Fused bicyclic compounds and medical uses thereof

Abstract

The invention belongs to the field of medical chemistry, relates to a fused bicyclic compound and medical application thereof, and particularly relates to a preparation method of the compound, a pharmaceutical composition and application of the compound in treating diseases, and the structure of the fused bicyclic compound is shown as a formula (I). # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to a fused bicyclic compound, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating diseases. Background Art

[0002] KIF18A is a mitotic kinesin that belongs to the Kinesin-8 family. KIF18A regulates correct chromosome positioning and spindle tension during mitosis. Loss of KIF18A in humans leads to longer spindles and increased chromosome oscillations in the G2 / M phase of the cell cycle. Studies have shown that KIF18A is overexpressed in whole-genome doubling (WGD) tumor cells, but is non-essential in normal cells. Inhibition of KIF18A can induce mitotic arrest in WGD tumor cells without affecting normal cells. Therefore, KIF18A is a potential anti-tumor target. DETAILED DESCRIPTION OF THE INVENTION

[0004] The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0005]

[0006] in,

[0007] Ring A is selected from a1 Substituted groups: 5-12 membered bridged cycloalkyl or 5-12 membered bridged heterocycloalkyl;

[0008] Each R a1 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, halo 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(C1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0009] Alternatively, two R on the same ring atom a1 together to form optionally one or more R a2 Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

[0010] Alternatively, two R located on two adjacent ring atoms a1 together to form optionally one or more R a2 Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

[0011] Each R a2 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, halo 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 1-12Alkyl)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;

[0012] X 1 , X 2 , X 3 , X 4 , X 5 , X 6 or X 7 Each independently selected from N or CR x ;

[0013] Each R x Each is independently selected from H, halogen, deuterium, -OH, -NH2, -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, halo 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;

[0014] 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)-, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, or -C=N(OH)-;

[0015] 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 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0016] 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, halo 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(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;

[0017] 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, or 5-10 membered heteroaryl;

[0018] 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, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halo 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;

[0019] L3 Selected from -CHR L3 -、-C(R L3 )(R L4 )-、-NR L3 -, -O-, -S-, -C(O)-, -S(O)-, or -S(O)2-;

[0020] Every R L3 or R L4 are each independently selected from H, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0021] L 2 Selected from single bond, -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 -, or -NR L2 S(O)2-;

[0022] R L2 Selected from H, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0023] R 2 is selected from H, deuterium, halogen, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 2a 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;

[0024] Each R 2a are each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-6 Alkyl, C 1-6 Deuterated 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 C1-6 Alkylthio, halo 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, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0025] R 3 , R 4 Each is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, 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, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 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 1-6Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0026] The R a1 , R a2 , R x , R L1a , R 1a , R L3 , R L4 , R L2 , R 2a , R 3 , R 4 Optionally substituted with one or more substituents.

[0027] In some embodiments, the R a1 , R a2 , R x , R L1a , R 1a , R L3 , R L4 , R L2 , R 2a , R 3 , R 4 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 1-12 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 2-12 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 1-12alkylthio, 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 group, oxo and thio, etc., wherein the substituent is optionally substituted by one or more substituents selected from the following: deuterium atom, 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, halo 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 cycloalkylC 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 Alkylene or 6-10 membered aryloxy.

[0028] In some embodiments, the R a1 , R a2 , R x , R L1a , R 1a , R L3 , R L4 , R L2 , R 2a , R 3 , R 4 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.

[0029] In some embodiments, Ring A is selected from a1 Substituted: 5-10 membered bridged cycloalkyl or 5-10 membered bridged heterocycloalkyl.

[0030] In some embodiments, Ring A is selected from a1 Substituted: 6-9 membered bridged cycloalkyl or 6-9 membered bridged heterocycloalkyl.

[0031] In some embodiments, Ring A is selected from a1 Substituted: 7-8 membered bridged cycloalkyl or 7-8 membered bridged heterocycloalkyl.

[0032] In some embodiments, Ring A is selected from a1 Substituted 5-12 membered bridged heterocycloalkyl. In some embodiments, the 5-12 membered bridged heterocycloalkyl is selected from 5-10 membered bridged heterocycloalkyl, 6-9 membered bridged heterocycloalkyl, or 7-8 membered bridged heterocycloalkyl.

[0033] In some embodiments, Ring A is selected from a1 Substituted with the following groups:

[0034] In some embodiments, the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.

[0035] In some embodiments, each R a1 are 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, C1-8 Alkylamino, di-C 1-8 Alkylamino, halo C 1-8 Alkyl, halogenated C 1-8 Alkoxy, halogenated C 1-8 Alkylthio, halo 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 1-8 Alkyl)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;

[0036] Alternatively, two R on the same ring atom a1 together to form optionally one or more R a2 Substituted: 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl or 3-10 membered heterocyclyl;

[0037] Alternatively, two R located on two adjacent ring atoms a1 together to form optionally one or more R a2 Substituted: 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl or 3-10 membered heterocyclyl.

[0038] In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.

[0039] In some embodiments, each R a1 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, halo C 1-8Alkyl, halogenated C 1-8 Alkoxy, halogenated C 1-8 Alkylthio, halo 1-8 Alkylamino, or halogenated di-C 1-8 Alkylamino;

[0040] Alternatively, two R on the same ring atom a1 together to form optionally one or more R a2 Substituted: 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;

[0041] Alternatively, two R located on two adjacent ring atoms a1 together to form optionally one or more R a2 Substituted: 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl.

[0042] In some embodiments, each R a1 are 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, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 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;

[0043] Alternatively, two R on the same ring atom a1 together to form optionally one or more R a2 Substituted: 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl;

[0044] Alternatively, two R located on two adjacent ring atoms a1 together to form optionally one or more R a2 Substituted: 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl.

[0045] In some embodiments, the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.

[0046] In some embodiments, each R a1 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, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino;

[0047] Alternatively, two R on the same ring atom a1 together to form optionally one or more R a2 Substituted as follows: 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;

[0048] Alternatively, two R located on two adjacent ring atoms a1 together to form optionally one or more R a2 Substituted: 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl.

[0049] In some embodiments, each R a1 are 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C1-4 Alkylthio, halo 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, 6 membered aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl;

[0050] Alternatively, two R on the same ring atom a1 together to form optionally one or more R a2 Substituted: 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl or 3-6 membered heterocyclyl;

[0051] Alternatively, two R located on two adjacent ring atoms a1 together to form optionally one or more R a2 Substituted: 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl or 3-6 membered heterocyclyl.

[0052] In some embodiments, the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.

[0053] In some embodiments, each R a1 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino;

[0054] Alternatively, two R on the same ring atom a1 together to form optionally one or more R a2 Substituted as follows: 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;

[0055] Alternatively, two R located on two adjacent ring atoms a1 together to form optionally one or more R a2 Substituted: 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.

[0056] In some embodiments, each R a1 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;

[0057] Alternatively, two R on the same ring atom a1 together to form optionally one or more R a2 substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl;

[0058] Alternatively, two R located on two adjacent ring atoms a1 together to form optionally one or more R a2 Substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl.

[0059] In some embodiments, each R a1 Each is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, methylamino, dimethylamino, trifluoromethyl, trifluoromethoxy;

[0060] Alternatively, two R on the same ring atom a1 together to form optionally one or more R a2 Substituted cyclopropyl.

[0061] In some embodiments, each R a2are 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, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 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.

[0062] In some embodiments, each R a2 are 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -COC 1-4 Alkyl, -OC(O)C 1-4 Alkyl, -C(O)OC 14Alkyl, -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.

[0063] In some embodiments, each R a2 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0064] In some embodiments, each R a2 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.

[0065] In some embodiments, each R a2 Each is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0066] In some embodiments, Ring A is selected from

[0067] In some embodiments, X 1 and X 2 Not N at the same time.

[0068] In some embodiments, X 1 and X 2 Selected from CR x .

