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the IC. 50 .

[1132] Some experimental results are shown in Table 2A.

[1133] Table 2A

[1134] Note: A stands for IC50 ≤150nM; B means 150nM<IC 50 ≤500nM; C means 500nM<IC 50 ≤1000nM.

[1135] 2.2 MDA-MB-468 cell proliferation inhibitory activity assay

[1136] Take MDA-MB-468 cells that are in good growth state, collect them into a centrifuge tube, and adjust the cell density to 2×10 4 Cells were inoculated with 100 μL / well of the sample into a 96-well plate and cultured overnight in a cell culture incubator. Compounds were added using a nanoliter pipette to a final concentration of 2000 nM to 0.91 nM in duplicate wells, with a control set. After 7 days of culture in the cell culture incubator, the detection reagent CCK-8 (Beijing Tongren Chemical, 10 μL / well) was added. After 2 hours of incubation in the cell culture incubator, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the IC. 50 .

[1137] The experimental results are shown in Table 2B.

[1138] Table 2B

[1139] Note: A stands for IC 50 ≤150nM; B means 150nM<IC 50 ≤500nM; C means 500nM<IC 50 ≤1000nM.

[1140] Test Example 3 Liver microsome stability experiment

[1141] Liver microsomal incubation samples were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml), test compound, and NADPH + MgCl₂ solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml), and test compound. The sample was added to acetonitrile containing an internal standard for protein precipitation, and the supernatant was prepared. The supernatant was diluted and used for LC / MS / MS analysis.

[1142] Some experimental results are shown in Tables 3 and 4.

[1143] Table 3 Stability of human liver microsomes

[1144] Table 4 Mouse liver microsome stability

[1145] Test Example 4 Pharmacokinetics in mice

[1146] ICR mice weighing 18-22 g were randomly divided into groups of 9 after acclimation for 3-5 days and injected intravenously with the test compound solution at a dose of 1 mg / kg body weight or orally with the test compound solution at a dose of 10 mg / kg body weight.

[1147] The time points for intravenous blood collection are 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, and 24h, and the time points for gavage blood collection are 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, and 24h. Blood is collected from the eye sockets to prepare plasma samples for testing.

[1148] 30 μL of plasma sample to be tested and standard curve sample were taken, and acetonitrile solution containing internal standard was added to obtain protein precipitation to obtain supernatant, which was diluted and used for LC / MS / MS determination.

[1149] The non-compartmental model was used to fit the pharmacokinetic parameters.

[1150] Conclusion: The compounds of the present application have good pharmacokinetic properties. For example, some of the compounds of the present application showed higher exposure, longer half-life and higher bioavailability in mice.

[1151] Test Example 5 In vivo efficacy evaluation

[1152] 5.1 Pharmacodynamic Evaluation in the OVCAR-3 Human Ovarian Cancer B-NDG Mouse Xenograft Model

[1153] OVCAR-3 cells (source: Zhejiang Meisen) were subcutaneously inoculated in the right axilla of SPF female B-NDG mice (source: Biocytogen). 1×10 7 F1 generation mice (PBS: Matrigel = 1:1) were used. F1 generation mouse tumor tissue was inoculated into the right axillary subcutaneous tissue of SPF female nude mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) using the plug method. When the average tumor volume reached 100-200mm 3 The animals were divided into a control group and a treatment group, with 6 animals in each group.

[1154] The day of grouping was designated Day 0. Dosing was performed by gavage once daily. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. General performance of the mice was observed and recorded daily. Tumors were removed, weighed, and photographed at the end of the experiment.

