Amide or urea compound

Abstract

The invention provides a compound shown in a formula (I), and the compound can regulate KIF18A protein, so that the cell cycle and the cell proliferation process are influenced to treat cancers and cancer-related diseases. The invention also includes pharmaceutical compositions comprising the compounds and methods for treating conditions associated with KIF18A activity. # imgabs0 #

Description

Amide or urea compounds

[0001] The relevant application documents claim the priority of Chinese invention patent application 202211538155.1 with an application date of December 2, 2022, Chinese invention patent application 202310522117.5 with an application date of May 9, 2023, Chinese invention patent application 202311071943.9 with an application date of August 23, 2023, and Chinese patent invention application 202311385406.1 with an application date of October 24, 2023, and all their contents are incorporated into this application by reference in their entirety. Technical Field

[0002] The present invention relates to the field of medicinal chemistry, and specifically relates to an amide or urea compound. Background Art

[0003] Chromosomal instability (CIN), defined as chromosomal instability, is caused by errors in chromosome segregation during mitosis. CIN is a hallmark of recurrent, metastatic, advanced malignancies, occurring in approximately 90% of solid tumors and affecting the genomes of approximately 25% of solid tumor cells. The causes of CIN are diverse, including mitotic errors, replication stress, homologous recombination repair, and breakage-fusion-bridge cycles. CIN is closely associated with cellular transformation, tumor progression and recurrence, chemotherapy resistance, and poor prognosis.

[0004] Kinesins are molecular motors that play important roles in cell division and the transport of intracellular vesicles and organelles. Mitotic kinesins play a role in multiple aspects of spindle assembly, chromosome segregation, centrosome separation, and dynamics. Human kinesins are classified into 14 subfamilies based on sequence homology within the motor domain. KIF18A, a member of the kinesin-8 family, is specifically expressed during the G2 / M phase of mitosis and plays a key role in maintaining bipolar spindle integrity during cell division, thereby regulating chromosome positioning. KIF18A uses energy released by ATP hydrolysis to move along microtubules toward the positive pole within the cell. Localized at the positive end of microtubules, it regulates microtubule dynamic instability, exerting an activity similar to that of a microtubule depolymerase. During mitosis, KIF18A regulates spindle microtubule dynamics and chromosome amplitude, playing a crucial role in the timely alignment of chromosomes during mitosis, maintaining genomic stability, and successfully completing mitosis.

[0005] Studies have shown that the kinesin KIF18A is an important factor affecting the proliferation of CIN tumor cells. After KIF18A knockout, tumor cells with CIN characteristics exhibit mitotic fragility associated with spindle assembly checkpoint (SAC) activation, multipolar spindle formation, and induction of apoptosis, leading to mitotic arrest, cell cycle arrest, and apoptosis. KIF18A is an essential gene for abnormal somatic cell division, but CIN tumor cells are highly sensitive to KIF18A knockout. Therefore, small molecule inhibitors of KIF18A can selectively target tumor cells with CIN characteristics. Compared with other drugs targeting mitotic mechanisms, KIF18A inhibition does not affect the proliferation of normal cells. Currently, there is a lack of effective therapies targeting CIN, and KIF18A is a highly promising new anti-tumor target.

[0006] Summary of the Invention

[0007] The present invention aims to provide an amide or urea compound having KIF18A inhibitory activity. To this end, the present invention also provides the use of these compounds and pharmaceutically acceptable salts thereof in the preparation and manufacture of pharmaceutical compositions or drugs for therapeutic, preventive, acute or chronic treatment of KIF18A-mediated diseases and disorders (including but not limited to cancer). Therefore, the compounds of the present invention can be used to manufacture anticancer drugs. The present invention also provides methods for preparing compounds of formula I, as well as intermediates useful in such methods.

[0008] In a first aspect, the present application provides a compound of formula (I) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,

[0009] A is a monocyclic aryl, a monocyclic heteroaryl, a bicyclic aryl, a bicyclic heteroaryl or a fused heterocyclic group, optionally, the monocyclic aryl, the monocyclic heteroaryl, the bicyclic aryl, the bicyclic heteroaryl or the fused heterocyclic group is optionally substituted by one or more R z replace;

[0010] L is selected from -NR 3 -CO- or -NR 3 CONR 3 -, each R 3 are independently H, deuterium, C1-C6 alkylene or C1-C6 haloalkylene;

[0011] R x-OR4 or -NR5R6, wherein R4 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, said 3-8 membered heterocyclyl containing at least one heteroatom selected from O, S and N; R5 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, R6 is selected from H or C1-C6 alkyl, or R5 and R6 together with the N atom to which they are attached form a 4-8 membered heterocyclyl; said 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl and 4-8 membered heterocyclyl containing 0, 1, 2 or 3 heteroatoms selected from O, S and N and optionally replaced by one or more R z replace;

[0012] R1 is -CN or -ZR 12 , wherein Z is a direct bond, -C1-C6 alkylene-, -C1-C6 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -NR 11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C6 alkylene-SO2-, -C1-C6 alkylene-SO2R 11 -, -(C=O)-, -(C=O)NR 11 -, -C=N(OH)- or -NR 11 (C=O)-; or -ZR 12 Yes-N=S(=O)-(R 12 )2, where two R 12 The pairs may combine with the sulfur atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S;

[0013] X7 is N or CR7; X8 is N or CR8; X9 is N or CR9;

[0014] R7, R8 and R9 are independently H, halogen, C1-C8 alkyl, C1-C6 haloalkyl, -OH, -OR 8a 、-OR 8b or -NR a R a When R7 and R8 are present at the same time, R7 and R8 can be combined with the atoms to which they are attached to form a saturated or partially saturated 3-membered, 4-membered, 5-membered or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R x When R and R9 exist at the same time, R xand R9 may be combined with the atoms to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S;

[0015] R 11 H, R 11a or R 11b ; R 12 H, R 12a or R 12b ;

[0016] R 8a 、R 11a and R 12a independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-C6 alkylene NR a R a 、-OC2-C6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NRa R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a 、R 14 and oxo;

[0017] R 8b 、R 11b and R 12b Independently selected from the group consisting of: selected from F, Cl, Br, -OR a , -OC1-C6 haloalkyl or C1-C6 alkyl substituted with 0, 1, 2, 3, 4 or 5 groups of CN;

[0018] R 14 is independently selected in each case from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a、-OC2-6 alkylene NR a R a 、-OC2-6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-C6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a and oxo;

[0019] Each R a Each independently is H or R b ;

[0020] Each R beach independently C1-C6 alkyl, phenyl or benzyl, wherein the C1-C6 alkyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)C1-C6 alkyl;

[0021] Each R z independently selected from the group consisting of deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -C1-C6 alkylene-O-C1-C6 alkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, -CN, -O-C1-C6 alkyl, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 、-S(O)2-R z1 、-C(O)-R z2 、-C(O)-NR z1 R z2 , phenyl, a 5-6 membered monocyclic heteroaryl containing 0, 1, 2 or 3 N atoms, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and two R attached to the same carbon atom z Can be formed or two R attached to the same carbon atom zThe C1-C6 alkyl, C3-C8 cycloalkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -O-C1-C6 alkyl, C3-C8 cycloalkyl-C1-C6 alkylene may be optionally substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C3-C8 halocycloalkyl;

[0022] Each R z1 Independently selected from the following groups: H, C1-C6 alkyl, C1-C6 haloalkyl;

[0023] Each R z2 Independently selected from the following groups: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C3-C8 cycloalkyl;

[0024] Q is O or CR Q1 R Q2 ;

[0025] R Q1 and R Q2 Independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0026] In some embodiments, the present application provides a compound of formula (I) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein:

[0027] A is a monocyclic aryl, a monocyclic heteroaryl, a bicyclic aryl, a bicyclic heteroaryl or a fused heterocyclic group, optionally, the monocyclic aryl, the monocyclic heteroaryl, the bicyclic aryl, the bicyclic heteroaryl or the fused heterocyclic group is optionally substituted by one or more R z replace;

[0028] L is selected from -NR 3 -CO- or -NR 3 CONR 3 -, each R 3 are independently H, deuterium, C1-C6 alkylene or C1-C6 haloalkylene;

[0029] R x-OR4 or -NR5R6, wherein R4 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, said 3-8 membered heterocyclyl containing at least one heteroatom selected from O, S and N; R5 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, R6 is selected from H or C1-C6 alkyl, or R5 and R6 together with the N atom to which they are attached form a 4-8 membered heterocyclyl; said 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl and 4-8 membered heterocyclyl containing 0, 1, 2 or 3 heteroatoms selected from O, S and N and optionally replaced by one or more R z replace;

[0030] R1 is -CN or -ZR 12 , wherein Z is a direct bond, -C1-C6 alkylene-, -C1-C6 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -NR 11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C6 alkylene-SO2-, -C1-C6 alkylene-SO2R 11 -, -(C=O)-, -(C=O)NR 11 -, -C=N(OH)- or -NR 11 (C=O)-; or -ZR 12 Yes-N=S(=O)-(R 12 )2, where two R 12 The pairs may combine with the sulfur atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S;

[0031] X7 is N or CR7; X8 is N or CR8; X9 is N or CR9;

[0032] R7, R8 and R9 are independently H, halogen, C1-C8 alkyl, C1-C6 haloalkyl, -OH, -OR 8a 、-OR 8b or -NR a R a When R7 and R8 are present at the same time, R7 and R8 can be combined with the atoms to which they are attached to form a saturated or partially saturated 3-membered, 4-membered, 5-membered or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R x When R and R9 exist at the same time, R xand R9 may be combined with the atoms to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S;

[0033] R 11 H, R 11a or R 11b ; R 12 H, R 12a or R 12b ;

[0034] R 8a 、R 11a and R 12a independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-C6 alkylene NR a R a 、-OC2-C6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NRa R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a 、R 14 and oxo;

[0035] R 8b 、R 11b and R 12b Independently selected from the group consisting of: selected from F, Cl, Br, -OR a , -OC1-C6 haloalkyl or C1-C6 alkyl substituted with 0, 1, 2, 3, 4 or 5 groups of CN;

[0036] R 14 is independently selected in each case from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a、-OC2-6 alkylene NR a R a 、-OC2-6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(= O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-C6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a and oxo;

[0037] Each R a Each independently is H or R b ;

[0038] Each R beach independently C1-C6 alkyl, phenyl or benzyl, wherein the C1-C6 alkyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)C1-C6 alkyl;

[0039] Each R z independently selected from the group consisting of deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -C1-C6 alkylene-O-C1-C6, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, -CN, -O-C1-C6 alkyl, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 、-S(O)2-R z1 、-C(O)-R z2 、-C(O)-NR z1 R z2 , a 5-6 membered monocyclic heteroaryl containing 0, 1, 2 or 3 N atoms, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and two R attached to the same carbon atom z Can be formed or two R attached to the same carbon atom zThe C1-C6 alkyl, C3-C8 cycloalkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -O-C1-C6 alkyl, C3-C8 cycloalkyl-C1-C6 alkylene may be optionally substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C3-C8 halocycloalkyl;

[0040] Each R z1 Independently selected from the following groups: H, C1-C6 alkyl, C1-C6 haloalkyl;

[0041] Each R z2 Independently selected from the following groups: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C3-C8 cycloalkyl;

[0042] Q is O or CR Q1 R Q2 ;

[0043] R Q1 and R Q2 Independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0044] In some embodiments, the present application provides a compound of formula (I) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein:

[0045] Each R z independently selected from the group consisting of deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -C1-C6 alkylene-O-C1-C6 alkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, -CN, -O-C1-C6 alkyl, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 、-S(O)2-R z1 、-C(O)-R z2 、-C(O)-NR z1 R z2, a 5-6 membered monocyclic heteroaryl containing 0, 1, 2 or 3 N atoms, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is substituted with 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and two R attached to the same carbon atom z Can be formed or two R attached to the same carbon atom z Together with the carbon atoms to which they are attached, they may form a C3-C8 cycloalkyl group; the C1-C6 alkyl group, C3-C8 cycloalkyl group, -O-C1-C6 alkyl group, C3-C8 cycloalkyl-C1-C6 alkylene group may optionally be substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group, C1-C4 haloalkyl group, C3-C8 halocycloalkyl group.

[0046] In some embodiments, the present application provides a compound of formula (I) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein:

[0047] A is a monocyclic aryl, a monocyclic heteroaryl, a bicyclic aryl, a bicyclic heteroaryl or a fused heterocyclic group, optionally, the monocyclic aryl, the monocyclic heteroaryl, the bicyclic aryl, the bicyclic heteroaryl or the fused heterocyclic group is optionally substituted by one or more R z replace;

[0048] L is selected from -NR 3 -CO- or -NR 3 CONR 3 -, each R 3 are independently H, deuterium, C1-C6 alkylene or C1-C6 haloalkylene;

[0049] R x-OR4 or -NR5R6, wherein R4 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl contains at least one heteroatom selected from O, S and N; R5 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, R6 is selected from H or C1-C6 alkyl, or R5 and R6 together with the N atom to which they are attached form a 4-8 membered heterocyclyl; wherein the 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl and 4-8 membered heterocyclyl contain 0, 1, 2 or 3 heteroatoms selected from O, S and N and are optionally replaced by one or more R z replace;

[0050] R1 is -CN or -ZR 12 , wherein Z is a direct bond, -C1-C6 alkylene-, -C1-C6 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -NR 11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C6 alkylene-SO2-, -C1-C6 alkylene-SO2R 11 -, -(C=O)-, -(C=O)NR 11 -, -C=N(OH)- or -NR 11 (C=O)-; or -ZR 12 Yes-N=S(=O)-(R 12 )2, where two R 12 The pairs may combine with the sulfur atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S;

[0051] X7 is N or CR7; X8 is N or CR8; X9 is N or CR9;

[0052] R7, R8 and R9 are independently H, halogen, C1-C8 alkyl, C1-C6 haloalkyl, -OH, -OR 8a 、-OR 8b or -NR a R a When R7 and R8 are present at the same time, R7 and R8 can be combined with the atoms to which they are attached to form a saturated or partially saturated 3-membered, 4-membered, 5-membered or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R x When R and R9 exist at the same time, R xand R9 may be combined with the atoms to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S;

[0053] R 11 H, R 11a or R 11b ; R 12 H, R 12a or R 12b ;

[0054] R 8a 、R 11a and R 12a independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-C6 alkylene NR a R a 、-OC2-C6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NRa R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a 、R 14 and oxo;

[0055] R 8b 、R 11b and R 12b Independently selected from the group consisting of: selected from F, Cl, Br, -OR a , -OC1-C6 haloalkyl or C1-C6 alkyl substituted with 0, 1, 2, 3, 4 or 5 groups of CN;

[0056] R 14 is independently selected in each case from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a、-OC2-6 alkylene NR a R a 、-OC2-6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-C6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a and oxo;

[0057] Each R a Each independently is H or R b ;

[0058] Each R beach independently C1-C6 alkyl, phenyl or benzyl, wherein the C1-C6 alkyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl);

[0059] Each R z independently selected from the group consisting of deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, -CN, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 、-S(O)2-R z1 , a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and two R attached to the same carbon atom z Can be formed or two R attached to the same carbon atom z The C1-C6 alkyl, C3-C8 cycloalkyl, -O-C1-C6 alkyl, C3-C8 cycloalkyl-C1-C6 alkylene may be optionally substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C3-C8 halocycloalkyl;

[0060] Each R z1 Independently selected from the following groups: C1-C6 alkyl, C1-C6 haloalkyl;

[0061] Q is O or CR Q1 R Q2 ;

[0062] R Q1 and R Q2 Independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0063] In some embodiments, each R z independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, -CN, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 、-S(O)2-R z1 , a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and two R attached to the same carbon atom z Can be formed or two R attached to the same carbon atom z Together with the carbon atoms to which they are attached, they may form a C3-C8 cycloalkyl group; the C1-C6 alkyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkyl-C1-C6 alkylene group may optionally be substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group, C1-C4 haloalkyl group, C3-C8 halocycloalkyl group.

[0064] In some embodiments, each R zindependently selected from the following groups: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 groups selected from the following : deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and two or more of the substituents and the carbon atoms to which they are attached may together constitute a C3-C8 cycloalkyl group; the C1-C6 alkyl, C3-C8 cycloalkyl, -O-C1-C6 alkyl may optionally be substituted by a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, , C1-C6 alkoxy or C1-C4 haloalkyl.

[0065] In some embodiments, formula (I) is as shown in formula (I)-1, formula (I)-2 or formula (I)-3:

[0066] The symbols in formula (I)-1 to formula (I)-3 are defined the same as in formula (I).

[0067] In some embodiments, R x Selected from the group consisting of:

[0068] Preferably, R x for

[0069] Among them, R 10a 、R 10b 、R 10c 、R 10d 、R 10e 、R 10f 、R 10g 、R 10h 、R 10i and R 10j 、R 10k and R 10lEach of them is H, deuterium, halogen, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C8 cycloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 1-3 heteroatoms selected from N, O, and S, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered monocyclic ring 12-membered bicyclic ring, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C3-C8 cycloalkyl is optionally substituted with 1-5 substituents selected from deuterium, halogen, -OH, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -O-C1-C6 haloalkyl; wherein the monocyclic or bicyclic ring is substituted with 0, 1, 2, or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR m 、-OC1-C6 haloalkyl、CN、-C(=O)R n 、-C(=O)OR m 、-C(=O)NR m R m 、-C(=NR m )NR m R m 、-OC(=O)R n 、-OC(=O)NR m R m 、-OC2-C6 alkylene NR m R m 、-OC2-C6 alkylene OR m 、-SR m 、-S(=O)R n 、-S(=O)2R n 、-S(=O)2NR m R m 、-NR m R m 、-N(R m )C(=O)R n 、-N(R m )C(=O)OR n 、-N(R m )C(=O)NR m R m 、-N(R m )C(=NR m )NR m R m 、-N(R m )S(=O)2R n 、-N(R m)S(=O)2NR m R m 、-NR m C2-6 alkylene NR m R m 、-NR m C2-C6 alkylene OR m 、-C1-C6 alkylene NR m R m 、-C1-C6 alkylene OR m 、-C1-C6 alkylene N(R m )C(=O)R n 、-C1-C6 alkyleneOC(=O)R n 、-C1-C6 alkylene C(=O)NR m R m 、-C1-C6 alkylene C(=O)OR m and oxo;

[0070] Or alternatively, R 10a and R 10b Yes, R 10c and R 10d Yes, R 10e and R 10f Yes, R 10g and R 10h Yes, R 10i and R 10j 、R 10k and R 10l Each of the pairs can independently combine with their respective attached carbon atoms to form a spiro-linked x wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, C1-C6 alkyl, C1-C4 haloalkyl, -OR m 、-OC1-C4 haloalkyl、CN、-NR m R m or oxo;

[0071] Each R m and R n Independently selected from H or -C1-C6 alkyl;

[0072] Or alternatively, R 10a and R 10b Yes, R 10c and R 10d Yes, R 10e and R10f Yes, R 10g and R 10 h for R 10i and R 10j Right or R 10k and R 10l Can form Where Q is CR Q1 R Q2 ; R Q1 and R Q2 Independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0073] In some embodiments, R x for

[0074] In some preferred embodiments, R 10c 、R 10d 、R 10e 、R 10f 、R 10g 、R 10h 、R 10i and R 10j Each of R10a and R10b is H, deuterium, halogen, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl), said C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl is optionally substituted with 1-5 substituents selected from deuterium, halogen, -OH, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O-C1-C6 haloalkyl; R10a and R10b form a Q is CR Q1 R Q2 ; R Q1 and R Q2 are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or R 10a and R 10b The C3-C8 cycloalkyl group together with the carbon atom to which it is attached forms a spiro-connected Rx ring, and further, the C3-C8 cycloalkyl group is substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, C1-C6 alkyl, C1-C4 haloalkyl, -OH, C1-C6 alkoxy, -OC1-C4 haloalkyl, -CN, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl) or oxo.

[0075] In some embodiments, R x Selected from:

[0076] Preferably, R x Selected from:

[0077] More preferably, R x Selected from:

[0078] In some embodiments, formula (I) is as shown in formula (I)-4-1, formula (I)-4-2, formula (I)-4-3, formula (I)-4-4, formula (I)-5-1, formula (I)-5-2, formula (I)-6-1 or formula (I)-6-2:

[0079] In some embodiments, R1 is a group -ZR 12 , wherein -Z is a single bond, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -NH-, -NHSO2-, -SONH-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C4 alkylene-SO2-, -(C=O)-, -(C=O)N-, -C=N(OH)-, or -NH(C=O)-; and / or

[0080] (a)R 12 is H;

[0081] (b)R 12 is oxetanyl, cyclopropyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (such as F, Cl), C1-C6 alkoxy; or

[0082] (c)R 12 is C1-C6 alkyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (eg F), C1-C6 alkoxy.

[0083] Preferably, the group -ZR 12 -N=S(=O)-(R 12 )2, where two R 12 pairs that can alternatively combine with their respective attached sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S;

[0084] Or the group -ZR 12 In the equation, Z is a single bond, R 12independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-C6 alkylene NR a R a 、-OC2-C6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene ORa 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a and oxo, and R a and R b Independently selected from H and -C1-C6 alkyl.

[0085] More preferably, R1 is a group -ZR 12 , wherein Z is -NHSO2- or -SO2NH-; and R 12 is oxetane, cyclopropyl, or R substituted by 0, 1, 2 or 3 groups selected from OH, halogen (such as F), C1-C6 alkoxy 12 is C1-C6 alkyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (eg F), C1-C6 alkoxy.

[0086] More preferably, R1 is selected from the following groups:

[0087] More preferably, R1 is selected from the following groups:

[0088] Most preferably, R1 is selected from

[0089] In some embodiments, formula (I) is as shown in formula (I)-1-1, formula (I)-1-2, formula (I)-2-1, formula (I)-2-2, formula (I)-3-1 or formula (I)-3-2:

[0090] Preferably, formula (I) is as shown in formula (I)-1-1, formula (I)-1-2, formula (I)-2-1 or formula (I)-2-2:

[0091] In some embodiments, each R 3 are independently H, C1-C4 alkyl or C1-C4 haloalkyl;

[0092] Preferably, each R 3 Independent of H.

[0093] In some embodiments, X7 is CR7.

[0094] In some embodiments, X7 is N.

[0095] In some embodiments, X8 is CR8.

[0096] In some embodiments, X8 is N.

[0097] In some embodiments, X9 is CR9.

[0098] In some embodiments, X9 is N.

[0099] In some embodiments, X7 is CR7, X8 is CR8, and X9 is CR9.

[0100] In some embodiments, X7 is CR7, X8 is CR8, and X9 is N.

[0101] In some embodiments, X7 is CR7, X8 is N, and X9 is CR9.

[0102] In some embodiments, X7 is CR7, X8 is N, and X9 is N.

[0103] In some embodiments, R7 is H, halogen, C1-C8 alkyl, C1-C6 haloalkyl, -OH, -OR 8a 、-OR 8b or -NR a R a ;

[0104] Preferably, R7 is H, halogen, C1-C8 alkyl, -NR a R a ;

[0105] More preferably, R7 is H or -NR a R a ;

[0106] More preferably, R7 is H, -NH2 or -NH-C1-C6 alkyl.

[0107] In some embodiments, R7 is H.

[0108] In some embodiments, R7 is -NR a R a .

[0109] In some embodiments, R7 is -NH2 or -NH-C1-C6 alkyl; preferably, R7 is -NH2 or -NHCH3.

[0110] In some embodiments, X7 is CR7 and R7 is -NH2 or -NH-C1-C6 alkyl, X8 is CH, and X9 is CH.

[0111] In some embodiments, X7 is CH, X8 is N or CR8, and X9 is N or CR9; preferably, X7 is CH, X8 is CR8, and X9 is CR9; more preferably, X7 is CH, X8 is CH, and X9 is CH.

[0112] In some embodiments, X7 is N and / or X8 is N.

[0113] In some embodiments, R8 and R9 are independently H, halogen, C1-C8 alkyl, C1-C6 haloalkyl, -OH, -OR 8a 、-OR 8b or -NR a R a ; Preferably, R8 and R9 are independently H, halogen, C1-C8 alkyl, -OH or -NR a R a ; More preferably, R8 and R9 are independently H or halogen; Most preferably, R8 and R9 are H.

[0114] In some embodiments, A is selected from phenyl, 5-6 membered nitrogen-containing heteroaryl, benzomonoheterocyclic group, benzobiheterocyclic group, 5-6 membered nitrogen-containing heteroaryl and monoheterocyclic group, 5-6 membered nitrogen-containing heteroaryl and biheterocyclic group, benzomonoheteroaromatic ring group, 5-6 membered nitrogen-containing heteroaryl and monoheteroaromatic ring group;

[0115] Optionally, the phenyl, 5-6 membered nitrogen-containing heteroaryl, benzomonoheterocyclic group, benzobiheterocyclic group, 5-6 membered nitrogen-containing heteroaryl and monoheterocyclic group, 5-6 membered nitrogen-containing heteroaryl and biheterocyclic group, benzomonoheteroaromatic ring group, 5-6 membered nitrogen-containing heteroaryl and monoheteroaromatic ring group are replaced by one or more R z replace,

[0116] The benzomonoheterocycle, 5-6-membered nitrogen-containing heteroaryl and monoheterocycle contain 0, 1, 2 or 3 atoms selected from N, O and S;

[0117] The benzomonoheteroaromatic ring group, the 5-6-membered nitrogen-containing heteroaromatic ring group and the monoheteroaromatic ring group contain 0, 1, 2 or 3 atoms selected from N, O and S;

[0118] The biheterocyclic group in the benzobiheterocyclic group and the 5-6-membered nitrogen-containing heteroarylbiheterocyclic group contains 0, 1, 2 or 3 atoms selected from N, O and S.

[0119] In some embodiments, A is selected from the group consisting of A1, A2, and A3.

[0120] Group A1 groups include the following:

[0121] In group A1, R A1R is each independently selected from a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is optionally substituted with 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); AI each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, -O-C1-C6 alkyl, C1-C6 alkylene-O-C1-C6 alkyl, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl);

[0122] m1 is selected from 0, 1, 2, 3 or 4; m2 is selected from 0, 1, 2 or 3; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1;

[0123] Group A2 groups include the following groups:

[0124] R in group A2 I and R II are each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and both R II The carbon atoms to which they are attached may together form a C3-C8 cycloalkyl group; the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group or C1-C4 haloalkyl group;

[0125] R A2 Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-Rz1 or -S(O)2-R z1 , the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl-C1-C6 alkylene, optionally substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C4 haloalkyl;

[0126] Each R z1 Independently selected from the following groups: C1-C6 alkyl, C1-C6 haloalkyl;

[0127] m5 is selected from 0, 1, 2 or 3; m6 is selected from 0, 1 or 2; n1 is selected from an integer of 0-4; n2 is selected from an integer of 0-6; n3 is selected from an integer of 0-8; n4 is selected from an integer of 0-2; n5 is selected from 0 or 1; n7 is selected from an integer of 0-3; q is 0 or 1; s is selected from an integer of 0-6; t is selected from an integer of 0-8; r is selected from 0 or 1.

[0128] Group A3 groups include the following groups:

[0129] In group A3,

[0130] Each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), and the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy may be optionally substituted with a substituent selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl, or two Gs attached to the same carbon atom form an oxo group (=O), or two Gs attached to the same carbon atom may form a C3-C8 cycloalkyl group together with the carbon atom to which they are attached;

[0131] R A3independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, -O-C3-C8 cycloalkyl, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -C(=O)C3-C8 cycloalkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl) (C1-C6 alkyl), phenyl, a 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms, a 5-6 membered monocyclic heteroaryl containing 0, 1, 2 or 3 N atoms and 1 or 2 atoms selected from O, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 5-6 membered monocyclic heteroaryl may be optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl;

[0132] R III independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, -O-C3-C8 cycloalkyl, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -C(=O)C3-C8 cycloalkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroaryl-C1-C6 alkyl containing 1, 2 or 3 N atoms, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms, and 5-6 membered monocyclic heteroaryl containing 0, 1, 2 or 3 N atoms and 1 or 2 atoms selected from O, said C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 5-6 membered monocyclic heteroaryl may be optionally substituted by a substituent selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl;

[0133] e is selected from 0, 1, 2 or 3; f is selected from 0, 1 or 2.

[0134] In some embodiments, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), and the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy may be optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl, or two Gs connected to the same carbon atom form an oxo group (=O) or two Gs connected to the same carbon atom may form a C3-C8 cycloalkyl group together with the carbon atom to which they are connected.

[0135] In some embodiments, R A3 and R III Each is independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, -O-C3-C8 cycloalkyl, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -C(=O)C3-C8 cycloalkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl) (C1-C6 alkyl), phenyl, a 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms, a 5-6 membered monocyclic heteroaryl containing 0, 1, 2 or 3 N atoms and 1 or 2 atoms selected from O, the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 5-6 membered monocyclic heteroaryl optionally being substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl.

[0136] In other embodiments, R A3 independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C4 haloalkyl.

[0137] In some embodiments, R A3 and RIII Each is independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), and the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy may be optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C4 haloalkyl.

[0138] In some embodiments, A is selected from the group consisting of A1, A2, and A3.

[0139] Group A1 groups include the following:

[0140] In group A1, R A1 R is each independently selected from a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is optionally substituted with 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); AI each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl);

[0141] m1 is selected from 0, 1, 2, 3 or 4; m2 is selected from 0, 1, 2 or 3; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1;

[0142] Group A2 groups include the following groups:

[0143] R in group A2 I and R IIare each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and both R II The carbon atoms to which they are attached may together form a C3-C8 cycloalkyl group; the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group or C1-C4 haloalkyl group;

[0144] R A2 Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 or -S(O)2-R z1 , the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl-C1-C6 alkylene, optionally substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl;

[0145] Each R z1 Independently selected from the following groups: C1-C6 alkyl, C1-C6 haloalkyl;

[0146] m5 is selected from 0, 1, 2 or 3; m6 is selected from 0, 1 or 2; n1 is selected from an integer of 0-4; n2 is selected from an integer of 0-6; n3 is selected from an integer of 0-8; n4 is selected from an integer of 0-2; n5 is selected from 0 or 1; n7 is selected from an integer of 0-3; q is 0 or 1; s is selected from an integer of 0-6; t is selected from an integer of 0-8; r is selected from 0 or 1.

[0147] Group A3 groups include the following groups:

[0148] In group A3,

[0149] G, R A3 and R IIIEach is independently as defined above; for example, in some embodiments, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl, or two Gs attached to the same carbon atom form an oxo group (=O); and / or, in some embodiments, R A3 independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), said C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy optionally being substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl, and R III is independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; in other embodiments, R A3 and R III each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, or C1-C4 haloalkyl;

[0150] e is selected from 0, 1, 2 or 3;

[0151] f is selected from 0, 1 or 2.

[0152] In some embodiments, A is selected from the group consisting of A1, A2, and A3.

[0153] Group A1 groups include the following:

[0154] In group A1, R A1 R is each independently selected from a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is optionally substituted with 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); AI each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl);

[0155] m1 is selected from 0, 1, 2, 3 or 4; m2 is selected from 0, 1, 2 or 3; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1;

[0156] Group A2 groups include the following groups:

[0157] R in group A2 I and R II are each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and both R II The carbon atoms to which they are attached may together form a C3-C8 cycloalkyl group; the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group or C1-C4 haloalkyl group;

[0158] R A2each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl) or C3-C8 cycloalkyl-C1-C6 alkylene, said C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl-C1-C6 alkylene being optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl;

[0159] m5 is selected from 0, 1, 2 or 3; m6 is selected from 0, 1 or 2; n1 is selected from an integer of 0-4; n2 is selected from an integer of 0-6; n3 is selected from an integer of 0-8; n4 is selected from an integer of 0-2; n5 is selected from 0 or 1; n7 is selected from an integer of 0-3; q is 0 or 1; s is selected from an integer of 0-6; t is selected from an integer of 0-8; r is selected from 0 or 1;

[0160] Group A3 groups include the following groups:

[0161] In group A3,

[0162] G, R A3 and R III Each is independently as defined above; for example, in some embodiments, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), and the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; and / or, in some embodiments, R A3 independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), said C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy optionally being substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl, and R IIIis independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; in other embodiments, R A3 and R III each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, or C1-C4 haloalkyl;

[0163] e is selected from 0, 1, 2 or 3; f is selected from 0, 1 or 2.