[0069] In some embodiments, X 1 and X 2 Selected from CH.

[0070] In some embodiments, X 3 , X 4 , X 5 Not N at the same time.

[0071] In some embodiments, X 3 , X 4 , X 5 At least one of them is N.

[0072] In some embodiments, X 3 , X 4 , X 5 At least two of them are N.

[0073] In some embodiments, X 3 , X 4 , X 5 Two of them are N and the other one is CR x .

[0074] In some embodiments, X 3 , X 5 Select from N, X 4 Selected from CR x .

[0075] In some embodiments, X 3 , X 5 Select from N, X 4 Selected from CH.

[0076] In some embodiments, X 3 , X 4 Select from N, X 5 Selected from CR x .

[0077] In some embodiments, X 3 , X 4 Select from N, X 5 Selected from CH.

[0078] In some embodiments, X 3 Selected from CR x, X 4 , X 5 Selected from N.

[0079] In some embodiments, X 3 Selected from CH, X 4 , X 5 Selected from N.

[0080] In some embodiments, X 6 , X 7 At least one of them is N.

[0081] In some embodiments, X 6 , X 7 One is N and the other is CR x .

[0082] In some embodiments, X 6 , X 7 are each independently selected from N.

[0083] In some embodiments, X 6 , X 7 Selected from CR x .

[0084] In some embodiments, X 1 , X 2 , X 4 Selected from CR x , X 3 , X 5 Selected from N.

[0085] In some embodiments, X 1 , X 2 , X 4 Selected from CH, X 3 , X 5 Selected from N.

[0086] In some embodiments, X 1 , X 2 , X 4 Selected from CH, X 3 , X 5 , X 6 , X 7 Selected from N.

[0087] In some embodiments, X 1 , X 2 , X 4 Selected from CH, X 3 , X 5 Select from N, X 6 , X 7 Each independently selected from CR x .

[0088] In some embodiments, X 1 , X 2 , X 4 , X 6 , X 7 Selected from CH, X 3 , X 5 Selected from N.

[0089] In some embodiments, X 1 , X 2 , X 3 Selected from CR x , X 4 , X 5 Selected from N.

[0090] In some embodiments, X 1 , X 2 , X 3 Selected from CH, X 4 , X 5 Selected from N.

[0091] In some embodiments, X 1 , X 2 , X 3 Selected from CH, X 4 , X 5 , X 6 , X 7 Selected from N.

[0092] In some embodiments, X 1 , X 2 , X 3 Selected from CH, X 4 , X 5 Select from N, X 6 , X 7 Each independently selected from CR x .

[0093] In some embodiments, X 1 , X 2 , X 3 , X 6 , X 7 Selected from CH, X 4 , X 5 Selected from N.

[0094] In some embodiments, X 1 , X 2 , X 5 Selected from CR x , X 3 , X 4 Selected from N.

[0095] In some embodiments, X 1 , X 2 , X 5 Selected from CH, X 3 , X 4 Selected from N.

[0096] In some embodiments, X 1 , X 2 , X 5 Selected from CH, X 3 , X 4 , X 6 , X 7 Selected from N.

[0097] In some embodiments, X 1 , X 2 , X 5 Selected from CH, X 3 , X 4 Select from N, X 6 , X 7 Each independently selected from CR x .

[0098] In some embodiments, X 1 , X 2 , X 5 , X 6 , X 7 Selected from CH, X 3 , X 4 Selected from N.

[0099] In some embodiments, each R x are 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, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 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 1-6Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

[0100] In some embodiments, each R x Each is independently selected from H, 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, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino.

[0101] In some embodiments, each R x are 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 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 1-4Alkyl, -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.

[0102] In some embodiments, each R x Each is 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0103] In some embodiments, each R x 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, or di(trifluoromethyl)amino.

[0104] In some embodiments, each R x Each is independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

[0105] In some embodiments, 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 L1C(O)-, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, or -C=N(OH)-.

[0106] 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)-, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, or -C=N(OH)-.

[0107] 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 L1 S(O)2-, or -S(O)(=NH)-.

[0108] In some embodiments, L 1 Selected from single bond, -O-, -S-, -NR L1 -, methylene, -C(O)NR L1 -、-S(O)2-、-S(O)2NR L1 -、-NR L1 S(O)2-, or -S(O)(=NH)-.

[0109] In some embodiments, L 1 Selected from -S(O)2NR L1 -. In some embodiments, L 1 Selected from -NR L1 S(O)2-.

[0110] In some embodiments, each R L1 Each independently selected from H, deuterium, or optionally one or more RL1a 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.

[0111] In some embodiments, 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 Alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0112] In some embodiments, each R L1 Each independently selected from H, deuterium, or optionally 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.

[0113] 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.

[0114] In some embodiments, each R L1 Each independently selected from H, deuterium, or optionally one or more R L1a Substituted C 1-4 alkyl.

[0115] In some embodiments, each R L1 Each independently selected from H, deuterium, or optionally one or more R L1a Substituted as follows: methyl, ethyl, n-propyl, or isopropyl.

[0116] In some embodiments, each R L1 are each independently selected from H.

[0117] In some embodiments, each R L1a are 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 1-6Alkylamino, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 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.

[0118] In some embodiments, each R L1a are 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 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 1-4Alkyl, -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.

[0119] 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0120] In some embodiments, each R L1a 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.

[0121] In some embodiments, each R L1a Each is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

[0122] In some embodiments, 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.

[0123] In some embodiments, R 1is 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, or 5-6 membered heteroaryl.

[0124] In some embodiments, 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, or 5-6 membered heteroaryl.

[0125] In some embodiments, 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, or 4-7 membered heterocycloalkyl.

[0126] In some embodiments, 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, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thiazetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl.

[0127] In some embodiments, R 1 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -SH, -COOH, -CN, or optionally with one or more R 1a Substituted: methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, azetidinyl, oxetanyl, or isothiazolidinyl.

[0128] In some embodiments, R 1 Selected from one or more R 1a Substituted ethyl.

[0129] In some embodiments, each R 1a are 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, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 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.

[0130] In some embodiments, each R 1a are 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 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 1-4Alkyl, -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.

[0131] In some embodiments, each R 1a 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0132] In some embodiments, each R 1a 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.

[0133] In some embodiments, each R 1a Each is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

[0134] In some embodiments, the structural unit -L 1 -R 1 Selected from

[0135] In some embodiments, the structural unit -L1 -R 1 Selected from

[0136] In some embodiments, the structural unit -L 1 -R 1 Selected from

[0137] In some embodiments, L 3 Selected from -CHR L3 -、-C(R L3 )(R L4 )-、-NR L3 -, -O-, or -S-.

[0138] In some embodiments, L 3 is selected from -CH2-, -NH-, -O-, or -S-.

[0139] In some embodiments, L 3 Selected from -NH-.

[0140] In some embodiments, each R L3 or R L4 are each independently selected from H, deuterium, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0141] In some embodiments, each R L3 or R L4 Each is independently selected from H, deuterium, methyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0142] In some embodiments, each R L3 or R L4 Each is independently selected from H or methyl.

[0143] In some embodiments, L 2 Selected from single bond, -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-.

[0144] In some embodiments, L 2Selected from single bond, -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-.

[0145] In some embodiments, L 2 Selected from single bond, -O-, -NR L2 -, -S(O)2-, or -S(O)2NR L2 -.

[0146] In some embodiments, L 2 is selected from a single bond, -O-, -NH-, -S(O)2-, or -S(O)2NH-.

[0147] In some embodiments, R L2 Selected from H, deuterium, C 1-4 Alkyl, deuterated C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0148] In some embodiments, R L2 is selected from H, deuterium, methyl, deuterated methyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0149] In some embodiments, R L2 Selected from H or methyl.

[0150] In some embodiments, R 2 is selected from H, deuterium, halogen, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 2a 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.

[0151] In some embodiments, R 2 is selected from H, deuterium, halogen, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 2a 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.