[1155] The detection indicators and calculation formulas are as follows:

[1156] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[1157] R...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, X 1 and Y 1 Connect to form structural units And Y 2 Select from N or CR Y2 ; Or, X 1 and Y 2 Connect to form structural units And Y 1 Select from N or CR Y1 ; X 1 Select from N or CR X1 ; X 2 Select from N or CR X2 ; X 1 With X 2 Connect via a single button; Z 1 , Z 2 or Z 3 Each independently selected from N or CR Z1 ; Z 4 or Z 5 Each independently selected from N or CR Z2 ; Ring A is selected from a Substituted: 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Each R X1 , R X2 , R Y1 , R Y2 , R Z1 or R Z2 are each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; Ring B is selected from optionally substituted with one or more R b Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Each R a or R b are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; Ring C is selected from optionally substituted with one or more R c1 Substituted as follows: 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl; Each R c1 are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1- 12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3- 12-membered heterocyclic group; Alternatively, two R on the same ring atom c1 and R c1 The connected ring atoms together form an optionally substituted ring with one or more R c2 Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl; Alternatively, two R located on two adjacent ring atoms c1 and R c1 The connected ring atoms together form an optionally substituted ring with one or more R c2 Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl; Each R c2 are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1- 12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; L 1 Selected from single bond, -O-, -S-, -NR L1 -、C 1-6 Alkylene, deuterated C 1-6 Alkylene, halogenated C 1-6 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)NR L1 -、-C(O)NR L1 -、-NR L1 C(O)-、-NR L1 C(O)O-、-NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, or -C=N(OH)-; Each R L1 Each independently selected from H, deuterium, or optionally one or more R L1a Substituted with the following groups: C 1-6 Alkyl, deuterated C 1- 6-membered alkyl, 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclyl, 6-10-membered aryl, or 5-10-membered heteroaryl; Each R L1a are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1- 12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally with one or more R 1a Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl 1-6 Alkylene, 3-12 membered cycloalkenyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 Alkylene; Each R 1a are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-12 Alkyl, deuterated C 1- 12 Alkyl, hydroxyl C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; L 2 Selected from -O-, -S-, -NR L2 -、C 1-6 Alkylene, deuterated C 1-6 Alkylene, halogenated C 1-6 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L2 -、-NR L2 S(O)2-, -S(O)(=NH)-, -NR L2 S(O)(=NH)-, or -C=N(OH)-; R L2 Selected from H, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl; The R X1 , R X2 , R Y1 , R Y2 , R Z1 , R Z2 , R a , R b , R c1 , R c2 , R L1 , R L1a , R 1 , R 1a , or R L2 Optionally substituted with one or more substituents.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: X 1 Selected from N; Or, X 1 Selected from CR X1 ; Or, X 1 Selected from CH; Or, X 2 Selected from N; Or, X 2 Selected from CR X2 ; Or, X 2 Selected from CH.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: X 1 and Y 1 Connect to form structural units And Y 2 Selected from CR Y2 ; or, X 1 and Y 2 Connect to form structural units And Y 1 Selected from CR Y1 ; Or, X 1 and Y 1 Connect to form structural units And Y 2 Selected from CR Y2 ; or, X 1 and Y 2 Connect to form structural units And Y 1 Selected from N; Or, X 1 and Y 1 Connect to form structural units And Y 2 Selected from N; or, X 1 and Y 2 Connect to form structural units And Y 1 Selected from CR Y1 ; Or, X 1 and Y 1 Connect to form structural units And Y 2 Selected from N; or, X 1 and Y 2 Connect to form structural units And Y 1 Selected from N; Or, X 1 and Y 1 Connect to form structural units And Y 2 Select from N or CR Y2 ; Or, X 1 and Y 2 Connect to form structural units And Y 1 Select from N or CR Y1 .

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: Z 1 、Z 2 和Z 3 are CR Z1 ; Or, Z 1 and Z 2 N, Z 3 CR Z1 ; Or, Z 1 and Z 3 N, Z 2 CR Z1 ; Or, Z 2 and Z 3 N, Z 1 CR Z1 ; Or, Z 1 N, Z 2 and Z 3 CR Z1 ; Or, Z 2 N, Z 1 and Z 3 CR Z1 ; Or, Z 3 N, Z 1 and Z 2 CR Z1 ; Or, Z 4 and Z 5 CR Z2 ; Or, Z 4 For CH, Z 5 CR Z2 ; Or, Z 4 and Z 5 is N; Or, Z 4 N, Z 5 CR Z2 ; Or, Z 5 N, Z 4 CR Z2 .