[0164] In some embodiments, A is selected from the group A1, wherein R A1 each independently selected from a saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic ring containing 0 or 1 N atom, optionally substituted with 0, 1, 2 or 3 groups selected from deuterium, halogen, -CN, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl);

[0165] R AI Each is independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl);

[0166] m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1.

[0167] In some embodiments, A is selected from the group A1, wherein R A1each independently selected from a saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic ring containing 0 or 1 N atom, optionally substituted with 0, 1, 2 or 3 groups selected from deuterium, halogen, -CN, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl);

[0168] R AI Each is independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl);

[0169] m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1.

[0170] In some embodiments, A is selected from the group consisting of A1,

[0171] R in group A1 A1 each independently selected from a saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic ring containing 0 or 1 N atom, optionally substituted with 0, 1, 2 or 3 groups selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl);

[0172] R AI Each is independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl);

[0173] m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1.

[0174] In some embodiments, A is selected from Group A1.

[0175] In some embodiments, R A1Each independently selected from a saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic ring containing 0 or 1 N atom, the monocyclic ring is optionally substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl); preferably, R A1 Each is independently selected from a saturated 5-membered or 6-membered monocyclic ring containing 0 or 1 N atom, which is optionally substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl).

[0176] In some embodiments, R AI Each is independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl); preferably, R AI Each is independently selected from deuterium, halogen, C1-C6 alkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl).

[0177] In some embodiments, m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; m3 is selected from 0, 1 or 2; and m4 is selected from 0 or 1.

[0178] In some embodiments, A is selected from the group A1, wherein R A1 R is independently selected from a saturated 5-membered or 6-membered monocyclic ring containing 0 or 1 N atom, which is optionally substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); AI Each is independently selected from deuterium, halogen, -CN, C1-C6 alkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl);

[0179] m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1.

[0180] In some embodiments, A is selected from the group A1, wherein R A1R is independently selected from a saturated 5-membered or 6-membered monocyclic ring containing 0 or 1 N atom, which is optionally substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); AI Each is independently selected from deuterium, halogen, C1-C6 alkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl);

[0181] m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1.

[0182] In some embodiments, A is selected from: where R A1 、R AI The optional ranges of m1, m3 are as defined above; preferably, A is selected from: where R A1 、R AI The optional ranges of m1, m3 are as defined above.

[0183] In some embodiments, A is selected from: where R A1 、R AI The optional ranges of m1, m3 are as defined above; preferably, A is selected from: where R A1 、R AI The optional ranges of m1, m3 are as defined above.

[0184] In some embodiments, A is selected from Group A2.

[0185] In some embodiments, A is selected from: where R I 、R II 、R A2 , n1, n2, n3, m5 are as defined above; preferably, R I and R II Each is independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), and both R II Together with the carbon atoms to which they are connected, they can form a C3-C6 cycloalkyl group. A2Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, and the C1-C6 alkyl may be optionally substituted by a substituent selected from deuterium, F, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; m5 is selected from 0, 1, 2 or 3, n1 is selected from an integer of 0-2, n2 is selected from an integer of 0-2, and n3 is selected from an integer of 0-2.

[0186] In some embodiments, A is selected from: where R I 、R II 、R A2 The optional ranges of n1, m5 are as defined above; preferably, R I and R II Each is independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), and both R II Together with the carbon atoms to which they are connected, they can form a C3-C6 cycloalkyl group. A2 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, and the C1-C6 alkyl may be optionally substituted by a substituent selected from deuterium, F, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy; m5 is selected from 0, 1, 2 or 3; n1 is selected from an integer of 0-2.

[0187] In some embodiments, A is selected from where R I 、R II 、R A2 The optional ranges of n1, m5 are as defined above; preferably, R I and R II Each is independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), and both R II Together with the carbon atoms to which they are connected, they can form a C3-C6 cycloalkyl group. A2 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, the C1-C6 alkyl optionally being substituted by a substituent selected from deuterium, F, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, m5 is selected from 0, 1, 2 or 3, and n1 is selected from an integer of 0-2.

[0188] In some embodiments, A is selected from where R I 、R II 、R A2 , n4, n5, m5, m6, q optional ranges are as defined above;

[0189] Preferably, R I and R II Each is independently selected from deuterium, halogen, C1-C6 alkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); R A2 Each is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl is optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; m5 is selected from 0 or 1; m6 is selected from 0 or 1; n4 is selected from 0 or 1; n5 is selected from 0 or 1; q is selected from 0 or 1;

[0190] More preferably, R A2 Each is independently selected from C1-C6 alkyl or C3-C6 cycloalkyl-C1-C2 alkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl-C1-C2 alkyl are optionally substituted by 1-3 substituents selected from deuterium, F, Cl, Br, -OH, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl;

[0191] More preferably, R A2 Each independently selected from methyl,

[0192] More preferably, R A2 Each independently selected

[0193] In some embodiments, A is selected from where R I 、R II 、R A2 , n4, m5 optional ranges are as defined above;

[0194] Preferably, R I and R II Each is independently selected from deuterium, halogen, C1-C6 alkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); R A2Each is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl is optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; m5 is selected from 0 or 1; n4 is selected from 0 or 1;

[0195] More preferably, R A2 Each is independently selected from C1-C6 alkyl or C3-C6 cycloalkyl-C1-C2 alkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl-C1-C2 alkyl are optionally substituted by 1-3 substituents selected from deuterium, F, Cl, Br, -OH, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl;

[0196] More preferably, R A2 Each independently selected from methyl,

[0197] More preferably, R A2 Each independently selected

[0198] In some embodiments, A is selected from Among them, R I 、R II 、R A2 , n5, m5 optional ranges are as defined above;

[0199] Preferably, R I and R II Each is independently selected from deuterium, halogen, C1-C6 alkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); R A2 Each is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, -S(O)-R z1 or -S(O)2-R z1 , the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl may be optionally substituted by 1-3 substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; each R z1Independently selected from C1-C6 alkyl, C1-C6 haloalkyl; m5 is selected from 0 or 1, n5 is selected from 0 or 1;

[0200] More preferably, R A2 Each independently selected Or -S(O)2-CF3.

[0201] In some embodiments, A is selected from Among them, R I 、R II 、R A2 , n5, m5 optional ranges are as defined above;

[0202] Preferably, R I and R II Each is independently selected from deuterium, halogen, C1-C6 alkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); R A2 Each is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, -S(O)-R z1 or -S(O)2-R z1 , the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl may be optionally substituted by 1-3 substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; each R z1 Independently selected from C1-C6 alkyl, C1-C6 haloalkyl; m5 is selected from 0 or 1, n5 is selected from 0 or 1;

[0203] More preferably, R A2 Each independently selected Or -S(O)2-CF3.

[0204] In some embodiments, A is selected from where R I 、R II 、R A2 The optional ranges of n1, m5, and m6 are as defined above.

[0205] In some embodiments, wherein A is selected from or, where R I 、R II 、R A2 The optional ranges of n1, m5, and m6 are as defined above.

[0206] In some embodiments, A is selected from where R I The optional ranges of m5, m6 are as defined above.

[0207] In some embodiments, A is selected from where R I The optional ranges of m5, m6 are as defined above.

[0208] In some embodiments, A is selected from Group A3.

[0209] In some embodiments, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O).

[0210] In some embodiments, R A3 independently selected from hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroarylene containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroaryl containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl).

[0211] In some embodiments, R III independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroarylene containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroaryl containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl).

[0212] In some embodiments, R A3 and R III Each is independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroarylene containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroaryl containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl).

[0213] In some embodiments, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O).

[0214] In some embodiments, R A3 are independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), and R III Independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl).

[0215] In some embodiments, R A3 and R III Each is independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl).

[0216] In some embodiments, e is selected from 0, 1 or 2.

[0217] In some embodiments, f is selected from 0 or 1.

[0218] In some embodiments, A is selected from any one of the following groups:

[0219] A is preferably selected from any one of the following groups:

[0220] In some embodiments, A is selected from any one of the following groups:

[0221] A is preferably selected from any one of the following groups:

[0222] In some embodiments, A is selected from any one of the following groups:

[0223] A is preferably selected from any one of the following groups:

[0224] In some embodiments, A is selected from any one of the following groups:

[0225] Among them, G, R III 、R A3 The optional range of e is as defined above.

[0226] In some embodiments, A is selected from any one of the following groups:

[0227] Among them, G, R III 、R A3 The optional range of e is as defined above.

[0228] In some embodiments, A is selected from the following groups: Among them, G, R III The optional range of e is as defined above; preferably, A is selected from

[0229] In some embodiments, A is selected from the following groups: Among them, G, R III The optional range of e is as defined above; preferably A is

[0230] In some embodiments, A is selected from the following groups: Among them, G, R III 、R A3 The optional range of e is as defined above; preferably, A is

[0231] In some embodiments, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, C1-C6 alkoxy, or two Gs attached to the same carbon atom form a 3-6 membered cycloalkyl, and the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl may be optionally substituted with 1-2 substituents selected from deuterium, F, Cl, Br;

[0232] Each R III independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, -O-C3-C8 cycloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroarylene containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroaryl containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl);

[0233] e is selected from 0, 1 or 2; f is selected from 0 or 1.

[0234] In some embodiments, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, and the C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy may be optionally substituted with 1-2 substituents selected from deuterium, F, Cl, and Br;

[0235] Each R III Independently selected from deuterium, halogen, -CN, C1-C6 alkyl or C1-C6 alkoxy;

[0236] e is selected from 0, 1 or 2; f is selected from 0 or 1.

[0237] In some embodiments, A is selected from the following groups: Among them, G, R III , e, f are as defined above; preferably, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, and the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy may be optionally substituted by 1-2 substituents selected from deuterium, F, Cl, Br, and each R IIIindependently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, e is selected from 0, 1 or 2, and f is selected from 0 or 1.

[0238] In some embodiments, A is selected from the following groups: Among them, G, R III , e, f are as defined above; preferably, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, and the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy may be optionally substituted by 1-2 substituents selected from deuterium, F, Cl, Br, and each R III independently selected from deuterium, halogen, -CN, C1-C6 alkyl or C1-C6 alkoxy, e is selected from 0, 1 or 2, and f is selected from 0 or 1.

[0239] In some embodiments, A is selected from the following groups: Among them, G, R III , the optional range of e is as defined above; preferably, wherein each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, and the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy may be optionally substituted by 1-2 substituents selected from deuterium, F, Cl, Br, each R III independently selected from deuterium, halogen, -CN, C1-C6 alkyl or C1-C6 alkoxy, e is selected from 0, 1 or 2, and f is selected from 0 or 1.

[0240] In some embodiments, A is selected from the following groups: Among them, G, R III , the optional range of e is as defined above; preferably, wherein each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy optionally can be substituted by 1-2 substituents selected from deuterium, F, Cl, Br, each R III independently selected from deuterium, halogen, -CN, C1-C6 alkyl or C1-C6 alkoxy, e is selected from 0, 1 or 2, and f is selected from 0 or 1.

[0241] In some embodiments, A is selected from the following groups: Among them, G, R III The optional range of e is as defined above.

[0242] In some embodiments, A is selected from the following groups: Among them, G, RIII The optional range of e is as defined above.

[0243] In some embodiments, A is selected from the following groups: Among them, G, R III The optional range of e is as defined above.

[0244] In some embodiments, A is selected from the following groups: Among them, G, R III The optional range of e is as defined above.

[0245] In some embodiments, A is selected from the following groups: Among them, G, R III The optional range of e is as defined above.

[0246] In some embodiments, A is selected from the following groups: Among them, G, R III The optional range of e is as defined above.

[0247] In some embodiments, A is selected from the following groups: Among them, G, R III The optional range of e is as defined above.

[0248] In some embodiments, A is selected from the following groups: Among them, G, R III The optional range of e is as defined above.

[0249] In some embodiments, A is selected from the following groups: Among them, G, R III The optional range of e is as defined above.

[0250] In some embodiments, A is selected from the following groups: Among them, G, R III The optional range of e is as defined above.

[0251] In some embodiments, A is selected from any one of the following groups:

[0252] In some embodiments, A is selected from any one of the following groups:

[0253] In some embodiments, A is selected from any one of the following groups:

[0254] In some embodiments, A is selected from any one of the following groups:

[0255] In some embodiments, A is selected from any one of the following groups:

[0256] In some embodiments, A is selected from any one of the following groups:

[0257] In some embodiments, A is selected from any one of the following groups:

[0258] In some embodiments, A is selected from any one of the following groups:

[0259] In some embodiments, A is selected from any one of the following groups:

[0260] In some embodiments, A is selected from any one of the following groups:

[0261] In some embodiments, L is selected from -NR 3 CONR 3 -; and / or X is CR7, R7 is -NR a R a .

[0262] In some embodiments, R1 is a group -ZR 12, wherein -Z is a single bond, -C1-C4 alkyl-, -C1-C4 alkyl-O-, -O-, -S-, -S(═O)-, -SO2-, -NH-, -NHSO2-, -SONH-, -NH-S(═O)(═NH)-, -S(═O)(═NH)-, -C1-C4 alkyl-SO2-, -(C═O)-, -(C═O)NH-, -C═N(OH)-, or -NH(C═O)-; and / or

[0263] (a)R 12 is H;

[0264] (b)R 12 is oxetanyl, cyclopropyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (such as F, Cl), C1-C6 alkoxy; or

[0265] (c)R 12 is C1-C6 alkyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (eg F), C1-C6 alkoxy.

[0266] In some embodiments, the group -ZR 12 -N=S(=O)-(R 12 )2, where two R 12 pairs that can alternatively combine with their respective attached sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S;

[0267] Or the group -ZR 12 In the equation, Z is a single bond, R 12 independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR m 、-OC1-C6 haloalkyl、CN、-C(=O)R n 、-C(=O)OR m 、-C(=O)NR m R m 、-C(=NR m )NR m R m 、-OC(=O)R n 、-OC(=O)NR m Rm 、-OC2-C6 alkyl NR m R m 、-OC2-C6 alkylOR m 、-SR m 、-S(=O)R n 、-S(=O)2R n 、-S(=O)2NR m R m 、-NR m R m 、-N(R m )C(=O)R n 、-N(R m )C(=O)OR n 、-N(R m )C(=O)NR m R m 、-N(R m )C(=NR m )NR m R m 、-N(R m )S(=O)2R n 、-N(R m )S(=O)2NR m R m 、-NR m C2-6 alkyl NR m R m 、-NR m C2-C6 alkyl OR m 、-C1-C6 alkyl NR m R m 、-C1-C6 alkylOR m 、-C1-C6 alkyl N(R m )C(=O)R n 、-C1-C6 alkylOC(=O)R n 、-C1-C6 alkyl C(=O)NR m R m 、-C1-C6 alkyl C(=O)OR m and oxo, and R m and R n Independently selected from H and -C1-C6 alkyl.

[0268] In some embodiments, R1 is a group -ZR 12 , wherein Z is -NHSO2- or -SO2NH-; and R 12 is oxetane, cyclopropyl, or R substituted by 0, 1, 2 or 3 groups selected from OH, halogen (such as F), C1-C6 alkoxy 12is C1-C6 alkyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (eg F), C1-C6 alkoxy.

[0269] In some embodiments, R1 is selected from the following groups:

[0270] In some embodiments, R x Selected from the group consisting of:

[0271] Or alternatively, R 10a and R 10b Yes, R 10c and R 10d Yes, R 10e and R 10f Yes, R 10g and R 10 h pair or R 10i and R 10j Each of the pairs can independently combine with their respective attached carbon atoms to form a spiro-linked x wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, C1-C6 alkyl, C1-C4 haloalkyl, -OR a 、-OC1-C4 haloalkyl、CN、-NR a R a or oxo;

[0272] R 10k selected from the group consisting of H, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)Rb 、-OC(=O)NR a R a 、-OC2-C6 alkyl NR a R a 、-OC2-C6 alkylOR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-6 alkyl NR a R a 、-NR a C2-C6 alkyl OR a 、-C1-C6 alkyl NR a R a 、-C1-C6 alkylOR a 、-C1-C6 alkyl N(R a )C(=O)R b 、-C1-C6 alkylOC(=O)R b 、-C1-C6 alkyl C(=O)NR a R a 、-C1-C6 alkyl C(=O)OR a and oxo, and R a and R b Independently selected from H and -C1-C6 alkyl;

[0273] R 10l Selected from the group consisting of C1-C6 alkyl substituted with 0, 1, 2, 3, 4 or 5 groups of F, Cl, Br, C1-C6 alkoxy, -O-C1-C6 haloalkyl or CN.

[0274] In some embodiments, R x Selected from:

[0275] In some embodiments, the compound of formula (I) is a compound of formula (IC-1) or formula (IC-1'):

[0276] wherein A is selected from the A1 group, R a is H or C1-C4 alkyl.

[0277] In some embodiments, the compound of formula (I) is a compound of formula (IC-2) or formula (IC-2'):

[0278] wherein A is selected from the A1 group, R a is H or C1-C4 alkyl.

[0279] In some embodiments, the compound of formula (I) is a compound represented by formula (IA-1) Among them, L, R X 、R1、X7、X8、X9、R A2 、R I 、R II The optional ranges of n4 and m5 are as defined above; preferably, the compound represented by formula (IA-1) is

[0280] In some embodiments, the compound of formula (I) is a compound represented by formula (IA-2) Among them, L, R X 、R1、X7、X8、X9、R A2 、R I 、R II The optional ranges of n5, m5 are as defined above; preferably, the compound represented by formula (IA-2) is

[0281] In some embodiments, the compound of formula (I) is a compound represented by formula (IA-3) Among them, L, R X 、R1、X7、X8、X9、R A2 、R I 、R II The optional ranges of n1 and m5 are as defined above; preferably, the compound represented by formula (IA-3) is

[0282] In some embodiments, the compound of formula (I) is a compound represented by formula (IA-4) Among them, L, RX 、R1、X7、X8、X9、R A2 、R I 、R II The optional ranges of n1, m6 are as defined above; preferably, the compound represented by formula (IA-4) is

[0283] In some embodiments, the compound of formula (I) is a compound represented by formula (IA-5) Among them, L, R X 、R1、X7、X8、X9、R A2 、R I 、R II The optional ranges of n1, m6 are as defined above; preferably, the compound represented by formula (IA-5) is

[0284] In some embodiments, the compound of formula (I) is a compound represented by formula (IA-6) Among them, L, R X 、R1、X7、X8、X9、R A2 、R I 、R II The optional ranges of n4 and m5 are as defined above; preferably, the compound represented by formula (IA-6) is

[0285] In some embodiments, the compound of formula (I) is a compound represented by formula (IA-7) Among them, L, R X 、R1、X7、X8、X9、R A2 、R I 、R II The optional ranges of n4 and m6 are as defined above; preferably, the compound represented by formula (IA-7) is

[0286] In some embodiments, the compound of formula (I) is a compound represented by formula (IA-8) Among them, L, R X 、R1、X7、X8、X9、R A2 、R I 、R II The optional ranges of n4 and m6 are as defined above; preferably, the compound represented by formula (IA-8) is

[0287] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-1) Among them, L, R X, R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-1) is

[0288] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-2) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-2) is

[0289] In some embodiments, the compound of formula (IB-2) is

[0290] In other embodiments, the compound of formula (IB-2) is

[0291] In some preferred embodiments, the compound of formula (IB-2) is:

[0292] In some more preferred embodiments, the compound of formula (IB-2) is:

[0293] In other preferred embodiments, the compound of formula (IB-2) is:

[0294] In some more preferred embodiments, the compound of formula (IB-2) is:

[0295] In some such embodiments, preferably, R IIIselected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroaryl-C1-C6 alkyl containing 1, 2 or 3 N atoms, -C1-C6 alkyl containing 1 or 2 N atoms and 1 or 2 wherein each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O). In some further preferred embodiments, each e is 1.

[0296] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-3) Among them, L, R X , R1, X7, X8, X9, G, R III 、R A3 The optional range of e is as defined above; preferably, the compound represented by formula (IB-3) is

[0297] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-4) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-4) is

[0298] In some embodiments, the compound of formula (IB-4) is:

[0299] In some preferred embodiments, the compound of formula (IB-4) is:

[0300] In some more preferred embodiments, the compound of formula (IB-4) is:

[0301] In other embodiments, the compound of formula (IB-4) is:

[0302] In some preferred embodiments, the compound of formula (IB-4) is:

[0303] In some more preferred embodiments, the compound of formula (IB-4) is:

[0304] In some such embodiments, preferably, R III Selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -containing wherein the alkyl radical is a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 N atoms, a 5-6 membered monocyclic heteroaryl having 1 or 2 N atoms and 1 or 2 atoms selected from O, a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 N atoms, or -N(C1-C6 alkyl)(C1-C6 alkyl); and / or, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O). In some further preferred embodiments, each e is 1.

[0305] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-5) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably the compound represented by formula (IB-5) is

[0306] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-6) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-6) is

[0307] In some embodiments, the compound of formula (IB-6) is:

[0308] In some preferred embodiments, the compound of formula (IB-6) is:

[0309] In some more preferred embodiments, the compound of formula (IB-6) is:

[0310] In other embodiments, the compound of formula (IB-6) is:

[0311] In some preferred embodiments, the compound of formula (IB-6) is:

[0312] In some more preferred embodiments, the compound of formula (IB-6) is:

[0313] In some such embodiments, preferably, R III selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroaryl-C1-C6 alkyl containing 1, 2 or 3 N atoms, -C1-C6 alkyl containing 1 or 2 N atoms and 1 or 2 wherein each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O). In some further preferred embodiments, each e is 1.

[0314] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-7) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-7) is

[0315] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-8) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-8) is

[0316] In some embodiments, the compound represented by formula (IB-8) is:

[0317] In some preferred embodiments, the compound represented by formula (IB-8) is:

[0318] In some more preferred embodiments, the compound represented by formula (IB-8) is:

[0319] In other embodiments, the compound represented by formula (IB-8) is:

[0320] In some preferred embodiments, the compound represented by formula (IB-8) is:

[0321] In some more preferred embodiments, the compound represented by formula (IB-8) is:

[0322] In some such embodiments, preferably, R IIIselected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroaryl-C1-C6 alkyl containing 1, 2 or 3 N atoms, -C1-C6 alkyl containing 1 or 2 N atoms and 1 or 2 wherein each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O). In a further preferred embodiment, each e is 1.

[0323] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-9) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-9) is In some embodiments, the compound of formula (I) is a compound represented by formula (IB-10) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-10) is

[0324] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-11) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-11) is

[0325] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-12) Among them, L, R X , R1, X7, X8, X9, G, R IIIThe optional range of e is as defined above; preferably, the compound represented by formula (IB-12) is

[0326] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-13) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-13) is

[0327] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-14) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-14) is

[0328] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-15) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-15) is

[0329] In some embodiments, the compound of formula (I) is a compound represented by formula (IB-16) Among them, L, R X , R1, X7, X8, X9, G, R III The optional range of e is as defined above; preferably, the compound represented by formula (IB-16) is

[0330] In some embodiments, the compound of formula (I) is selected from the group consisting of:

[0331] In some embodiments, the compound of formula (I) is selected from the group consisting of:

[0332] Furthermore, the present application provides a pharmaceutical composition comprising a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable diluent or carrier.

[0333] Furthermore, the present application provides a method for treating a condition that can be treated with a KIF18A inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition as described above.

[0334] In some embodiments, the condition is a cancer selected from the group consisting of: (a) a solid tumor or a hematogenic tumor selected from the group consisting of bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkett lymphoma; (c) a hematopoietic tumor of the myeloid lineage selected from the group consisting of (c) neoplasms of the central and peripheral nervous systems selected from the group consisting of astrocytomas, neuroblastomas, gliomas, and schwannomas; or (d) melanomas, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0335] Furthermore, the present application provides a method for reducing the size of a solid tumor in a subject, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition as described above.

[0336] Furthermore, the present application provides a method for treating a cell proliferation disorder in a subject, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition as described above.

[0337] Furthermore, the cell proliferation disorder, ie, abnormal cell proliferation, preferably mediates abnormal cell proliferation by affecting the cell cycle and mitosis.

[0338] Furthermore, the present application provides a method for inhibiting KIF18A in cells, comprising contacting the cells with a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions as described above.

[0339] Furthermore, the present application provides a use of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or said pharmaceutical composition in the preparation of a medicament for treating a disease that can be treated with a KIF18A inhibitor.

[0340] In some embodiments, the condition is a cancer selected from the group consisting of: (a) a solid tumor or a hematogenic tumor selected from the group consisting of bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkett lymphoma; (c) a hematopoietic neoplasm of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, a xeroderma pigmentosum, a keratoacanthoma, a follicular thyroid carcinoma, or a Kaposi's sarcoma.

[0341] Furthermore, the present application provides a use of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition thereof in the preparation of a drug for reducing the size of a solid tumor in a subject.

[0342] Furthermore, the present application provides a use of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition thereof in the preparation of a drug for treating a cell proliferation disorder in a subject.

[0343] Furthermore, the present application provides a use of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition thereof in the preparation of a drug for inhibiting KIF18A in cells.

[0344] The compound represented by formula (I) provided by the present invention has a novel structure and good KIF18A inhibitory activity, and can be used for therapeutic, preventive, acute or chronic treatment of KIF18A-mediated diseases and disorders (including but not limited to cancer). DETAILED DESCRIPTION

[0345] definition

[0346] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0347] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of and "consisting of").

[0348] As used herein, term " alkyl " is defined as straight chain or branched saturated aliphatic hydrocarbon.In some embodiments, alkyl has 1 to 12, for example 1 to 6 carbon atoms.For example, as used herein, term " C1-6 alkyl " refers to the linear or branched group (for example methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl, sec-butyl, the tert-butyl, n-pentyl or n-hexyl) of 1 to 6 carbon atoms, it is optionally replaced (this group is referred to as " haloalkyl ") (for example CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl or-CH2CH2CF3 etc.) of 1 to 4 carbon atoms' straight chain or branched aliphatic hydrocarbon chain (i.e. methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl, sec-butyl or the tert-butyl).

[0349] As used herein, the term "alkylene" means a divalent straight or branched saturated aliphatic hydrocarbon group obtained by losing 1 H from an alkyl group as defined above. In some embodiments, the alkylene group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C1-6 alkylene" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene or n-hexylene), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as "haloalkylene") (e.g., -CF2-, -C2F4, -CF2-, -CHF-, -CHCF2-, -CHCl- or -CHCH2CF2-, etc.). The term "C1-4 alkylene" refers to a divalent straight or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene).

[0350] Those skilled in the art will readily understand that, in the case where an alkyl group is part of a substituent and is attached to another group on both sides, if the term "alkyl" is still used, the term "alkyl" actually refers to the corresponding alkylene group. For example, "-OC2-C6alkylNR a R a The “C2-C6 alkyl” in the formula “C2-C6 alkyl” is actually “C2-C6 alkylene”.

[0351] As used herein, the term "alkoxy" refers to -O-alkyl, wherein the alkyl is as defined above. The term "C1-6 alkoxy" refers to a linear or branched alkoxy group (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy, or n-hexoxy) having 1 to 6 carbon atoms, which is optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as a "haloalkoxy group") (e.g., -OCF3, -OC2F5, -OCHF2, -OCH2F, -OCH2CF3, -OCH2Cl, or -OCH2CH2CF3, etc.) having 1 to 4 carbon atoms.

[0352] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), optionally substituted with one or more (such as The cycloalkyl group is optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms, suitably 3 to 10 carbon atoms. For example, the term "C3-6 cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) of 3 to 6 ring-forming carbon atoms. The cycloalkyl group is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0353] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more (e.g., one, two, three or four) heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O)2 and NRa', wherein Ra' represents a hydrogen atom or a C1-6 alkyl group or a halo-C1-6 alkyl group. The heterocyclyl group may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom (if present) in the ring. In particular, a 3-10 membered heterocyclyl group is a group having 3-10 (e.g., 3-7, 4-6, or 5-6) carbon atoms and heteroatoms in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0354] As used herein, the term "heterocyclyl" encompasses a ring structure, and the connection point of the ring structure to the other groups can be on any ring in the ring structure. Therefore, the heterocyclyl of the present invention also includes but is not limited to heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, such as 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C4-6 (mono) cycloalkyl, examples of which include but are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,

[0355] As used herein, the term "heterocyclyl" encompasses bridged heterocyclyls and spiro heterocyclyls.

[0356] As used herein, the term "bridged heterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including but not limited to 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example The “nitrogen-containing bridged heterocycle”, “oxygen-containing bridged heterocycle” and “sulfur-containing bridged heterocycle” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.

[0357] As used herein, the term "fused heterocyclic group" refers to a two-membered or multi-membered heterocyclic group (e.g., a two-membered heterocyclic group, a three-membered heterocyclic group, etc.) that includes a fused ring structure, and the connection point between the fused ring structure and other groups can be on any ring in the fused ring structure. Therefore, the fused heterocyclic group of the present invention also includes, but is not limited to, an aromatic ring group and a heterocyclic group, a heterocyclic group and a cycloalkyl group, a monoheterocyclic group and a monoheterocyclic group, a monoheterocyclic group and a monocycloalkyl group, and a heteroaromatic ring group and a heterocyclic group, such as a 3-7-membered (mono)heterocyclic group and a 3-7-membered (mono)heterocyclic group, a 3-7-membered (mono)heterocyclic group and a (mono)cycloalkyl group, a 3-7-membered (mono)heterocyclic group and a C4-6 (mono)cycloalkyl group, a 6-10-membered (mono)aromatic ring group and a 3-7-membered (mono)heterocyclic group, a 6-10-membered (mono)aromatic ring group and a 6-10-membered (bi)heterocyclic group, a 6-10-membered (bi)aromatic ring group and a 6-10-membered (mono)heterocyclic group, and a 6-10-membered (bi)heterocyclic group.

[0358] As used herein, the term "aryl" refers to a full carbon monocyclic or fused ring polycyclic aromatic group with a conjugated π electron system. For example, as used herein, the term "C6-14 aryl" means an aromatic group containing 6 to 14 (e.g., 6 to 12) carbon atoms, such as phenyl or naphthyl. Aryl is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C1-6 alkyl, etc.).

[0359] As used herein, the term "heteroaryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case, may be benzo-fused. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), thiadiazolyl and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof.

[0360] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0361] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) identical or different halogen atoms, as defined herein. The terms "C1-8haloalkyl", "C1-6haloalkyl" and "C1-4haloalkyl" refer to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0362] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0363] If a substituent is described as being "optionally substituted with," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0364] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0365] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0366] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0367] When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such substituent may be bonded to any ring atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown as carrying a substitutable hydrogen atom, the substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is to the available ring member.

[0368] As used herein, NRa groups and the like include substituents wherein two Ra groups together with the N to which they are attached form a ring (optionally containing N, O or S atoms), and include groups such as: The group N(Cα-βalkyl)Cα-βalkyl (wherein α and β are as defined above and are the carbon atoms in the alkyl group) includes substituents wherein two Cα-βalkyl groups are taken together to form a ring (optionally containing N, O or S atoms), and includes, for example:

[0369] "Bicyclic" means a group having two connected rings. A bicyclic ring can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, 1, 2, or 3 heteroatoms, such as N, O, or S). Both rings can be aliphatic (e.g., decalin and norbornane), or aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic rings (e.g., tetralin).

[0370] Bicyclic rings include (a) spirocyclic compounds, in which the two rings share only one single atom (the spiro atom, which is usually a quaternary carbon). Examples of spirocyclic compounds include, but are not limited to:

[0371] (b) Fused bicyclic compounds, where the two rings share two adjacent atoms. In other words, the rings share a single covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thujene and decalin). Examples of fused bicyclic rings include, but are not limited to: and (c) bridged bicyclic compounds in which the two rings share three or more atoms and are separated by a bridge comprising at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be considered a pair of cyclopentane rings, each sharing three of their five carbon atoms. Examples of bridged bicyclic rings include, but are not limited to:

[0372] Benzomonoheterocyclic ring refers to a bicyclic ring formed by condensing a phenyl group with a (mono)heterocyclic group.

[0373] Benzomonoheteroaryl ring refers to a bicyclic ring formed by condensing a phenyl group with one (mono)heteroaryl group.

[0374] Benzobiheterocycle refers to a tricyclic ring formed by condensing a phenyl group with a bicyclic heterocyclic group.

[0375] The nitrogen-containing heteroaryl and monocyclic heterocyclic ring refers to a bicyclic ring formed by condensing a nitrogen heteroaryl group and one (mono) heterocyclic group.