[0152] In some embodiments, R2 is selected from H, deuterium, halogen, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 2a Substituted with the following groups: C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-7 membered cycloalkenyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0153] In some embodiments, R 2 is selected from H, deuterium, halogen, -OH, -NH2, -SH, -COOH, -CN, or optionally replaced by one or more R 2a Substituted with the following groups: C 1-4 alkyl, 3-6 membered cycloalkyl, or 4-7 membered heterocycloalkyl.

[0154] In some embodiments, R 2 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -SH, -COOH, -CN, or optionally with one or more R 2a Substituted with the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or

[0155] In some embodiments, R 2 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -SH, -COOH, -CN, or optionally with one or more R 2a Substituted with the following groups: methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, cyclopentyl, azetidinyl, piperidinyl, morpholinyl, or

[0156] In some embodiments, R 2 Selected from one or more R 2a Substituted: azetidinyl, piperidinyl, or morpholinyl.

[0157] In some embodiments, each R 2a are 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, halo C 1-6 Alkyl, halogenated C 1-6Alkoxy, halogenated C 1-6 Alkylthio, halo 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.

[0158] In some embodiments, each R 2a are 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 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, -CONHC1-4 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.

[0159] In some embodiments, each R 2a 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0160] In some embodiments, each R 2a 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.

[0161] In some embodiments, each R 2a Each is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

[0162] In some embodiments, the structural unit -L 2 -R 2 Selected from methyl,

[0163] In some embodiments, the structural unit -L 2 -R 2 Selected from methyl, In some embodiments, the structural unit -L 2 -R 2 Selected from

[0164] In some embodiments, the structural unit -L 2 -R 2 Selected from

[0165] In some embodiments, the structural unit -L 2 -R 2 Selected from

[0166] In some embodiments, R 3 , R 4 are 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, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 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.

[0167] In some embodiments, R 3 , R 4 are each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, -SH, -COOH, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 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.

[0168] In some embodiments, R 3 , R 4 Each is 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, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0169] In some embodiments, R 3 , R 4Each 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, or di(trifluoromethyl)amino.

[0170] In some embodiments, R 3 , R 4 Each is independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

[0171] In some embodiments, the heterocyclic group disclosed herein is selected from heterocyclic alkyl. In some embodiments, the heterocyclic group disclosed herein is selected from partially unsaturated heterocyclic groups.

[0172] In some embodiments, the 3-12-membered, 3-10-membered, 3-8-membered, or 4-7-membered heterocyclyl group disclosed herein is selected from 3-12-membered, 3-10-membered, 3-8-membered, or 4-7-membered heterocycloalkyl groups.

[0173] 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 .

[0174] In some embodiments, the C 1-6 The alkyl group is selected from C 1-4 Alkyl, C 1-3 Alkyl, or C 1-2 alkyl.

[0175] In some embodiments, the C 1-6 The alkylene group is selected from C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 Alkylene.

[0176] In some embodiments, the halogen described herein is selected from F, Cl, Br, or I.

[0177] 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.

[0178] In some embodiments, the "one or more" described in the present disclosure may refer to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine or ten; or, "one or more" refers to one, two, three, four, five or six; or, "one or more" refers to one, two, three or four.

[0179] 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.

[0180] In some embodiments, the heterocycloalkyl group disclosed herein contains 1 or 2 heteroatoms selected from N or O.

[0181] In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 N atom.

[0182] In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 O atom.

[0183] In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 N atom and 1 O atom.

[0184] In some embodiments, the heterocyclic or heteroaryl groups disclosed herein contain 1 or 2 heteroatoms selected from N, O, or S.

[0185] In some embodiments, the heterocyclyl or heteroaryl groups disclosed herein contain 1 or 2 N atoms.

[0186] In some embodiments, the heterocyclyl or heteroaryl groups disclosed herein contain 1 N atom and 1 O atom.

[0187] In some embodiments, the heterocyclyl or heteroaryl groups disclosed herein contain 1 N atom and 1 S atom.

[0188] In some embodiments, the heterocyclic group or heterocycloalkyl group disclosed herein includes a monocyclic ring, a spirocyclic ring, a cyclic ring or a bridged ring. In some embodiments, the heterocyclic group or heterocycloalkyl group disclosed herein includes a monocyclic ring or a spirocyclic ring. In some embodiments, the heterocyclic group or heterocycloalkyl group disclosed herein includes a monocyclic ring or a bridged ring.

[0189] In some embodiments, in the compounds of formula (I) or pharmaceutically acceptable salts thereof described in the present disclosure, all hydrogen atoms may be optionally substituted with one or more deuteriums.

[0190] The present disclosure relates to a compound of formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or formula (V) or a pharmaceutically acceptable salt thereof,

[0191]

[0192] Among them, X 6 , X 7 , L 1 , R 1 , L 3 , L 2 , R 2 , R 3 , R 4 and Ring A moiety are as defined in the present disclosure.

[0193] In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0194] The present disclosure also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0195]

[0196] On the other hand, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), (II), (II-2), (II-1), (III), (III-1), (III-2), (IV), (IV-1), (IV-2) or (V) 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.

[0197] On the other hand, the present disclosure relates to a method for treating a mammalian disease, comprising administering a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or formula (V) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure to a mammal in need of such treatment, preferably a human.

[0198] On the other hand, the present disclosure relates to the use of a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2) or (V) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating a disease.

[0199] On the other hand, the present disclosure relates to the use of a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2) or (V) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in the treatment of a disease.

[0200] On the other hand, the present disclosure relates to a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2) or formula (V) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for treating a disease.

[0201] In some embodiments of the present disclosure, the disease is selected from a KIF18A-related disease.

[0202] In some embodiments of the present disclosure, the disease (eg, a KIF18A-related disease) is selected from cancer (eg, ovarian cancer, breast cancer).

[0203] Technical Effects

[0204] 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 pharmacokinetics, bioavailability, and / or pharmacodynamic studies. For example, in a mouse pharmacokinetic study, the compounds disclosed herein exhibited good pharmacokinetic properties in terms of oral absorption exposure, half-life, and absolute bioavailability; in a mouse transplant tumor model, the compounds disclosed herein exhibited good tumor inhibition effects.

[0205] definition

[0206] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be considered as indefinite or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

[0207] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced 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 oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

[0208] The "substituent" described herein includes all substituents mentioned herein, for example, including the definitions of 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, heterocyclyl alkylene, heterocyclyl alkoxy, heterocyclyl alkylthio, 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.

[0209] In some embodiments herein, 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 1-12 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 group, oxo and thio, etc., wherein the substituent is optionally substituted by one or more substituents selected from the following: deuterium atom, 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, halo 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 cycloalkylC 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 heteroarylC1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 Alkylene or 6-10 membered aryloxy.

[0210] 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.

[0211] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. 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 appreciated by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0212] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0213] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 2 R's, each R has an independent choice.

[0214] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0215] 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.

[0216] When the listed linking group does not specify its connection direction, its connection direction is arbitrary. For example, in ALZ, the linking group L is -MW-, which means that the structure can be AMWZ or AWMZ.

[0217] 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.

[0218] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0219] The term "hydroxy" refers to an -OH group.

[0220] The term "cyano" refers to a -CN group.

[0221] The term "mercapto" refers to a -SH group.

[0222] The term "amino" refers to a -NH2 group.

[0223] The term "nitro" refers to a -NO2 group.

[0224] The term "alkylene" refers to a group of the formula C n H 2n A saturated straight or branched 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.

[0225] The term "alkyl" refers to a group of the formula C n H 2n+1The alkyl group may be straight chain or branched, 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 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, heterocyclylalkyl, heterocyclylalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy. Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino and alkylthio has the same definition as above.

[0226] 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 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkyl group (e.g., internal or terminal position), including the position that connects the heteroalkyl group 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 following: 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.

