Amide or urea compounds

Abstract

The present application provides a compound represented by formula (I), which can affect cell cycle and cell proliferation processes to treat cancer and cancer-related diseases by regulating KIF18A protein. The present invention further includes pharmaceutical compositions containing the compounds and methods for treating pathologies associated with KIF18A activity. [Formula 1] TIFF2026508745000671.tif39170

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The related application documents claim priority to Chinese Patent Application No. 202211538155.1, filed December 2, 2022, Chinese Patent Application No. 202310522117.5, filed May 9, 2023, Chinese Patent Application No. 202311071943.9, filed August 23, 2023, and Chinese Patent Application No. 202311385406.1, filed October 24, 2023, the contents of which are incorporated by reference in their entirety into this application. [Technical Field]

[0002] The present application is in the field of medicinal chemistry, specifically relating to amide or urea based compounds. [Background technology]

[0003] CIN is defined as chromosomal instability resulting from chromosomal segregation errors during mitosis. CIN is one of the key features of recurrent, metastatic, and 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 break-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 intracellular vesicle and organelle transport. Mitotic kinesins play multiple roles in spindle assembly, chromosome segregation, centrosome separation, and dynamics. Based on sequence homology within the "motor domain," human kinesins are classified into 14 subfamilies. KIF18A, a member of the kinesin-8 family, is a mitotic G2 / M phase-specific protein that plays an important role in maintaining the integrity of the bipolar spindle during cell division, thereby regulating chromosome localization during this process. KIF18A can move microtubules toward the positive pole using energy released by intracellular ATP hydrolysis. It also localizes to the positive pole end of microtubules, where it regulates microtubule dynamic instability and exerts microtubule depolymerase-like activity. During mitosis, KIF18A can regulate spindle microtubule dynamics and chromosome amplitude, and plays an important role in ensuring timely mitotic chromosome alignment, maintaining genomic stability, and successfully completing mitosis.

[0005] Studies have shown that the kinesin KIF18A is a key factor affecting CIN tumor cell proliferation. KIF18A knockout results in tumor cells with CIN characteristics exhibiting mitotic vulnerability associated with spindle assembly checkpoint (SAC) activation, multipolar spindle formation, and apoptosis induction, leading to mitotic arrest, cell cycle arrest, and apoptosis. KIF18A is an essential gene for abnormal somatic cell division, and CIN tumor cells are highly sensitive to KIF18A knockout. Therefore, small molecule inhibitors of KIF18A can selectively target tumor cells with CIN characteristics. Compared to 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, making KIF18A a promising new anti-tumor target. Summary of the Invention

[0006] The object of the present invention is to provide amide or urea-based compounds, which have KIF18A inhibitory activity. Therefore, the present invention further provides the use of these compounds and pharmaceutically acceptable salts thereof in the manufacture and production of pharmaceutical compositions or medicaments for the treatment, prevention, 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 in the production of anti-cancer drugs. The present invention also provides methods for producing compounds of Formula I, and intermediates usable in such methods.