[0376] The nitrogen-containing heteroaryl and monoheteroaryl ring refers to a bicyclic ring formed by condensing a nitrogen heteroaryl group and one (mono)heteroaryl group.

[0377] The nitrogen-containing heteroaryl and bicyclic heterocyclic ring refers to a tricyclic ring formed by condensing a nitrogen heteroaryl group and a bicyclic heterocyclic group.

[0378] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2H), tritium (T, 3H)); isotopes of carbon (e.g., 11C, 13C, and 14C); isotopes of chlorine (e.g., 36Cl); isotopes of fluorine (e.g., 18F); isotopes of iodine (e.g., 123I and 125I); isotopes of nitrogen (e.g., 13N and 15N); isotopes of oxygen (e.g., 15O, 17O, and 18O); isotopes of phosphorus (e.g., 32P); and isotopes of sulfur (e.g., 35S). Certain isotopically labeled compounds of the present invention (e.g., those incorporating radioisotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). The radioisotopes tritium (i.e., 3H) and carbon-14 (i.e., 14C) are particularly useful for this purpose because they are easily incorporated and easily detected. Substitution with positron-emitting isotopes (e.g., 11C, 18F, 15O, and 13N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0379] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0380] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0381] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0382] Wavy lines may be used in this article Depicting chemical bonds of compounds of the invention. The use of wavy lines to depict bonds to asymmetric carbon atoms is intended to indicate that the absolute configuration (eg, R or S) at that carbon atom is included.

[0383] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0384] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

[0385] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

[0386] For a review of suitable salts see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0387] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0388] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0389] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0390] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0391] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0392] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0393] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0394] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally based on conventional conditions.

[0395] Some representative compounds of the present invention can be prepared by the following synthetic methods. In the following reaction formulas, the reagents and conditions of each step can be selected from conventional reagents or conditions for such preparation methods in the art. After the structures of the compounds of the present invention are disclosed, the above selection can be made by those skilled in the art based on their knowledge in the art.

[0396] Example 1: Synthesis of 2-amino-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-4-((2-hydroxyethyl)sulfonamide)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (1)

[0397] Step 1: Synthesis of compound 1-2

[0398] Compound 1-1 (2.0 g, 7.967 mmol) and (2,4-dimethoxyphenyl)methylamine (1.20 mL, 7.97 mmol) were dissolved in a DMF (10 mL) solution, and Cs2CO3 (5191.62 mg, 15.93 mmol) was added thereto. The reaction mixture was placed in a 60 ° C oil bath and stirred for 1 hour. After the reaction was completed, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE:EA = 40:1-20:1) to obtain compound 1-2.

[0399] Step 2: Synthesis of Compounds 1-3

[0400] 6-Azaspiro [2.5] octane hydrochloride (714.04 mg, 4.84 mmol) was dissolved in DMSO (10 mL), and NaH (338.52 mg, 14.11 mmol) was added and stirred for a while. Compound 1-2 (1.6 g, 4.03 mmol) was then added and stirred at 125 ° C overnight. After the reaction was completed, the reaction mixture was diluted with EA (60 mL), and the organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE: EA = 100: 0-49: 1) to give compound 1-3.

[0401] Step 3: Synthesis of Compounds 1-4

[0402] To a solution of compound 1-3 (325 mg, 0.66 mmol) in MeOH (2 mL) and H2O (0.1 mL) was added NaOH (79.69 mg, 1.99 mmol) and the reaction was stirred at 60°C overnight. The reaction mixture was diluted with EA (50 mL). The organic layer was washed with brine (80 mL) and then dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE:EA=100:0-90:10-80:20) to give compound 1-4.

[0403] Step 4: Synthesis of Compounds 1-5

[0404] Compound 1-4 (150 mg, 0.32 mmol) and 3-(4,4-difluorohexahydropyridin-1-yl)aniline (73.67 mg, 0.35 mmol) were dissolved in DMF (2 mL) and HATU (143.98 mg, 0.38 mmol) and DIEA (0.10 mL, 0.63 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EA (20 mL), and the organic layer was washed with brine (180 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE:EA=100:0-95:5-90:10) to obtain compound 1-5.

[0405] Step 5: Synthesis of Compounds 1-6

[0406] Compound 1-5 (116 mg, 0.17 mmol), 2-hydroxyethyl-1-sulfonamide (85.10 mg, 0.68 mmol), catalyst CAS: 1599466-85-9 (14.46 mg, 0.02 mmol), and Cs2CO3 (110.78 mg, 0.34 mmol) were added to a reaction flask. Anhydrous 1,4-dioxane (2 mL) was added under argon protection, and the reaction was stirred at 100°C for 4 hours. The reaction mixture was diluted with EA (12 mL), and the organic layer was washed with brine (180 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 100:0-90:10-60:40) to obtain the product compound 1-6.

[0407] Step 6: Synthesis of Compound 1

[0408] Compound 1-6 (85 mg, 0.13 mmol) was added to a reaction flask, followed by DCM (1 mL) and CF3COOH (0.3 mL, 0.13 mmol), and the reaction was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with DCM (30 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative purification to obtain product compound 1.

[0409] 1 H NMR (400MHz, DMSO-d6) δ=10.31-9.95(m,1H),9.41-9.32(m,1H),7.83(br d,J=8.4Hz,1H),7.04(br d,J=8.1Hz,2H),7.00-6.95(m,1H),6.89(br d,J=8.5Hz,1H),6.33(br d,J=7.6Hz,1H),4.99-4.87(m,2H),3.81-3.73(m,2H),3.48-3.41(m,2H),3.38-3.33(m, 4H),2.97-2.91(m,2H),2.90-2.81(m,2H),2.07-1.99(m,2H),1.90-1.81(m,2H),1.72(br s, 2H), 1.67-1.58 (m, 2H), 0.50 (br d, J = 7.3Hz, 2H), 0.21 (br d, J = 4.3Hz, 2H).

[0410] Example 3: Synthesis of 2-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(2-hydroxyethylsulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (3)

[0411] Step 1: Synthesis of compound 3-2

[0412] Compound 3-1 (5.0 g, 19.92 mmol) and 6-azaspiro [2.5] octane hydrochloride (3.53 g, 23.90 mmol) were dissolved in a mixed solvent of N, N-dimethylformamide (15 mL) and water (15 mL), and N, N-diisopropyl-ethylamine (7.72 g, 59.75 mmol) was added thereto. The reaction mixture was placed in a 100 ° C oil bath and stirred for 6 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE: EA = 98: 2-95: 5). Compound 3-2 was obtained.

[0413] Step 2: Synthesis of compound 3-3

[0414] Compound 3-2 (5.9 g, 17.24 mmol) was dissolved in a mixed solvent of MeOH (32 mL) and H₂O (8 mL). NaOH (4.14 g, 103.45 mmol) was added and the reaction mixture was stirred in a 60°C oil bath for 3 hours. After completion of the reaction, 2M HCl was added to acidify the reaction solution. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain compound 3-3.

[0415] Step 3: Synthesis of compound 3-4

[0416] Compound 3-3 (3.0 g, 9.14 mmol) was dissolved in 1,4-dioxane (20 mL), and dibenzylamine (9.02 g, 45.71 mmol) was added. The reaction mixture was placed in an oil bath and stirred at 100°C overnight. After the reaction was completed, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (60 × 3 mL). The organic layer was washed with brine (60 × 3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0-99:10-97:30). Compound 3-4 was obtained.

[0417] Step 4: Synthesis of Compound 3-5

[0418] Compound 3-4 (159 mg, 0.31 mmol) was dissolved in DCM (2 mL), the reaction solution was cooled to 0°C, and oxalyl chloride (119.78 mg, 0.94 mmol) was slowly added thereto. The reaction mixture was stirred at room temperature for half an hour. After the reaction was completed, the reaction solution was directly spin-dried and used in the next step. 2-Chloro-6-methylpyrimidin-4-amine (87.14 mg, 0.61 mmol) was dissolved in DMF (1 mL), the reaction solution was cooled to 0°C, NaH (14.57 mg, 0.61 mmol) was added, and the reaction solution was placed in a 60°C oil bath and stirred for 30 minutes. The reaction solution was then cooled to 0°C, the acid chloride obtained above was added, and the mixed reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30×3 mL). The organic layer was washed with brine (30×3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA=97:3-95:5) to obtain compound 3-5.

[0419] Step 5: Synthesis of Compounds 3-6

[0420] Compound 3-5 (53 mg, 0.08 mmol) was dissolved in 1-methyl-2-pyrrolidone (1 mL), and 4,4-difluoropiperidine hydrochloride (26.47 mg, 0.17 mmol) was added thereto. The reaction mixture was placed in an oil bath and stirred at 180 ° C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 × 3 mL). The organic layer was washed with brine (10 × 3 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0-97:3) to obtain compound 3-6.

[0421] Step 6: Synthesis of Compounds 3-7

[0422] Compound 3-6 (34 mg, 0.05 mmol) and 2-hydroxyethane-1-sulfonamide (23.78 g, 0.19 mmol) were dissolved in 1,4-dioxane (1 mL), and catalyst CAS: 1599466-83-7 (8.74 mg, 0.01 mmol) and cesium carbonate (30.96 mg, 0.10 mmol) were added thereto. The reaction mixture was stirred in a 95 ° C oil bath for 3 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 × 3 mL). The organic layer was washed with brine (10 × 3 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE: EA = 100: 0-90: 10-80: 20) to give compound 3-7.

[0423] Step 7: Synthesis of compound 3

[0424] Compound 3-7 (28 mg, 0.04 mmol) was dissolved in methanol (1 mL), and 10% palladium on carbon (0.43 mg) was added thereto. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. After completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 × 3 mL). The organic layer was washed with brine (10 × 3 mL), dried over Na2SO4, filtered, and concentrated. Compound 3 was obtained by purification. MS (ESI, pos.ion) m / z: 580.2 [M+1] + .

[0425] 1H NMR (400MHz, DMSO-d6): δ=13.62-13.54(m,1H),7.39-7.35(m,1H),7.29-7.19(m,2H),6.48-6.44(m,1H),6.39-6.34(m,1H),3.97-3.87(m, 4H),3.78-3.72(m,2H),3.33-3.29(m,2H),2.96-2.81(m,4H),2.53-2 .51(m,4H),2.31-2.27(m,3H),2.04-1.94(m,4H),0.38-0.33(m,4H).

[0426] Example 4: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(2-hydroxyethylsulfonamide)-2-methylamino-6-(6-azaspiro[2.5]octan-6-yl)benzamide (4)

[0427] Step 1: Synthesis of compound 4-2

[0428] Compound 4-1 (5.0 g, 19.92 mmol) and 6-azaspiro[2.5]octane hydrochloride (3.53 g, 23.90 mmol) were dissolved in a mixed solvent of DMF (25 mL) and H2O (25 mL), and Cs2CO3 (7.72 g, 59.75 mmol) was added thereto. The reaction mixture was placed in a 100°C oil bath and stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 98:2-95:5) to give compound 4-2.

[0429] Step 2: Synthesis of compound 4-3

[0430] Compound 4-2 (5.8 g, 16.95 mmol) was dissolved in a mixture of MeOH (32 mL) and H₂O (8 mL). NaOH (4.07 g, 101.69 mmol) was added, and the reaction mixture was stirred in a 60°C oil bath for 3 hours. After completion of the reaction, 2M HCl was added to acidify the reaction solution, which was then diluted with water (50 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to yield compound 4-3.

[0431] Step 3: Synthesis of compound 4-4

[0432] Compound 4-3 (2.0 g, 6.09 mmol) was dissolved in N-methylbenzylamine (10 mL), and the reaction mixture was placed in a microwave reactor and stirred at 150 ° C for 30 minutes. After the reaction was completed, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (60 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 99:1-97:3) to obtain compound 4-4.

[0433] Step 4: Synthesis of compound 4-5

[0434] Compound 4-4 (400 mg, 0.93 mmol) was dissolved in DCM (6 mL). The reaction mixture was cooled to 0°C and oxalyl chloride (355 mg, 2.79 mmol) was slowly added. The reaction mixture was stirred at room temperature for half an hour. After completion of the reaction, the reaction mixture was directly spin-dried and used in the next step. 2-Chloro-6-methylpyrimidin-4-amine (200.63 mg, 1.40 mmol) was dissolved in DMF (4 mL). After the reaction mixture was cooled to 0°C, NaH (33.54 mg, 1.40 mmol) was added and the reaction mixture was stirred in a 60°C oil bath for 30 minutes. The reaction mixture was then cooled to 0°C and the acid chloride obtained above was added. The mixed reaction mixture was reacted at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA=100:0-97:3) to give compound 4-5.

[0435] Step 5: Synthesis of Compounds 4-6

[0436] Compound 4-5 (140 mg, 0.25 mmol) and 4,4-difluoropiperidine hydrochloride (47.71 mg, 0.30 mmol) were dissolved in 1-methyl-2-pyrrolidone (3 mL), and N,N-diisopropylethylamine (97.82 mg, 0.76 mmol) was added thereto. The reaction mixture was placed in an oil bath and stirred at 180 ° C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10×3 mL). The organic layer was washed with brine (10×3 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE:EA=100:0-97:3) to obtain compound 4-6.

[0437] Step 6: Synthesis of Compounds 4-7

[0438] Compound 4-6 (90 mg, 0.14 mmol) and 2-hydroxyethane-1-sulfonamide (70.08 mg, 0.86 mmol) were dissolved in dioxane (2 mL), and catalyst CAS: 1599466-89-3 (22.62 mg, 0.03 mmol) and Cs2CO3 (136.84 mg, 0.42 mmol) were added. The reaction mixture was stirred in a 95°C oil bath for 2 hours. After completion of the reaction, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 95:5) to obtain compound 4-7.

[0439] Step 7: Synthesis of compound 4

[0440] Compound 4-7 (76 mg, 0.11 mmol) was dissolved in methanol (1 mL), and 10% palladium on carbon (1.18 mg, 0.01 mmol) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 × 3 mL). The organic layer was washed with brine (10 × 3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified to obtain compound 4. MS (ESI, pos.ion) m / z: 594.3 [M+1] + .

[0441] 1 H NMR (400MHz, DMSO-d6) δ=13.72(s,1H),8.84-8.74(m,1H),7.40-7.31(m,1H),6.52-6.46(m,1H),6.37(s,1H),4.09(q,J=4.8Hz,1H),3.89(br s,4H),3.75(t,J=6.5Hz,2H),3.37-3.36(m,4H),3.17-3.16(d,J=4.6Hz,2H),2.92(br s,4H),2.79(br d,J=4.6Hz,3H),2.29(s,3H),2.04-1.94(m,4H),0.36(s,4H).

[0442] Example 5: Synthesis of N-(1-(cyclopropylmethyl)indoline-4-(2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (5)

[0443] Step 1: Synthesis of compound 5-2

[0444] To a suspension of compound 5-1 (250 mg, 0.48 mmol) in AcOH (5 mL) was added NaBH3CN (89.93 mg, 1.43 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was poured into a 2N NaOH solution (40 mL) and extracted with EA (80 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The yellow residue was purified by column chromatography (PE:EA = 95:5-90:10) to obtain compound 5-2.

[0445] Step 2: Synthesis of compound 5

[0446] To a solution of compound 5-2 (100 mg, 0.21 mmol) in DMSO (2 mL) were added copper iodide (79.28 mg, 0.42 mmol), catalyst CAS: 68737-65-5 (29.61 mg, 0.21 mmol), tripotassium phosphate (132.54 mg, 0.62 mmol), and 2-hydroxyethane-1-sulfonamide (52.09 mg, 0.42 mmol). The reaction mixture was stirred at 120° C. under a N atmosphere overnight. The reaction mixture was poured into water (10 mL) and extracted with EA (30 mL×3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The crude product was purified to yield compound 5.

[0447] 1 H NMR(DMSO-d6)δ:11.18(s,1H),9.99-10.21(m,1H),7.94(d,J=7.6Hz,1H),7.88(d,J=8.5Hz,1H),7.47(d,J=3.1Hz,1H),7.3 0(d,J=8.3Hz,1H),7.20(d,J=1.9Hz,1H),7.12(t,J=8.0Hz,1H),7.04(dd,J=8.5,1.9Hz,1H),6.67(d,J=3.1Hz,1H),4.96(br s,1H),4.05(d,J=7.0Hz,2H),3.77(br t,J=6.4Hz,2H),3.33-3.42(m,4H),3.03(br t,J=4.7Hz,4H),1.47(br s,4H),1.27(br s,1H),0.47-0.59(m,2H),0.35-0.46(m,2H),0.28(s,4H).

[0448] Example 6: Synthesis of 4-(N-(2-hydroxyethyl)sulfonamido)-N-(1-methylindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (6)

[0449] Step 1: Synthesis of compound 6-2

[0450] NaH (125 mg, 3 mmol) was added to a DMF solution of compound 6-1 (500 mg, 3 mmol). Methyl iodide (0.2 mL) was added dropwise and the reaction was stirred for 2 hours. The reaction was quenched with water and EA. The organic layer was dried over sodium sulfate, and the solvent was removed. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 6-2.

[0451] Step 2: Synthesis of compound 6-3

[0452] A solution of compound 6-2 (520 mg, 2.95 mmol) and 10% Pd / C (63 mg, 0.6 mmol) in methanol (5 mL) was stirred under a hydrogen atmosphere overnight, filtered, and concentrated under reduced pressure to obtain compound 6-3.

[0453] Step 3: Synthesis of compound 6-4

[0454] A mixture of compound 6-3a (468 mg, 1.3 mmol), compound 6-3 (230 mg, 1.6 mmol), HATU (598 mg, 1.57 mmol) and DIPEA (340 mg, 2.6 mmol) in DMF (10 mL) was stirred at room temperature for 3 h. The reaction was then quenched with water and a saturated NaHCO solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 4 / 1) to give compound 6-4.

[0455] Step 4: Synthesis of compound 6-5

[0456] Compound 6-4 (350 mg, 0.72 mmol) was stirred in AcOH (1 mL) at room temperature, and NaBH3CN (168 mg, 2.1 mmol) was slowly added. Stirring was continued at room temperature for 2 h. The reaction was then quenched with water and a saturated NaHCO3 solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 4 / 1) to give compound 6-5.

[0457] Step 5: Synthesis of compound 6

[0458] Compound 6-5 (150 mg, 0.31 mmol) and 2-hydroxyethane-1-sulfonamide (154 mg, 1.23 mmol) were dissolved in DMSO (2 mL) and potassium phosphate (327 mg, 1.54 mmol), cuprous iodide (30 mg, 0.15 mmol) and sarcosine (14 mg, 0.15 mmol) were added. After nitrogen protection, the reaction was heated at 120 ° C overnight. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3x30 mL). The organic solution was taken and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=1 / 0 to 1 / 1) to give compound 6. MS (ESI, pos.ion) m / z: 485.3 [M+1] + .

[0459] 1 H NMR(DMSO-d6)δ:10.74-10.80(m,1H),10.02-10.11(m,1H),7.79-7.85(m,1H),7. 18-7.22(m,1H),7.14-7.17(m,1H),6.96-7.06(m,2H),6.29-6.37(m,1H),4.81-5. 03(m,1H),3.72-3.80(m,2H),3.32-3.37(m,2H),3.23-3.30(m,2H),2.95-3.02(m ,4H),2.88-2.95(m,2H),2.68-2.73(m,3H),1.41-1.54(m,4H),0.25-0.40(m,4H).

[0460] Example 7: Synthesis of 4-(2-hydroxyethyl)sulfonamido-N-(8-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0461] Step 1: Synthesis of compound 7-2

[0462] LDA (3.46 g, 32.3 mmol) was added to a solution of compound 7-1 (6 g, 26.9 mmol) in THF (80 mL). The mixture was cooled to -78°C. After 1 hour, 1-chloro-3-iodopropane (16 g, 80.72 mmol) was added dropwise to the solution. The reaction was stirred at room temperature overnight. The reaction was quenched with water and EA. The layers were separated, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to provide compound 7-2.

[0463] Step 2: Synthesis of compound 7-3

[0464] Compound 7-3 (600 mg, 2 mmol), methylamine hydrochloride (540 mg, 8 mmol), potassium iodide (665 mg, 4 mmol), potassium carbonate (1385 mg, 10 mmol), and DMF (6 mL) were added to a round-bottom flask and reacted in an oil bath at 60°C under nitrogen for 5 hours. The reaction was then cooled to room temperature, quenched with cold water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to provide compound 7-3.

[0465] Step 3: Synthesis of compound 7-4

[0466] Compound 7-3 (2.5 g, 9.12 mmol), H2NBoc (1.6 g, 13.68 mmol), Cs2CO3 (5.95 g, 18.2 mmol), Pd2(dba)3 (0.42 g, 0.46 mmol), and Xantphos (0.8 g, 1.37 mmol) were added to 1,4-dioxane. The mixture was then heated at 110°C overnight under a N2 atmosphere. The reaction was cooled to room temperature, quenched with cold water, and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to give compound 7-4.

[0467] Step 4: Synthesis of compound 7-5

[0468] Compound 7-4 (2 g, 7.6 mmol) was dissolved in HCl-EA (10 mL) and stirred at room temperature for 3 hours. The HCl-EA was removed by rotary evaporation, and the pH of the reaction mixture was adjusted to 8-9 with water and saturated NaHCO₃ solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to yield compound 7-5.

[0469] Step 5: Synthesis of compound 7-6

[0470] A: To a solution of 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoic acid (1.3 g, 3.6 mmol) in DCM (10 mL) was added oxalyl chloride (770 mg, 6 mmol) dropwise at 0 ° C., followed by the addition of DMF (0.10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure and co-distilled with toluene to give crude 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoyl chloride. It was used in the next step without further purification.

[0471] B: To a solution of compound 7-5 in DMF (5 mL) was added NaH (220 mg, 9.1 mmol) at 0°C, followed by the addition of 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoyl chloride at 0°C. The reaction mixture was stirred at room temperature for 3 hours, then quenched with cold water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 0 to 4 / 1) to give compound 7-6.

[0472] Step 6: Synthesis of compound 7

[0473] Compound 7-6 (170 mg, 1.35 mmol) was dissolved in DMSO (2 mL) and potassium phosphate (372 mg, 1.75 mmol), cuprous iodide (34 mg, 0.17 mmol) and sarcosine (32 mg, 0.34 mmol) were added. The reaction was heated at 120 ° C overnight under nitrogen protection. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was then washed with EtOAc (3x30 mL). The organic solution was taken and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=1 / 0 to 1 / 1) to obtain compound 7.

[0474] MS (ESI, pos.ion) m / z: 500.3 [M+1] + .

[0475] 1H NMR(DMSO-d6)δ:11.08-11.21(m,1H),10.14-10.23(m,1H),7.78-7.88(m,2H),7.49-7.60(m,1H),7.17 -7.23(m,1H),7.00-7.09(m,1H),4.82-5.12(m,1H),3.76(t,J=6.5Hz,2H),3.41-3.50(m,4H),3.12(br s,3H),2.99(br t,J=4.9Hz,4H),2.78(br d,J=12.3Hz,2H),1.85-1.96(m,2H),1.40-1.52(m,4H),0.29-0.38(m,4H).

[0476] Example 8: Synthesis of 4-(2-hydroxyethyl)sulfonamido-N-(8-cyclopropylmethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (8)

[0477] Step 1: Synthesis of compound 8-2

[0478] Compound 8-1 (1.2 g, 4 mmol), cyclopropylmethylamine hydrochloride (1.14 g, 16 mmol), potassium iodide (1.33 g, 8 mmol), potassium carbonate (2.77 g, 20 mmol), and DMF (30 mL) were added to a round-bottom flask. After reacting in a 60°C oil bath under nitrogen for 5 hours, the reaction mixture was cooled to room temperature, quenched with cold water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to provide compound 8-2.

[0479] Step 2: Synthesis of compound 8-3

[0480] Compound 8-2 (1.1 g, 3.5 mmol), H2NBoc (0.65 g, 5.25 mmol), Cs2CO3 (2.28 g, 7 mmol), Pd2(dba)3 (0.16 g, 0.18 mmol) and Xantphos (0.31 g, 0.53 mmol) were added to 1,4-dioxane. The mixture was then heated at 110°C overnight under a N2 atmosphere. The reaction was cooled to room temperature, quenched with cold water and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to give compound 8-3.

[0481] Step 3: Synthesis of compound 8-4

[0482] Compound 8-3 (1.5 g, 4.94 mmol) was dissolved in HCl-EA (10 mL) and stirred at room temperature for 3 hours. The HCl-EA was removed by rotary evaporation, and the pH of the reaction was adjusted to 8-9 with water and saturated NaHCO₃ solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to yield compound 8-4.

[0483] Step 4: Synthesis of compound 8-5

[0484] Step a: To a solution of 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoic acid (515 mg, 1.44 mmol) in DMF (4 mL) was added pentafluorophenyl trifluoroacetate (530 mg, 1.89 mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour to give crude perfluorophenyl 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoate, which was used in the next step without further purification.

[0485] Step b: NaHMDS (1.44 mL, 3.6 mmol) was added to a DMF (5 mL) solution of compound 8-4 at 0°C. After 10 minutes of reaction, perfluorophenyl 4-iodo-2-(6-azaspiro[2.5]octyl)benzoate was added at 0°C. The reaction mixture was stirred at 60°C for 5 hours, then quenched with cold water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 4 / 1) to provide compound 8-5.

[0486] Step 5: Synthesis of compound 8

[0487] Compound 8-5 (85 mg, 0.16 mmol) and 2-hydroxyethane-1-sulfonamide (78 mg, 0.63 mmol) were dissolved in 1,4-dioxane (2 mL) and tBuXPhos Pd G4 (6 mg, 0.01 mmol) and cesium carbonate (102 mg, 0.31 mmol) were added. After nitrogen protection, the reaction was heated at 100 ° C overnight. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was then washed with EtOAc (3x30 mL). The organic solution was taken and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=1 / 0 to 1 / 1) to give compound 8. MS (ESI, pos.ion) m / z: 540.3 [M+1] + .

[0488] 1H NMR(DMSO-d6)δ:10.84-10.91(m,1H),10.07-10.13(m,1H),7.79-7.87(m,2H),7.20-7.26 (m,1H),7.16-7.20(m,1H),7.00-7.06(m,1H),4.90-4.97(m,1H),3.72-3.79(m,2H),3.42 -3.48(m,4H),3.32-3.37(m,2H),2.95-3.02(m,4H),2.70-2.77(m,2H),1.83-1.92(m,2H) ,1.42-1.52(m,4H),1.00-1.09(m,1H),0.40-0.46(m,2H),0.34(s,4H),0.21-0.26(m,2H).

[0489] Example 9: Synthesis of N-(1-(cyclopropylmethyl)-1H-indole-4-(2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (9)

[0490] Step 1: Synthesis of compound 9-2

[0491] To a solution of compound 9-1 (0.23 mL, 1.85 mmol) in DMF (5 mL) was added NaH (118.41 mg, 2.96 mmol) at 0°C under an N2 atmosphere. The reaction mixture was stirred at room temperature under an N2 atmosphere for 15 min. To this solution was added (bromomethyl)cyclopropane (0.20 mL, 2.04 mmol). The reaction mixture was stirred at room temperature under an N2 atmosphere for 2 h. The reaction mixture was poured into water (50 mL) and extracted with EA (100 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 90:10) to yield compound 9-2.

[0492] Step 2: Synthesis of compound 9-3

[0493] To a solution of compound 9-2 (35 mg, 1.62 mmol) in MeOH (5 mL) was added Pd / C (40 mg, 0.2 mmol) and the mixture was replaced with H2 at room temperature. The reaction mixture was stirred at room temperature overnight. The filtrate was concentrated to give compound 9-3, which was used directly in the next step.

[0494] Step 3: Synthesis of compound 9-4

[0495] 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (675.03 mg, 1.89 mmol) and HATU (783.42 mg, 2.06 mmol) were added to DMF (5 mL), followed by compound 9-3 (320 mg, 1.72 mmol) and DIEA (443.25 mg, 3.44 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water (10 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 9:1) to yield compound 9-4.

[0496] Step 4: Synthesis of compound 9

[0497] Compound 9-4 (50 mg, 0.10 mmol), copper iodide (39.81 mg, 0.21 mmol), catalyst: CAS: 68737-65-5 (14.87 mg, 0.10 mmol), potassium phosphate (66.55 mg, 0.31 mmol), and 2-hydroxyethane-1-sulfonamide (26.16 mg, 0.21 mmol) were added to DMSO (1 mL). The reaction mixture was stirred at 120°C overnight under a N2 atmosphere. The reaction mixture was poured into water (10 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified to yield compound 9.

[0498] 1 H NMR(DMSO-d6)δ:11.18(s,1H),9.96-10.23(m,1H),7.94(d,J=7.8Hz,1H),7.8 5-7.91(m,1H),7.47(d,J=3.1Hz,1H),7.30(d,J=8.3Hz,1H),7.17-7.23(m,1H) ,7.12(t,J=8.0Hz,1H),6.99-7.09(m,1H),6.66(d,J=3.1Hz,1H),4.81-5.08(m ,1H),4.05(d,J=7.0Hz,2H),3.77(t,J=6.5Hz,2H),3.34-3.39(m,2H),3.03(br s,4H),1.47(br s,4H),1.17-1.35(m,1H),0.46-0.59(m,2H),0.35-0.46(m,2H),0.28(s,4H).

[0499] Example 10: Synthesis of 4-((2-hydroxyethyl)sulfonamido)-N-(1-methyl-1H-indol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (10)

[0500] Compound 10-1 (50 mg, 0.1 mmol) and 2-hydroxyethane-1-sulfonamide (52 mg, 0.41 mmol) were dissolved in DMF (2 mL), potassium phosphate (110 mg, 0.52 mmol), cuprous iodide (10 mg, 0.05 mmol) and sarcosine (5 mg, 0.05 mmol) were added, and the mixture was heated at 100 ° C for overnight under nitrogen protection. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was then washed with EtOAc (3*30 mL). The organic solution was taken and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=1 / 0 to 1 / 1) to give compound 10. MS (ESI, pos.ion) m / z: 483.2 [M+1] + .

[0501] 1 H NMR(DMSO-d6)δ:11.15-11.23(m,1H),10.06-10.14(m,1H),7.95-8.01( m,1H),7.84-7.90(m,1H),7.33-7.37(m,1H),7.10-7.25(m,3H),7.01-7. 06(m,1H),6.64-6.69(m,1H),4.93-4.99(m,1H),3.73-3.83(m,5H),3.3 3-3.39(m,2H),2.97-3.07(m,4H),1.39-1.52(m,4H),0.23-0.31(m,4H).

[0502] Example 11: Synthesis of 4-((2-hydroxyethyl)sulfonamido)-N-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (11)

[0503] Step 1: Synthesis of compound 11-2

[0504] Compound 11-1 (4.5 g, 20 mmol) and hydroxylamine hydrochloride (1.32 g, 40 mmol) were dissolved in pyridine (20 mL) and allowed to react at room temperature for 1 h. The reaction was quenched with water and EA. The organic layer was dried over sodium sulfate, and the solvent was removed. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to provide compound 11-2.

[0505] Step 2: Synthesis of compound 11-3

[0506] Under a nitrogen atmosphere, at 0-5°C, DIBAL-H (5.78 mL) was added to a solution of compound 11-2 (3 g, 12.5 mmol) in DCM (20 mL) over 10 minutes. Stirring was continued at 0°C for 5 minutes and then at room temperature for 2 hours. KF powder (9.4 g, 25 mmol) and water (10 mL) were added to the reaction mixture at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction was cooled to room temperature, then quenched with cold water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=1 / 0 to 10 / 1) to give compound 11-3.

[0507] Step 3: Synthesis of compound 11-4

[0508] Compound 11-3 (700 mg, 3.1 mmol) was dissolved in THF, and NaH (186 mg, 4.64 mmol) was added. The mixture was allowed to react at room temperature for 20 min, followed by the dropwise addition of iodomethane (660 mg, 4.64 mmol) at 0°C. The reaction was then continued at room temperature for 2 hours, quenched with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 20 / 1) to afford compound 11-4.

[0509] Step 4: Synthesis of compound 11-5

[0510] Compound 11-4 (350 mg, 1.46 mmol) and H2NBoc (256 mg, 2.19 mmol), catalyst CAS: 1599466-89-3 (59 mg, 0.07 mmol), tBuONa (280 mg, 2.91 mmol) was added to toluene. The mixture was then heated at 105 ° C overnight under a N2 atmosphere. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was then washed with EtOAc (3x30 mL). The organic solution was taken and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=1 / 0 to 1 / 1) to obtain compound 11-5.