[0227] 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, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0228] The term "alkylamino" refers to -NH-alkyl groups, 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, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0229] 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, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0230] 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, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0231] The term "alkenyl" refers to a linear 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, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc. The alkenyl is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

[0232] The term "alkynyl" refers to a linear 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), etc. The alkynyl is optionally substituted with one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

[0233] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10-membered ring, a 4 to 8-membered ring, a 5 to 8-membered ring or a 5 to 6-membered 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, 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.

[0234] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic ring with at least one double bond and which can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 10 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 is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, carboxyl,-C (O) O-alkyl,-OC (O)-alkyl,-C (O) NH2,-C (O) NH-alkyl,-C (O) N (alkyl) 2,-NHC (O)- Alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0235] The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, and ring or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is generally 3 to 12 yuan, 3 to 10 yuan, 4 to 8 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan of heteroatoms (preferably 1 or 2 heteroatoms) containing 1 to 3 independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron. The non-limiting examples of heterocyclic radicals include but are not limited to oxirane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc. The heterocyclic group is optionally substituted by 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.

[0236] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 12-membered, 3 to 10-membered, 4 to 8-membered, 5 to 8-membered, 5 to 6-membered, 3 to 7-membered or 4 to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and cyclonitriles; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl. The heterocycloalkyl radical 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.

[0237] The term "aryl" refers to an aromatic ring group of an all-carbon monocyclic or fused polycyclic ring having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl, etc. The aryl group is optionally substituted with one or more substituents selected from the group consisting of 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, heterocyclylalkyl, heterocyclylalkylene, heterocyclyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0238] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, S, and the remaining ring atoms are C, typically having 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7 or 5 to 6 rings. Preferred heteroaryls have a single 4 to 8 ring, especially a 5 to 6 ring, 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, furanyl, 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, 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, heterocyclylalkyl, heterocyclylalkylene, heterocyclyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0239] Unless otherwise specified, the term "deuterated C1-12 "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 The deuterated alkyl group may be C 1-6 Deuterated alkyl or C 1-3 Deuterated alkyl. Examples of deuterated alkyl include, but are not limited to, -CH2D, -CHD2,

[0240]

[0241] wait.

[0242] The group -L in the present disclosure 1 -optionally read from left to right, corresponding to the left side group and the right side group connected to the group in the general formula, for example, when -L 1 When - is -S(O)2NH-, the structure for

[0243] The group -L in the present disclosure 2 -optionally read from right to left, corresponding to the right side group and the left side group connected to the group in the general formula, for example, when -L 2 When - is -S(O)2NH-, the structure for

[0244] The term "treatment" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0245] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0246] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0247] The term "prevention" 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.

[0248] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular 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 the present disclosure.

[0249] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with 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.

[0250] 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.

[0251] 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.

[0252] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0253] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0254] 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 an imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0255] 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 may be incorporated into 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 Cl, etc. 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.

[0256] 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.

[0257] 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.

[0258] 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 form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

[0259]

[0260] The compounds of the present disclosure may have one or more atropisomers, and unless otherwise specified, the atropisomers refer to optically active isomers produced due to the obstruction of free rotation between single bonds. The compounds containing chiral axes of the present disclosure can be separated in racemic form. When the energy barrier for free rotation of single bonds of the compounds containing chiral axes of the present disclosure is high enough, the atropisomers thereof can be separated in an optically pure form.

[0261] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0262] The pharmaceutical composition of the present invention 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.

[0263] In all administration methods of the compounds of formula I described herein, the daily dosage is 0.001 to 2000 mg / kg body weight. The compounds disclosed herein can be prepared by a variety of synthesis 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 substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.

[0264] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes 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 the synthesis steps or reaction processes based on the existing embodiments.

[0265] The compound of formula (II-1) disclosed herein can be prepared by a person skilled in the art of organic synthesis via route 1, wherein R 1 , R 2 , R 3 , R 4 , X 6 , X 7 and the Ring A moiety are as defined in the present disclosure.

[0266]

[0267] The compound of formula (II-2) disclosed herein can be prepared by a person skilled in the art of organic synthesis via route 2, wherein R 1 , R 2 , R 3 , R 4 , X 6 , X 7 and the Ring A moiety are as defined in the present disclosure.

[0268]

[0269] Each product obtained by the reaction in the above route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatographic separation, 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 the present disclosure can be used to obtain a single isomer or a mixture of isomers using synthetic methods.

[0270] This disclosure uses the following abbreviations:

[0271] NMP stands for N-methylpyrrolidone; DIPEA 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; Et stands for ethyl; 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; Me stands for methyl; DMSO stands for dimethyl sulfoxide.

[0272] Commercially available compounds were given by their supplier catalog names.

[0273] For the sake of clarity, the present invention is further described with examples, but the examples are not intended to limit the scope of the present 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.

[0274] All reagents used in this disclosure were commercially available and used without further purification. Example

[0275] Preparation Example A-2

[0276]

[0277] Compound A-1 (3 g), 4,4-difluoropiperidine hydrochloride (4.94 g), NMP (30 mL) and DIPEA (7.3 mL) were added to a 100 mL single-mouth bottle in sequence, and heated to 180°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and 100 mL of water was added, extracted with ethyl acetate (3×40 mL), the organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (eluent: PE / EA=10 / 1) to obtain compound A-2 (2.54 g). 1 H NMR(500MHz,DMSO-d6)δ6.31(s,2H),5.63(s,1H),3.83–3.76(m,4H),2.06(s,3H),1.94-1.86(m,4H).MS(ESI+,[M+H] + )m / z:229.06.

[0278] Preparation Example B-2

[0279]

[0280] Referring to the synthesis method of Preparation Example A-2, morpholine was used instead of 4,4-difluoropiperidine hydrochloride to synthesize compound B-2 (900 mg). 1 H NMR(500MHz,DMSO-d6)δ6.26(s,2H),5.63(s,1H),3.58(s,8H),2.05(s,3H).MS(ESI+,[M+H] + )m / z:195.03.

[0281] Preparation Example C-3

[0282]

[0283] Step A: Compound C-1 (1 g), 4,4-difluoropiperidine hydrochloride (0.87 g), dioxane (25 mL), sodium tert-butoxide (1.34 g), Xant-Phos (0.27 g) and Pd2(dba)3 (0.21 g) were added to a 100 mL single-mouth bottle in sequence, and heated at 100 ° C for 4 h under N2 protection. After the reaction was completed, the filter was filtered, the filter cake was washed with EA (30 mL), the filtrate was concentrated, and the silica gel column chromatography was purified (eluent: PE / EA = 12.5 / 1) to obtain compound C-2 (0.7 g). 1H NMR (500MHz, DMSO-d6) δ7.54(d,J=2.3Hz,1H),7.45(s,1H),7.34–7.28(m,1H),3.46(t,J=5.8Hz,4H),2.36(s,3H),2.05(tt,J=14.0,5.8Hz,4H).

[0284] Step B: Compound C-2 (0.75 g), ethanol (10 mL), saturated ammonium chloride solution (10 mL) and iron powder (0.98 g) were added to a 100 mL single-mouth bottle in sequence, and heated at 80 ° C for 4 h under N2 protection. After the reaction was completed, the filter was filtered, and the filter cake was washed with EA (30 mL). 30 mL of water was added to the filtrate, and ethyl acetate (3×15 mL) was extracted. The organic phase was separated, washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound C-3 (0.6 g). MS (ESI+, [M+H] + )m / z:227.07. 1 H NMR (500MHz, DMSO-d6) δ6.00(s,2H),5.89(s,1H),4.79(s,2H),3.23–3.16(m,4H),2.09(s,3H),2.04–1.95(m,4H).

[0285] Example 1

[0286]

[0287]

[0288] Step A: Compound 1-1 (4.00 g), isopropanol (10 ml), and ammonia (16 ml) were added to a 35 ml microwave tube in sequence, and microwaved (reaction conditions: 150 W, 80 ° C) for 3 h. After the reaction, 50 ml of ice water was added to precipitate a large amount of white solid, which was filtered and dried in vacuo to obtain compound 1-2 (3.60 g). 1 H NMR (500MHz, DMSO-d6) δ6.82 (s, 1H), 6.78 (dd, J = 9.2, 1.6Hz, 1H), 6.74 (s, 2H).