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: Ring A is selected from a Substituted: 4-12 membered cycloalkenyl or 4-12 membered heterocycloalkenyl; Alternatively, ring A is selected from a Substituted: 4-10 membered cycloalkenyl or 4-10 membered heterocycloalkenyl; Alternatively, ring A is selected from a Substituted: 4-8 membered cycloalkenyl or 4-8 membered heterocycloalkenyl; Alternatively, ring A is selected from a Substituted as follows: 5-7 membered cycloalkenyl or 5-7 membered heterocycloalkenyl; Alternatively, ring A is selected from a Substituted 4-12 membered heterocycloalkenyl; Alternatively, ring A is selected from a Substituted 6-7 membered heterocycloalkenyl, wherein the 6 membered heterocycloalkenyl contains 2 N atoms, and the 7 membered heterocycloalkenyl contains 1 or 2 heteroatoms selected from N or O; Alternatively, ring A is selected from a Substituted with the following groups: Alternatively, ring A is selected from a Substituted with the following groups: Alternatively, ring A is selected from the following groups:

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: Ring B is selected from optionally substituted with one or more R b Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl; Alternatively, Ring B is selected from optionally substituted with one or more R b Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocycloalkyl; Alternatively, Ring B is selected from optionally substituted with one or more R b Substituted: 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl; Alternatively, Ring B is selected from optionally substituted with one or more R b Substituted: 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl; Alternatively, Ring B is selected from optionally substituted with one or more R b Substituted as follows: 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl; Alternatively, Ring B is selected from optionally substituted with one or more R b Substituted as follows: 6-8 membered cycloalkyl or 6-8 membered heterocycloalkyl; Alternatively, Ring B is selected from optionally substituted with one or more R b Substituted as follows: 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl; Alternatively, Ring B is selected from optionally substituted with one or more R b Substituted 3-12 membered heterocycloalkyl; Alternatively, Ring B is selected from optionally substituted with one or more R b Substituted groups: cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, Alternatively, Ring B is selected from optionally substituted with one or more R b Substituted with the following groups: Alternatively, ring B is selected from Alternatively, the structural unit Selected from optionally one or more R b Substituted with the following groups: in The other end is connected to Y 1 or Y 2 ; Alternatively, the structural unit Selected from in The other end is connected to Y 1 or Y 2 .