[0511] Step 5: Synthesis of compound 11-6

[0512] Compound 11-5 (300 mg, 1.09 mmol) was dissolved in HCl-EA (10 mL) and stirred at room temperature for 3 hours. The HCl-EA was removed by rotary evaporation, and the pH of the reaction was adjusted to 8-9 with water and saturated NaHCO₃ solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford compound 11-6.

[0513] Step 6: Synthesis of compound 11-7

[0514] A mixture of 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoic acid (413 mg, 1.16 mmol), compound 11-6 (170 mg, 0.96 mmol), HATU (514 mg, 1.35 mmol) and DIPEA (250 mg, 1.93 mmol) in DMF (10 mL) was stirred at room temperature for 3 h. The reactant was then quenched with water and a saturated NaHCO solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 0 to 4 / 1) to give compound 11-7.

[0515] Step 7: Synthesis of compound 11

[0516] Compound 11-7 (150 mg, 0.29 mmol) and 2-hydroxyethane-1-sulfonamide (150 mg, 1.2 mmol) were dissolved in DMSO (2 mL), potassium phosphate (318 mg, 1.5 mmol), cuprous iodide (29 mg, 0.15 mmol) and sarcosine (29 mg, 0.3 mmol) were added, and the reaction was heated at 120 ° C overnight under nitrogen protection. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was then washed with EtOAc (3*30 mL). The organic solution was taken and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=1 / 0 to 1 / 1) to obtain compound 11. MS m / z (ESI): 513.3 [M+1] + .

[0517] 1 H NMR(DMSO-d6)δ:11.50-11.55(m,1H),8.07-8.12(m,1H),7.33-7.35(m,1H),7.10 -7.20(m,3H),6.93-6.98(m,1H),6.84-6.88(m,1H),3.98-4.03(m,2H),3.21-3.2 7(m,2H),3.04-3.10(m,4H),2.95-3.00(m,2H),2.87-2.91(m,3H),2.76-2.82(m, 2H),1.69-1.78(m,2H),1.59-1.64(m,2H),1.46-1.54(m,4H),0.32-0.36(m,4H).

[0518] Example 12: Synthesis of N-(1-cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (12)

[0519] Step 1: Synthesis of compound 12-2

[0520] Compound 12-1 (1400 mg, 6.19 mmol) was dissolved in DMF, and NaH (496 mg, 12.4 mmol) was added. The mixture was allowed to react at room temperature for 20 minutes, followed by the dropwise addition of bromomethylcyclopropane (1254 mg, 9.29 mmol) at 0°C. The reaction was then continued at 70°C for 2 hours, quenched with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 20 / 1) to afford compound 12-2.

[0521] Step 2: Synthesis of compound 12-3

[0522] Compound 12-2 (360 mg, 1.28 mmol) and H2NBoc (226 mg, 1.93 mmol), catalyst CAS: 1599466-89-3 (52 mg, 0.06 mmol), t BuONa (247 mg, 2.57 mmol) was added to toluene. The mixture was then heated at 105°C overnight under a N2 atmosphere. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3 x 30 mL). The organic solution was taken and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to obtain compound 12-3.

[0523] Step 3: Synthesis of compound 12-4

[0524] Compound 12-3 (310 mg, 0.98 mmol) was dissolved in HCl-EA (10 mL) and stirred at room temperature for 3 hours. The HCl-EA was removed by rotary evaporation, and the pH of the reaction was adjusted to 8-9 with water and saturated NaHCO₃ solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford compound 12-4.

[0525] Step 4: Synthesis of compound 12-5

[0526] A mixture of 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoic acid (277 mg, 0.78 mmol), compound 12-4 (140 mg, 0.78 mmol), HATU (345 mg, 0.91 mmol), and DIPEA (168 mg, 1.29 mmol) in DMF (10 mL) was stirred at room temperature for 3 h. The reaction was then quenched with water and a saturated NaHCO solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 4 / 1) to give compound 12-5.

[0527] Step 5: Synthesis of compound 12

[0528] Compound 12-5 (150 mg, 0.27 mmol) and 2-hydroxyethane-1-sulfonamide (135 mg, 1.08 mmol) were dissolved in DMSO (2 mL), potassium phosphate (287 mg, 1.35 mmol), cuprous iodide (26 mg, 0.14 mmol) and sarcosine (26 mg, 0.27 mmol) were added, and the reaction was heated at 120 ° C overnight under nitrogen protection. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3x30 mL). The organic solution was taken and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=1 / 0 to1 / 1) to obtain compound 12. MS m / z (ESI): 553.3 [M+1] + .

[0529] 1H NMR(DMSO-d6)δ:11.34-11.51(m,1H),8.14-8.20(m,1H),7.32-7.36(m,1H),7.13-7.2 5(m,3H),6.96-7.04(m,2H),4.04-4.12(m,2H),3.27-3.33(m,2H),3.16-3.26(m,2H), 3.04-3.14(m,6H),2.80-2.89(m,2H),1.76-1.83(m,2H),1.64-1.71(m,4H),1.17-1.3 7(m,2H),0.97-1.08(m,1H),0.51-0.58(m,2H),0.32-0.39(m,4H),0.19-0.25(m,2H).

[0530] Example 13: Synthesis of N-(2-chloro-1-(cyclopropylmethyl)-1H-indol-4-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (13)

[0531] Step 1: Synthesis of compound 13-2

[0532] Compound 13-1 (450 mg, 1.80 mmol) was added to AcOH (9 mL), cooled to 0°C, and zinc powder (0.35 g, 5.39 mmol) was added. The mixture was returned to room temperature and stirred overnight. The reaction solution was extracted with EA (10 mL × 3). The combined organic phases were washed with water (10 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain compound 13-2. MS m / z (ESI): 221.0 [M+1] + .

[0533] Step 2: Synthesis of compound 13-3

[0534] Compound 13-2 (300 mg, 1.36 mmol), 4-bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoic acid (421.64 mg, 1.36 mmol), HATU (620.24 mg, 1.63 mmol), and DIEA (0.68 mL, 4.08 mmol) were added to DMF (9 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, it was extracted with EA (10 mL × 3). The combined organic phases were washed sequentially with water (10 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain compound 13-3. MS m / z (ESI): 512.0 [M+1] + .

[0535] Step 3: Synthesis of compound 13

[0536] Compound 13-3 (100 mg, 0.19 mmol), 2-hydroxyethane-1-sulfonamide (29.28 mg, 0.23 mmol), Cs2CO3 (127.06 mg, 0.39 mmol), and catalyst CAS: 1599466-89-3 (0.17 mg, 0.02 mmol) were added to 1,4-dioxane (5 mL) and stirred at 80°C overnight under N2 protection. The reaction solution was extracted with EA (5 mL × 3), and the combined organic phases were washed sequentially with water (5 mL × 2) and saturated brine (5 mL × 1), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 13. MS m / z (ESI): 557.0 [M+1] +

[0537] 1 HNMR(DMSO-d6)δ:11.09(s,1H),9.94-10.22(m,1H),7.85(dd,J=19.1,8.1Hz,2H),7.33(d,J=8.3Hz,1H),7.12-7.22(m,2H),7.02 (dd,J=8.4,1.9Hz,1H),6.81(s,1H),4.85-5.11(m,1H),4.14(d,J=6.9Hz,2H),3.77(t,J=6.6Hz,2H),3.33-3.37(m,2H),3.01(br t,J=4.6Hz,4H),1.44(br s,4H),1.16-1.28(m,1H),0.36-0.56(m,4H),0.27(s,4H).

[0538] Example 14: Synthesis of N-(1-(cyclobutylmethyl)indolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0539] Step 1: Synthesis of compound 14-2.

[0540] 14-1 (500 mg, 3.08 mmol) and Cs2CO3 (2009.37 mg, 6.17 mmol) were dissolved in DMF (10 mL), and (bromomethyl)cyclobutane (505.50 mg, 3.39 mmol) was slowly added dropwise. The reaction mixture was stirred at 90°C for 3 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20-1 / 10) to afford 14-2.

[0541] Step 2: Synthesis of compound 14-3.

[0542] 14-2 (700 mg, 3.04 mmol) and Pd / C 10% (70 mg, 0.66 mmol) were stirred in MeOH (10 mL) under H2 at room temperature for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 14-3.

[0543] Step 3: Synthesis of compound 14-4.

[0544] 14-3 (480 mg, 2.40 mmol), 2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzoic acid (676 mg, 2.18 mmol), and HATU (994.15 mg, 2.61 mol) were added to a CH3CN (5 mL) solution. A solution of DIEA (563.21 mg, 4.36 mmol) was slowly added dropwise. After stirring at room temperature for 18 hours, the reaction mixture was diluted with EA (20 mL). The organic layer was washed with NaCl (60 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EA = 4:1) to afford 14-4.

[0545] Step 4: Synthesis of compound 14-5.

[0546] Sodium cyanoboroate (114.84 mg, 1.83 mmol) was added to a solution of 14-4 (300 mg, 0.61 mmol) in acetic acid (8 mL). The reaction mixture was stirred at room temperature for 3 hours. The pH was adjusted to approximately 7-8 with aqueous sodium bicarbonate solution and the reaction mixture was diluted with EA (20 mL). The organic layer was washed with NaCl (60 mL), dried over NaSO, filtered, and concentrated to afford 14-5.

[0547] Step 5: Synthesis of compound 14.

[0548] 14-5 (200 mg, 0.4 mmol), 2-hydroxyethane-1-sulfonamide (202.46 mg, 1.62 mmol), Cs2CO3 (395.3 mg, 1.21 mmol), and a palladium catalyst (CAS: 1599466-89-3, 16.17 mg, 0.02 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction mixture was stirred at 95°C under reflux for 18 hours. The reaction mixture was then diluted with EA (20 mL). The organic layer was washed with NaCl (60 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 14.

[0549] MS m / z(ESI):539.3[M+1] + .

[0550] 1 H NMR (400MHz, DMSO-d6) δ = 10.77 (s, 1H), 7.82 (d, J = 8.4Hz, 1H), 7.19-7.12 (m, 2H), 7.05-6.97 (m, 2H), 6.34 (d,J=7.8Hz,1H),3.82-3.72(m,2H),3.35-3.33(m,2H),3.31-3.26(m,2H),3.05(d,J=7.1Hz,2H),2.98(br s,4H),2.94-2.88(m,2H),2.69-2.57(m,1H),2.11-2.02(m,2H),1.94-1.82(m,2H),1.80-1.70(m,2H),1.49(br s,4H),0.35(s,4H).

[0551] Example 15: Synthesis of N-(1-(cyclopentylmethyl)indolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0552] Step 1: Synthesis of compound 15-2.

[0553] 15-1 (500 mg, 3.08 mmol) and Cs2CO3 (2007.05 mg, 6.16 mmol) were dissolved in DMF (10 mL), and (bromoethyl)cyclopentane (502.81 mg, 3.08 mmol) was slowly added dropwise. The reaction mixture was stirred at 90°C for 18 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 15-2.

[0554] Step 2: Synthesis of compound 15-3.

[0555] 15-2 (570 mg, 2.33 mmol) and Pd / C 10% (57 mg, 0.54 mmol) were stirred in MeOH (10 mL) under H2 at room temperature for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain compound 15-3.

[0556] Step 3: Synthesis of compound 15-4.

[0557] To a solution of 15-3 (320 mg, 1.49 mmol), 2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzoic acid (421.06 mg, 1.36 mmol), and HATU (625 mg, 1.63 mol) in acetonitrile (10 mL) was added dropwise a solution of DIEA (353 mg, 2.71 mmol). After stirring at room temperature for 18 hours, the reaction mixture was diluted with EA (20 mL). The organic layer was washed with NaCl (60 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EA = 4:1) to afford compound 15-4.

[0558] Step 4: Synthesis of compound 15-5.

[0559] Sodium cyanoborocyanide (148.88 mg, 2.37 mmol) was added to a solution of 15-4 (400 mg, 0.79 mmol) in acetic acid (8 mL). The reaction mixture was stirred at room temperature for 3 hours and diluted with EA (20 mL). The organic layer was washed with NaCl (60 mL), dried over Na2SO4, filtered, and concentrated to afford compound 15-5.

[0560] Step 5: Synthesis of compound 15.

[0561] 15-5 (300 mg, 0.59 mmol), 2-hydroxyethane-1-sulfonamide (295.32 mg, 1.62 mmol), Cs2CO3 (576.70 mg, 1.77 mmol), and palladium catalyst (CAS: 1599466-89-3, 23.85 mg, 0.03 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction mixture was stirred at 95°C under reflux for 18 hours and then diluted with EA (20 mL). The organic layer was washed with NaCl (60 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 20:1) to give compound 15. MS (ESI, pos. ion) m / z: 553.4 [M+1] + .

[0562] 1 H NMR (400MHz, DMSO-d6) δ=10.79(s,1H),7.82(d,J=8.5Hz,1H),7.18-7.10(m,2H),7.05-6.96(m,2H),6.32(d,J=7.9Hz,1 H),3.81-3.72(m,2H),3.40-3.33(m,4H),3.02-2.96(m,4H),2.96-2.90(m,4H),2.20(s,1H),1.81-1.70(m,2H),1.62(br d,J=6.4Hz,2H),1.58-1.52(m,2H),1.49(br s,4H),1.26(br dd,J=6.6,12.0Hz,2H),0.35(s,4H).

[0563] Example 16: Synthesis of N-(1-cyclopropylmethyl)-1H-benzimidazol-4-yl)-4-(2-hydroxyethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (16)

[0564] Step 1: Synthesis of compound 16-2

[0565] Compound 16-1 (1 g, 4.55 mmol) and cyclopropylmethylamine (0.47 mL, 5.45 mmol) were dissolved in 1,4-dioxane (5 mL), and potassium carbonate (1.26 g, 9.09 mmol) was added thereto. The reaction mixture was placed in an oil bath at 60°C and stirred for 4 hours. After completion of the reaction, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0-98:2) to obtain compound 16-2.

[0566] Step 2: Synthesis of compound 16-3

[0567] Compound 16-2 (989 mg, 3.65 mmol) was dissolved in ethanol (5 mL) and water (5 mL), and iron powder (1.02 g, 18.24 mmol) and ammonium chloride (975.65 mg, 18.24 mmol) were added thereto. The reaction mixture was placed in an 80 ° C oil bath and stirred for 3 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0-97:3) to obtain compound 16-3.

[0568] Step 3: Synthesis of compound 16-4

[0569] Compound 16-3 (735 mg, 3.05 mmol) was dissolved in isopropanol (5 mL), and formic acid (701.53 mg, 15.24 mmol) was added thereto. The reaction mixture was placed in a 70°C oil bath and stirred for 18 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0-95:5-80:20) to obtain compound 16-4.

[0570] Step 4: Synthesis of compound 16-5

[0571] Compound 16-4 (400 mg, 1.59 mmol) and tert-butyl carbamate (466.49 mg, 3.98 mmol) were dissolved in 1,4-dioxane (4 mL), and BrettPhos Pd G4 (293.24 mg, 0.32 mmol) and cesium carbonate (2.08 g, 6.37 mmol) were added thereto. The reaction mixture was placed in a 95 ° C oil bath and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was diluted with water (60 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0-90:10-80:20) to obtain compound 16-5.

[0572] Step 5: Synthesis of compound 16-6

[0573] Compound 16-5 (28 mg, 0.97 mmol) was dissolved in 1,4-dioxane (3 mL), and hydrochloric acid (142.10 mg, 3.90 mmol) was added thereto. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was quenched with sodium bicarbonate, diluted with water (30 mL), and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0-80:20-0:100) to obtain compound 16-6.

[0574] Step 6: Synthesis of compound 16-7

[0575] Compound 16-6 (100 mg, 0.53 mmol) and 4-bromo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid (165.66 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (3 mL), and tetramethyluronium hexafluorophosphate (297.41 mg, 1.06 mmol) and N,N-diisopropylethylamine (276.08 mg, 2.14 mmol) were added thereto. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=100:0-95:5-90:10) to obtain compound 16-7.

[0576] Step 7: Synthesis of compound 16

[0577] Compound 16-7 (44 mg, 0.09 mmol) and 2-hydroxyethane-1-sulfonamide (45.94 mg, 0.37 mmol) were dissolved in 1,4-dioxane (2 mL), and catalyst CAS: 1599466-83-7 (16.90 mg, 0.02 mmol) and cesium carbonate (59.81 mg, 0.18 mmol) were added thereto. The reaction mixture was placed in a 95°C oil bath and stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (30×3 mL). The organic layer was washed with brine (30×3 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by preparation to obtain compound 16. MS (ESI, pos.ion) m / z: 524.2 [M+1] + .

[0578] 1 H NMR(400MHz, DMSO-d6)δ=12.34-12.23(m,1H),8.37-8.30(m,1H),8.30-8.24(m,1H),8.02-7.93(m,1H),7 .36(d,J=8.1Hz,1H),7.26-7.20(m,2H),7.07-7.01(m,1H),4.21-4.06(m,2H),3.82-3.72(m,2H),3.31(br s,2H),3.07-2.94(m,4H),1.93-1.46(m,4H),1.36-1.30(m,1H),0.59-0.49(m,2H),0.47-0.39(m,2H),0.33-0.22(m,4H).

[0579] Example 17 Synthesis of N-(1'-(cyclopropylmethyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (17)

[0580] Step 1: Synthesis of compound 17-2

[0581] Compound 17-1 (1 g, 4.72 mmol) was dissolved in ultra-dry tetrahydrofuran (10 mL). LDA (4.72 mL, 9.44 mmol) was slowly added dropwise at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 1 hour. 1,2-Dibromoethane (1.22 mL, 14.15 mmol) was then added dropwise, the mixture was slowly warmed to room temperature, and stirred overnight. The reaction mixture was quenched with ice water, the pH was adjusted to 5 with 2N HCl, and the mixture was extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1-10:1) to obtain compound 17-2. MS (ESI, pos. ion) m / z: 238.0 / 240.0 [M+1] + .

[0582] Step 2: Synthesis of compound 17-3

[0583] Compound 17-2 (310 mg, 1.30 mmol) and cesium carbonate (848 mg, 2.60 mmol) were dissolved in DMF (3 mL), and bromomethylcyclopropane (0.15 mL, 1.56 mmol) was added. The mixture was reacted at 70°C for 30 minutes. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound 17-3.

[0584] Step 3: Synthesis of compound 17-4

[0585] Compound 17-3 (330 mg, 1.13 mmol), NH2Boc (265 mg, 2.26 mmol), cesium carbonate (1.10 g, 3.39 mmol), and palladium catalyst (CAS: 1599466-85-9, 48 mg, 0.06 mmol) were dissolved in dioxane (5 mL) and reacted at 90°C for 2 h under nitrogen protection. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 17-4. MS (ESI, pos. ion) m / z: 329.2 [M+1] +

[0586] Step 4: Synthesis of compound 17-5

[0587] Compound 17-4 (248 mg, 0.76 mmol) was dissolved in DCM (1 mL), and HCl / EA (3 mL) was added. The mixture was allowed to react overnight at 25°C. The reaction solution was quenched with ice water, neutralized with saturated NaHCO₃ solution, and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and dried to afford compound 17-5. MS (ESI, pos. ion) m / z: 229.1 [M+1] + .

[0588] Step 5: Synthesis of compound 17-6

[0589] 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (181 mg, 0.58 mmol) was dissolved in DCM (1 mL), and oxalyl chloride (0.10 mL, 1.16 mmol) and a catalytic amount of DMF were added. The mixture was allowed to react at 25°C for 10 minutes. The reaction solution was concentrated and pumped dry to obtain 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride. Compound 17-5 (90 mg, 0.39 mmol) was dissolved in pyridine (2 mL), and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride was added. The mixture was allowed to react at 60°C for 1 hour. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 17-6.

[0590] Step 6: Synthesis of compound 17

[0591] Compound 17-6 (60 mg, 0.12 mmol), 2-hydroxyethane-1-sulfonamide (25 mg, 0.20 mmol), cesium carbonate (72 mg, 0.60 mmol), and palladium catalyst (CAS: 1599466-89-3, 5 mg) were dissolved in dioxane (2 mL) and reacted at 100°C for 2 h under nitrogen protection. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified to yield compound 17. MS (ESI, pos. ion) m / z: 565.3 [M+1]. + .

[0592] 1H NMR (400MHz, DMSO-d6) δ = 10.78 (s, 1H), 10.11 (s, 1H), 7.78 (d, J = 8.5Hz, 1H), 7.34-7.28 (m, 1H), 7.22-7.16 (m, 2H), 7.04 (br d,J=8.4Hz,1H),6.98-6.94(m,1H),3.77(s,2H),3.68-3.65(m,2H),3.38-3.32(m,2H),3.06-3.00(m,4H),1.8 0-1.73(m,2H),1.51-1.45(m,4H),1.42-1.37(m,2H),1.21-1.16(m,1H),0.51-0.45(m,2H),0.38-0.32(m,6H).

[0593] Example 18 Synthesis of N-(3-(cyclopropylmethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (18)

[0594] Step 1: Synthesis of compound 18-2

[0595] Compound 18-1 (500 mg, 2.34 mmol) and cesium carbonate (1.52 g, 4.68 mmol) were dissolved in ultra-dry DMF (5 mL), and bromomethylcyclopropane (0.27 mL, 2.81 mmol) was added thereto. The mixture was reacted at 70° C. for 30 minutes. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain compound 18-2.

[0596] 1 H NMR (400MHz, DMSO-d6) δ = 7.40 (dd, J = 0.8, 7.8Hz, 1H), 7.35 (dd, J = 0.9, 8.3Hz, 1H), 7.23-7. 15(m,1H),3.72(d,J=7.1Hz,2H),1.24-1.17(m,1H),0.55-0.49(m,2H),0.43-0.37(m,2H).

[0597] Step 2: Synthesis of compound 18-3

[0598] Compound 18-2, NH2Boc (538 mg, 4.60 mmol), cesium carbonate (2.25 g, 6.89 mmol), and palladium catalyst (CAS: 1599466-85-9, 195 mg, 0.23 mmol) were dissolved in dioxane (10 mL) and reacted at 90°C for 2 h under nitrogen. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 18-3.

[0599] Step 3: Synthesis of compound 18-4

[0600] Compound 18-3 (527 mg, 1.73 mmol) was dissolved in dichloromethane (2 mL), and a hydrogen chloride-ethyl acetate solution (5 mL) was added thereto, and the mixture was reacted overnight at 25° C. The reaction solution was filtered and dried to obtain compound 18-4.

[0601] Step 4: Synthesis of compound 18-5

[0602] Compound 18-4 (200 mg, 0.83 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (310 mg, 1.00 mmol), and TCFH (351 mg, 1.25 mmol) were dissolved in ultra-dry acetonitrile (2 mL). N-methylimidazole (0.33 mL, 4.17 mmol) was added and the mixture was allowed to react at 25°C for 1 hour. The reaction mixture was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 18-5. MS (ESI, pos. ion) m / z: 496.1 / 498.1 [M+1] + .

[0603] Step 5: Synthesis of compound 18

[0604] Compound 18-5 (261 mg, 0.53 mmol), 2-hydroxyethane-1-sulfonamide (329 mg, 2.65 mmol), cesium carbonate (514 mg, 1.59 mmol), and palladium catalyst (CAS: 1599466-87-1, 42 mg, 0.05 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 100°C under nitrogen protection for 3 hours. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified to obtain compound 18. MS (ESI, pos. ion) m / z: 541.3 [M+1] + .

[0605] 1 H NMR (400MHz, DMSO-d6) δ = 12.31 (s, 1H), 8.07 (d, J = 8.4Hz, 1H), 8.04-7.97 (m, 1H), 7.32-7.27 (m,1H),7.25-7.18(m,1H),7.18-7.07(m,2H),3.80-3.70(m,4H),3.38-3.35(m,2H),2.99(br s,4H),1.64(br s,4H),1.28-1.19(m,1H),0.56-0.48(m,2H),0.44-0.38(m,2H),0.38-0.30(m,4H).

[0606] Example 19: Synthesis of 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)benzamide (19)

[0607] Step 1: Synthesis of compound 19-2

[0608] Compound 19-1 (900 mg, 7.95 mmol) and 2-aminoacetonitrile (800 mg, 8.65 mmol) were dissolved in IPA (10 mL) and stirred at 85°C for 3 h. The reaction mixture was diluted with EA (20 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 20 / 1) to afford compound 19-2.

[0609] Step 2: Synthesis of compound 19-3

[0610] Compound 19-2 (400 mg, 2.92 mmol), HATU (1330 mg, 3.50 mmol), DIEA (1130.5 mg, 8.75 mmol), and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (995 mg, 3.21 mmol) were added to DMF (5 mL) and allowed to react overnight at room temperature. The reaction solution was diluted with EA (20 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to afford compound 19-3.

[0611] Step 3: Synthesis of compound 19

[0612] Compound 19-3 (200 mg, 0.47 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) [CAS: 1599466-83-7] (43 mg, 0.05 mmol), cesium carbonate (455.4 mg, 1.40 mmol), and 2-hydroxyethane-1-sulfonamide (233.17 mg, 1.86 mmol) were dissolved in tert-butanol (5 mL) and stirred at 80°C for 3 hours under nitrogen. The reaction mixture was diluted with EA (20 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to provide compound 19.

[0613] MS m / z(ESI):474.6[M+1] + .

[0614] 1 H NMR(METHANOL-d 4)δ:8.01(d,J=8.5Hz,1H),7.30(d,J=2.0Hz,1H),7.11(dd,J=8.5,2.1Hz,1H),6.88(s,1H),3.94-3.98(m,2H),3.84(t,J =5.8Hz,2H),3.34-3.39(m,2H),3.09(t,J=5.3Hz,4H),2.78-2.90(m,2H),1.98-2.05(m,2H),1.92-1.98(m,2H),1.60(br s,4H),0.42(s,4H).

[0615] Example 22: Synthesis of 2-(cyclohexyloxy)-N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-(2-hydroxyethyl)sulfonamido)benzamide (22)

[0616] Step 1: Synthesis of compound 22-2

[0617] Cyclohexanol (4.5 g, 44.9 mmol) was dissolved in DMF (20 mL), cooled to 0°C, and NaH (1.8 g, 44.9 mg) was slowly added. The mixture was stirred at room temperature for 30 min, followed by the addition of compound 22-1 (2 g, 9.13 mmol). The mixture was incubated at 50°C overnight under nitrogen. The reaction mixture was diluted with EA (50 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to afford compound 22-2.

[0618] Step 2: Synthesis of compound 22-3

[0619] Compound 22-2 (500 mg, 1.67 mmol) was dissolved in DCM (5 mL) under nitrogen atmosphere. Oxalyl chloride (350 mg, 2.7 mmol) was added dropwise at 0°C and allowed to react at room temperature for 1 hour. The reaction solution was concentrated to dryness and sealed for later use. 2-(4,4-Difluoropiperidin-1-yl)pyridin-4-amine (270 mg, 1.27 mmol) was dissolved in pyridine (5 mL) and stirred at room temperature for 20 minutes under nitrogen atmosphere. The crude product was dissolved in DCM (2 mL) and added dropwise to the reaction solution. The reaction solution was allowed to react at room temperature for 3 hours. The reaction solution was diluted with EA (20 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 22-3.

[0620] Step 3: Synthesis of compound 22

[0621] Compound 22-3 (150 mg, 0.30 mmol), cuprous iodide (28.8 mg, 0.15 mmol), potassium phosphate (321.5 mg, 1.5 mmol), sarcosine (64.3 mg, 0.3 mmol), and 2-hydroxyethane-1-sulfonamide (38.0 mg, 0.60 mmol) were dissolved in DMF (3 mL) and reacted at 100°C overnight under nitrogen atmosphere. The reaction solution was diluted with EA (20 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 20 / 1) to obtain compound 22.

[0622] MS (ESI, pos.ion) m / z: 539.1 [M+1] + .

[0623] 1 H NMR(DMSO-d6)δ:10.00-10.23(m,2H),7.99-8.08(m,1H),7.62-7.77(m, 1H),7.34-7.50(m,1H),6.96-7.06(m,1H),6.81-6.93(m,2H),4.87-5.0 3(m,1H),4.34-4.48(m,1H),3.72-3.82(m,2H),3.60-3.70(m,4H),1.96 -2.08(m,6H),1.66-1.77(m,2H),1.54-1.65(m,2H),1.21-1.52(m,6H).

[0624] Example 23: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-((2-hydroxyethyl)sulfonamide)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzamide (23)

[0625] Step 1: Synthesis of compound 23-2

[0626] Tetrahydro-2H-pyran-4-ol (700 mg, 6.85 mmol) was dissolved in DMF (10 mL). Sodium hydride (330 mg, 8.22 mmol) was added in an ice bath and stirred at room temperature for 30 minutes. Compound 23-1 (300 mg, 1.37 mmol) was then added in an ice bath and stirred at 80°C overnight. After cooling, the reaction mixture was poured into an appropriate amount of ice water and extracted three times with ethyl acetate (20 mL). The mixture was washed twice with brine (60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-50%) to afford compound 23-2.

[0627] Step 2: Synthesis of compound 23-3

[0628] Compound 23-2 (280 mg, 0.93 mmol) was dissolved in dichloromethane, and oxalyl chloride (0.16 mL, 1.86 mmol) was added dropwise under ice-cooling. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in dichloromethane (5 mL) and added dropwise to a solution of 2-(4,4-difluoropiperidin-1-yl)pyridin-4-amine (218 mg, 1.02 mmol) in pyridine (10 mL) under ice-cooling. The reaction mixture was allowed to react at 50°C for 2 hours. After cooling, the reaction mixture was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (20 mL), washed twice with brine (60 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-30%) to obtain compound 23-3.

[0629] Step 3: Synthesis of compound 23

[0630] Compound 23-3 (200 mg, 0.403 mmol), cesium carbonate (394 mg, 1.209 mmol), catalyst CAS: 1599466-85-9 (34 mg, 0.04 mmol), and 2-hydroxyethane-1-sulfonamide (252 mg, 2.016 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 105°C under nitrogen for 16 hours. After cooling, the reaction solution was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (20 mL), and washed twice with brine (60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-80%) to obtain compound 23. MS m / z (ESI): 541.2 [M+1]+ .

[0631] 1 H NMR(DMSO-d6)δ:10.07(s,2H),8.04(d,J=5.6Hz,1H),7.66(d,J=8.5Hz,1H),7.36(s,1H),7.00-7.03(m,1H),6.87-6.96(m,2H),4.97(br t,J=5.0Hz,1H),4.58-4.66(m,1H),3.79-3.85(m,2H),3.74-3.77(m,1H),3.61-3.68(m,4H),3.46-3.53(m,2H),3.35(br s,2H),1.92-2.07(m,6H),1.69-1.77(m,2H).

[0632] Example 24: Synthesis of 2-((4,4-difluorocyclohexyl)oxy)-N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-((2-hydroxyethyl)sulfonamide)benzamide (24)

[0633] Step 1: Synthesis of compound 24-2

[0634] Compound 24-1 (1 g, 7.46 mmol) was dissolved in methanol (20 mL). Sodium borohydride (851 mg, 22.39 mmol) was added under ice-cooling and allowed to react at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 24-2, which was used directly in the next reaction.

[0635] Step 2: Synthesis of compound 24-3

[0636] Compound 24-2 (800 mg, 5.88 mmol) was dissolved in DMF (10 mL). Sodium hydride (282 mg, 7.06 mmol) was added in an ice bath and stirred at room temperature for 30 minutes. 2-Fluoro-4-iodobenzoic acid (300 mg, 1.13 mmol) was then added in an ice bath and stirred at 80°C overnight. After cooling, the reaction mixture was poured into an appropriate amount of ice water and extracted three times with ethyl acetate (20 mL). The mixture was washed twice with brine (60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-50%) to afford compound 24-3.

[0637] Step 3: Synthesis of compound 24-4

[0638] Compound 24-3 (170 mg, 0.445 mmol) was dissolved in dichloromethane, and oxalyl chloride (0.08 mL, 0.89 mmol) was added dropwise under ice-cooling. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in dichloromethane (5 mL) and added dropwise to a solution of 2-(4,4-difluoropiperidin-1-yl)pyridin-4-amine (218 mg, 1.02 mmol) in pyridine (10 mL) under ice-cooling. The reaction mixture was allowed to react at 50°C for 2 hours. After cooling, the reaction mixture was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (20 mL), washed twice with brine (60 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-30%) to obtain compound 24-4.