[0289] Step B: Compound 1-2 (3.20 g), triethyl orthoformate (13.4 g), and acetic anhydride (1.52 g) were added to a 35 mL microwave tube in sequence, and the reaction was carried out under microwave (reaction conditions: 100 W, 145 ° C) for 1.5 h. After the reaction was completed, the reaction solution was dried, 100 mL of ice water was added, a yellow solid was precipitated, filtered, and vacuum dried to obtain compound 1-3 (3.50 g). 1H NMR (500MHz, DMSO-d6) δ8.22(s,1H),7.63(d,J=8.2Hz,1H),7.46(s,1H),4.32(q,J=7.0Hz,2H),1.34(t,J=7.1Hz,3H).

[0290] Step C: Compound 1-3 (3.50 g), compound A-1 (1.47 g), and acetic acid (20 mL) were added to a 100 mL single-mouth bottle in sequence, and reacted at 125°C for 1 h under N2 protection. After the reaction was completed, the heating was turned off, cooled to room temperature, 100 mL of water was added, a large amount of solid precipitated, filtered, 50 mL of ethyl acetate was added to the filter cake, stirred for 1 h, filtered, and the filter cake was vacuum dried to obtain compound 1-4 (1.00 g). 1 H NMR(500MHz,DMSO-d6)δ9.13(d,J=14.6Hz,1H),8.88(s,1H),8.00–7.97(m,1H),7.87(dd,J=12 .2,1.5Hz,1H),7.64(s,1H),3.93–3.83(m,4H),2.35(s,3H),2.02–1.95(m,4H).MS(ESI+,[M+H] + )m / z:453.24.

[0291] Step D: Compound 1-4 (190 mg), compound D-1 (335 mg), DMF (15 mL) and triethylamine (424 mg) were added to a 35 mL microwave tube in sequence, and the mixture was reacted for 2 h under microwave (reaction conditions: 120 ° C, 150 W). After the reaction, 20 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and chromatographed on a silica gel column (PE / EA = 20 / 1) to obtain compound 1-5 (200 mg). MS (ESI+, [M+H] + )m / z:556.16.

[0292] Step E: Compound 1-5 (150 mg), 2-hydroxy-1-sulfonamide (67.5 mg), dioxane (10 mL), potassium carbonate (74.5 mg), allylpalladium (II) chloride dimer (4.93 mg), t-BuXPhos (11.45 mg) were added to a 50 mL single-mouth bottle in sequence, and heated to 100° C. for 2 h under N2 protection. After the reaction was completed, the mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and chromatographed on a silica gel column (DCM / MeOH=20 / 1) to obtain compound 1 (90 mg). 1H NMR(500MHz,DMSO-d6)δ12.91(s,1H),10.55(s,1H),8.67(s,1H),7.96(s,1H),7.79–7.71(m,1H),7 .45(d,J=1.7Hz,1H),4.94(t,J=5.5Hz,1H),3.93–3.84(m,4H),3.80(q,J=6.0Hz,2H),3.57(d,J=9.1 Hz,2H),3.43(t,J=6.3Hz,2H),3.31-3.29(m,2H),2.86(d,J=8.8Hz,1H),2.47–2.39(m,1H),2.34(s ,3H),2.22–2.14(m,2H),2.03-1.98(m,4H),0.84–0.76(m,2H),0.55–0.45(m,2H).HRMS(ESI+,[M+H] + )m / z:601.2531.

[0293] Example 2

[0294]

[0295]

[0296] Step A: Compound 1-4 (250 mg), compound E-1 (287 mg), DMSO (15 mL) and DIPEA (0.482 ml) were added to a 35 mL microwave tube in sequence, and microwaved (reaction conditions: 120°C, 150 W) for 2 h. After the reaction, 20 mL of water was added, extracted with ethyl acetate (30 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and silica gel column chromatography (PE / EA = 20 / 1) was performed to obtain compound 2-1 (130 mg). MS (ESI+, [M+H] + )m / z:570.18.

[0297] Step B: Referring to step E of Example 1, compound 2-1 was used to replace compound 1-5 to synthesize compound 2. 1HNMR(500MHz,DMSO-d6)δ12.41(s,1H),10.35(s,1H),8.64(s,1H),7.92(s,1H),7.2 8(d,J=1.5Hz,1H),7.25–7.21(m,1H),4.91(s,1H),3.94–3.87(m,4H),3.78(d,J=14. 7Hz,4H),3.39(t,J=6.3Hz,2H),2.67(d,J=12.4Hz,2H),2.34(s,3H),2.06-1.97(m, 8H),1.06(d,J=12.0Hz,2H),0.69–0.60(m,2H),0.23–0.16(m,2H).HRMS(ESI+,[M+H] + )m / z:615.2682.

[0298] Example 3

[0299]

[0300] Step A: Referring to step A of Example 2, compound F-1 was substituted for compound E-1 to synthesize compound 3-1. MS (ESI+, [M+H] + )m / z:570.20.

[0301] Step B: Referring to step E of Example 1, compound 3-1 was used to replace compound 1-5 to synthesize 3. 1 H NMR(500MHz,DMSO-d6)δ11.94(s,1H),10.40(s,1H),8.64(s,1H),7.96(s,1H),7.60 (d,J=1.7Hz,1H),7.42(d,J=1.8Hz,1H),4.93(s,1H),3.94–3.86(m,4H),3.80–3.75 (m,2H),3.41(t,J=6.3Hz,2H),3.07(s,4H),2.34(s,3H),2.30(d,J=7.6Hz,2H),2.0 1-1.98(m,6H),1.55(s,2H),0.73–0.65(m,2H),0.49–0.43(m,2H).HRMS(ESI+,[M+H] + )m / z:615.2691.

[0302] Example 4

[0303]

[0304]

[0305] Step A: Referring to step C of Example 1, compound B-2 was used instead of compound A-2 to synthesize compound 4-1 (250 mg). MS (ESI+, [M+H] + )m / z:419.13.

[0306] Step B: Compound 4-1 (220 mg), compound E-1 (400 mg), n-butanol (5 mL) and DIPEA (5 mL) were added to a 30 mL microwave tube in sequence, and heated and stirred at 150°C for 9.5 h. After the reaction was completed, the reaction solution was concentrated, 30 mL of water was added, and ethyl acetate (3×15 mL) was extracted, the organic phase was separated, washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA=6.5 / 1) to obtain compound 4-2 (190 mg). 1 H NMR (500MHz, DMSO-d6) δ12.27(s,1H),8.72(s,1H),7.90(s,1H),7.71(d,J=1.7Hz,1H),7.35(d,J=1.8Hz,1H),3.94–3.86(m,2H),3.71–3.66(m,8H ),2.71–2.65(m,2H),2.34(s,3H),2.05–1.99(m,2H),1.95–1.86(m,2H), 1.07–0.99(m,2H),0.68–0.60(m,2H),0.20–0.13(m,2H).MS(ESI+,[M+H] + )m / z:536.19.

[0307] Step C: Referring to step E of Example 1, compound 4-2 was used instead of compound 1-5 to synthesize compound 4 (90 mg). 1H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.34 (s, 1H), 8.63 (s, 1H), 7.91 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 4.91 (s, 1H), 3.79-3.75 (m, 4H), 3.71-3.66 (m, 8H), 3 .38(t,J=6.4Hz,2H),2.72–2.65(m,2H),2.33(s,3H),2.06–2.01(m,2H),2.00–1.94(m,2 H),1.07–1.01(m,2H),0.64(dd,J=8.6,6.2Hz,2H),0.19–0.13(m,2H).HRMS(ESI+,[M+H] + )m / z:581.2669.