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: Ring C is selected from optionally substituted with one or more R c1 Substituted: 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl; Alternatively, Ring C is selected from optionally substituted with one or more R c1 Substituted as follows: 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl; Alternatively, Ring C is selected from optionally substituted with one or more R c1 Substituted as follows: 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl; Alternatively, Ring C is selected from optionally substituted with one or more R c1 Substituted as follows: 6-8 membered cycloalkyl or 6-8 membered heterocycloalkyl; Alternatively, Ring C is selected from optionally substituted with one or more R c1 Substituted 3-12 membered heterocycloalkyl; Alternatively, Ring C is selected from optionally substituted with one or more R c1 Substituted with the following groups: Alternatively, Ring C is selected from optionally substituted with one or more R c1 Substituted with the following groups: Alternatively, ring C is selected from Alternatively, ring C is selected from 8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: L 1 Selected from single bond, -O-, -S-, -NR L1 -、C 1-4 Alkylene, deuterated C 1-4 Alkylene, halogenated C 1-4 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -、-NR L1 C(O)-、-NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, -C=N(OH)-, -OC(O)O-, -OC(O)NR L1 -, or -NR L1 C(O)O-; Or, L 1 Selected from single bond, -O-, -S-, -NR L1 -, methylene, deuterated methylene, ethylene, deuterated ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -、-NR L1 C(O)-、-NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, -C=N(OH)-, -OC(O)O-, -OC(O)NR L1 -, or -NR L1 C(O)O-; Or, L 1 Selected from single bond, -O-, -S-, -NR L1 -, methylene, ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -、-NR L1 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -, or -S(O)(=NH)-; Or, L 1 Selected from single bond, -O-, -S-, -NR L1 -、-C(O)NR L1 -、-NR L1 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-、-NR L1 S(O)2NR L1 -, or -S(O)(=NH)-; Or, L 1 Selected from -S(O)2NR L1 -or-NR L1 S(O)2-.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally with one or more R 1a Substituted with the following groups: C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Or, R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally with one or more R 1a Substituted with the following groups: C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl 1-4 Alkylene, 3-10 membered cycloalkenyl C 1-4 Alkylene, 3-10 membered heterocyclic group C 1-4 Alkylene, 6-10 membered aryl C 1-4 Alkylene, or 5-10 membered heteroaryl C 1-4 Alkylene; Or, R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally with one or more R 1a Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl 1-4 Alkylene, 3-8 membered cycloalkenyl C 1-4 Alkylene, 3-8 membered heterocyclic group C 1-4 Alkylene, phenyl C 1-4 Alkylene, or 5-6 membered heteroaryl C 1- 4 Alkylene; Or, R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally with one or more R 1a Substituted with the following groups: C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-7 membered cycloalkenyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl 1-3 Alkylene, 4-7 membered cycloalkenyl C 1-3 Alkylene, 4-7 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1- 3 alkylene; Or, R 1 is selected from H, halogen, deuterium, -OH, -NH2, -SH, -COOH, -CN, or optionally with one or more R 1a Substituted with the following groups: C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, 3-6 membered cycloalkylC 1-2 Alkylene, or 4-7 membered heterocycloalkyl C 1- 2 alkylene; Or, R 1 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -SH, -COOH, -CN, or optionally with one or more R 1a substituted with: methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thiazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, piperidinyl, piperazinyl, morpholinyl, cyclopropylmethylene, cyclobutylmethylene, azetidinylmethylene, or oxetanylmethylene; Or, R 1 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -SH, -COOH, -CN, or optionally with one or more R 1a Substituted with the following groups: methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thiazinyl, isothiazolidinyl, thiadiazolidinyl, tetrahydrofuranyl, or cyclopropylmethylene; Or, R 1 is selected from methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, tert-butyl, cyclopropyl, 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: L 2 Selected from -O-, -S-, -NR L2 -、C 1-4 Alkylene, deuterated C 1-4 Alkylene, halogenated C 1-4 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L2 -, or -NR L2 S(O)2-; Or, L 2 Selected from -O-, -S-, -NR L2 -, methylene, deuterated methylene, ethylene, deuterated ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L2 -, or -NR L2 S(O)2-; Or, L 2 Selected from ethylene, -C(O)O-, -OC(O)-, -C(O)NR L2 -、-NR L2 C(O)-、-S(O)2NR L2 -, or -NR L2 S(O)2-; Or, L 2 Selected from -C(O)NR L2 -, or -NR L2 C(O)-.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is selected from a compound of formula (II) or formula (II-1) or formula (II-2) or formula (II-3) or formula (III) or formula (III-1) or formula (III-2) or formula (III-3) or a pharmaceutically acceptable salt thereof, in, X 1 , X 2 , Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , L 1 , R 1 , L 2 , Ring A, Ring B and Ring C are as defined in any one of claims 1 to 10; Alternatively, the structural unit Selected from n is selected from 0, 1, 2, 3, 4, 5, or 6; m is selected from 0, 1, 2, 3, 4, 5, or 6; Alternatively, the structural unit Selected from 12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, selected from:

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, selected from:

14. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13; optionally, further comprising a pharmaceutically acceptable excipient.

15. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating a disease.

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