[0007] In a first aspect, the present application provides a compound of formula (I) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, [ka] A is a monocyclic aryl group, a monocyclic heteroaryl group, a bicyclic aryl group, a bicyclic heteroaryl group, or a fused heterocyclyl group, and optionally the monocyclic aryl group, the monocyclic heteroaryl group, the bicyclic aryl group, the bicyclic heteroaryl group, or the fused heterocyclyl group optionally comprises one or more R z is replaced by L is -NR 3 -CO- or -NR 3 CONR 3 -Selected from each R 3 are independently H, deuterium, a C1-C6 alkylene group, or a C1-C6 haloalkylene group; R xis selected from -OR4 or -NR5R6, wherein R4 is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group, wherein the 3- to 8-membered heterocyclyl group contains at least one heteroatom selected from O, S, and N; R5 is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group; R6 is selected from H or a C1-C6 alkyl group; or R5 and R6 together with the N atom to which they are linked form a 4- to 8-membered heterocyclyl group, wherein the 3- to 8-membered cycloalkyl group, the 3- to 8-membered cycloalkenyl group, the 3- to 8-membered heterocyclyl group, and the 4- to 8-membered heterocyclyl group contain 0, 1, 2, or 3 heteroatoms selected from O, S, and N and optionally one or more R z is replaced by R1 is -CN or -ZR 12 wherein Z is a direct bond, —C1-C6 alkylene-, —C1-C6 alkylene-O—, —O—, —S—, —S(═O)—, —SO2—, or —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 is -N=S(=O)-(R 12 )2, where two R 12 can combine with the sulfur atom to which they are each 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, and X9 is N or CR9; R7, R8, and R9 are independently H, halogen, a C1-C8 alkyl group, a C1-C6 haloalkyl group, -OH, -OR 8a , -OR8b or -NR a R a and when R7 and R8 are present together, R7 and R8 can combine with the atoms to which they are each 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, and R x and R9 are present at the same time, R x and R9 can combine with the atoms to which they are each 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 and R 12 H, R 12a or R 12b and R 8a , R 11a and R 12a is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are selected from the group consisting of F, Cl, Br, C1-C6 alkyl groups, C1-C6 haloalkyl groups, -OR a , -OC1-C6 haloalkyl group, 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 alkyleneNR 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)NR a R a , -NR a C2-6 alkylene NR a R a , -NR a C2-C6 alkylene OR a , -C1-C6 alkyleneNR a R a , -C1-C6 alkylene OR a , -C1-C6 alkyleneN(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 are independently F, Cl, Br, -OR a , —OC1-C6 haloalkyl, or C1-C6 alkyl substituted with 0, 1, 2, 3, 4, or 5 groups selected from CN; R 14is, in each occurrence, independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which are selected from F, Cl, Br, a C1-C6 alkyl group, -OR a , -OC1-C6 haloalkyl group, 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 alkyleneNR 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)NR a R a , -NR a C2-C6 alkylene NR a R a , -NR a C2-C6 alkylene OR a , -C1-C6 alkyleneNR a R a, -C1-C6 alkylene OR a , -C1-C6 alkyleneN(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 are each independently H or R b and Each R b are each independently a C1-C6 alkyl group, a phenyl group, or a benzyl group, wherein the C1-C6 alkyl group is substituted with 0, 1, 2, or 3 substituents selected from halogen, —OH, —O—C1-C6 alkyl group, —NH2, —NH—C1-C6 alkyl group, —O—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and the phenyl or benzyl group is substituted with 0, 1, 2, or 3 substituents selected from halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH2, —NH—C1-C6 alkyl group, —O—C1-C6 alkyl group, or —N(C1-C6 alkyl)C1-C6 alkyl group; Each R z are independently deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, -C1-C6 alkylene-O-C1-C6 alkyl group, C3-C8 cycloalkyl-C1-C6 alkylene group, -OH, -CN, -O-C1-C6 alkyl group, -O-C3-C8 cycloalkyl group, -NH2, -NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, -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 z2a phenyl group, a 5- to 6-membered monocyclic heteroaryl group containing 0, 1, 2 or 3 N atoms, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 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 or bicyclic ring is substituted with 0, 1, 2 or 3 groups selected from deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, —OH, —O—C1-C6 alkyl group, —NH2, —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group or —N(C1-C6 alkyl)(C1-C6 alkyl), and two R z teeth, [ka] or two R z may together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and said C1-C6 alkyl group, C3-C8 cycloalkyl group, -C1-C6 alkylene-O-C1-C6 alkyl group, -O-C1-C6 alkyl group, and C3-C8 cycloalkyl-C1-C6 alkylene group may optionally be substituted with one or more substituents selected from deuterium, F, Cl, Br, I, -OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, a C1-C4 haloalkyl group, and a C3-C8 halocycloalkyl group; Each R z1 are independently selected from the group consisting of H, C1-C6 alkyl groups, and C1-C6 haloalkyl groups; Each R z2 are independently selected from the group consisting of H, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 deuterated alkyl groups, and C3-C8 cycloalkyl groups; Q is O or CR Q1 R Q2 and R Q1 and R Q2are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group.