[0308] Example 5

[0309]

[0310] Step A: Referring to step B of Example 4, compound F-1 was used instead of compound E-1 to synthesize 5-1 (82 mg). MS (ESI+, [M+H] + )m / z:536.12.

[0311] Step B: Referring to step E of Example 1, compound 5-1 was used instead of compound 1-5 to synthesize 5 (80 mg). 1 HNMR(500MHz,DMSO-d6)δ11.94(s,1H),10.40(s,1H),8.64(s,1H),7.93(s,1H),7.60(d,J=2.2H z,1H),7.42(d,J=2.2Hz,1H),5.01–4.82(m,1H),3.78(t,J=6.3Hz,2H),3.73–3.69(m,4H),3.67 –3.63(m,4H),3.41(t,J=6.1Hz,2H),3.09–2.99(m,4H),2.33(s,3H),2.29(q,J=6.6,6.2Hz,2H) ,1.97–1.90(m,2H),1.54(s,2H),0.69(t,J=7.3Hz,2H),0.45(t,J=7.3Hz,2H).HRMS(ESI+,[M+H] + )m / z:581.2663.

[0312] Example 6

[0313]

[0314] Step A: Add formic acid (5 mL) and concentrated sulfuric acid (0.14 mL) to a 50 mL single-mouth bottle, heat and stir at 100 ° C for 5 min, then add compound 1-2 (750 mg), continue heating and stirring at 100 ° C overnight. After the reaction is completed, stop the reaction and cool to room temperature, add 40 mL of water, stir at room temperature for 10 min, filter with suction, and dry the filter cake to obtain compound 6-1 (750 mg). 1 H NMR (500MHz, DMSO-d6) δ12.43(s,1H),8.12(s,1H),7.70(t,J=1.5Hz,1H),7.60(dd,J=10.4,1.9Hz,1H).

[0315] Step B: Compound 6-1 (350 mg), compound E-1 (375 mg), DIPEA (1 mL) and NMP (8 mL) were added to a 30 mL microwave tube in sequence, and heated and stirred at 140 ° C for 2 h. After the reaction was completed, 40 mL of water was added and extracted with ethyl acetate (3×20 mL). The organic phase was separated, washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA=5 / 1) to obtain compound 6-2 (410 mg). 1 H NMR (500MHz, DMSO-d6) δ11.85(s,1H),7.94(s,1H),7.09(d,J=1.8Hz,1H),6.98(d,J=1.9Hz,1H),4.17–4.06(m,2H),2.33(dd ,J=13.3,2.8Hz,2H),1.95–1.83(m,4H),0.84(dd,J=13.7,2.7Hz,2H),0.62–0.51(m,2H),0.13–0.03(m,2H).MS(ESI+,[M+H] + )m / z:360.00.

[0316] Step C: Compound 6-2 (100 mg), toluene (6 mL) and DIPEA (0.1 mL) were added to a 50 mL single-mouth bottle in sequence, and phosphorus oxychloride (0.05 mL) was slowly added dropwise. After the addition was completed, the mixture was heated to 120°C for 2 h. After the reaction was completed, the reaction solution was concentrated, 15 mL of ice water, 15 mL of saturated sodium carbonate solution, and ethyl acetate (3×10 mL) was added to extract the organic phase, which was washed with 20 mL of saturated brine and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA=20 / 1) to obtain compound 6-3 (105 mg). 1H NMR(500MHz,DMSO-d6)δ8.45(s,1H),7.24(s,1H),7.16(s,1H),4.18–4.14(m,2H),2.41–2.31(m, 2H),2.03–1.87(m,4H),0.95–0.87(m,2H),0.64–0.53(m,2H),0.16–0.08(m,2H).MS(ESI+,[M+H] + )m / z:378.25.

[0317] Step D: Compound 6-3 (150 mg), compound C-3 (134 mg), NMP (6 mL) and DIPEA (0.14 mL) were added to a 50 mL single-mouth bottle in sequence, and heated and stirred at 120 ° C for 4 h under N2 protection. After the reaction was completed, 40 mL of water was added and extracted with ethyl acetate (3×15 mL). The organic phase was separated, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA=6.5 / 1) to obtain compound 6-4 (180 mg). 1 H NMR (500MHz, DMSO-d6) δ11.90(s,1H),8.54(s,1H),7.63(d,J=1.8Hz,1H),7.46(s,1H),7.28(d,J=1.9Hz,1H),7.14(s,1H),6.63(s,1H),3.87(s,2 H),3.37–3.34(m,4H),2.47–2.44(m,2H),2.30(s,3H),2.07–1.96(m,8H) ,1.11–1.06(m,2H),0.65–0.61(m,2H),0.20–0.15(m,2H).MS(ESI+,[M+H] + )m / z:568.23.

[0318] Step E: Referring to step E of Example 1, compound 6-4 was used instead of compound 1-5 to synthesize compound 6 (100 mg). 1 H NMR(500MHz,DMSO-d6)δ12.10(s,1H),10.23(s,1H),8.47(s,1H),7.46(s,1H),7. 22(d,J=2.0Hz,1H),7.16(d,J=2.1Hz,1H),7.14(s,1H),6.60(s,1H),4.92(s,1H), 3.78–3.73(m,4H),3.37–3.34(m,6H),2.48–2.44(m,2H),2.29(s,3H),2.12–2.02( m,8H),1.13–1.07(m,2H),0.66–0.62(m,2H),0.21–0.17(m,2H).HRMS(ESI+,[M+H] + )m / z:613.2778.

[0319] Example 7

[0320]

[0321] Step A: Referring to step B of Example 6, compound F-1 was used to replace compound E-1 to synthesize compound 7-2. 1H NMR (500 MHz, DMSO-d6) δ 11.92 (d, J = 3.7 Hz, 1H), 7.99 (d, J = 3.7 Hz, 1H), 7.25 (d, J = 1.9 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 3.34 (d, J = 3.7 Hz, 2H), 2.98 (d, J = 10.6 Hz, 2H), 2.20 (q, J = 5.8 Hz, 2H), 1.79–1.69 (m, 2H), 1.41 (s, 2H), 0.60 (dd, J = 8.6, 5.9 Hz, 2H), 0.37 (dd, J = 8.6, 5.9 Hz, 2H). MS (ESI+, [M+H] + )m / z:359.96.

[0322] Step B: Referring to step C of Example 6, compound 7-2 was substituted for compound 6-1 to synthesize compound 7-3. MS (ESI+, [M+H] + )m / z:377.97.

[0323] Step C: Referring to step D of Example 6, compound 7-3 was substituted for compound 6-3 to synthesize 7-4. NMR(500MHz,DMSO-d6)δ11.78(s,1H),8.41(s,1H),7.73(dd,J=16.1,1.9Hz,2 H),7.11(s,1H),6.99(t,J=2.1Hz,1H),6.70(s,1H),3.36(t,J=5.8Hz,4H),3. 19–3.04(m,4H),2.30(s,3H),2.04(tt,J=14.0,5.8Hz,4H),1.90–1.80(m,4H) ,1.51(s,2H),0.72(dd,J=8.6,6.0Hz,2H),0.47–0.35(m,2H).MS(ESI+,[M+H] + )m / z:568.22.

[0324] Step D: Referring to step E of Example 6, compound 7 was obtained by replacing compound 6-4 with compound 7-4. 1H NMR (500MHz, DMSO) δ11.72(s,1H),10.26(s,1H),8.34(s,1H),7.49(d,J=2.3Hz,1H),7.33(d, J=2.1Hz,1H),7.12(s,1H),6.97(d,J=2.2Hz,1H),6.67(s,1H),4.94(s,1H),3.78(t,J=6.4Hz, 2H),3.36(dt,J=12.1,6.1Hz,6H),3.13–2.97(m,4H),2.29(s,3H),2.04(tt,J=11.6,5.5Hz,4H ),1.86(s,4H),1.53(s,2H),0.69(dd,J=8.7,5.9Hz,2H),0.47–0.36(m,2H).HRMS(ESI+,[M+H] + )m / z:613.2783.