[0639] Step 4: Synthesis of compound 24

[0640] Compound 24-4 (120 mg, 0.208 mmol), cesium carbonate (203 mg, 0.624 mmol), catalyst CAS: 1599466-85-9 (18 mg, 0.02 mmol), and 2-hydroxyethane-1-sulfonamide (130 mg, 1.04 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 105°C under nitrogen for 16 hours. After cooling, the reaction solution was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (20 mL), and washed twice with brine (60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-80%) to yield compound 24. MS (ESI) m / z: 575.2 [M+1] + .

[0641] 1 H NMR(CHLOROFORM-d)δ:9.64(s,1H),8.17(d,J=8.5Hz,1H),8.11(d,J=5.5Hz,1H),7.58(d,J=1.3Hz,1H),7.16(d,J=1.8Hz,1H),6.86(dd,J=8.5,2.0Hz ,1H),6.44(dd,J=5.5,1.6Hz,1H),4.67-4.75(m,1H),4.14-4.19(m,2H),3 .74-3.80(m,4H),3.29-3.36(m,2H),2.16-2.29(m,4H),2.00-2.10(m,8H).

[0642] Example 25: Synthesis of N-(1-(cyclopropylmethyl)indolin-4-yl)-8-((2-hydroxyethyl)sulfonamido)-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxamide (25)

[0643] Step 1: Synthesis of compound 25-2

[0644] 2-Methylpropan-2-amine (1.26 mL, 11.90 mmol) was dissolved in toluene (12 mL) and dichloromethane (7 mL) at 25°C, cooled to -78°C, and bromine (0.37 mL, 7.14 mmol) was slowly added dropwise, stirring for 10 minutes. Compound 25-2 (1 g, 5.95 mmol) dissolved in dichloromethane (7 mL) was added dropwise over 20 minutes. The reaction mixture was stirred at -78°C for 30 minutes, then slowly warmed to room temperature. Ethyl acetate (25 mL) and 1M dilute hydrochloric acid (25 mL x 2) were added and washed with water. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 5-10%) to obtain compound 25-2. MS m / z (ESI): 246.9 [M+H] +

[0645] Step 2: Synthesis of compound 25-3

[0646] Compound 25-2 (190 mg, 0.77 mmol) was dissolved in DMF (3 mL) at 25°C, cesium carbonate (1002.30 mg, 3.08 mmol) was added, and the mixture was heated to 70°C and stirred for 1 hour. 1,2-Dibromoethane (0.27 mL, 3.08 mmol) was then added and the reaction was stirred at 110°C overnight. The temperature was then slowly lowered to room temperature. Ethyl acetate (5 mL) was added and washed with water (5 mL*2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 5-10%) to obtain compound 25-3. MS m / z (ESI): 272.9 [M+H] +

[0647] Step 3: Synthesis of compound 25-4

[0648] Compound 25-3 (145 mg, 0.53 mmol) was dissolved in tetrahydrofuran (1 mL) at 25°C, and lithium hydroxide (0.04 mL, 2.12 mmol) and water (0.25 mL) were added and stirred at room temperature for 2 hours. 1M dilute hydrochloric acid was then added and the pH was adjusted to 5. Ethyl acetate (5 mL) was added and washed with water (5 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 25-4, which was used directly in the next step. MS m / z (ESI): 258.9 [M+H] +

[0649] Step 4: Synthesis of compound 25-5

[0650] Compound 25-4 (140 mg, 0.54 mmol) was dissolved in DMF (1.5 mL) at 25°C, and 1-(cyclopropylmethyl)indole-4-amine (120.79 mg, 0.65 mmol), HATU (410.98 mg, 1.08 mmol), and DIEA (174.61 mg, 1.35 mmol) were added. The mixture was stirred at 25°C for 2 hours, and ethyl acetate (5 mL) was added. The mixture was washed with water (5 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 5-70%) to obtain compound 25-5. MS m / z (ESI): 427.06 [M+H] +

[0651] Step 5: Synthesis of compound 25-6

[0652] Compound 25-5 (222 mg, 0.52 mmol) was dissolved in acetic acid (5 mL) at 25°C, and sodium cyanoborohydride (97.94 mg, 1.56 mmol) was added and stirred for 1 hour. Sodium carbonate was added to adjust the pH to 8, and ethyl acetate (5 mL) was added and washed with water (5 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. This was used directly in the next step. The crude product was purified by flash silica gel column chromatography (PE:EA = 20-50%) to obtain compound 25-6. MS m / z (ESI): 429.07 [M+H] +

[0653] Step 6: Synthesis of compound 25

[0654] Compound 25-6 (80 mg, 0.19 mmol) was dissolved in 1,4-dioxane (5 mL) at 25°C. 2-Hydroxyethane-1-sulfonamide (93.28 mg, 0.75 mmol), catalyst CAS: 1599466-89-3 (15.06 mg, 0.02 mmol), and cesium carbonate (242.86 mg, 0.75 mmol) were added. The atmosphere was replaced with nitrogen, the temperature was raised to 100°C, and the mixture was stirred overnight. Ethyl acetate (5 mL) was added, and the mixture was washed with water (5 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by flash silica gel column chromatography (dichloromethane / methanol = 2-5%) to obtain compound 25. MS m / z (ESI): 474.2 [M+H] +

[0655] H NMR(CHLOROFORM-d)δ:9.08-9.22(m,1H),7.79-7.89(m,1H),7.40-7.48(m,1H),7.09(t,J=7. 9Hz,1H),6.93-7.04(m,1H),6.26-6.37(m,1H),4.48-4.57(m,2H),4.38-4.46(m,2H),4.07(br d,J=4.8Hz,2H),3.49-3.59(m,2H),3.36-3.44(m,2H),2.96(d,J=6.6Hz,2H),2.88-2.94(m,2H),2.54(br s,1H),0.94-1.05(m,1H),0.52-0.59(m,2H),0.15-0.28(m,2H).

[0656] Example 26: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(spiro[3.3]heptane-2-yloxy)benzamide (26)

[0657] Step 1: Synthesis of compound 26-2

[0658] Spiro[3.3]heptan-2-ol (770 mg, 6.88 mmol) was dissolved in DMF (10 ml) and sodium hydride (459 mg, 11.5 mmol) was added under ice-cooling. The mixture was allowed to react at room temperature for 1 hour. Compound 26-1 (1 g, 4.59 mmol) was then added under ice-cooling and allowed to react at room temperature for 16 hours. The reaction mixture was poured into an appropriate amount of ice water and extracted three times with ethyl acetate (20 ml), washed twice with brine (60 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-30%) to afford compound 26-2.

[0659] Step 2: Synthesis of compound 26-3

[0660] Compound 26-2 (700 mg, 2.26 mmol) was dissolved in dichloromethane (10 mL). Oxalyl chloride (711 mg, 5.65 mmol) was added dropwise under ice-cooling. The mixture was allowed to react at room temperature for 1 hour, and the reaction mixture was concentrated for later use. 2-Chloro-6-methylpyrimidin-4-amine (387 mg, 2.7 mmol) was dissolved in DMF (10 mL). Sodium hydroxide (180 mg, 4.5 mmol) was added under ice-cooling. The mixture was allowed to react at room temperature for 1 hour, and the previously prepared acyl chloride was then added to the reaction mixture under ice-cooling. The reaction mixture was allowed to react at 70°C for 16 hours. After cooling, the reaction mixture was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (50 mL), washed twice with brine (80 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-70%) to afford compound 26-3.

[0661] Step 3: Synthesis of compound 26-4

[0662] Compound 26-3 (300 mg, 0.690 mmol), 4,4-difluoropyridine (108 mg, 0.896 mmol), and DIEA (267 mg, 2.068 mmol) were dissolved in NMP (10 mL) and reacted at 180°C under nitrogen for 5 hours. After cooling, the reaction solution was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (50 mL), and washed twice with brine (80 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-50%) to obtain compound 26-4.

[0663] Step 4: Synthesis of compound 26-5

[0664] Compound 26-4 (150 mg, 0.288 mmol), cesium carbonate (282 mg, 0.865 mmol), catalyst CAS: 1599466-89-3 (24 mg, 0.0288 mmol), and 2-hydroxyethane-1-sulfonamide (72 mg, 0.577 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 90°C under nitrogen for 16 hours. After cooling, the reaction solution was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (20 mL), and washed twice with brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-80%) to yield 26. MS (ESI, pos. ion) m / z: 566.22 [M+1] + .

[0665] 1H NMR(DMSO-d6)δ:10.46(s,1H),10.28(br s,1H),7.95(d,J=8.6Hz,1H),7.34(s,1H),6.94(dd,J=8.6,1.9Hz,1H),6.84(d,J=1.6Hz,1H),4.95(br s,1H),4.81(quin,J=6.5Hz,1H),3.89(br t,J=5.3Hz,4H),3.71-3.82(m,2H),3.35-3.42(m,2H),2.63-2.72(m,2H),2.31(s ,3H),2.19-2.26(m,2H),2.02-2.11(m,4H),1.96-2.02(m,4H),1.80-1.89(m,2H).

[0666] Example 27: Synthesis of 2-(cyclohexyloxy)-N-(1-(cyclopropylmethyl)indolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (27)

[0667] Step 1: Synthesis of compound 27-2

[0668] NaH (752 mg, 18.8 mmol) was added to a DMF solution of cyclohexanol (1.5 g, 15 mmol). After reacting for 30 minutes, compound 27-1 (1 g, 3.76 mmol) was added and stirred at 80°C for 3 hours. The reaction was cooled to room temperature, quenched with cold water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 3 / 1) to provide compound 27-2.

[0669] Step 2: Synthesis of compound 27-3

[0670] A mixture of compound 27-2 (161 mg, 4.51 mmol), 1-(cyclopropylmethyl)indole-4-amine (700 mg, 3.76 mmol), HATU (2 g, 5.26 mmol), and DIPEA (972 mg, 7.52 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. The reaction was then quenched with water and a saturated NaHCO solution. The resulting mixture was extracted with EtOAc, and the organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 4 / 1) to provide compound 27-3.

[0671] Step 3: Synthesis of compound 27-4

[0672] Compound 27-3 (110 mg, 0.21 mmol) was dissolved in acetic acid (3 mL) and NaBH3CN (41 mg, 0.64 mmol) was added. The mixture was stirred at room temperature for 1 hour. The acetic acid was removed by rotary evaporation, and then water was added and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 4 / 1) to provide compound 27-4.

[0673] Step 4: Synthesis of compound 27

[0674] Compound 27-4 (20 mg, 0.04 mmol) and 2-hydroxyethane-1-sulfonamide (20 mg, 0.15 mmol) were dissolved in 1,4-dioxane (2 mL), and catalyst CAS: 1599466-85-9 (2 mg, 0.001 mmol) and cesium carbonate (26 mg, 0.08 mmol) were added. The mixture was heated at 100°C under nitrogen protection and reacted overnight. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3 x 30 mL). The organic solution was collected and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to obtain compound 27. MS m / z (ESI): 514.3 [M+1] + .

[0675] 1 H NMR(CHLOROFORM-d)δ:9.54(s,1H),8.15(d,J=8.5Hz,1H),7.16(br d,J=8.0Hz,1H),7.05-7.20(m,1H),7.02-7.20(m,1H),7.00-7.14(m,1H),6.79(dd,J=8.5,1.8Hz,1 H),6.34(d,J=7.8Hz,1H),4.46-4.54(m,1H),4.07(q,J=4.8Hz,2H),3.52(t,J=8.3Hz,2H),3.23(br t,J=4.9Hz,2H),2.91-2.98(m,4H),2.14(br dd,J=12.0,3.0Hz,2H),1.75-1.85(m,2H),1.59-1.65(m,2H),1.36-1.49(m,2H ),1.20-1.36(m,2H),0.95-1.06(m,1H),0.51-0.61(m,2H),0.19-0.25(m,2H),

[0676] Example 28 Synthesis of 2-(cyclopentyloxy)-N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (28)

[0677] Step 1: Synthesis of compound 28-2

[0678] Sodium hydride (601 mg, 15 mmol) was added to a DMF solution of cyclopentanol (972 mg, 11.28 mmol). After 30 minutes of reaction, compound 28-1 (1 g, 3.76 mmol) was added and the reaction was stirred at 80°C for 3 hours. The reaction was cooled to room temperature, quenched with cold water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 3 / 1) to provide compound 28-2.

[0679] Step 2: Synthesis of compound 28-3

[0680] A: To a solution of compound 28-2 (373 mg, 1.3 mmol) in DCM (6 mL) was added oxalyl chloride (286 mg, 2.25 mmol) dropwise at 0° C., followed by the addition of DMF (0.10 mL). The reaction mixture was stirred at room temperature for 1 hour, and the reaction mixture was evaporated under reduced pressure and co-distilled with toluene to give crude 2-(cyclopentyloxy)-4-iodobenzoyl chloride, which was used in the next step without further purification.

[0681] B: To a solution of 2-(4,4-difluorohexahydropyridin-1-yl)pyridin-4-amine (200 mg, 0.94 mmol) in pyridine (2 mL) was added the product obtained in step A at 0°C, and the reaction mixture was stirred at 50°C overnight, then quenched with cold water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 0 to 4 / 1) to give compound 28-3.

[0682] Step 3: Synthesis of compound 28

[0683] Compound 28-3 (150 mg, 0.28 mmol) and 2-hydroxyethane-1-sulfonamide (143 mg, 1.14 mmol) were dissolved in 1,4-dioxane (2 mL), and catalyst CAS: 1599466-85-9 (12 mg, 0.01 mmol) and cesium carbonate (186 mg, 0.57 mmol) were added. The mixture was heated at 100 ° C under nitrogen protection and reacted overnight. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was then washed with EtOAc (3x30 mL). The organic solution was taken and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=1 / 0 to 1 / 1) to obtain compound 28. MS m / z (ESI): 525.2 [M+1] + .

[0684] 1 HNMR(DMSO-d6)δ:10.09-10.22(m,1H),10.02(s,1H),8.04(d,J=5.6Hz,1H),7.71(d,J=8.5Hz,1H),7 .32(s,1H),7.00(d,J=1.8Hz,1H),6.83-6.93(m,2H),4.92-5.00(m,1H),4.85-4.91(m,1H),3.76(br t,J=6.2Hz,2H),3.65(br t,J=5.6Hz,4H),3.34-3.37(m,2H),1.91-2.06(m,6H),1.83-1.91(m,2H),1.70(br d,J=7.0Hz,2H),1.63(br d,J=6.8Hz,2H).

[0685] Example 29: Synthesis of N-(1-(cyclopropylmethyl)indolin-4-yl)-2-((4,4-difluorocyclohexyl)oxy)-4-((2-hydroxyethyl)sulfonamido)benzamide (29)

[0686] Step 1: Synthesis of compound 29-2

[0687] Compound 29-1 (2000 mg, 12.33 mmol) was dissolved in N,N-dimethylformamide (20 mL) at 25°C, cooled to 0°C, and sodium hydroxide (986.74 mg, 24.67 mmol) was slowly added. The temperature was raised to room temperature and stirred for 0.5 hours. Bromomethylcyclopropane (1.33 mL, 13.57 mmol) was added and stirred for 1 hour. Water (50 mL) was added and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 5-10%) to obtain compound 29-2. MS m / z (ESI): 217.09 [M+H] +

[0688] Step 2: Synthesis of compound 29-3

[0689] Compound 29-2 (560 mg, 2.59 mmol) was dissolved in methanol (7 mL) at 25°C, and 10% palladium on carbon (56 mg, 0.3 mmol) was added to displace the hydrogen atmosphere. The mixture was stirred overnight. Filtered and concentrated to dryness under reduced pressure to obtain compound 29-3. MS m / z (ESI): 187.12 [M+H] +

[0690] Step 3: Synthesis of compound 29-4

[0691] Compound 29-3 (243 mg, 1.30 mmol) and 2-[(4,4-difluorocyclohexyl)oxy]-4-iodobenzoic acid (498.56 mg, 1.30 mmol) were dissolved in N,N-dimethylformamide (7 mL) at 25°C. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (992.14 mg, 2.61 mmol) and N,N-diisopropylethylamine (421.53 mg, 3.26 mmol) were added dropwise and stirred for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 5-13%) to obtain compound 29-4. MS m / z(ESI):551.09[M+H] +

[0692] Step 4: Synthesis of compound 29-5

[0693] N-(1-(cyclopropylmethyl)-1H-indol-4-yl)-2-((4,4-difluorocyclohexyl)oxy)-4-iodobenzamide (18 mg, 0.03 mmol)) was dissolved in acetic acid (0.5 mL) at 25°C, sodium cyanoborohydride (6.17 mg, 0.10 mmol) was added, and the mixture was stirred for 1 hour. Water (2 mL) was added, and the pH was adjusted to 8 with sodium carbonate. Ethyl acetate (2 mL*3) was added for extraction. The organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 10-15%) to obtain compound 29-5. MS m / z (ESI): 553.11 [M+H] + .

[0694] Step 5: Synthesis of compound 29

[0695] Compound 29-5 (108 mg, 0.20 mmol) was dissolved in 1,4-dioxane (2 mL) at 25°C. Catalyst CAS: 1599466-85-9 (16.63 mg, 0.02 mmol) and cesium carbonate (191.10 mg, 0.59 mmol) were added. The atmosphere was replaced with nitrogen, and the temperature was raised to 100°C under nitrogen protection and stirred overnight. The reaction solution was cooled to 25°C, water (5 mL) was added, and ethyl acetate (5 mL*3) was added for extraction. The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 20-50%) to obtain compound 29. MS m / z (ESI): 550.21 [M+H] + .

[0696] 1H NMR(CHLOROFORM-d)δ:9.09-9.30(m,1H),8.11(d,J=8.5Hz,1H),7.27-7.33(m,1H),7.16(d,J=1.5Hz ,1H),7.05-7.13(m,2H),6.81(dd,J=8.4,1.8Hz,1H),6.36(dd,J=6.8,1.6Hz,1H),4.61-4.70(m,1H), 4.04-4.11(m,2H),3.50-3.56(m,2H),3.18-3.25(m,2H),2.97(d,J=6.6Hz,2H),2.90(t,J=8.3Hz,2H ),2.08-2.22(m,4H),1.94-2.05(m,4H),0.95-1.06(m,1H),0.53-0.60(m,2H),0.22(q,J=4.8Hz,2H).

[0697] Example 30 Synthesis of 2-(cyclopentyloxy)-N-(1-(cyclopropylmethyl)indolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (30)

[0698] Step 1: Synthesis of compound 30-2

[0699] 1-(Cyclopropylmethyl)indole-4-amine (123 mg, 0.66 mmol) and compound 30-1 (200 mg, 0.6 mmol) were dissolved in DMF (3 mL) and HATU (273.77 mg, 0.72 mmol) and DIEA (0.2 mL, 1.2 mmol) were added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with EA (20 mL), and the organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0-95:5-90:10). Compound 30-2 was obtained.

[0700] Step 2: Synthesis of compound 30-3

[0701] To a solution of compound 30-2 (200 mg, 0.40 mmol) in CH 3 COOH (5 mL) was added NaBH 3 CN (0.04 mL, 1.20 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with EA (90 mL), and the organic layer was washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated. The crude product was purified by column chromatography (PE:EA=100:0-95:5-90:10). Compound 30-3 was obtained.

[0702] Step 3: Synthesis of compound 30

[0703] Compound 30-3 (100 mg, 0.20 mmol) and 2-hydroxyethyl-1-sulfonamide (99.63 mg, 0.80 mmol) were dissolved in 1,4-dioxane (3 mL) and CsCO (64.85 mg, 0.20 mmol) and catalyst CAS: 1599466-89-3 (8.89 mg, 0.01 mmol) were added. The reaction mixture was stirred at 100 ° C overnight. The reaction mixture was diluted with EA (90 mL), the organic layer was washed with salt water (20 mL), dried over NaSO, filtered and concentrated. The residue was purified by column chromatography (PE:EA=100:0-90:10-60:40). Compound 30 was obtained.

[0704] 1 H NMR (400MHz, DMSO-d6)δ=11.22-11.18(m,1H),7.38-7.35(m,1H),7.28-7.24(m,1H),7.21-7.16(m,1H),6 .74-6.70(m,1H),6.46-6.39(m,2H),6.37-6.35(m,1H),6.29-6.26(m,1H),3.75(t,J=6.8Hz,2H),3.35(br d,J=5.9Hz,4H),3.31-3.27(m,2H),2.92-2.87(m,4H),2.11-2.01(m,4H),1.50-1.36(m,4H),0.28(s,4H).

[0705] Example 32 Synthesis of N-(1-(cyclopropylmethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)-4-benzamide (32)

[0706] Step 1: Synthesis of compound 32-2

[0707] Compound 32-1 (1 g, 6.57 mmol) and cesium carbonate (6.4 g, 19.65 mmol) were dissolved in DMF (10 ml). Bromomethylcyclopropane (0.5 ml, 7.2 mmol) was added at room temperature. The reaction was allowed to react at 50°C for 2 hours under N₂ protection. The reaction mixture was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to afford compound 32-2.

[0708] Step 2: Synthesis of compound 32-3

[0709] Compound 32-2 (1 g, 4.85 mmol) was dissolved in glacial acetic acid (5 ml). Sodium cyanoborohydride (1.5 g, 24.25 mmol) was added to the reaction system at 0°C, followed by reaction at 50°C for 12 hours. The reaction mixture was diluted with EA (5 mL), washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to afford compound 32-3.

[0710] Step 3: Synthesis of compound 32-4

[0711] Compound 32-3 (300 mg, 1.44 mmol), tert-butyl carbamate (338 mg, 2.88 mmol), cesium carbonate (1408 mg, 4.32 mmol), and catalyst CAS: 1599466-85-9 (61.3 mg, 0.07 mmol) were dissolved in dioxane (2 mL) and reacted at 90°C under nitrogen for 3 hours. The reaction solution was diluted with EA (10 mL), washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to obtain compound 32-4.

[0712] Step 4: Synthesis of compound 32-5

[0713] Compound 32-4 (400 mg, 1.38 mmol) was dissolved in hydrochloric acid-ethyl acetate and allowed to react at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and washed with saturated sodium bicarbonate aqueous solution until the pH reached 9. The mixture was extracted with EA (10 mL). The organic phase was washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield compound 32-5. This was used directly in the next step without purification.

[0714] Step 5: Synthesis of compound 32-6

[0715] 4-Bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoic acid (246 mg, 0.79 mmol) was dissolved in DCM (3 ml). Oxalyl chloride (0.13 ml, 1.58 mmol) and a catalytic amount of DMF were added at 0°C under nitrogen. The mixture was allowed to react at room temperature for 30 minutes. After concentration under reduced pressure, the mixture was dissolved in DMF (1 ml). Compound 32-5 (100 mg, 0.53 mmol) was dissolved in pyridine (5 ml). 4-Bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoic acid chloride was added to the reaction mixture at 0°C. The reaction was allowed to react at 80°C for 24 hours. The reaction mixture was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to give compound 32-6.

[0716] Step 6: Synthesis of compound 32

[0717] Compound 32-6 (30 mg, 0.062 mmol), 2-hydroxyethylsulfonamide (39 mg, 0.31 mmol), cesium carbonate (61 mg, 0.19 mmol), and catalyst CAS: 1599466-89-3 (5 mg, 0.0062 mmol) were dissolved in dioxane (3 mL) and reacted at 80°C under nitrogen for 3 hours. The reaction mixture was quenched with water (10 mL) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 2 / 1) to yield compound 32. MS (ESI, pos. ion) m / z: 526.3 [M+1] + .

[0718] 1 HNMR(DMSO-d6)δ:10.79-10.85(m,1H),7.75-7.81(m,1H),7.67-7.73(m,1H),7.16-7.22(m,1H),7.11-7.16(m,1H),6.9 8-7.03(m,1H),3.73-3.79(m,2H),3.52-3.61(m,2H),3.32-3.35(m,2H),3.12-3.19(m,2H),3.00-3.05(m,2H),2.97(br t,J=5.0Hz,4H),1.44-1.53(m,4H),0.93-1.01(m,1H),0.44-0.51(m,2H),0.31-0.38(m,4H),0.18-0.24(m,2H).

[0719] Example 33: Synthesis of N-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)-4-benzamide (33)

[0720] Step 1: Synthesis of compound 33-2

[0721] Compound 33-1 (500 mg, 3.27 mmol) and cesium carbonate (3.2 g, 9.8 mmol) were dissolved in DMF (10 ml). Bromomethylcyclopropane (0.35 ml, 3.6 mmol) was added at room temperature. The reaction was allowed to react at 50°C for 2 hours under N₂ protection. The reaction mixture was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to afford compound 33-2.

[0722] Step 2: Synthesis of compound 33-3

[0723] Compound 33-2 (300 mg, 1.45 mmol), tert-butyl carbamate (341 mg, 2.9 mmol), cesium carbonate (1400 mg, 4.35 mmol), and catalyst CAS: 1599466-85-9 (61.8 mg, 0.07 mmol) were dissolved in dioxane (2 mL) and reacted at 90°C under nitrogen for 3 hours. The reaction solution was diluted with EA (10 mL), washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to obtain compound 33-3.

[0724] Step 3: Synthesis of compound 33-4

[0725] Compound 33-3 (280 mg, 0.97 mmol) was dissolved in hydrochloric acid-ethyl acetate solution and reacted at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and washed with saturated sodium bicarbonate aqueous solution to a pH of 9. The solution was extracted with EA (10 mL). The organic phase was washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 33-4, which was used directly in the next step without purification.

[0726] Step 4: Synthesis of compound 33-5

[0727] 4-Bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoic acid (297 mg, 0.96 mmol) was dissolved in DCM (3 ml). Oxalyl chloride (0.16 ml, 1.92 mmol) and a catalytic amount of DMF were added at 0°C under nitrogen protection. The mixture was allowed to react at room temperature for 30 minutes. After concentration under reduced pressure, the mixture was dissolved in DMF (1 ml). Compound 33-4 (150 mg, 0.8 mmol) was slowly added with NaH (35 mg, 0.8 mmol) at 0°C under nitrogen protection and reacted at 60°C for 30 minutes. 4-Bromo-5-chloro-2-(6-azaspiro[2.5]octyl-6-yl)benzoic acid chloride was added to the reaction mixture at 0°C and reacted at 80°C for 2 hours. The reaction mixture was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to give compound 35-5.

[0728] Step 5: Synthesis of compound 33

[0729] Compound 33-5 (45 mg, 0.094 mmol), 2-hydroxyethylsulfonamide (58.8 mg, 0.47 mmol), cesium carbonate (92 mg, 0.28 mmol), and catalyst CAS: 1599466-89-3 (8 mg, 0.0094 mmol) were dissolved in dioxane (3 mL) and reacted at 80°C under nitrogen for 3 hours. The reaction solution was quenched with water (10 mL) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 3 / 1) to obtain compound 33. MS (ESI, pos. ion) m / z: 524.3 [M+1] + .

[0730] 1HNMR(DMSO-d6)δ:11.24-11.30(m,1H),8.19(d,J=5.5Hz,1H),8.02-8.09(m,1 H),7.80-7.86(m,1H),7.58-7.63(m,1H),7.15-7.21(m,1H),7.04(d,J=8.4Hz ,1H),6.75-6.80(m,1H),4.12(d,J=7.1Hz,2H),3.78(t,J=6.5Hz,2H),3.33-3 .38(m,2H),2.98-3.06(m,4H),1.42-1.51(m,4H),1.27-1.34(m,1H),0.51(br d,J=8.0Hz,2H),0.40-0.46(m,2H),0.25-0.31(m,4H).

[0731] Example 34: Synthesis of N-(7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (34)

[0732] Step 1: Synthesis of compound 34-2

[0733] Compound 34-1 (500 mg, 3.73 mmol) and DMAP (683 mg, 5.59 mmol) were dissolved in THF (10 ml). Tert-butyl tert-butoxycarbonyl ester (3.19 ml, 14.91 mmol) was added under ice-cooling. The mixture was reacted at room temperature under N2 protection for 2 hours. The reaction solution was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 34-2.

[0734] Step 2: Synthesis of compound 34-3

[0735] Compound 34-2 (1 g, 2.3 mmol) was dissolved in methanol (10 ml), and saturated aqueous sodium bicarbonate (2.3 ml) was added. The mixture was reacted at room temperature under N2 protection for 3 hours. The reaction mixture was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to afford compound 34-3.

[0736] Step 3: Synthesis of compound 34-4

[0737] Compound 34-3 (670 mg, 2 mmol) and cesium carbonate (1.96 g, 6 mmol) were dissolved in DMF (10 ml), and bromomethylcyclopropane (0.22 ml, 2.2 mmol) was added at room temperature. The reaction mixture was allowed to react at 50°C for 2 hours under N₂ protection. The reaction mixture was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to afford compound 34-4.

[0738] Step 4: Synthesis of compound 34-5

[0739] Compound 34-4 (670 mg, 1.72 mmol) was dissolved in hydrochloric acid-ethyl acetate solution and reacted at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and washed with saturated sodium bicarbonate aqueous solution to a pH of 9. The solution was extracted with EA (10 mL). The organic phase was washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 34-5, which was used directly in the next step without purification.

[0740] Step 5: Synthesis of compound 34-6

[0741] 4-Bromo-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid (297 mg, 0.96 mmol) was dissolved in DCM (3 ml). Oxalyl chloride (0.16 ml, 1.92 mmol) and a catalytic amount of DMF were added at 0°C under nitrogen protection. The mixture was allowed to react at room temperature for 30 minutes. After concentration under reduced pressure, the mixture was dissolved in DMF (1 ml). Compound 34-5 (150 mg, 0.8 mmol) was slowly added with NaH (35 mg, 0.8 mmol) at 0°C under nitrogen protection and reacted at 60°C for 30 minutes. 4-Bromo-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid chloride was added to the reaction mixture at 0°C and reacted at 80°C for 2 hours. The reaction solution was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 2 / 1) to give compound 34-6.

[0742] Step 6: Synthesis of compound 34

[0743] Compound 34-6 (45 mg, 0.094 mmol), 2-hydroxyethylsulfonamide (58.8 mg, 0.47 mmol), cesium carbonate (92 mg, 0.28 mmol), and catalyst CAS: 1599466-89-3 (8 mg, 0.0094 mmol) were dissolved in dioxane (3 mL) and reacted at 80°C under nitrogen for 3 hours. The reaction mixture was quenched with water (10 mL) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 3 / 1) to yield compound 34. MS (ESI, pos. ion) m / z: 525.3 [M+1] + .

[0744] 1 HNMR(ACETONITRILE-d3)δ:13.00-13.08(m,1H),8.39-8.45(m,1H),8.07-8.12(m,1H) ,7.27-7.31(m,1H),7.21-7.24(m,1H),7.07(dd,J=8.6,2.1Hz,1H),7.03-7.05(m,1H) ,4.02-4.06(m,2H),3.80-3.84(m,2H),3.22-3.26(m,2H),2.97-3.03(m,4H),1.59-1. 72(m,4H),0.78-0.80(m,1H),0.44-0.50(m,2H),0.34-0.37(m,2H),0.32-0.34(m,4H).

[0745] Example 37: Synthesis of N-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0746] Step 1: Synthesis of compound 37-2

[0747] Compound 37-1 (500 mg, 3.00 mmol) and cesium carbonate (1.95 g, 6.00 mmol) were dissolved in DMF (5 mL). Bromomethylcyclopropane (0.35 mL, 3.60 mmol) was added and allowed to react at 70°C for 2 hours. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1-10:1) to obtain compound 37-2. MS (ESI, pos. ion) m / z: 221.0 [M+1] + .

[0748] Step 2: Synthesis of compound 37-3

[0749] Compound 37-2 (270 mg, 1.22 mmol), NH2Boc (287 mg, 2.45 mmol), cesium carbonate (1.20 g, 3.67 mmol), and palladium catalyst (CAS: 1599466-85-9, 52 mg, 0.06 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 90°C for 2 h under nitrogen. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1-10:1) to obtain compound 37-3. MS (ESI, pos. ion) m / z: 302.2 [M+1] + .

[0750] Step 3: Synthesis of compound 37-4

[0751] Compound 37-3 was dissolved in DCM (1 mL) and HCl / EA (5 mL) was added. The reaction mixture was allowed to react at 25°C for 2 h. The reaction solution was quenched with ice water, neutralized with saturated NaHCO₃ solution, and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and dried to afford compound 37-4. MS (ESI, pos. ion) m / z: 202.1 [M+1] + .