[0008] In some embodiments, the present application provides a compound of formula (I) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is a monocyclic aryl group, a monocyclic heteroaryl group, a bicyclic aryl group, a bicyclic heteroaryl group, or a fused heterocyclyl group, and optionally the monocyclic aryl group, the monocyclic heteroaryl group, the bicyclic aryl group, the bicyclic heteroaryl group, or the fused heterocyclyl group optionally comprises one or more R z is replaced by L is -NR 3 -CO- or -NR 3 CONR 3 -Selected from each R 3 are independently H, deuterium, a C1-C6 alkylene group, or a C1-C6 haloalkylene group; R x is selected from -OR4 or -NR5R6, wherein R4 is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group, wherein the 3- to 8-membered heterocyclyl group contains at least one heteroatom selected from O, S, and N; R5 is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group; R6 is selected from H or a C1-C6 alkyl group; or R5 and R6 together with the N atom to which they are linked form a 4- to 8-membered heterocyclyl group, wherein the 3- to 8-membered cycloalkyl group, the 3- to 8-membered cycloalkenyl group, the 3- to 8-membered heterocyclyl group, and the 4- to 8-membered heterocyclyl group contain 0, 1, 2, or 3 heteroatoms selected from O, S, and N and optionally one or more R z is replaced by R1 is -CN or -ZR 12wherein Z is a direct bond, —C1-C6 alkylene-, —C1-C6 alkylene-O—, —O—, —S—, —S(═O)—, —SO2—, or —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 is -N=S(=O)-(R 12 )2, where two R 12 can combine with the sulfur atom to which they are each 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, and X9 is N or CR9; R7, R8, and R9 are independently H, halogen, a C1-C8 alkyl group, a C1-C6 haloalkyl group, -OH, -OR 8a , -OR 8b or -NR a R a and when R7 and R8 are present together, R7 and R8 can combine with the atoms to which they are each 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, and R x and R9 are present at the same time, R x and R9 can combine with the atoms to which they are each 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 and R 12 H, R12a or R 12b and R 8a , R 11a and R 12a is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are selected from the group consisting of F, Cl, Br, C1-C6 alkyl groups, C1-C6 haloalkyl groups, -OR a , -OC1-C6 haloalkyl group, 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 alkyleneNR 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)NR a R a , -NR a C2-6 alkylene NR aR a , -NR a C2-C6 alkylene OR a , -C1-C6 alkyleneNR a R a , -C1-C6 alkylene OR a , -C1-C6 alkyleneN(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 are independently F, Cl, Br, -OR a , —OC1-C6 haloalkyl, or C1-C6 alkyl substituted with 0, 1, 2, 3, 4, or 5 groups selected from CN; R 14 is, in each occurrence, independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which are selected from F, Cl, Br, a C1-C6 alkyl group, -OR a , -OC1-C6 haloalkyl group, 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 alkyleneNR a R a , -OC2-6 alkylene OR a , -SR a , -S(=O)R b , -S(=O)2Rb , -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)NR a R a , -NR a C2-C6 alkylene NR a R a , -NR a C2-C6 alkylene OR a , -C1-C6 alkyleneNR a R a , -C1-C6 alkylene OR a , -C1-C6 alkyleneN(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 are each independently H or R b and Each R bare each independently a C1-C6 alkyl group, a phenyl group, or a benzyl group, wherein the C1-C6 alkyl group is substituted with 0, 1, 2, or 3 substituents selected from halogen, —OH, —O—C1-C6 alkyl group, —NH2, —NH—C1-C6 alkyl group, —O—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and the phenyl or benzyl group is substituted with 0, 1, 2, or 3 substituents selected from halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH2, —NH—C1-C6 alkyl group, —O—C1-C6 alkyl group, or —N(C1-C6 alkyl)C1-C6 alkyl group; Each R z are independently deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, -C1-C6 alkylene-O-C1-C6 alkyl group, C3-C8 cycloalkyl-C1-C6 alkylene group, -OH, -CN, -O-C1-C6 alkyl group, -O-C3-C8 cycloalkyl group, -NH2, -NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, -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- to 6-membered monocyclic heteroaryl group containing 0, 1, 2 or 3 N atoms, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 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 or bicyclic ring is substituted with 0, 1, 2 or 3 groups selected from deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, —OH, —O—C1-C6 alkyl group, —NH2, —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group or —N(C1-C6 alkyl)(C1-C6 alkyl), and two R z teeth, [ka] or two R z may together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and said C1-C6 alkyl group, C3-C8 cycloalkyl group, -C1-C6 alkylene-O-C1-C6 alkyl group, -O-C1-C6 alkyl group, and C3-C8 cycloalkyl-C1-C6 alkylene group may optionally be substituted with one or more substituents selected from deuterium, F, Cl, Br, I, -OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, a C1-C4 haloalkyl group, and a C3-C8 halocycloalkyl group; Each R z1 are independently selected from the group consisting of H, C1-C6 alkyl groups, and C1-C6 haloalkyl groups; Each R z2 are independently selected from the group consisting of H, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 deuterated alkyl groups, and C3-C8 cycloalkyl groups; Q is O or CR Q1 R Q2 and R Q1 and R Q2 are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group.