[0325] Experimental Example 1 KIF18A protein motor activity inhibition experiment

[0326] KIF18A (1-374) protein (manufacturer: Cytoskeleton Inc) was diluted to 50 nM with a buffer containing tubulin (manufacturer: Cytoskeleton Inc) and paclitaxel, and 3 μL was added to each well. Different compounds dissolved in DMSO were added to the test wells using a nanoliter pipette to make the final concentration of the compound 1000 nM-0.244 nM. Two replicate wells were set up at the same time, and the above system was incubated for 15 min. ATP (187.5 nM) was added to the test wells at 2 μL per well, reacted at room temperature for 15 min, and then ADP-Glo ​​reagent (manufacturer: Promega) was added to the test wells at 5 μL per well, and incubated at room temperature for 40 min. Kinase Detection reagent (manufacturer: Promega) was added at 10 μL per well, and incubated at room temperature for 40 min. Luminescence module detection was performed using Envision multifunctional microplate reader, and IC was calculated using four-parameter fitting. 50 .

[0327] The experimental results are shown in Table 1.

[0328] Table 1

[0329] Example <![CDATA[KIF18A IC 50 (nM)]]> 2 B 3 B 4 A 5 A 6 A

[0330] Note: A stands for IC 50 ≤50nM; B means 50nM<IC 50 ≤150nM.

[0331] Test Example 2 Cell proliferation inhibitory activity

[0332] 2.1 Determination of OVCAR3 cell proliferation inhibitory activity

[0333] Take OVCAR3 cells that are in good growth state, collect them into a centrifuge tube, and adjust the cell density to 4×10 4 / mL, inoculated on a 96-well plate (100μL / well), cultured overnight in a cell culture incubator, and the compound was added using a nanoliter pipette to make the final concentration of the compound 2000nM-0.91nM, 2 replicates, and a control was set at the same time. After continuing to culture in the cell culture incubator for 7 days, the detection reagent CCK-8 (Beijing Tongren Chemical, 10μL / well) was added. After incubation in the cell culture incubator for 2 hours, the absorbance value was detected at 450nm using an Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .

[0334] The experimental results are shown in Table 2.

[0335] Table 2

[0336] Example <![CDATA[OVCAR3IC 50 (nM)]]> 1 C 2 B 3 A 4 A 5 A 6 A 7 B

[0337] Note: A stands for IC 50 ≤150nM; B means 150nM<IC 50 ≤500nM; C means 500nM<IC 50 ≤1000nM.

[0338] 2.2 MDA-MB-468 cell proliferation inhibitory activity assay

[0339] Take the 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 / mL, inoculated on a 96-well plate (100μL / well), cultured overnight in a cell culture incubator, and the compound was added using a nanoliter pipette to make the final concentration of the compound 2000nM-0.91nM, 2 replicates, and a control was set at the same time. After continuing to culture in the cell culture incubator for 7 days, the detection reagent CCK-8 (Beijing Tongren Chemical, 10μL / well) was added. After incubation in the cell culture incubator for 2 hours, the absorbance value was detected at 450nm using an Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .

[0340] Test Example 3 Liver microsome stability test

[0341] The liver microsome incubation sample was prepared by mixing PBS buffer (pH 7.4), liver microsome 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 microsome solution (0.5 mg / ml), test compound. The sample was added with acetonitrile solution containing internal standard to prepare supernatant by protein precipitation, which was diluted for LC / MS / MS determination.

[0342] Experimental Example 4 Pharmacokinetics in mice

[0343] ICR mice weighing 18-22 g were randomly divided into groups of 9 mice after acclimation for 3-5 days. The test compound solution was injected intravenously at a dose of 1 mg / kg and was gavaged orally at a dose of 10 mg / kg.

[0344] The time points for intravenous blood collection were 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, and 24h. The time points for intragastric blood collection were 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, and 24h. Blood was collected from the eye sockets to prepare the plasma samples to be tested.

[0345] 30 μL of the plasma sample to be tested and the standard curve sample were taken, and acetonitrile solution containing the internal standard was added to obtain the supernatant after protein precipitation, which was diluted for LC / MS / MS determination.

[0346] The non-compartmental model was used to fit the pharmacokinetic parameters.

[0347] Test Example 5 In vivo efficacy evaluation

[0348] 5.1 Pharmacodynamic evaluation of OVCAR-3 human ovarian cancer B-NDG mouse transplant tumor model

[0349] OVCAR-3 cells (source: Zhejiang Meisen) were subcutaneously inoculated in the right axilla of SPF female B-NDG mice (source: Biocytogen). 1×10 7 The tumor tissue of F1 mice was inoculated into the right axillary subcutaneous tissue of SPF female nude mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) by 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.

[0350] The day of grouping was day 0, and drugs were administered by gavage once a day. The tumor volume was measured 2-3 times a week, and the mice were weighed and the data were recorded; the general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.

[0351] The detection indicators and calculation formula are as follows:

[0352] 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.

[0353] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0354] Relative tumor proliferation rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The solvent control group RTV.

[0355] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0356] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[0357] 5.2 Pharmacodynamic evaluation in JIMT-1 human breast cancer xenograft model in nude mice

[0358] JIMT-1 cells (source: AddexBio) were subcutaneously inoculated in the right axilla of SPF female nude mice (source: Hangzhou Medical College), 2×10 6 When the average tumor volume reaches 100-200mm 3 The animals were divided into a control group and a treatment group, with 5 animals in each group.

[0359] The day of grouping was day 0, and drugs were administered by gavage once a day. The tumor volume was measured 2-3 times a week, and the mice were weighed and the data were recorded; the general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.

[0360] The detection indicators and calculation formula are as follows:

[0361] 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.

[0362] Relative tumor volume, RTV = TVt / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0363] Relative tumor proliferation rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The solvent control group RTV.