[0752] Step 4: Synthesis of compound 37-5

[0753] 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (240 mg, 0.78 mmol) was dissolved in DCM (5 mL), and oxalyl chloride (0.13 mL, 1.55 mmol) and a catalytic amount of DMF were added. The mixture was reacted at 25°C for 10 minutes. The reaction solution was concentrated and pumped dry with an oil pump to obtain 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride. Compound 37-4 (104 mg, 0.52 mmol) was dissolved in DMF (1 mL), and NaH (21 mg, 0.52 mmol) was added. The mixture was reacted at 60°C for 30 minutes. 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride was then added, and the mixture was reacted at 90°C for 2 hours. The reaction mixture was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to give compound 37-5 (4-bromo-N-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide). MS (ESI, pos. ion) m / z: 493.2\495.2 [M+1]+.

[0754] Step 5: Synthesis of compound 37

[0755] Compound 37-5 (30 mg, 0.06 mmol), 2-hydroxyethanesulfonamide (38 mg, 0.30 mmol), cesium carbonate (59 mg, 0.18 mmol), and palladium catalyst (CAS: 1599466-89-3, 3 mg) were dissolved in 1,4-dioxane (2 mL) and reacted at 100°C for 2 h under nitrogen. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified to yield compound 37. MS (ESI, pos. ion) m / z: 538.3 [M+1]+.

[0756] 1H NMR (400MHz, DMSO-d6) δ = 11.21 (s, 1H), 7.97 (s, 1H), 7.82 (d, J = 8.5Hz, 1H), 7.48 (d, J = 3.5Hz, 1H), 7.19-7.14 (m, 1H), 7.02 (dd, J = 1.7, 8. 4Hz,1H),6.69(d,J=3.5Hz,1H),4.07(d,J=7.0Hz,2H),3.77(t,J=6.6Hz,2H),3.36-3.32(m,2H),3.05-2.96(m,4H),2.53(s,3H),1.47(br s,4H),1.31-1.26(m,1H),0.54-0.39(m,4H),0.28(s,4H).

[0757] Example 38: Synthesis of N-(1-(cyclopropylmethyl)-1H-indol-4-yl)-6-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide

[0758] Step 1: Synthesis of compound 38-2

[0759] 38-1 (800 mg, 4.93 mmol) and Cs2CO3 (3.2 g, 9.87 mmol) were dissolved in DMF (15 mL), and (bromomethyl)cyclobutane (733 mg, 5.43 mmol) was slowly added dropwise. The reaction mixture was stirred at 90°C for 3 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20-1 / 10) to obtain 38-2.

[0760] Step 2: Synthesis of compound 38-3

[0761] 38-2 (800 mg, 3.7 mmol) and Pd / C 10% (80 mg, 0.75 mmol) were stirred in MeOH (10 mL) at room temperature under H2 for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 38-3. MS m / z (ESI): 187.1 [M+1] + .

[0762] Step 3: Synthesis of compound 38-5

[0763] 38-4 (1 g, 5.21 mmol) and 6-azaspiro[2.5]octane (579 mg, 5.21 mmol) were dissolved in acetonitrile (10 mL). DIEA (2019.5 mg, 15.6 mmol) was slowly added dropwise, and the reaction mixture was stirred at 60°C for 3 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20-1 / 10) to obtain compound 38-5. MS m / z (ESI): 267.0 [M+1] + .

[0764] Step 4: Synthesis of compound 38-6

[0765] Compound 38-5 (90 mg, 0.34 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (63 mg, 0.34 mmol), and HATU (128 mg, 0.34 mmol) were dissolved in DMF (2 mL). DIEA (87 mg, 0.67 mmol) was added and the mixture was allowed to react at 25°C for 2 h. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 10-1 / 5) to afford compound 38-6. MS m / z (ESI): 435.2 [M+1] + .

[0766] Step 5: Synthesis of compound 38

[0767] Compound 38-6 (100 mg, 0.23 mmol), 2-hydroxyethanesulfonamide (143.85 mg, 1.15 mmol), cesium carbonate (224.7 mg, 0.69 mmol), and palladium catalyst (1599466-85-9, 10 mg, 0.01 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 80°C under nitrogen protection for 10 h. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by preparative method to obtain compound 38. MS m / z (ESI): 524.3 [M+1] + .

[0768] 1H NMR (400MHz, DMSO-d6) δ = 10.67 (s, 1H), 10.26 (s, 1H), 7.89 (d, J = 8.0Hz, 1H), 7.83 (br d,J=7.6Hz,1H),7.43(d,J=3.1Hz,1H),7.28(d,J=8.3Hz,1H),7.14-7.08( m,1H),6.71(d,J=3.1Hz,1H),6.47(d,J=8.1Hz,1H),4.04(d,J=7.0Hz,2H) ,3.82-3.79(m,2H),3.78-3.75(m,2H),3.40-3.32(m,4H),1.47-1.37(m,4 H),1.28-1.22(m,1H),0.55-0.47(m,2H),0.44-0.36(m,2H),0.26(s,4H).

[0769] Example 39: Synthesis of N-(1-cyclopropylmethyl)-1H-indol-4-yl)-4-(2-hydroxyethyl)sulfonamido-2-methylamino-6-(6-azaspiro[2.5]octan-6-yl)benzamide (39)

[0770] Step 1: Synthesis of compound 39-2

[0771] Compound 39-1 (10 g, 39.84 mmol) and (2,4-dimethoxyphenyl)methylamine (6.00 mL, 39.84 mmol) were dissolved in DMF (60 mL) solution, and Cs2CO3 (25.96 g, 79.67 mmol) was added thereto. The reaction mixture was placed in a 60°C oil bath and stirred for 4 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0-98:2-95:5) to give compound 39-2.

[0772] Step 2: Synthesis of compound 39-3

[0773] 6-Azaspiro[2.5]octane hydrochloride (1.85 g, 12.56 mmol) was dissolved in DMF (15 mL) and water (15 mL). N,N-diisopropylethylamine (3.25 g, 25.11 mmol) was added and stirred for a while. Compound 39-2 (2.5 g, 6.28 mmol) was then added and stirred at 100 ° C for 4 hours. After the reaction was completed, the reaction mixture was diluted with EA (120 mL), and the organic layer was washed with brine (180 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0-49:1) to obtain compound 39-3.

[0774] Step 3: Synthesis of compound 39-4

[0775] To a solution of compound 39-3 (1.38 g, 2.82 mmol) in methanol (10 mL) and water (2.5 mL) was added sodium hydroxide (0.68, 16.92 mmol) and stirred at 60 ° C for 18 hours. The reaction mixture was diluted with EA (120 mL). The organic layer was washed with brine (180 mL) and then dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE:EA=100:0-90:10-80:20) to give compound 39-4.

[0776] Step 4: Synthesis of compound 39-5

[0777] Compound 39-4 (1.2 g, 2.52 mmol) and 1-cyclopropylmethyl-1H-indole-4-amine (517.19 mg, 2.78 mmol) were dissolved in DMF (10 mL) and azabenzotriazolyl tetramethyluronium hexafluorophosphate (1.15 g, 3.03 mmol) and N, N-diisopropylethylamine (0.84 mL, 5.05 mmol) were added and stirred at room temperature for 1 hour. The reaction mixture was diluted with EA (120 mL), the organic layer was washed with brine (180 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE:EA=100:0-90:10-80:20) to obtain compound 39-5.

[0778] Step 5: Synthesis of compound 39-6

[0779] Compound 39-5 (600 mg, 0.93 mmol) was dissolved in methanol (6 mL) and acetic acid (0.5 mL), and formaldehyde (83.98 mg, 2.80 mmol) and sodium cyanoborohydride (175.74 mg, 2.80 mmol) were added thereto, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EA (120 mL), and the organic layer was washed with brine (180 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 100:0-90:10-80:20) to give compound 39-6.

[0780] Step 6: Synthesis of compound 39-7

[0781] Compound 39-6 (497 mg, 0.76 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL, 40.26 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with EA (100 mL), and the organic layer was washed with brine (180 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 100:0-90:10-80:20) to obtain compound 39-7.

[0782] Step 7: Synthesis of compound 39

[0783] Compound 39-7 (167 mg, 0.33 mmol) and 2-hydroxyethane-1-sulfonamide (164.72 mg, 1.32 mmol) were dissolved in 1,4-dioxane (2 mL), and catalyst CAS: 1599466-83-7 (30.47 mg, 0.03 mmol) and cesium carbonate (214.44 mg, 0.66 mmol) were added thereto. The reaction solution was placed in a 95 ° C oil bath and stirred for 1.5 hours. The reaction mixture was diluted with EA (100 mL), and the organic layer was washed with brine (180 mL), dried over Na2SO4, filtered and concentrated. The residue was purified to obtain compound 39. MS (ESI, pos.ion) m / z: 552.3 [M+1] + .

[0784] 1H NMR (400MHz, METHANOL-d4)δ=7.75-7.75(m,1H),7.76-7.71(m,1H),7.33-7.29(m,1H),7.28-7.24(m,1H),7.19-7.13(m,1H) ,6.55-6.52(m,1H),6.51-6.48(m,1H),6.41-6.38(m,1H),4.08-4.03(m,2H),3.98-3.94(m,2H),3.41--3.37(m,2H),3.09(br d,J=4.4Hz,4H),2.88-2.83(m,3H),1.52-1.41(m,4H),1.29(br s,1H),0.63-0.57(m,2H),0.43-0.38(m,2H),0.27-0.23(m,4H).

[0785] Example 40: Synthesis of N-(1-cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2-hydroxyethylsulfonamide)-2-methylamino-6-(6-azaspiro[2.5]octan-6-yl)benzamide (40)

[0786] Step 1: Synthesis of compound 40-2

[0787] Compound 40-1 (5.0 g, 19.92 mmol) and 6-azaspiro [2.5] octane hydrochloride (3.53 g, 23.90 mmol) were dissolved in a mixed solvent of DMF (25 mL) and H2O (25 mL), and Cs2CO3 (7.72 g, 59.75 mmol) was added thereto. The reaction mixture was placed in a 100 ° C oil bath and stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated. Purification by column chromatography (PE: EA = 98: 2-95: 5) gave compound 40-2.

[0788] Step 2: Synthesis of compound 40-3

[0789] Compound 40-2 (5.8 g, 16.95 mmol) was dissolved in a mixed solvent of MeOH (32 mL) and H₂O (8 mL). NaOH (4.07 g, 101.69 mmol) was added, and the reaction mixture was stirred in a 60°C oil bath for 3 hours. After completion of the reaction, 2M HCl was added to acidify the reaction solution, which was then diluted with water (50 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to yield compound 40-3.

[0790] Step 3: Synthesis of compound 40-4

[0791] Compound 40-3 (2.0 g, 6.09 mmol) was dissolved in N-methylbenzylamine (10 mL), and the reaction mixture was placed in a microwave reactor and stirred at 150°C for 30 minutes. After completion of the reaction, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (60 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (DCM:MeOH = 99:1-97:3) gave compound 40-4.

[0792] Step 4: Synthesis of compound 40-5

[0793] Compound 40-4 (300 mg, 0.70 mmol) was dissolved in DCM (6 mL). The reaction solution was cooled to 0°C, and oxalyl chloride (56.45 mg, 2.10 mmol) was slowly added. The reaction mixture was stirred at room temperature for half an hour. After completion of the reaction, the reaction solution was directly spin-dried and used in the next step. 1-Cyclopropylmethyl-1H-pyrrolo[2,3-b]pyridin-4-amine (200.63 mg, 1.40 mmol) was dissolved in DMF (4 mL). After the reaction solution was cooled to 0°C, NaH (33.54 mg, 1.40 mmol) was added, and the reaction solution was stirred in a 60°C oil bath for 30 minutes. The reaction solution was then cooled to 0°C, and the acid chloride obtained above was added. The mixed reaction solution was reacted at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA=100:0-97:3) gave compound 40-5.

[0794] Step 5: Synthesis of compound 40-6

[0795] Compound 40-5 (128 mg, 0.21 mmol) and 2-hydroxyethane-1-sulfonamide (107 mg, 0.86 mmol) were dissolved in dioxane (2 mL), and catalyst CAS: 1599466-89-3 (35 mg, 0.04 mmol) and Cs2CO3 (139 mg, 0.43 mmol) were added thereto. The reaction mixture was placed in a 95°C oil bath and stirred for 2 hours. After completion of the reaction, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (DCM: MeOH = 95:5) to give compound 40-6.

[0796] Step 6: Synthesis of compound 40

[0797] Compound 40-6 (56 mg, 0.09 mmol) was dissolved in methanol (1 mL), and 10% palladium on carbon (0.93 mg, 0.01 mmol) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 × 3 mL). The organic layer was washed with brine (10 × 3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative purification to obtain compound 40. MS (ESI, pos.ion) m / z: 553.3 [M+1] + .

[0798] 1 H NMR (400MHz, METHANOL-d4)δ=8.18-8.13(m,1H),8.10-8.04(m,1H),7.48-7.45(m,1H),6.70-6.67(m,1H),6.50-6.45(m,1H),6.42-6 .39(m,1H),4.15(d,J=7.1Hz,2H),3.98-3.94(m,2H),3.43-3.38(m,2H),3.13-3.06(m,4H),2.86(s,3H),1.54-1.44(m,4H),0.90(br t,J=6.8Hz,1H),0.59(br d,J=7.6Hz,2H),0.46-0.42(m,2H),0.28-0.24(m,4H).

[0799] Example 41: Synthesis of 2-amino-N-(1-cyclopropylmethyl)-1H-indol-4-yl)-4-(2-hydroxyethyl)sulfonamido-6-(6-azaspiro[2.5]octan-6-yl)benzamide (41)

[0800] Step 1: Synthesis of compound 41-2

[0801] Methyl 4-bromo-2,6-difluorobenzoate (4.98 g, 19.84 mmol) and (2,4-dimethoxyphenyl)methylamine (3.35 g, 20.04 mmol) were dissolved in N,N-dimethylformamide (40 mL), and cesium carbonate (12.93 g, 39.68 mmol) was added thereto. The reaction mixture was placed in a 60 ° C oil bath and stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with water (120 mL) and extracted with ethyl acetate (60 × 3 mL). The organic layer was washed with brine (60 × 3 mL), dried over Na2SO4, filtered and concentrated. Purification by column chromatography (PE: EA = 98: 2-95: 5) gave compound 41-2.

[0802] Step 2: Synthesis of compound 41-3

[0803] 6-Azaspiro[2.5]octane hydrochloride (1.24 g, 8.37 mmol) and sodium hydride (0.50 g, 20.94 mmol) were dissolved in N,N-dimethylformamide (25 mL) and stirred in a 70°C oil bath for 10 minutes. Compound 41-3 (2.78 g, 6.98 mmol) was then added, and the reaction mixture was stirred in a 125°C oil bath for 18 hours. After completion of the reaction, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford compound 41-3.

[0804] Step 3: Synthesis of compound 41-4

[0805] Compound 41-3 (498 mg, 1.02 mmol) was dissolved in methanol (4 mL) and water (0.4 mL), and then LiOH (74 mg, 3.06 mmol) was added. The reaction mixture was placed in a 60°C oil bath and stirred for 7 hours. After the reaction was completed, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (60 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA = 100:0-90:10-80:20) gave compound 41-4.

[0806] Step 4: Synthesis of compound 41-5

[0807] Compound 41-4 (170 mg, 0.36 mmol) and 1-cyclopropylmethyl-1H-indole-4-amine (66.61 mg, 0.36 mmol) were dissolved in N, N-dimethylformamide (3 mL), and azabenzotriazolyl tetramethyluronium hexafluorophosphate (135.98 mg, 0.36 mmol) and N, N-diisopropylethylamine (46.22 mg, 0.36 mmol) were added thereto. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with water (90 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated. Purification by column chromatography (PE:EA = 100:0-90:10-80:20) gave compound 41-5.

[0808] Step 5: Synthesis of compound 41-6

[0809] Compound 41-5 (118 mg, 0.18 mmol) and 2-hydroxyethane-1-sulfonamide (91.77 mg, 0.73 mmol) were dissolved in dioxane (3 mL), and catalyst CAS: 1599466-89-3 (7.41 mg, 0.01 mmol) and Cs2CO3 (119.47 mg, 0.37 mmol) were added thereto. The reaction mixture was placed in a 95°C oil bath and stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with water (90 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated. Purification by column chromatography (PE:EA = 100:0-90:10-80:20) gave compound 41-6.

[0810] Step 6: Synthesis of compound 41

[0811] Compound 41-6 (40 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL, 13.42 mmol) was added. The reaction mixture was stirred at room temperature for 6 minutes. After completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 × 3 mL). The organic layer was washed with brine (10 × 3 mL), dried over Na2SO4, filtered, and concentrated. Compound 41 was prepared and purified by HPLC. MS (ESI, pos. ion) m / z: 538.3 [M+1]+.

[0812] 1H NMR (400MHz, DMSO-d6)δ=11.12-11.05(m,1H),7.92-7.86(m,1H),7.43(br s,1H),7.46-7.40(m,1H),7.29-7.23(m,1H),7.13-7.07(m,1H),6.66-6.61(m,1H) ,6.56-6.48(m,2H),6.40-6.36(m,1H),6.34-6.30(m,1H),4.08-4.01(m,2H),3.80- 3.73(m,2H),3.30-3.27(m,2H),2.96-2.96(m,1H),3.00-2.91(m,3H),1.42-1.31( m,4H),1.24-1.22(m,1H),0.56-0.49(m,2H),0.42-0.37(m,2H),0.25-0.18(m,4H).

[0813] Example 42: Synthesis of 2-amino-N-(1-cyclopropylmethyl)indolin-4-yl)-4-(2-hydroxyethylsulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (42)

[0814] Step 1: Synthesis of compound 42-2

[0815] Methyl 4-bromo-2,6-difluorobenzoate (4.98 g, 19.84 mmol) and (2,4-dimethoxyphenyl)methylamine (3.35 g, 20.04 mmol) were dissolved in N,N-dimethylformamide (40 mL), and cesium carbonate (12.93 g, 39.68 mmol) was added thereto. The reaction mixture was placed in a 60 ° C oil bath and stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with water (120 mL) and extracted with ethyl acetate (60 × 3 mL). The organic layer was washed with brine (60 × 3 mL), dried over Na2SO4, filtered and concentrated. Purification by column chromatography (PE: EA = 98: 2-95: 5) gave compound 42-2.

[0816] Step 2: Synthesis of compound 42-3

[0817] 6-Azaspiro[2.5]octane hydrochloride (1.24 g, 8.37 mmol) and sodium hydride (0.50 g, 20.94 mmol) were dissolved in N,N-dimethylformamide (25 mL) and stirred in an oil bath at 70°C for 10 minutes. Compound 42-2 (2.78 g, 6.98 mmol) was then added, and the reaction mixture was stirred in an oil bath at 125°C for 18 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to yield compound 42-3.

[0818] Step 3: Synthesis of compound 42-4

[0819] Compound 42-3 (498 mg, 1.02 mmol) was dissolved in methanol (4 mL) and water (0.4 mL), and the reaction mixture was stirred in a 60°C oil bath for 7 hours. After completion of the reaction, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (60 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA = 100:0-90:10-80:20) gave compound 42-4.

[0820] Step 4: Synthesis of compound 42-5

[0821] Compound 42-4 (160 mg, 0.34 mmol) and 1-cyclopropylmethyl-1H-indole-4-amine (63.37 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (3 mL), and azabenzotriazolyl tetramethyluronium hexafluorophosphate (153.57 mg, 0.40 mmol) and N,N-diisopropylethylamine (87.00 mg, 0.67 mmol) were added thereto. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with water (90 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (PE:EA = 100:0-90:10-80:20) gave compound 42-5.

[0822] Step 5: Synthesis of compound 42-6

[0823] Compound 42-5 (97 mg, 0.15 mmol) and 2-hydroxyethane-1-sulfonamide (75.20 mg, 0.60 mmol) were dissolved in 1,4-dioxane (4 mL), and catalyst CAS: 1599466-89-3 (6.07 mg, 0.01 mmol) and Cs2CO3 (97.90 mg, 0.30 mmol) were added thereto. The reaction mixture was placed in a 95°C oil bath and stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with water (90 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. Compound 42-6 was obtained by column chromatography (PE:EA = 100:0-90:10-80:20).

[0824] Step 6: Synthesis of compound 42

[0825] Compound 42-6 (70 mg, 0.10 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.6 mL, 8.05 mmol) was added. The reaction mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 × 3 mL). The organic layer was washed with brine (10 × 3 mL), dried over Na2SO4, filtered, and concentrated to obtain compound 42 through purification. MS (ESI, pos. ion) m / z: 540.3 [M+1] + .

[0826] 1 H NMR(400MHz, DMSO-d6)δ=10.64-10.58(m,1H),7.14-7.09(m,1H),7.00-6.94(m,1H),6.51-6.4 3(m,2H),6.38-6.35(m,1H),6.34-6.28(m,2H),3.78-3.72(m,2H),3.44-3.39(m,2H),3.29(br s,2H),2.96-2.88(m,8H),1.45-1.35(m,4H),0.88-0.84(m,1H),0.53-0.48(m,2H),0.34-0.28(m,4H),0.24-0.19(m,2H).

[0827] Example 44: Synthesis of N-(1-(cyclopropylmethyl)-1H-indol-4-yl)-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (44)

[0828] Step 1: Synthesis of compound 44-2

[0829] Compound 44-1 (150 mg, 0.81 mmol), 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (345 mg, 0.97 mmol), HATU (336 mg, 0.89 mmol), and N,N-diisopropylethylamine (0.53 ml, 3.22 mmol) were dissolved in DMF (5 ml) and reacted at room temperature under nitrogen at 0°C for 2 hours. The reaction solution was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain compound 44-2.

[0830] Step 2: Synthesis of compound 44

[0831] Compound 44-2 (100 mg, 0.19 mmol), DABSO (137 mg, 0.57 mmol), palladium acetate (7 mg, 0.028 mmol), n-butyldi(1-adamantyl)phosphine (14 mg, 0.038 mmol), and triethylamine (0.05 ml, 0.38 mmol) were dissolved in isopropanol (5 ml) and reacted at 85°C under a nitrogen atmosphere for 1 hour. After the reaction was complete, the temperature was cooled to room temperature, and 3-methyloxetan-3-amine (0.1 ml, 1.14 mmol) and aqueous sodium hypochlorite (0.3 ml, 3.8 mmol) were added. The reaction was allowed to react overnight at room temperature. The reaction mixture was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to yield compound 44. MS (ESI, pos.ion) m / z: 549.3 [M+1] + .

[0832] 1HNMR(DMSO-d6)δ:10.81-10.84(m,1H),7.91-7.95(m,1H),7.87-7.91(m,1H),7.64-7.67(m ,1H),7.56-7.60(m,1H),7.44-7.47(m,1H),7.31-7.35(m,1H),7.11-7.17(m,1H),6.74-6. 76(m,1H),4.57-4.61(m,2H),4.15-4.18(m,2H),4.03-4.07(m,2H),3.07-3.13(m,4H),1.4 2-1.48(m,7H),1.22-1.24(m,1H),0.50-0.56(m,2H),0.37-0.42(m,2H),0.25-0.30(m,4H).

[0833] Example 50: Synthesis of N-(1-cyclopropylmethyl)-6-fluoro-1H-indol-4-yl)-4-(2-hydroxyethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (50)

[0834] Step 1: Synthesis of compound 50-2

[0835] Compound 50-1 (500 mg, 2.34 mmol) and (bromomethyl)cyclopropane (379 mg, 2.81 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (1.52 g, 4.67 mmol) was added. The reaction mixture was stirred in a 70°C oil bath for 1.5 hours. After completion of the reaction, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. The mixture was purified by column chromatography (PE:EA = 100:0-90:10) to obtain compound 50-2.

[0836] Step 2: Synthesis of compound 50-3

[0837] Compound 50-3 (260 mg, 0.97 mmol) and NH2Boc (227 mg, 1.94 mmol) were dissolved in 1,4-dioxane (5 mL), and catalyst CAS: 1599466-83-7 (179 mg, 0.19 mmol) and cesium carbonate (948 mg, 2.91 mmol) were added. The reaction mixture was stirred in a 95°C oil bath for 1.5 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was diluted with water (60 mL), and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. The mixture was purified by column chromatography (PE:EA = 100:0-90:10-80:20) to obtain compound 50-3.

[0838] Step 3: Synthesis of compound 50-4

[0839] Compound 50-3 (195 mg, 0.64 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.14 mL, 1.92 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with sodium bicarbonate, diluted with water (30 mL), and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. The mixture was purified by column chromatography (PE:EA = 100:0-90:10-80:20) to obtain compound 50-4.

[0840] Step 4: Synthesis of compound 50-5

[0841] Compound 50-4 (60 mg, 0.29 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (100 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (2 mL), and azabenzotriazolyl tetramethyluronium hexafluorophosphate (134 mg, 0.35 mmol) and N,N-diisopropylethylamine (76 mg, 0.59 mmol) were added thereto. The reaction mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (PE:EA = 100:0-95:5-90:10) to obtain compound 50-5.

[0842] Step 5: Synthesis of compound 50

[0843] Compound 50-5 (71 mg, 0.14 mmol) and 2-hydroxyethane-1-sulfonamide (72 mg, 0.57 mmol) were dissolved in 1,4-dioxane (3 mL), and catalyst CAS: 1599466-83-7 (13 mg, 0.01 mmol) and cesium carbonate (93 mg, 0.29 mmol) were added thereto. The reaction mixture was placed in a 95°C oil bath and stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (30×3 mL). The organic layer was washed with brine (30×3 mL), dried over Na2SO4, filtered and concentrated. Compound 50 was obtained by purification. MS (ESI, pos.ion) m / z: 541.2 [M+1] +

[0844] 1 H NMR (400MHz, DMSO-d6)δ=11.24-11.15(m,1H),7.98-7.89(m,1H),7.88-7.81(m,1H) ),7.52-7.44(m,1H),7.23-7.15(m,2H),7.07-7.00(m,1H),6.77-6.70(m,1H),4.07 -3.98(m,2H),3.82-3.74(m,2H),3.40-3.33(m,2H),3.10-2.97(m,4H),1.54-1.39( m,4H),1.27-1.21(m,1H),0.56-0.49(m,2H),0.44-0.38(m,2H),0.32-0.23(m,4H).

[0845] Example 56: Synthesis of N-(1-(cyclopropylmethyl)-7-fluoro-1H-indol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (56)

[0846] Step 1: Synthesis of compound 56-2

[0847] Compound 56-1 (300 mg, 1.40 mmol) and cesium carbonate (913 mg, 2.80 mmol) were dissolved in DMF (4 mL). (Bromomethyl)cyclopropane (0.16 mL, 1.68 mmol) was added and the mixture was allowed to react at 70°C for 30 minutes. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20-1 / 10) to obtain compound 56-2. MS (ESI, pos. ion) m / z: 267.9 / 269.9 [M+1]+ .

[0848] Step 2: Synthesis of compound 56-3

[0849] Compound 56-2 (350 mg, 1.31 mmol), NH2Boc (306 mg, 2.62 mmol), and cesium carbonate (1.28 g, 3.93 mmol) were dissolved in dioxane (5 mL), and catalyst CAS: 1599466-83-7 (241 mg, 0.26 mmol) was added. The mixture was reacted at 90°C for 3 h. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1:20-1:10) to obtain compound 56-3.

[0850] Step 3: Synthesis of compound 56-4

[0851] Compound 56-3 (369 mg, 1.21 mmol) was dissolved in dichloromethane (2 mL), and a hydrogen chloride-dioxane solution (3 mL) was added. The mixture was reacted at 25°C for 2 hours. The reaction solution was filtered and dried to obtain the hydrochloride salt of compound 56-4. MS (ESI, pos.ion) m / z: 205.0 [M+1-HCl] + .

[0852] Step 4: Synthesis of compound 56-5

[0853] The hydrochloride salt of compound 56-4 (155 mg, 0.65 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (220 mg, 0.71 mmol), and HATU (270 mg, 0.71 mmol) were dissolved in ultra-dry DMF (2 mL). DIEA (0.43 mL, 2.58 mmol) was added and reacted at 25°C for 1 hour. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 56-5.

[0854] Step 5: Synthesis of compound 56

[0855] Compound 56-5 (269 mg, 0.54 mmol), 2-hydroxyethanesulfonamide (101.72 mg, 0.81 mmol), cesium carbonate (530 mg, 1.63 mmol), and catalyst CAS: 1599466-83-7 (100 mg, 0.11 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 100°C under nitrogen protection for 2 hours. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified to obtain compound 56. MS (ESI, pos. ion) m / z: 541.3 [M+1] + .

[0856] 1 H NMR (400MHz, DMSO-d6) δ = 11.16 (s, 1H), 10.09 (br s,1H),7.86(d,J=8.5Hz,1H),7.80(dd,J=3.8,8.5Hz,1H),7.49(d,J=3.1Hz,1H),7.22-7.16(m,1H),7.03(dd, J=1.7,8.4Hz,1H),6.97-6.89(m,1H),6.71(t,J=2.6Hz,1H),5.04-4.86(m,1H),4.16(d,J=7.0Hz,2H),3.77(br t,J=6.5Hz,2H),3.35(t,J=6.6Hz,2H),3.08-2.95(m,4H),1.45(br s,4H),1.33-1.26(m,1H),0.54-0.48(m,2H),0.39(q,J=4.9Hz,2H),0.28(s,4H).

[0857] Example 68: Synthesis of N-(1-(cyclopropylmethyl)-1H-indol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0858] Step 1: Synthesis of compound 68-2

[0859] 68-1 (1 g, 4.63 mmol) was dissolved in methanol (10 mL), palladium on carbon (200 mg) was added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain 68-2.

[0860] Step 2: Synthesis of compound 68-3

[0861] 68-2 (800 mg, 4.3 mmol), HATU (2.45 g, 6.45 mmol), DIEA (1.66 g, 12.9 mmol), and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.33 g, 4.3 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for 2 hours. The reaction mixture was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (20 mL), and washed twice with brine (60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-80%) to afford 68-3.

[0862] Step 3: Synthesis of compound 68

[0863] Compound 68-3 (700 mg, 1.47 mmol), cesium carbonate (1.44 g, 4.4 mmol), tBuXPhos Pd G4 (119 mg, 0.147 mmol), and 2-hydroxyethane-1-sulfonamide (367 mg, 2.94 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 90°C under nitrogen for 16 hours. The reaction mixture was cooled and poured into an appropriate amount of ice water. The mixture was extracted three times with ethyl acetate (20 mL) and washed twice with brine (60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-80%) to afford compound 68.

[0864] MS (ESI, pos.ion) m / z: 523.2 [M+1] + .

[0865] 1 H NMR(DMSO-d6)δ:11.18(s,1H),10.10(br s,1H),7.94(d,J=7.6Hz,1H),7.88(d,J=8.5Hz,1H),7.47(d,J=3.1Hz,1H),7.29(d,J=8.3Hz,1H),7.2 0(d,J=1.9Hz,1H),7.12(t,J=8.0Hz,1H),7.04(dd,J=8.5,1.9Hz,1H),6.67(d,J=3.0Hz,1H),4.96(br s,1H),4.05(d,J=7.0Hz,2H),3.77(br t,J=6.2Hz,2H),3.33-3.39(m,2H),2.96-3.09(m,4H),1.47(br s,4H),1.23-1.30(m,1H),0.50-0.56(m,2H),0.37-0.44(m,2H),0.28(s,4H).

[0866] Example 126: Synthesis of 4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6,7,8,9-tetrahydropyrido[1,2-a]indole-1)benzamide (126)

[0867] Step 1: Synthesis of compound 126-2

[0868] Compound 126-1 (100 mg, 0.350 mmol) and palladium on carbon (20 mg) were dissolved in methanol (10 mL) and stirred at room temperature for 16 hours under a hydrogen atmosphere. The palladium on carbon was filtered off and the organic phase was concentrated under reduced pressure to obtain compound 126-2.

[0869] Step 2: Synthesis of compound 126-3

[0870] Compound 126-2 (95 mg, 0.33 mmol) was dissolved in ethyl acetate (5 mL), and hydrochloric acid in ethyl acetate (0.5 mL, 1.98 mmol) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to obtain compound 126-3.

[0871] Step 3: Synthesis of compound 126-4

[0872] Compound 126-3 (60 mg, 0.319 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (108 mg, 0.351 mmol), HATU (182 mg, 0.479 mmol), and DIPEA (0.51 mL, 0.957 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for two hours. The reaction mixture was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (10 mL), and washed twice with brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-20%) to obtain compound 126-4.