[0009] In some embodiments, the present application provides a compound of formula (I) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: Each R zare independently deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, -C1-C6 alkylene-O-C1-C6 alkyl group, C3-C8 cycloalkyl-C1-C6 alkylene group, -OH, -CN, -O-C1-C6 alkyl group, -O-C3-C8 cycloalkyl group, -NH2, -NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, -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- to 6-membered monocyclic heteroaryl group containing 0, 1, 2 or 3 N atoms, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 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 or bicyclic ring is substituted with 0, 1, 2 or 3 groups selected from deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, -OH, -O-C1-C6 alkyl group, -NH2, -NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group or -N(C1-C6 alkyl)(C1-C6 alkyl), and two R z teeth, [ka] or two R z can together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, —O—C1-C6 alkyl group, and C3-C8 cycloalkyl-C1-C6 alkylene group may optionally be substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, a C1-C4 haloalkyl group, and a C3-C8 halocycloalkyl group.

[0010] In some embodiments, the present application provides a compound of formula (I) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein: A is a monocyclic aryl group, a monocyclic heteroaryl group, a bicyclic aryl group, a bicyclic heteroaryl group, or a fused heterocyclyl group, and optionally the monocyclic aryl group, the monocyclic heteroaryl group, the bicyclic aryl group, the bicyclic heteroaryl group, or the fused heterocyclyl group optionally comprises one or more R z is replaced by L is -NR 3 -CO- or -NR 3 CONR 3 -Selected from each R 3 are independently H, deuterium, a C1-C6 alkylene group, or a C1-C6 haloalkylene group; R x is selected from -OR4 or -NR5R6, wherein R4 is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group, wherein the 3- to 8-membered heterocyclyl group contains at least one heteroatom selected from O, S, and N; R5 is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group; R6 is selected from H or a C1-C6 alkyl group; or R5 and R6 together with the N atom to which they are linked form a 4- to 8-membered heterocyclyl group, wherein the 3- to 8-membered cycloalkyl group, the 3- to 8-membered cycloalkenyl group, the 3- to 8-membered heterocyclyl group, and the 4- to 8-membered heterocyclyl group contain 0, 1, 2, or 3 heteroatoms selected from O, S, and N and optionally one or more R z is replaced by R1 is -CN or -ZR 12 wherein Z is a direct bond, —C1-C6 alkylene-, —C1-C6 alkylene-O—, —O—, —S—, —S(═O)—, —SO2—, or —NR 11 -, -NR11 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 is -N=S(=O)-(R 12 )2, where two R 12 can combine with the sulfur atom to which they are each 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, and X9 is N or CR9; R7, R8, and R9 are independently H, halogen, a C1-C8 alkyl group, a C1-C6 haloalkyl group, -OH, -OR 8a , -OR 8b or -NR a R a and when R7 and R8 are present together, R7 and R8 can combine with the atoms to which they are each 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, and R x and R9 are present at the same time, R x and R9 can combine with the atoms to which they are each 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 and R 12 H, R 12a or R 12b and R 8a , R 11a and R 12ais independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are selected from the group consisting of F, Cl, Br, C1-C6 alkyl groups, C1-C6 haloalkyl groups, -OR a , -OC1-C6 haloalkyl group, 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 alkyleneNR 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)NR a R a , -NR a C2-6 alkylene NR a R a , -NR a C2-C6 alkylene OR a , -C1-C6 alkyleneNR a Ra , -C1-C6 alkylene OR a , -C1-C6 alkyleneN(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 are independently F, Cl, Br, -OR a , —OC1-C6 haloalkyl, or C1-C6 alkyl substituted with 0, 1, 2, 3, 4, or 5 groups selected from CN; R 14 is, in each occurrence, independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which are selected from F, Cl, Br, a C1-C6 alkyl group, -OR a , -OC1-C6 haloalkyl group, 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 alkyleneNR 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(Ra )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)NR a R a , -NR a C2-C6 alkylene NR a R a , -NR a C2-C6 alkylene OR a , -C1-C6 alkyleneNR a R a , -C1-C6 alkylene OR a , -C1-C6 alkyleneN(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 are each independently H or R b and Each R bare each independently a C1-C6 alkyl group, a phenyl group, or a benzyl group, wherein the C1-C6 alkyl group is substituted with 0, 1, 2, or 3 substituents selected from halogen, —OH, —O—C1-C6 alkyl group, —NH, —NH—C1-C6 alkyl group, —O—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and the phenyl or benzyl group is substituted with 0, 1, 2, or 3 substituents selected from halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH, —NH—C1-C6 alkyl group, —O—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl); Each R z are independently deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C3-C8 cycloalkyl-C1-C6 alkylene group, -OH, -CN, -O-C1-C6 alkyl group, -NH2, -NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, -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 with 0, 1, 2 or 3 groups selected from deuterium, halogen, C-C alkyl group, C-C cycloalkyl group, C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group or —N(C-C alkyl)(C-C alkyl), and wherein two R z teeth, [ka] or two R zmay together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, —O—C1-C6 alkyl group, and C3-C8 cycloalkyl-C1-C6 alkylene group may optionally be substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, a C1-C4 haloalkyl group, and a C3-C8 halocycloalkyl group; Each R z1 are independently selected from the group consisting of C1-C6 alkyl groups, C1-C6 haloalkyl groups; Q is O or CR Q1 R Q2 and R Q1 and R Q2 are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group.