[0364] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0365] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, Ring A is selected from optionally substituted with one or more R a1 Substituted as follows: 5-12 membered bridged cycloalkyl or 5-12 membered bridged heterocycloalkyl; Each R a1 are each independently selected from oxo, deuterium, halogen, -OH, -NH 2 、-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, -SO 2 C 1-12 Alkyl, -NHSO 2 C 1-12 Alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 Alkyl, -SO 2 NH 2 、-SO 2 NHC 1-12 Alkyl, -SO 2 N(C 1-12 alkyl) 2 、-CONH 2 、-CONHC 1-12 Alkyl, -CON(C 1-12 alkyl) 2 、-NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; Alternatively, two R on the same ring atom a1 together to form optionally one or more R a2 Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl; Alternatively, two R located on two adjacent ring atoms a1 together to form optionally one or more R a2 Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl; Each R a2 are each independently selected from oxo, deuterium, halogen, -OH, -NH 2 、-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, -SO 2 C 1-12 Alkyl, -NHSO 2 C 1-12 Alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 Alkyl, -SO 2 NH 2 、-SO 2 NHC 1-12 Alkyl, -SO 2 N(C 1-12 alkyl) 2 、-CONH 2 、-CONHC 1-12 Alkyl, -CON(C 1-12 alkyl) 2 、-NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 or X 7 Each independently selected from N or CR x ; Each R x are each independently selected from H, halogen, deuterium, -OH, -NH 2 、-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 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, -SO 2 C 1-12 Alkyl, -NHSO 2 C 1-12 Alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 Alkyl, -SO 2 NH 2 、-SO 2 NHC 1-12 Alkyl, -SO 2 N(C 1-12 alkyl) 2 、-CONH 2 、-CONHC 1-12 Alkyl, -CON(C 1-12 alkyl) 2 、-NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, 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)-, -C(O)NR L1 -、-NR L1 C(O)-, -S(O)-, -S(O) 2 -、-S(O) 2 NR L1 -、-NR L1 S(O) 2 -, -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 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, -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 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, -SO 2 C 1-12 Alkyl, -NHSO 2 C 1-12 Alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 Alkyl, -SO 2 NH 2 、-SO 2 NHC 1-12 Alkyl, -SO 2 N(C 1-12 alkyl) 2 、-CONH 2 、-CONHC 1-12 Alkyl, -CON(C 1-12 alkyl) 2 、-NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; R 1 Selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or optionally 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 are each independently selected from oxo, deuterium, halogen, -OH, -NH 2 、-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, -SO 2 C 1-12 Alkyl, -NHSO 2 C 1-12 Alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 Alkyl, -SO 2 NH 2 、-SO 2 NHC 1-12 Alkyl, -SO 2 N(C 1-12 alkyl) 2 、-CONH 2 、-CONHC 1-12 Alkyl, -CON(C 1-12 alkyl) 2 、-NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; L 3 Selected from -CHR L3 -、-C(R L3 )(R L4 )-、-NR L3 -, -O-, -S-, -C(O)-, -S(O)-, or -S(O) 2 -; Every R L3 or R L4 are each independently selected from H, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl; L 2 Selected from single bond, -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) 2 NR L2 -, or -NR L2 S(O) 2 -; R L2 Selected from H, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl; R 2 Selected from H, deuterium, halogen, -OH, -NH 2 , -SH, -COOH, -CN, or optionally one or more R 2a 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 2a are each independently selected from oxo, deuterium, halogen, -OH, -NH 2 、-CN、-SH、-COOH、C 1-6 Alkyl, C 1-6 Deuterated 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 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, -SO 2 C 1-6 Alkyl, -NHSO 2 C 1-6 Alkyl, -N(C 1-6 alkyl)SO 2 C 1-6 Alkyl, -SO 2 NH 2 、-SO 2 NHC 1-6 Alkyl, -SO 2 N(C 1-6 alkyl) 2 、-CONH 2 、-CONHC 1-6 Alkyl, -CON(C 1-6 alkyl) 2 、-NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; R 3 , R 4 are each independently selected from H, deuterium, halogen, -OH, -NH 2 、-CN、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 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, -SO 2 C 1-6 Alkyl, -NHSO 2 C 1-6 Alkyl, -N(C 1-6 alkyl)SO 2 C 1-6 Alkyl, -SO 2 NH 2 、-SO 2 NHC 1-6 Alkyl, -SO 2 N(C 1-6 alkyl) 2 、-CONH 2 、-CONHC 1-6 Alkyl, -CON(C 1-6 alkyl) 2 、-NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; The R a1 , R a2 , R x , R L1a , R 1a , R L3 , R L4 , R L2 , R 2a , R 3 , R 4 Optionally substituted with one or more substituents.

2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, in, Ring A is selected from optionally substituted with one or more R a1 Substituted as follows: 5-10 membered bridged cycloalkyl or 5-10 membered bridged heterocycloalkyl; Alternatively, Ring A is selected from optionally substituted with one or more R a1 Substituted as follows: 6-9 membered bridged cycloalkyl or 6-9 membered bridged heterocycloalkyl; Alternatively, Ring A is selected from optionally substituted with one or more R a1 Substituted as follows: 7-8 membered bridged cycloalkyl or 7-8 membered bridged heterocycloalkyl; Alternatively, Ring A is selected from optionally substituted with one or more R a1 Substituted 5-12 membered bridged heterocycloalkyl; Alternatively, Ring A is selected from optionally substituted with one or more R a1 Substituted with the following groups: Alternatively, ring A is selected from 3. A compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, in, 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)-, -S(O)-, -S(O) 2 -、-S(O) 2 NR L1 -、-NR L1 S(O) 2 -, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, or -C=N(OH)-; 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)-, -S(O)-, -S(O) 2 -、-S(O) 2 NR L1 -、-NR L1 S(O) 2 -, -S(O)(=NH)-, -NR L1 S(O)(=NH)-, or -C=N(OH)-; 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) 2 NR L1 -、-NR L1 S(O) 2 -, or -S(O)(=NH)-; Or, L 1 Selected from single bond, -O-, -S-, -NR L1 -, methylene, -C(O)NR L1 -、-S(O) 2 -、-S(O) 2 NR L1 -、-NR L1 S(O) 2 -, or -S(O)(=NH)-; Or, L 1 Selected from -S(O) 2 NR L1 -, or -NR L1 S(O) 2 -.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, in, R 1 Selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or optionally 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 Selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or optionally 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; Or, R 1 Selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or optionally 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, or 5-6 membered heteroaryl; Or, R 1 Selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or optionally one or more R 1a Substituted with the following groups: C 1-4 Alkyl, 3-6 membered cycloalkyl, or 4-7 membered heterocycloalkyl; Or, R 1 Selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -SH, -COOH, -CN, or optionally one or more R 1a substituted with: methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thiazetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; Or, R 1 Selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -SH, -COOH, -CN, or optionally one or more R 1a Substituted with the following groups: methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, azetidinyl, oxetanyl, or isothiazolidinyl; Or, R 1 Selected from one or more R 1a Substituted ethyl.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, in, R 2 Selected from H, deuterium, halogen, -OH, -NH 2 , -SH, -COOH, -CN, or optionally one or more R 2a 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 2 Selected from H, deuterium, halogen, -OH, -NH 2 , -SH, -COOH, -CN, or optionally one or more R 2a 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; Or, R 2 Selected from H, deuterium, halogen, -OH, -NH 2 , -SH, -COOH, -CN, or optionally one or more R 2a Substituted with the following groups: C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-7 membered cycloalkenyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; Or, R 2 Selected from H, deuterium, halogen, -OH, -NH 2 , -SH, -COOH, -CN, or optionally one or more R 2a Substituted with the following groups: C 1-4 Alkyl, 3-6 membered cycloalkyl, or 4-7 membered heterocycloalkyl; Or, R 2 Selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -SH, -COOH, -CN, or optionally one or more R 2a Substituted with the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or Or, R 2 Selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -SH, -COOH, -CN, or optionally one or more R 2a Substituted with the following groups: methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, cyclopentyl, azetidinyl, piperidinyl, morpholinyl, or Or, R 2 Selected from one or more R 2a Substituted: azetidinyl, piperidinyl, or morpholinyl.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, in, R 3 , R 4 are each independently selected from H, deuterium, halogen, -OH, -NH 2 、-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 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, -SO 2 C 1-6 Alkyl, -NHSO 2 C 1-6 Alkyl, -N(C 1-6 alkyl)SO 2 C 1-6 Alkyl, -SO 2 NH 2 、-SO 2 NHC 1-6 Alkyl, -SO 2 N(C 1-6 alkyl) 2 、-CONH 2 、-CONHC 1-6 Alkyl, -CON(C 1-6 alkyl) 2 、-NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl; Or, R 3 , R 4 are each independently selected from H, deuterium, halogen, -OH, -NH 2 、-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 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, -SO 2 C 1-4 Alkyl, -NHSO 2 C 1-4 Alkyl, -N(C 1-4 alkyl)SO 2 C 1-4 Alkyl, -SO 2 NH 2 、-SO 2 NHC 1-4 Alkyl, -SO 2 N(C 1-4 alkyl) 2 、-CONH 2 、-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; Or, R 3 , R 4 are each independently selected from H, deuterium, halogen, -OH, -NH 2 、-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 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino; Or, R 3 , R 4 are each independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -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; Or, R 3 , R 4 are each independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is selected from a compound of formula (II), formula (II-1), formula (III), formula (III-1), formula (IV), formula (IV-1) or formula (V) or a pharmaceutically acceptable salt thereof, in, X 6 , X 7 , L 1 , R 1 , L 3 , L 2 , R 2 , R 3 , R 4 and the Ring A moiety is as defined in any one of claims 1-6.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, selected from:

9. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8; optionally, further comprising a pharmaceutically acceptable excipient.

10. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating a disease.

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