[0873] Step 4: Synthesis of compound 126

[0874] Compound 126-4 (40 mg, 0.083 mmol), cesium carbonate (81 mg, 0.25 mmol), catalyst CAS: 1599466-89-3 (6.7 mg, 0.008 mmol), and 2-hydroxyethane-1-sulfonamide (52 mg, 0.417 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 80°C under nitrogen for 16 hours. After cooling, the reaction solution was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (20 mL), and washed twice with brine (60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-80%) to obtain compound 126. MS (ESI, pos. ion) m / z: 525.2 [M+1] + .

[0875] 1 H NMR(DMSO-d6)δ:10.71-10.79(m,1H),7.76-7.84(m,1H),7.11-7.20(m,2H),6.9 3-7.03(m,2H),6.24-6.32(m,1H),3.72-3.79(m,2H),3.58-3.67(m,1H),3.30(br s,2H),3.19-3.29(m,2H),2.97(br d,J=6.5Hz,4H),2.51-2.67(m,2H),1.72-1.82(m,2H),1.59-1.66(m,1H),1.36-1.54(m,4H),0.28-0.37(m,4H).

[0876] Example 127: Synthesis of N-(1-(cyclopropylmethyl)-1H-indol-4-yl)-4-methoxy-2-(6-azaspiro[2.5]octan-6-yl)benzamide (127)

[0877] Step 1: Synthesis of compound 127-2

[0878] Compound 127-1 (6 g, 23.62 mmol), ethyl 4-bromobutyrate (5.5 g, 28.35 mmol), and potassium carbonate (9.8 g, 70.87 mmol) were dissolved in DMF (100 mL) and stirred at room temperature for two hours. The reaction mixture was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (60 mL), and washed twice with brine (60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-20%) to obtain compound 127-2.

[0879] Step 2: Synthesis of compound 127-3

[0880] Compound 127-2 (5 g, 13.59 mmol) and potassium tert-butoxide (3.04 g, 27.17 mmol) were dissolved in tetrahydrofuran (50 mL) and stirred at room temperature for two hours. The reaction mixture was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (30 mL), and washed twice with brine (30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-10%) to obtain compound 127-3.

[0881] Step 3: Synthesis of compound 127-4

[0882] Compound 127-3 (3.7 g, 11.01 mmol) was dissolved in ethanol (30 mL), and concentrated hydrochloric acid (35 mL) was added under ice bath. The mixture was refluxed at 80°C for 2 hours. After the reaction solution was cooled, solid precipitated. The crude product 127-4 was obtained by filtration and used directly in the next reaction.

[0883] Step 4: Synthesis of compound 127-5

[0884] Compound 127-4 (1 g, 3.79 mmol) was dissolved in tetrahydrofuran (10 mL), and then a tetrahydrofuran solution of borane (11.36 mL, 11.36 mmol) was added under ice-bath. The reaction solution was stirred at 70°C overnight. After cooling, the reaction solution was quenched with dilute hydrochloric acid under ice-bath, extracted three times with ethyl acetate (10 mL), washed twice with brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-10%) to obtain 127-5.

[0885] Step 5: Synthesis of Compound 127-6

[0886] Compound 127-5 (100 mg, 0.4 mmol), cesium carbonate (391 mg, 1.2 mmol), catalyst CAS: 1599466-89-3 (32 mg, 0.04 mmol), and tert-butyl carbamate (140 mg, 1.2 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 80°C under nitrogen for 2 hours. After cooling, the reaction solution was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (10 mL), washed twice with brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-20%) to obtain compound 127-6.

[0887] Step 6: Synthesis of Compound 127-7

[0888] Compound 127-6 (110 mg, 11.01 mmol) was dissolved in ethyl acetate (5 mL). Hydrochloric acid in ethyl acetate (1.92 mL, 3.85 mmol) was added under ice-cooling and stirred at room temperature for 2 hours. Solid precipitated from the reaction solution, which was concentrated to obtain crude product 127-7, which was used directly in the next reaction.

[0889] Step 7: Synthesis of Compound 127-8

[0890] Compound 127-7 (70 mg, 0.376 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (140 mg, 0.452 mmol), HATU (215 mg, 0.565 mmol), and DIPEA (0.33 mL, 1.88 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred at room temperature for two hours. The reaction mixture was poured into an appropriate amount of ice water and extracted three times with ethyl acetate (10 mL), washed twice with brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-20%) to afford compound 127-8.

[0891] Step 8: Synthesis of compound 127

[0892] Compound 127-8 (100 mg, 0.208 mmol), cesium carbonate (205 mg, 0.628 mmol), catalyst CAS: 1599466-89-3 (17 mg, 0.02 mmol), and 2-hydroxyethane-1-sulfonamide (130 mg, 1.05 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 105°C under nitrogen for 16 hours. After cooling, the reaction solution was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (20 mL), and washed twice with brine (60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-80%) to obtain compound 127. MS (ESI) m / z: 523.2 [M+1] + .

[0893] 1H NMR(CHLOROFORM-d)δ:11.56(s,1H),8.09(d,J=8.5Hz,1H),7.79(d,J=7.4Hz,1H),7.31(d,J=1.9Hz,1H),7.10-7.18 (m,2H),6.95(dd,J=8.4,1.9Hz,1H),6.25(s,1H),4.05-4.10(m,2H),4.00-4.05(m,2H),3.19-3.24(m,2H),3.09(br t,J=5.2Hz,4H),2.95-3.00(m,2H),2.06-2.15(m,2H),1.88-1.95(m,2H),1.54(br s,4H),0.30(s,4H).

[0894] Example 128: Synthesis of 2-(6-azaspiro[2.5]octan-6-yl)-N-(8,8-difluoro-6,7,8,9-tetrahydropyridin[1,2-a]indol-1-yl)-4-{[(2-hydroxyethyl)sulfonamide]}benzamide (128)

[0895] Step 1: Synthesis of compound 128-2

[0896] Compound 128-1 (1.50 g, 7.39 mmol) was dissolved in DMSO (15 mL), and 4,4-difluorohexahydropyridine hydrochloride (1.40 g, 8.87 mmol) and potassium carbonate (2.55 g, 18.47 mmol) were added. The mixture was reacted at 95°C for 2 h. The reaction solution was quenched with water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 10-1 / 5) to obtain compound 128-2.

[0897] Step 2: Synthesis of compound 128-3

[0898] Compound 128-2 (1.50 g, 4.93 mmol) was dissolved in toluene (30 mL), and N-amino-4-toluenesulfonamide (1.10 g, 5.92 mmol) was added thereto. The mixture was reacted at room temperature for 20 min to obtain a reaction solution containing compound 128-3, which was directly used in the next reaction.

[0899] Step 3: Synthesis of compound 128-4

[0900] Sodium hydride (0.22 g, 5.43 mmol) was added to the reaction mixture from step 2, and the mixture was reacted at 135°C for 20 min. The reaction mixture was quenched with water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20-1 / 10) to obtain compound 128-4.

[0901] Step 4: Synthesis of compound 128-5

[0902] Compound 128-4 (560 mg, 1.94 mmol) was dissolved in 1,2-dichloroethane (5 mL), and DDQ (883.03 mg, 3.89 mmol) was added. The mixture was allowed to react at room temperature for 2 h. The reaction mixture was quenched with water and extracted with DCM. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20-1 / 10) to afford compound 128-5.

[0903] Step 5: Synthesis of compound 128-6

[0904] Compound 128-5 (672 mg, 2.35 mmol), NH2Boc (550.29 mg, 4.70 mmol), cesium carbonate (2.30 g, 7.05 mmol), and RuPhos Pd G4 (199.73 mg, 0.23 mmol) were dissolved in 1,4-dioxane (15 mL) and reacted at 95°C under N2 protection for 4 h. The reaction solution was quenched with water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20 to 1 / 5) to obtain compound 128-6.

[0905] Step 6: Synthesis of compound 128-7.

[0906] Compound 128-6 (800 mg, 1.72 mmol) was dissolved in DCM (5 mL) and 1,4-dioxane hydrochloride (5 mL) was added. The mixture was reacted at room temperature for 0.5 h and concentrated under reduced pressure to obtain the hydrochloride salt of compound 128-7, which was used directly in the next reaction.

[0907] Step 7: Synthesis of compound 128-8.

[0908] The hydrochloride salt of compound 128-7 (551.53 mg, 2.48 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (923.75 mg, 2.98 mmol), and HATU (1133.12 mg, 2.98 mmol) were dissolved in DMF (10 mL). DIEA (1283.45 mg, 9.93 mmol) was added and allowed to react at room temperature for 4 h. The reaction solution was quenched with water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 10-1 / 5) to afford compound 128-8.

[0909] Step 8: Synthesis of compound 128

[0910] Compound 128-8 (500 mg, 0.97 mmol), 2-hydroxyethanesulfonamide (486.54 mg, 3.89 mmol), cesium carbonate (633.39 mg, 1.94 mmol), and BrettPhos Pd G4 (89.47 mg, 0.10 mmol) were dissolved in 1,4-dioxane (15 mL) and reacted at 95°C under nitrogen protection for 4 h. The reaction solution was quenched with water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography to yield compound 128. MS m / z (ESI): 559.2 [M+1] + .

[0911] 1 H NMR(DMSO-d6)δ=11.25(s,1H),7.89-7.80(m,2H),7.24-7.18(m,1H),7.17-7.10(m,2H),6.98(d d,J=1.9,8.5Hz,1H),6.51(s,1H),4.34-4.18(m,2H),3.76(t,J=6.6Hz,2H),3.63-3.48(m,2H), 3.30-3.26(m,2H),3.01(brt,J=4.8Hz,4H),2.72-2.59(m,2H),1.47(br s,4H),0.28(s,4H).

[0912] Example 129: Synthesis of N-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-8-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (129)

[0913] Step 1: Synthesis of compound 129-2

[0914] Compound 129-1 (3 g, 11.81 mmol) was dissolved in toluene (15 mL), and potassium tert-butoxide (0.88 g, 11.81 mmol) and ethyl acrylate (2.57 mL, 23.61 mmol) were added. The mixture was reacted at 110°C overnight. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20-1 / 10) to obtain compound 129-2. MS m / z (ESI): 322.0 [M+1] + .

[0915] Step 2: Synthesis of compound 129-3

[0916] Compound 129-2 (2.28 g, 7.08 mmol) was dissolved in super dry ethanol (30 mL). 12 mol / L hydrochloric acid (20 mL) was added and the mixture was reacted at 80°C for 1 h. The reaction solution was concentrated and slowly poured into ice water, whereupon solid precipitated. The residue was filtered and dried to obtain compound 129-3, which was used directly in the next reaction.

[0917] Step 3: Synthesis of compound 129-4

[0918] Compound 129-3 (1.7 g, 6.8 mmol) was dissolved in trifluoroacetic acid (10 mL). Triethylsilane (3.25 mL, 20.39 mmol) and trifluoromethanesulfonic acid (0.18 mL, 2.04 mmol) were added under an ice bath and nitrogen protection. The mixture was allowed to react at 25°C for 2 h. The reaction solution was quenched with ice water, neutralized with saturated NaHCO₃ solution, and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (pure petroleum ether) to obtain compound 129-4.

[0919] Step 4: Synthesis of compound 129-5

[0920] Compound 129-4 (300 mg, 1.27 mmol), NH2Boc (297 mg, 2.54 mmol), cesium carbonate (1.24 g, 3.81 mmol), and palladium catalyst (CAS: 1599466-89-3, 52 mg, 0.06 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 90°C for 2 h under nitrogen. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20-1 / 10) to obtain compound 129-5. MS m / z (ESI): 273.2 [M+1] + .

[0921] Step 5: Synthesis of compound 129-6

[0922] Compound 129-5 (260 mg, 0.95 mmol) was dissolved in DCM (1 mL), and HCl\EA (2 mL) was added. The mixture was reacted at 25°C for 2 h. The solid precipitated, was filtered, and dried to give the hydrochloride salt of compound 129-6, which was used directly in the next reaction.

[0923] Step 6: Synthesis of compound 129-7

[0924] The hydrochloride salt of compound 129-6 (130 mg, 0.75 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (281 mg, 0.91 mmol), and HATU (316 mg, 0.83 mmol) were dissolved in DMF (1 mL). DIEA (0.5 mL, 3.02 mmol) was added and the mixture was allowed to react at 25°C for 1 h. The reaction mixture was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 10-1 / 5) to afford compound 129-7. MS m / z (ESI): 464.1\466.1 [M+1] + .

[0925] Step 7: Synthesis of compound 129

[0926] Compound 129-7 (198 mg, 0.43 mmol), 2-hydroxyethanesulfonamide (267 mg, 2.13 mmol), cesium carbonate (417 mg, 1.28 mmol), and palladium catalyst (CAS: 1599466-89-3, 18 mg, 0.02 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 80°C for 3 h under nitrogen. The reaction mixture was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 1 / 20-1 / 10) to obtain compound 129. MS m / z (ESI): 509.2 [M+1] + .

[0927] 1H NMR(DMSO-d6)δ:11.19(s,1H),7.83-7.88(m,2H),7.15(s,1H),7.07-7.11(m,1H),6.98-7.05(m,2H),6.32(s,1H),4 .09(t,J=6.9Hz,2H),3.76(t,J=6.6Hz,2H),3.28-3.31(m,2H),2.93-3.06(m,7H),2.58(quin,J=7.2Hz,2H),1.47(br s,4H),0.28(s,4H).

[0928] Example 130: Synthesis of 4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)-N-(2,3,9,9a-tetrahydro-1H-pyrrolo[1,2a]indol-8-yl)benzamide (130)

[0929] Step 1: Synthesis of compound 130-2

[0930] Compound 130-1 (220 mg, 0.93 mmol), NH2Boc (218 mg, 1.86 mmol), cesium carbonate (911 mg, 2.80 mmol), and palladium catalyst (CAS: 1599466-89-3, 38 mg, 0.05 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 90°C for 2 h under nitrogen. The reaction mixture was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20-1 / 10) to obtain compound 130-2. MS m / z (ESI): 273.2 [M+1] + .

[0931] Step 2: Synthesis of compound 130-3

[0932] Compound 130-2 (215 mg, 0.79 mmol) was dissolved in MeOH (2 mL), and Pd / C (50 mg) and 12 mol / L hydrochloric acid (0.02 mL) were added. The mixture was allowed to react overnight at 25°C. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 10 - DCM:EA = 1 / 10) to obtain compound 130-3. MS m / z (ESI): 275.2 [M+1] + .

[0933] Step 3: Synthesis of compound 130-4

[0934] Compound 130-3 (86 mg, 0.32 mmol) was dissolved in DCM (1 mL), and HCl\EA (1 mL) was added. The mixture was reacted at 25°C for 2 h. A solid precipitated, which was filtered and dried to obtain the hydrochloride salt of compound 130-4, which was used directly in the next reaction.

[0935] Step 4: Synthesis of compound 130-5

[0936] The hydrochloride salt of compound 130-4 (67 mg, 0.38 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (143 mg, 0.46 mmol), and HATU (161 mg, 0.42 mmol) were dissolved in DMF (1 mL). DIEA (0.25 mL, 1.54 mmol) was added and the mixture was allowed to react at 25°C for 1 h. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 10-1 / 5) to obtain compound 130-5.

[0937] Step 5: Synthesis of compound 130

[0938] Compound 130-5 (85 mg, 0.18 mmol), 2-hydroxyethanesulfonamide (114 mg, 0.91 mmol), cesium carbonate (178 mg, 0.55 mmol), and palladium catalyst (CAS: 1599466-89-3, 8 mg, 0.01 mmol) were dissolved in 1,4-dioxane (2 mL) and reacted at 80°C for 2 h under nitrogen protection. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified to provide compound 130. MS m / z (ESI): 511.2 [M+1] + .

[0939] 1 H NMR(DMSO-d6)δ:10.70(br s,1H),7.79(d,J=8.5Hz,1H),7.34-7.38(m,1H),7.12(s,1H),7.04(t,J=7.9Hz,1H),6.94-7.01(m,1H),6.38(d,J=7.8Hz,1H),3.88(br d,J=8.9Hz,1H),3.75(t,J=6.6Hz,2H),3.03-3.30(m,6H),2.98(br t,J=4.8Hz,4H),1.70-1.91(m,4H),1.45-1.52(m,4H),0.31-0.34(m,4H).

[0940] Example 147: Synthesis of N-(4-(3-(3-(4,4-difluoropiperidin-1-yl)phenyl)urea)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (147)

[0941] Step 1: Synthesis of compound 147-2

[0942] Compound 147-1 (100 mg, 0.472 mmol) was slowly added to a solution of triphosgene (42 mg, 0.142 mmol) in dichloromethane (5 mL) under ice-bath, and then triethylamine (0.195 mL, 1.42 mmol) was added dropwise. The reaction solution was stirred at room temperature for 30 minutes. 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)aniline (133 mg, 472 mmol) was added under ice-bath, and the reaction solution was stirred at room temperature for 30 minutes. After cooling, the reaction solution was poured into an appropriate amount of ice water, extracted three times with dichloromethane (20 mL), washed twice with brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-20%) to give compound 147-2.

[0943] Step 2: Synthesis of compound 147

[0944] Compound 147-2 (80 mg, 0.154 mmol), cesium carbonate (150 mg, 0.462 mmol), catalyst CAS: 1599466-89-3 (13 mg, 0.015 mmol), and 2-hydroxyethane-1-sulfonamide (96 mg, 0.771 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 100°C under nitrogen for 16 hours. After cooling, the reaction solution was poured into an appropriate amount of ice water, extracted three times with ethyl acetate (20 mL), and washed twice with brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-80%) to obtain compound 147. MS (ESI) m / z: 564.2 [M+1] + .

[0945] 1H NMR(ACETONITRILE-d3)δ:7.99(br d,J=8.8Hz,1H),7.62-7.84(m,2H),7.18-7.34(m,1H),6.98-7.18(m,3H),6.75-6.96(m,2H),6.60(br d,J=7.1Hz,1H),3.80(q,J=5.6Hz,2H),3.17-3.38(m,4H),3.01-3.17(m,3H),2.73(br t,J=4.7Hz,4H),1.91-2.05(m,4H),1.32-1.59(m,4H),0.17-0.38(m,4H).

[0946] Example 150: Synthesis of N-(4-(3-(1-(cyclopropylmethyl)indolin-6-yl)urea)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (150)

[0947] Step 1: Synthesis of compound 150-2

[0948] Compound 150-1 (2 g, 12.18 mmol) and potassium carbonate (5.05 g, 36.55 mmol) were dissolved in DMF (10 mL). (Bromomethyl)cyclopropane (1.43 mL, 14.62 mmol) was added and allowed to react at 80°C overnight. The reaction mixture was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20-1 / 10) to obtain compound 150-2. MS m / z (ESI): 219.1 [M+1] + .

[0949] Step 2: Synthesis of compound 150-3

[0950] Compound 150-2 (600 mg, 2.75 mmol), ammonium chloride (1.47 g, 27.49 mmol), and iron powder (1.54 g, 27.49 mmol) were dissolved in EtOH (15 mL) and H₂O (5 mL) and reacted at 80°C for 2 h. The reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20-1 / 10) to obtain compound 150-3. MS m / z (ESI): 189.1 [M+1] + .

[0951] Step 3: Synthesis of compound 150-4

[0952] Compound 150-3 (180 mg, 0.96 mmol) and triphosgene (113 mg, 0.38 mmol) were dissolved in DCM (10 mL) and stirred at 0°C for 10 minutes. 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)aniline (269 mg, 0.96 mmol) was added under ice-cooling conditions and allowed to react at 25°C for 2 hours. The reaction mixture was quenched with ice water and extracted with DCM. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 10) to afford compound 150-4.

[0953] Step 4: Synthesis of compound 150

[0954] Compound 150-4 (160 mg, 0.32 mmol), 2-hydroxyethanesulfonamide (202 mg, 1.61 mmol), cesium carbonate (316 mg, 0.97 mmol), and palladium catalyst (CAS: 1599466-89-3, 13 mg, 0.02 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 80°C under nitrogen protection for 3 h. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified to obtain compound 150. MS m / z (ESI): 540.4 [M+1] + .

[0955] 1 H NMR(DMSO-d6)δ:9.20(s,2H),7.94(d,J=8.8Hz,1H),7.87(s,1H),7.03(d,J =2.1Hz,1H),6.85-6.94(m,2H),6.74(s,1H),6.58(d,J=7.9Hz,1H),4.90(br s,1H),3.73(br d,J=4.5Hz,2H),3.37-3.45(m,2H),3.13-3.20(m,2H),2.88-2.91(m,2H),2.79-2.85(m,2H),2.73-2.78(m,4H),1.57(br s,5H),0.97(br s,2H),0.47-0.53(m,2H),0.35(s,4H),0.18-0.23(m,2H).

[0956] Example 151: Synthesis of N-(4-(3-(1-(cyclopropylmethyl)indolin-5-yl)urea)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (151)

[0957] Step 1: Synthesis of compound 151-2

[0958] Compound 151-1 (2.0 g, 12.191 mmol) and NaH (585 mg, 24.375 mmol) were weighed into a reaction flask and DMF (10 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes. (Bromomethyl)cyclopropane (1.81 g, 13.410 mmol) was then added to the reaction mixture. The reaction mixture was placed in a 70°C oil pan and reacted for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. Concentration afforded compound 151-2, which was used directly in the next step.

[0959] Step 2: Synthesis of compound 151-3

[0960] Compound 151-2 (1.5 g, 6.877 mmol), reduced iron powder (3.85 g, 68.77 mmol), and ammonium chloride (3.68 g, 68.77 mmol) were added to a reaction flask and reacted at 80°C for 3 hours using EtOH:H2O = 3:1 (12 mL) as the solvent. After completion of the reaction, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was washed with brine (30 × 3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0-90:10-70:30). Compound 151-3 was obtained.

[0961] Step 3: Synthesis of compound 151-4

[0962] Triphosgene (79 mg, 0.266 mmol) and compound 151-3 (100 mg, 0.532 mmol) were dissolved in DCM, followed by the addition of triethylamine (162 mg, 1.601 ...

Claims

1. A compound represented by formula (I) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, A is a monocyclic aryl, a monocyclic heteroaryl, a bicyclic aryl, a bicyclic heteroaryl or a fused heterocyclic group, optionally, the monocyclic aryl, the monocyclic heteroaryl, the bicyclic aryl, the bicyclic heteroaryl or the fused heterocyclic group is optionally substituted by one or more R z replace; L is selected from -NR 3 -CO- or -NR 3 CONR 3 -, each R 3 are independently H, deuterium, C1-C6 alkylene or C1-C6 haloalkylene; R x -OR4 or -NR5R6, wherein R4 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, said 3-8 membered heterocyclyl containing at least one heteroatom selected from O, S and N; R5 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, R6 is selected from H or C1-C6 alkyl, or R5 and R6 together with the N atom to which they are attached form a 4-8 membered heterocyclyl; said 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl and 4-8 membered heterocyclyl containing 0, 1, 2 or 3 heteroatoms selected from O, S and N and optionally replaced by one or more R z replace; R1 is -CN or -ZR 12 , wherein Z is a direct bond, -C1-C6 alkylene-, -C1-C6 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -NR 11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C6 alkylene-SO2-, -C1-C6 alkylene-SO2R 11 -, -(C=O)-, -(C=O)NR 11 -, -C=N(OH)- or -NR 11 (C=O)-; or -ZR 12 Yes-N=S(=O)-(R 12 )2, where two R 12 The pairs may combine with the sulfur atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; X7 is N or CR7; X8 is N or CR8; X9 is N or CR9; R7, R8 and R9 are independently H, halogen, C1-C8 alkyl, C1-C6 haloalkyl, -OH, -OR 8a 、-OR 8b or -NR a R a When R7 and R8 are present at the same time, R7 and R8 can be combined with the atoms to which they are attached to form a saturated or partially saturated 3-membered, 4-membered, 5-membered or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R x When R and R9 exist at the same time, R x and R9 may be combined with the atoms to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R 11 H, R 11a or R 11b ; R 12 H, R 12a or R 12b ; R 8a 、R 11a and R 12a independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-C6 alkylene NR a R a 、-OC2-C6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a 、R 14 and oxo; R 8b 、R 11b and R 12b Independently selected from the group consisting of: selected from F, Cl, Br, -OR a , -OC1-C6 haloalkyl or C1-C6 alkyl substituted with 0, 1, 2, 3, 4 or 5 groups of CN; R 14 is independently selected in each case from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-6 alkylene NR a R a 、-OC2-6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-C6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a and oxo; Each R a Each independently is H or R b ; Each R b each independently C1-C6 alkyl, phenyl or benzyl, wherein the C1-C6 alkyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); Each R z independently selected from the group consisting of deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -C1-C6 alkylene-O-C1-C6 alkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, -CN, -O-C1-C6 alkyl, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 、-S(O)2-R z1 、-C(O)-R z2 、-C(O)-NR z1 R z2 , phenyl, a 5-6 membered monocyclic heteroaryl containing 0, 1, 2 or 3 N atoms, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and two R attached to the same carbon atom z Can be formed or two R attached to the same carbon atom z The C1-C6 alkyl, C3-C8 cycloalkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -O-C1-C6 alkyl, C3-C8 cycloalkyl-C1-C6 alkylene may be optionally substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C3-C8 halocycloalkyl; Each R z1 Independently selected from the following groups: H, C1-C6 alkyl, C1-C6 haloalkyl; Each R z2 Independently selected from the following groups: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C3-C8 cycloalkyl; Q is O or CR Q1 R Q2 ; R Q1 and R Q2 Independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

2. The compound of formula (I) according to claim 1 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is a monocyclic aryl, a monocyclic heteroaryl, a bicyclic aryl, a bicyclic heteroaryl or a fused heterocyclic group, optionally, the monocyclic aryl, the monocyclic heteroaryl, the bicyclic aryl, the bicyclic heteroaryl or the fused heterocyclic group is optionally substituted by one or more R z replace; L is selected from -NR 3 -CO- or -NR 3 CONR 3 -, each R 3 are independently H, deuterium, C1-C6 alkylene or C1-C6 haloalkylene; R x -OR4 or -NR5R6, wherein R4 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, said 3-8 membered heterocyclyl containing at least one heteroatom selected from O, S and N; R5 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, R6 is selected from H or C1-C6 alkyl, or R5 and R6 together with the N atom to which they are attached form a 4-8 membered heterocyclyl; said 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl and 4-8 membered heterocyclyl containing 0, 1, 2 or 3 heteroatoms selected from O, S and N and optionally replaced by one or more R z replace; R1 is -CN or -ZR 12 , wherein Z is a direct bond, -C1-C6 alkylene-, -C1-C6 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -NR 11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C6 alkylene-SO2-, -C1-C6 alkylene-SO2R 11 -, -(C=O)-, -(C=O)NR 11 -, -C=N(OH)- or -NR 11 (C=O)-; or -ZR 12 Yes-N=S(=O)-(R 12 )2, where two R 12 The pairs may combine with the sulfur atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; X7 is N or CR7; X8 is N or CR8; X9 is N or CR9; R7, R8 and R9 are independently H, halogen, C1-C8 alkyl, C1-C6 haloalkyl, -OH, -OR 8a 、-OR 8b or -NR a R a When R7 and R8 are present at the same time, R7 and R8 can be combined with the atoms to which they are attached to form a saturated or partially saturated 3-membered, 4-membered, 5-membered or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R x When R and R9 exist at the same time, R x and R9 may be combined with the atoms to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R 11 H, R 11a or R 11b ; R 12 H, R 12a or R 12b ; R 8a 、R 11a and R 12a independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-C6 alkylene NR a R a 、-OC2-C6 Alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a 、R 14 and oxo; R 8b 、R 11b and R 12b Independently selected from the group consisting of: selected from F, Cl, Br, -OR a , -OC1-C6 haloalkyl or C1-C6 alkyl substituted with 0, 1, 2, 3, 4 or 5 groups of CN; R 14 is independently selected in each case from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-6 alkylene NR a R a 、-OC2-6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-C6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a and oxo; Each R a Each independently is H or R b ; Each R b each independently C1-C6 alkyl, phenyl or benzyl, wherein the C1-C6 alkyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); Each R z independently selected from the group consisting of deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, -C1-C6 alkylene-O-C1-C6 alkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, -CN, -O-C1-C6 alkyl, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 、-S(O)2-R z1 、-C(O)-R z2 、-C(O)-NR z1 R z2 , a 5-6 membered monocyclic heteroaryl containing 0, 1, 2 or 3 N atoms, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is substituted with 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and two R attached to the same carbon atom z Can be formed or two R attached to the same carbon atom z The C1-C6 alkyl, C3-C8 cycloalkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -O-C1-C6 alkyl, C3-C8 cycloalkyl-C1-C6 alkylene may be optionally substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C3-C8 halocycloalkyl; Each R z1 Independently selected from the following groups: H, C1-C6 alkyl, C1-C6 haloalkyl; Each R z2 Independently selected from the following groups: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C3-C8 cycloalkyl; Q is O or CR Q1 R Q2 ; R Q1 and R Q2 Independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

3. The compound of formula (I) according to claim 1, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, in, A is a monocyclic aryl, a monocyclic heteroaryl, a bicyclic aryl, a bicyclic heteroaryl or a fused heterocyclic group, optionally, the monocyclic aryl, the monocyclic heteroaryl, the bicyclic aryl, the bicyclic heteroaryl or the fused heterocyclic group is optionally substituted by one or more R z replace; L is selected from -NR 3 -CO- or -NR 3 CONR 3 -, each R 3 are independently H, deuterium, C1-C6 alkylene or C1-C6 haloalkylene; R x -OR4 or -NR5R6, wherein R4 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl contains at least one heteroatom selected from O, S and N; R5 is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl, R6 is selected from H or C1-C6 alkyl, or R5 and R6 together with the N atom to which they are attached form a 4-8 membered heterocyclyl; wherein the 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl and 4-8 membered heterocyclyl contain 0, 1, 2 or 3 heteroatoms selected from O, S and N and are optionally replaced by one or more R z replace; R1 is -CN or -ZR 12 , wherein Z is a direct bond, -C1-C6 alkylene-, -C1-C6 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-、-NR 11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C6 alkylene-SO2-, -C1-C6 alkylene-SO2R 11 -, -(C=O)-, -(C=O)NR 11 -, -C=N(OH)- or -NR 11 (C=O)-; or -ZR 12 Yes-N=S(=O)-(R 12 )2, where two R 12 The pairs may combine with the sulfur atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; X7 is N or CR7; X8 is N or CR8; X9 is N or CR9; R7, R8 and R9 are independently H, halogen, C1-C8 alkyl, C1-C6 haloalkyl, -OH, -OR 8a 、-OR 8b or -NR a R a When R7 and R8 are present at the same time, R7 and R8 can be combined with the atoms to which they are attached to form a saturated or partially saturated 3-membered, 4-membered, 5-membered or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R x When R and R9 exist at the same time, R x and R9 may be combined with the atoms to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R 11 H, R 11a or R 11b ; R 12 H, R 12a or R 12b ; R 8a 、R 11a and R 12a independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-C6 alkylene NR a R a 、-OC2-C6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a 、R 14 and oxo; R 8b 、R 11b and R 12b Independently selected from the group consisting of: selected from F, Cl, Br, -OR a , -OC1-C6 haloalkyl or C1-C6 alkyl substituted with 0, 1, 2, 3, 4 or 5 groups of CN; R 14 is independently selected in each case from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-6 alkylene NR a R a 、-OC2-6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-C6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a and oxo; Each R a Each independently is H or R b ; Each R b each independently C1-C6 alkyl, phenyl or benzyl, wherein the C1-C6 alkyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); Each R z independently selected from the group consisting of deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, -CN, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 、-S(O)2-R z1 , a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and two R attached to the same carbon atom z Can be formed or two R attached to the same carbon atom z The C1-C6 alkyl, C3-C8 cycloalkyl, -O-C1-C6 alkyl, C3-C8 cycloalkyl-C1-C6 alkylene may be optionally substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C3-C8 halocycloalkyl; Each R z1 Independently selected from the following groups: C1-C6 alkyl, C1-C6 haloalkyl; Q is O or CR Q1 R Q2 ; R Q1 and R Q2 Independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

4. The compound according to claim 1 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: Each R z independently selected from the following groups: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is replaced by 0, 1, 2 or 3 groups selected from the following Substituents: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and two or more of the substituents and the carbon atoms to which they are attached may together constitute a C3-C8 cycloalkyl group; the C1-C6 alkyl, C3-C8 cycloalkyl, -O-C1-C6 alkyl may optionally be substituted by a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl.

5. The compound according to any one of claims 1 to 4, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein formula (I) is as shown in formula (I)-1, formula (I)-2 or formula (I)-3: Each symbol in formula (I)-1 to formula (I)-3 is as defined in any one of claims 1 to 4.

6. The compound according to any one of claims 1 to 5, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: R x Selected from the group consisting of: R 10a 、R 10b 、R 10c 、R 10d 、R 10e 、R 10f 、R 10g 、R 10h 、R 10i and R 10j 、R 10k and R 10l Each of them is H, deuterium, halogen, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C8 cycloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 1-3 heteroatoms selected from N, O, and S, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered monocyclic ring 12-membered bicyclic ring, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C3-C8 cycloalkyl is optionally substituted with 1-5 substituents selected from deuterium, halogen, -OH, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -O-C1-C6 haloalkyl; wherein the monocyclic or bicyclic ring is substituted with 0, 1, 2, or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR m 、-OC1-C6 haloalkyl、CN、-C(=O)R n 、-C(=O)OR m 、-C(=O)NR m R m 、-C(=NR m )NR m R m 、-OC(=O)R n 、-OC(=O)NR m R m 、-OC2-C6 alkylene NR m R m 、-OC2-C6 alkylene OR m 、-SR m 、-S(=O)R n 、-S(=O)2R n 、-S(=O)2NR m R m 、-NR m R m 、-N(R m )C(=O)R n 、-N(R m )C(=O)OR n 、-N(R m )C(=O)NR m R m 、-N(R m )C(=NR m )NR m R m 、-N(R m )S(=O)2R n 、-N(R m )S(=O)2NR m R m 、-NR m C2-6 alkylene NR m R m 、-NR m C2-C6 alkylene OR m 、-C1-C6 alkylene NR m R m 、-C1-C6 alkylene OR m 、-C1-C6 alkylene N(R m )C(=O)R n 、-C1-C6 alkyleneOC(=O)R n 、-C1-C6 alkylene C(=O)NR m R m 、-C1-C6 alkylene C(=O)OR m and oxo; Or alternatively, R 10a and R 10b Yes, R 10c and R 10d Yes, R 10e and R 10f Yes, R 10g and R 10h Yes, R 10i and R 10j 、R 10k and R 10l Each of the pairs can independently combine with their respective attached carbon atoms to form a spiro-linked x wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, C1-C6 alkyl, C1-C4 haloalkyl, -OR m 、-OC1-C4 haloalkyl、CN、-NR m R m or oxo; Each R m and R n Independently selected from H or -C1-C6 alkyl; Or alternatively, R 10a and R 10b Yes, R 10c and R 10d Yes, R 10e and R 10f Yes, R 10g and R 10 h for R 10i and R 10j Right or R 10k and R 10l Can form Where Q is CR Q1 R Q2 ; R Q1 and R Q2 Independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

7. The compound according to any one of claims 1 to 6, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: R x for 8. The compound according to any one of claims 1 to 7, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: R 10c 、R 10d 、R 10e 、R 10f 、R 10g 、R 10h 、R 10i and R 10j Each of R is H, deuterium, halogen, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl), said C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl is optionally substituted with 1-5 substituents selected from deuterium, halogen, -OH, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O-C1-C6 haloalkyl; 10a and R 10b Pair formation Q is CR Q1 R Q2 ; R Q1 and R Q2 are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or R 10a and R 10b Together with the carbon atom to which it is attached, it forms a spiral bond to R x The C3-C8 cycloalkyl group is substituted with 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C4 haloalkyl, -OH, C1-C6 alkoxy, -OC1-C4 haloalkyl, -CN, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl) or oxo.

9. The compound according to claim 8 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: R x Selected from:

10. The compound according to any one of claims 1 to 9, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: Formula (I) is shown in Formula (I)-4-1, Formula (I)-4-2, Formula (I)-5-1, Formula (I)-5-2, Formula (I)-6-1 or Formula (I)-6-2:

11. The compound according to any one of claims 1 to 10, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein: R1 is a group -ZR 12 , wherein -Z is a single bond, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -NH-, -NHSO2-, -SONH-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C4 alkylene-SO2-, -(C=O)-, -(C=O)N-, -C=N(OH)-, or -NH(C=O)-; and / or (a)R 12 is H; (b)R 12 is oxetanyl, cyclopropyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (such as F, Cl), C1-C6 alkoxy; or (c)R 12 is C1-C6 alkyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (eg F), C1-C6 alkoxy.

12. The compound according to any one of claims 1 to 10, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein: The group -ZR 12 -N=S(=O)-(R 12 )2, where two R 12 pairs that can alternatively combine with their respective attached sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; Or the group -ZR 12 In the equation, Z is a single bond, R 12 independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-C6 alkylene NR a R a 、-OC2-C6 alkylene OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a and oxo, and R a and R b Independently selected from H and -C1-C6 alkyl.

13. The compound according to any one of claims 1 to 12, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein: R1 is a group -ZR 12 , wherein Z is -NHSO2- or -SO2NH-; and R 12 is oxetane, cyclopropyl, or R substituted by 0, 1, 2 or 3 groups selected from OH, halogen (such as F), C1-C6 alkoxy 12 is C1-C6 alkyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (eg F), C1-C6 alkoxy.

14. The compound according to any one of claims 1 to 13, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein: R1 is selected from the following groups:

15. A compound according to any one of claims 1 to 14, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein Formula (I) is represented by Formula (I)-1-1, Formula (I)-1-2, Formula (I)-2-1, Formula (I)-2-2, Formula (I)-3-1 or Formula (I)-3-2:

16. The compound according to any one of claims 1 to 15, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein: Each R 3 are independently H, C1-C4 alkyl or C1-C4 haloalkyl.

17. The compound according to any one of claims 1 to 16, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein: Each R 3 Independent of H.

18. The compound according to any one of claims 1 to 17, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein: X7 is CR7.

19. The compound according to any one of claims 1 to 18, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein: R7 is -NR a R a .

20. The compound according to any one of claims 1 to 19, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein: R7 is -NH2 or -NH-C1-C6 alkyl.

21. The compound according to any one of claims 1 to 20, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: X7 is CR7, X8 is CR8, X9 is CR9.

22. The compound according to any one of claims 1 to 21, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: X7 is CR7 and R7 is -NH2 or -NH-C1-C6 alkyl, X8 is CH, and X9 is CH.

23. The compound according to any one of claims 1 to 22, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: X7 is CH, X8 is N or CR8 and X9 is N or CR9; preferably, X7 is CH, X8 is CR8 and X9 is CR9; more preferably, X7 is CH, X8 is CH and X9 is CH.

24. The compound according to any one of claims 1 to 23, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: X9 is N.

25. The compound according to any one of claims 1 to 17, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: X7 is N and / or X8 is N.

26. The compound according to any one of claims 1 to 25, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: A is selected from phenyl, 5-6 membered nitrogen-containing heteroaryl, benzomonoheterocyclic group, benzobiheterocyclic group, 5-6 membered nitrogen-containing heteroaryl and monoheterocyclic group, 5-6 membered nitrogen-containing heteroaryl and biheterocyclic group, benzomonoheteroaromatic ring group, 5-6 membered nitrogen-containing heteroaryl and monoheteroaromatic ring group; Optionally, the phenyl, 5-6 membered nitrogen-containing heteroaryl, benzomonoheterocyclic group, benzobiheterocyclic group, 5-6 membered nitrogen-containing heteroaryl and monoheterocyclic group, 5-6 membered nitrogen-containing heteroaryl and biheterocyclic group, benzomonoheteroaromatic ring group, 5-6 membered nitrogen-containing heteroaryl and monoheteroaromatic ring group are replaced by one or more R z replace, The benzomonoheterocycle, 5-6-membered nitrogen-containing heteroaryl and monoheterocycle contain 0, 1, 2 or 3 atoms selected from N, O and S; The benzomonoheteroaromatic ring group, the 5-6-membered nitrogen-containing heteroaromatic ring group and the monoheteroaromatic ring group contain 0, 1, 2 or 3 atoms selected from N, O and S; The biheterocyclic group in the benzobiheterocyclic group and the 5-6-membered nitrogen-containing heteroarylbiheterocyclic group contains 0, 1, 2 or 3 atoms selected from N, O and S.

27. The compound according to any one of claims 1 to 26, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: A is selected from the group consisting of A1, A2 and A3, Group A1 groups include the following groups: In group A1, R A1 R is each independently selected from a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is optionally substituted with 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); AI each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, -O-C1-C6 alkyl, C1-C6 alkylene-O-C1-C6 alkyl, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1, 2, 3 or 4; m2 is selected from 0, 1, 2 or 3; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1; Group A2 groups include the following groups: R in group A2 I and R II are each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and both R II The carbon atoms to which they are attached may together form a C3-C8 cycloalkyl group; the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group or C1-C4 haloalkyl group; R A2 Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 or -S(O)2-R z1 , the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl-C1-C6 alkylene, optionally substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C4 haloalkyl; Each R z1 Independently selected from the following groups: C1-C6 alkyl, C1-C6 haloalkyl; m5 is selected from 0, 1, 2 or 3; m6 is selected from 0, 1 or 2; n1 is selected from an integer of 0-4; n2 is selected from an integer of 0-6; n3 is selected from an integer of 0-8; n4 is selected from an integer of 0-2; n5 is selected from 0 or 1; n7 is selected from an integer of 0-3; q is 0 or 1; s is selected from an integer of 0-6; t is selected from an integer of 0-8; r is selected from 0 or 1; Group A3 groups include the following groups: In group A3, Each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), and the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy may be optionally substituted with a substituent selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl, or two Gs attached to the same carbon atom form an oxo group (=O), or two Gs attached to the same carbon atom may form a C3-C8 cycloalkyl group together with the carbon atom to which they are attached; R A3 independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, -O-C3-C8 cycloalkyl, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -C(=O)C3-C8 cycloalkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl) (C1-C6 alkyl), phenyl, a 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms, a 5-6 membered monocyclic heteroaryl containing 0, 1, 2 or 3 N atoms and 1 or 2 atoms selected from O, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 5-6 membered monocyclic heteroaryl may be optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; R III independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, -O-C3-C8 cycloalkyl, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -C(=O)C3-C8 cycloalkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroaryl-C1-C6 alkyl containing 1, 2 or 3 N atoms, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms, and 5-6 membered monocyclic heteroaryl containing 0, 1, 2 or 3 N atoms and 1 or 2 atoms selected from O, said C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 5-6 membered monocyclic heteroaryl may be optionally substituted by a substituent selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; e is selected from 0, 1, 2 or 3; f is selected from 0, 1 or 2.

28. The compound according to any one of claims 1 to 27, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the group consisting of A1, A2 and A3, Group A1 groups include the following groups: In group A1, R A1 R is each independently selected from a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is optionally substituted with 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); AI each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1, 2, 3 or 4; m2 is selected from 0, 1, 2 or 3; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1; Group A2 groups include the following groups: R in group A2 I and R II Each is independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl); and two R II The carbon atoms to which they are attached may together form a C3-C8 cycloalkyl group; the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group or C1-C4 haloalkyl group; R A2 Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 or -S(O)2-R z1 , the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl-C1-C6 alkylene, optionally substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; Each R z1 Independently selected from the following groups: C1-C6 alkyl, C1-C6 haloalkyl; m5 is selected from 0, 1, 2 or 3; m6 is selected from 0, 1 or 2; n1 is selected from an integer of 0-4; n2 is selected from an integer of 0-6; n3 is selected from an integer of 0-8; n4 is selected from an integer of 0-2; n5 is selected from 0 or 1; n7 is selected from an integer of 0-3; q is 0 or 1; s is selected from an integer of 0-6; t is selected from an integer of 0-8; r is selected from 0 or 1; Group A3 groups include the following groups: In group A3, G, R A3 and R III Each independently as defined in claim 27; e is selected from 0, 1, 2 or 3; f is selected from 0, 1 or 2.

29. The compound according to any one of claims 1 to 28, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the group consisting of A1, A2 and A3, Group A1 groups include the following groups: In group A1, R A1 R is each independently selected from a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is optionally substituted with 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); AI each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1, 2, 3 or 4; m2 is selected from 0, 1, 2 or 3; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1; Group A2 groups include the following groups: R in group A2 I and R II are each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and both R II The carbon atoms to which they are attached may together form a C3-C8 cycloalkyl group; the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group or C1-C4 haloalkyl group; R A2 Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl-C1-C6 alkylene, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 or -S(O)2-R z1 , the C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl-C1-C6 alkylene, optionally substituted by one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; Each R z1 Independently selected from the following groups: C1-C6 alkyl, C1-C6 haloalkyl; m5 is selected from 0, 1, 2 or 3; m6 is selected from 0, 1 or 2; n1 is selected from an integer of 0-4; n2 is selected from an integer of 0-6; n3 is selected from an integer of 0-8; n4 is selected from an integer of 0-2; n5 is selected from 0 or 1; n7 is selected from an integer of 0-3; q is 0 or 1; s is selected from an integer of 0-6; t is selected from an integer of 0-8; r is selected from 0 or 1; Group A3 groups include the following groups: In group A3, G, R A3 and R III Each independently as defined in claim 27; e is selected from 0, 1, 2 or 3; f is selected from 0, 1 or 2.

30. The compound according to any one of claims 1 to 29, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the group consisting of A1, A2 and A3, Group A1 groups include the following groups: In group A1, R A1 R is each independently selected from a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is optionally substituted with 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); AI each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1, 2, 3 or 4; m2 is selected from 0, 1, 2 or 3; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1; Group A2 groups include the following groups: R in group A2 I and R II are each independently selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); and both R II The carbon atoms to which they are attached may together form a C3-C8 cycloalkyl group; the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group or C1-C4 haloalkyl group; R A2 each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, -OC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl) or C3-C8 cycloalkyl-C1-C6 alkylene, said C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl-C1-C6 alkylene being optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; m5 is selected from 0, 1, 2 or 3; m6 is selected from 0, 1 or 2; n1 is selected from an integer of 0-4; n2 is selected from an integer of 0-6; n3 is selected from an integer of 0-8; n4 is selected from an integer of 0-2; n5 is selected from 0 or 1; n7 is selected from an integer of 0-3; q is 0 or 1; s is selected from an integer of 0-6; t is selected from an integer of 0-8; r is selected from 0 or 1; Group A3 groups include the following groups: In group A3, G, R A3 and R III Each independently as defined in claim 27; e is selected from 0, 1, 2 or 3; f is selected from 0, 1 or 2.

31. The compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the group A1, and R A1 each independently selected from a saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic ring containing 0 or 1 N atom, optionally substituted with 0, 1, 2 or 3 groups selected from deuterium, halogen, -CN, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl); R AI Each is independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1.

32. The compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the group A1, and R A1 each independently selected from a saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic ring containing 0 or 1 N atom, optionally substituted with 0, 1, 2 or 3 groups selected from deuterium, halogen, -CN, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl); R AI Each is independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1.

33. The compound according to any one of claims 26 to 29, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the group A1, and R A1 each independently selected from a saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic ring containing 0 or 1 N atom, optionally substituted with 0, 1, 2 or 3 groups selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl); R AI Each is independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1.

34. The compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the group A1, and R A1 R is independently selected from a saturated 5-membered or 6-membered monocyclic ring containing 0 or 1 N atom, which is optionally substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); AI Each is independently selected from deuterium, halogen, -CN, C1-C6 alkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1.

35. The compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the group A1, and R A1 R is independently selected from a saturated 5-membered or 6-membered monocyclic ring containing 0 or 1 N atom, which is optionally substituted by 0, 1, 2 or 3 groups selected from the following: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); AI Each is independently selected from deuterium, halogen, C1-C6 alkyl, -OH, -O-C1-C6 alkyl, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)(C1-C6 alkyl); m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; m3 is selected from 0, 1 or 2; m4 is selected from 0 or 1.

36. The compound according to any one of claims 1 to 35, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from:

37. The compound according to any one of claims 1 to 36, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from:

38. The compound according to any one of claims 1 to 37, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from:

39. The compound according to any one of claims 1 to 38, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from:

40. The compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the group A2.

41. The compound of claim 40 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from 42. The compound of claim 41 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from 43. The compound of claim 42 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from 44. The compound according to any one of claims 41 to 43, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: R I and R II are each independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl); and both R II Together with the carbon atoms to which they are attached, they can form a C3-C6 cycloalkyl group; R A2 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, and the C1-C6 alkyl group may be optionally substituted with a substituent selected from deuterium, F, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; m5 is selected from 0, 1, 2 or 3; n1 is selected from an integer of 0-2; n2 is selected from an integer of 0-2; n3 is selected from an integer of 0-2.

45. The compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein A is selected from 46. ​​The compound of claim 45 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein A is selected from 47. The compound of claim 45 or 46, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: R I and R II Each is independently selected from deuterium, halogen, C1-C6 alkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); R A2 each independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl is optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; m5 is selected from 0 or 1; m6 is selected from 0 or 1; n4 is selected from 0 or 1; n5 is selected from 0 or 1; q is selected from 0 or 1.

48. The compound of claim 47 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein R A2 Each is independently selected from C1-C6 alkyl or C3-C6 cycloalkyl-C1-C2 alkyl, and the C1-C6 alkyl, C3-C6 cycloalkyl-C1-C2 alkyl may be optionally substituted by 1-3 substituents selected from deuterium, F, Cl, Br, -OH, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl.

49. The compound of claim 48, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein R A2 Each independently selected from methyl, 50. The compound of claim 49 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein R A2 Each independently selected 51. The compound according to any one of claims 40-50, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein A is selected from 52. The compound of claim 51 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, N-oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein A is selected from 53. The compound of claim 51 or 52, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: R I and R II Each is independently selected from deuterium, halogen, C1-C6 alkyl, -OH, -CN, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); R A2 Each is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, -S(O)-R z1 or -S(O)2-R z1 , the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl may be optionally substituted by 1-3 substituents selected from deuterium, F, Cl, Br, I, -OH, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C4 haloalkyl; each R z1 Independently selected from C1-C6 alkyl, C1-C6 haloalkyl; m5 is selected from 0 or 1, n5 is selected from 0 or 1.

54. The compound of claim 53 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: R A2 Each independently selected -S(O)2-CF3.

55. The compound according to any one of claims 40 to 50, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein A is selected from 56. The compound of claim 55 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein A is selected from 57. The compound according to any one of claims 40-50, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein A is selected from 58. The compound of claim 57 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein A is selected from 59. The compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from Group A3.

60. The compound of claim 59 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from Group A3, and each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O); R A3 independently selected from hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroarylene containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroaryl containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl); R III independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroarylene containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroaryl containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl); e is selected from 0, 1 or 2; f is selected from 0 or 1.

61. The compound of claim 60 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from Group A3, and each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O); R A3 and R III each independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroarylene containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroaryl containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl); e is selected from 0, 1 or 2; f is selected from 0 or 1.

62. The compound of claim 61 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from Group A3, and each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O); R A3 independently selected from H, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); R III independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); e is selected from 0, 1 or 2; f is selected from 0 or 1.

63. The compound of claim 62 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from Group A3, and each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O); R A3 and R III Each is independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl); e is selected from 0, 1 or 2; f is selected from 0 or 1.

64. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from any one of the following groups: A is preferably selected from any one of the following groups:

65. The compound of claim 64 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from any one of the following groups: A is preferably selected from any one of the following groups:

66. The compound of claim 64 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from any one of the following groups: A is preferably selected from any one of the following groups:

67. The compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from any one of the following groups: A is preferably selected from any one of the following groups:

68. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups: Preferred 69. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups: Preferred 70. The compound of any one of claims 27-30 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from the following groups: Preferred 71. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups:

72. The compound of claim 71 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: A is selected from the following groups:

73. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups: Preferred 74. The compound according to any one of claims 62-73, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: Each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, C1-C6 alkoxy, or two Gs attached to the same carbon atom form a 3-6 membered cycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl may be optionally substituted with 1-2 substituents selected from deuterium, F, Cl, and Br; Each R III independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, -O-C3-C8 cycloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroarylene containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroarylene containing 1 or 2 N atoms and 1 or 2 atoms selected from O, alkyl, a 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl); e is selected from 0, 1 or 2; f is selected from 0 or 1.

75. A compound according to any one of claims 62 to 74, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: Each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, and the C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy may be optionally substituted with 1-2 substituents selected from deuterium, F, Cl, and Br; Each R III Independently selected from deuterium, halogen, -CN, C1-C6 alkyl or C1-C6 alkoxy; e is selected from 0, 1 or 2; f is selected from 0 or 1.

76. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups:

77. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups:

78. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups:

79. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups:

80. The compound of any one of claims 27-30 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: A is selected from the following groups:

81. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups:

82. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups:

83. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups:

84. A compound according to any one of claims 27 to 30, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from the following groups:

85. The compound of any one of claims 27-30 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: A is selected from the following groups:

86. A compound according to any one of claims 1 to 85, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from any one of the following groups:

87. A compound according to any one of claims 1 to 86, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from any one of the following groups:

88. A compound according to any one of claims 1 to 87, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from any one of the following groups:

89. A compound according to any one of claims 1 to 85, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from any one of the following groups:

90. A compound according to any one of claims 1 to 85, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from any one of the following groups:

91. A compound according to any one of claims 1 to 85, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from any one of the following groups:

92. A compound according to any one of claims 1 to 85, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from any one of the following groups:

93. A compound according to any one of claims 1 to 85, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from any one of the following groups:

94. A compound according to any one of claims 1 to 85, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is selected from any one of the following groups:

95. A compound according to any one of claims 1 to 94, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: L is selected from -NR 3 CONR 3 -; and / or X7 is CR7, R7 is -NR a R a .

96. A compound according to any one of claims 1 to 95, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: R1 is a group -ZR 12 , wherein -Z is a single bond, -C1-C4 alkyl-, -C1-C4 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -NH-, -NHSO2-, -SO2NH-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C4 alkylene-SO2-, -(C=O)-, -(C=O)NH-, -C=N(OH)- or -NH(C=O)-; and / or (a)R 12 is H; (b)R 12 is oxetanyl, cyclopropyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (such as F, Cl), C1-C6 alkoxy; or (c)R 12 is C1-C6 alkyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (eg F), C1-C6 alkoxy.

97. A compound according to any one of claims 1 to 96, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: The group -ZR 12 -N=S(=O)-(R 12 )2, where two R 12 pairs that can alternatively combine with their respective attached sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; Or the group -ZR 12 In the equation, Z is a single bond, R 12 independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR m 、-OC1-C6 haloalkyl、CN、-C(=O)R n 、-C(=O)OR m 、-C(=O)NR m R m 、-C(=NR m )NR m R m 、-OC(=O)R n 、-OC(=O)NR m R m 、-OC2-C6 alkylene NR m R m 、-OC2-C6 alkylene OR m 、-SR m 、-S(=O)R n 、-S(=O)2R n 、-S(=O)2NR m R m 、-NR m R m 、-N(R m )C(=O)R n 、-N(R m )C(=O)OR n 、-N(R m )C(=O)NR m R m 、-N(R m )C(=NR m )NR m R m 、-N(R m )S(=O)2R n 、-N(R m )S(=O)2NR m R m 、-NR m C2-6 alkylene NR m R m 、-NR m C2-C6 alkylene OR m 、-C1-C6 alkylene NR m R m 、-C1-C6 alkylene OR m 、-C1-C6 alkylene N(R m )C(=O)R n 、-C1-C6 alkyleneOC(=O)R n 、-C1-C6 alkylene C(=O)NR m R m 、-C1-C6 alkylene C(=O)OR m and oxo, and R m and R n Independently selected from H and -C1-C6 alkyl.

98. A compound according to any one of claims 1 to 97, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: R1 is a group -ZR 12 , wherein Z is -NHSO2- or -SO2NH-; and R 12 is oxetane, cyclopropyl, or R substituted by 0, 1, 2 or 3 groups selected from OH, halogen (such as F), C1-C6 alkoxy 12 is C1-C6 alkyl substituted by 0, 1, 2 or 3 groups selected from OH, halogen (eg F), C1-C6 alkoxy.

99. A compound according to any one of claims 1 to 95, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: R1 is selected from the following groups:

100. A compound according to any one of claims 1 to 99, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: R x Selected from the group consisting of: Or alternatively, R 10a and R 10b Yes, R 10c and R 10d Yes, R 10e and R 10f Yes, R 10g and R 10 h pair or R 10i and R 10j Each of the pairs can independently combine with their respective attached carbon atoms to form a spiro-linked x wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, C1-C6 alkyl, C1-C4 haloalkyl, -OR a 、-OC1-C4 haloalkyl、CN、-NR a R a or oxo; R 10k selected from the group consisting of H, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-OC1-C6 haloalkyl、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC2-C6 alkyl NR a R a 、-OC2-C6 alkylOR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C2-C6 alkylene NR a R a 、-NR a C2-C6 alkylene OR a 、-C1-C6 alkylene NR a R a 、-C1-C6 alkylene OR a 、-C1-C6 alkylene N(R a )C(=O)R b 、-C1-C6 alkyleneOC(=O)R b 、-C1-C6 alkylene C(=O)NR a R a 、-C1-C6 alkylene C(=O)OR a and oxo, and R a and R b Independently selected from H and -C1-C6 alkyl; R 10l Selected from the group consisting of C1-C6 alkyl substituted with 0, 1, 2, 3, 4 or 5 groups of F, Cl, Br, C1-C6 alkoxy, -O-C1-C6 haloalkyl or CN.

101. A compound according to any one of claims 1 to 100, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: R x Selected from:

102. A compound of formula (IC-1) or formula (IC-1′) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein A is selected from any one of the A1 groups in claims 27 to 30, R a is H or C1-C4 alkyl.

103. A compound of formula (IC-2) or formula (IC-2′) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein A is selected from the A1 group in any one of claims 27 to 30, R a is H or C1-C4 alkyl.

104. A compound of formula (IA-1) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, R A2 、R I 、R II , n4, m5 are as defined in any one of claims 27-30, 47-50.

105. The compound of formula (IA-1) according to claim 104, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 106. A compound of formula (IA-2) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, R A2 、R I 、R II , n5, m5 are as defined in any one of claims 27-30, 53-54.

107. The compound of formula (IA-2) according to claim 106, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 108. A compound of formula (IA-3) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, R A2 、R I 、R II , n1, m5 are as defined in any one of claims 27-30.

109. The compound of formula (IA-3) according to claim 108, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 110. A compound of formula (IA-4) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, R A2 、R I 、R II , n1, m6 are as defined in any one of claims 27-30.

111. The compound of formula (IA-4) according to claim 110, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 112. A compound of formula (IA-5) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, R A2 、R I 、R II , n1, m6 are as defined in any one of claims 27-30.

113. The compound of formula (IA-5) according to claim 112, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 114. A compound of formula (IA-6) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, R A2 、R I 、R II , n4, m5 as defined in any one of claims 27-30.

115. The compound of formula (IA-6) according to claim 114, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 116. A compound of formula (IA-7) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, R A2 、R I 、R II , n4, m6 as defined in any one of claims 27-30.

117. The compound of formula (IA-7) according to claim 116, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 118. A compound of formula (IA-8) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, R A2 、R I 、R II , n4, m6 as defined in any one of claims 27-30.

119. The compound of formula (IA-8) according to claim 118, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 120. A compound of formula (IB-1) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

121. The compound of formula (IB-1) according to claim 120, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 122. A compound of formula (IB-2) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, R III , G, e as defined in any one of claims 27-30.

123. The compound of formula (IB-2) according to claim 122, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 124. The compound of formula (IB-2) according to claim 123, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is or The compound is Preferably, the compound is More preferably, the compound is or Preferably, the compound is More preferably, the compound is More preferably, each R III independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroaryl containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl); and / or, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O); More preferably, each e is 1.

125. A compound of formula (IB-3) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III 、R A3 , e as defined in any one of claims 27-30.

126. The compound of formula (IB-3) according to claim 125, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 127. A compound of formula (IB-4) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

128. The compound of formula (IB-4) according to claim 127, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 129. The compound of formula (IB-4) according to claim 128, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: The compound is Preferably, the compound is More preferably, the compound is or The compound is Preferably, the compound for More preferably, the compound is More preferably, each R III independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroaryl containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl); and / or, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O); More preferably, each e is 1.

130. A compound of formula (IB-5) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

131. A compound of formula (IB-5) according to claim 130, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 132. A compound of formula (IB-6) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

133. A compound of formula (IB-6) according to claim 132, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 134. A compound of formula (IB-6) according to claim 133, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: The compound is Preferably, the compound is More preferably, the compound is or The compound is Preferably, the compound is More preferably, the compound is More preferably, each R III independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroaryl containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl); and / or, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O); More preferably, each e is 1.

135. A compound of formula (IB-7) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

136. A compound of formula (IB-7) according to claim 135, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 137. A compound of formula (IB-8) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

138. A compound of formula (IB-8) according to claim 137, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 139. The compound of formula (IB-8) according to claim 138, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: The compound is Preferably, the compound is More preferably, the compound is or The compound is Preferably, the compound is More preferably, the compound is More preferably, each R III independently selected from deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, -O-C3-C8 cycloalkyl, -NH2, -NH-C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl, -5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms-C1-C6 alkyl, 5-6 membered monocyclic heteroaryl containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl); and / or, each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, -NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs attached to the same carbon atom form an oxo group (=O); More preferably, each e is 1.

140. A compound of formula (IB-9) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

141. The compound of formula (IB-9) according to claim 140, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 142. A compound of formula (IB-10) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

143. The compound of formula (IB-10) according to claim 142, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 144. A compound of formula (IB-11) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

145. A compound of formula (IB-11) according to claim 144, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 146. A compound of formula (IB-12) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

147. The compound of formula (IB-12) according to claim 146, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 148. A compound of formula (IB-13) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

149. A compound of formula (IB-13) according to claim 148, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 150. A compound of formula (IB-14) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, R III , G, e as defined in any one of claims 27-30.

151. A compound of formula (IB-14) according to claim 150, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 152. A compound of formula (IB-15) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, R III , G, e as defined in any one of claims 27-30.

153. A compound of formula (IB-15) according to claim 152, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 154. A compound of formula (IB-16) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, Among them, L, R X , R1, X7, X8, X9 are as defined in any one of claims 1 to 26, G, R III , e as defined in any one of claims 27-30.

155. A compound of formula (IB-16) according to claim 154, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is 156. A compound according to any one of claims 1 to 155, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: The compound is selected from the group consisting of the following compounds:

157. The compound of any one of claims 1-155, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: The compound is selected from the group consisting of the following compounds:

158. A pharmaceutical composition comprising a compound according to any one of claims 1 to 157 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable diluent or carrier.

159. A method of treating a condition treatable with a KIF18A inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-157, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 158.

160. The method of claim 159, wherein the condition is a cancer selected from the group consisting of: (a) a solid tumor or a hematogenic tumor selected from the group consisting of bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell (c) a hematopoietic neoplasm of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, a xeroderma pigmentosum, a keratoacanthoma, a follicular thyroid carcinoma, or a Kaposi's sarcoma.

161. A method of reducing the size of a solid tumor in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-157, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, or a composition according to claim 158.

162. A method of treating a cell proliferative disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-157, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, or a composition according to claim 158.

163. A method of inhibiting KIF18A in a cell, the method comprising contacting the cell with a compound according to any one of claims 1-157, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, or a composition according to claim 158.

164. Use of a compound according to any one of claims 1 to 157, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 158, in the preparation of a medicament for treating a condition treatable with a KIF18A inhibitor.

165. The use according to claim 164, wherein the condition is a cancer selected from the group consisting of: (a) a solid tumor or a hematogenic tumor selected from the group consisting of bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T cell (c) a hematopoietic neoplasm of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, a xeroderma pigmentosum, a keratoacanthoma, a follicular thyroid carcinoma, or a Kaposi's sarcoma.

166. Use of a compound according to any one of claims 1-157, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, or the composition according to claim 158, in the preparation of a medicament for reducing the size of a solid tumor in a subject.

167. Use of a compound according to any one of claims 1-157, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or the composition according to claim 158, in the preparation of a medicament for treating a cell proliferative disorder in a subject.

168. Use of a compound according to any one of claims 1 to 157 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, or the composition according to claim 158 in the preparation of a medicament for inhibiting KIF18A in a cell.

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