[0011] In some embodiments, each R z are independently hydrogen, deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C3-C8 cycloalkyl-C1-C6 alkylene group, -OH, -CN, -O-C1-C6 alkyl group, -NH2, -NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 , -S(O)2-R z1a 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 deuterium, halogen, C-C alkyl group, C-C cycloalkyl group, C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group or —N(C-C alkyl)(C-C alkyl), and wherein two R z teeth, [ka] or two R z can together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, and C3-C8 cycloalkyl-C1-C6 alkylene group may optionally be substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, a C1-C4 haloalkyl group, and a C3-C8 halocycloalkyl group.

[0012] In some embodiments, each R zare independently selected from the group consisting of deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, -OH, -O-C1-C6 alkyl group, -NH2, -NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group 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 or bicyclic ring is independently selected from the group consisting of deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1 and is substituted with 0, 1, 2 or 3 groups selected from a -C6 haloalkyl group, -OH, -O-C1-C6 alkyl group, -NH2, -NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group or -N(C1-C6 alkyl)(C1-C6 alkyl), and two or more of the substituents together with the carbon atom to which they are attached can form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group or -O-C1-C6 alkyl group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group or a C1-C4 haloalkyl group.

[0013] In some embodiments, Formula (I) is as shown in Formula (I)-1, Formula (I)-2, or Formula (I)-3. [ka]

[0014] The definitions of the symbols in formulas (I)-1 to (I)-3 are the same as in formula (I).

[0015] In some embodiments, R x teeth, [ka] is selected from the group consisting of Preferably, R x teeth, [ka] and where 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 which is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-membered ring containing 1 to 3 heteroatoms selected from H, deuterium, halogen, -CN, -OH, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, C3-C8 cycloalkyl group, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), N, O, S or a 12-membered bicyclic ring, wherein the C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C3-C8 cycloalkyl group are optionally substituted with 1 to 5 substituents selected from deuterium, halogen, —OH, —CN, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, and —O—C1-C6 haloalkyl group, and the monocyclic or bicyclic ring is optionally substituted with F, Cl, Br, C1-C6 alkyl group, C1-C6 haloalkyl group, —OR m , -OC1-C6 haloalkyl group, 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 alkyleneNR m R m , -OC2-C6 alkylene OR m , -SRm , -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)NR m R m , -NR m C2-6 alkylene NR m R m , -NR m C2-C6 alkylene OR m , -C1-C6 alkyleneNR m R m , -C1-C6 alkylene OR m , -C1-C6 alkyleneN(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 vs. R 10c and R 10d vs. R 10e and R 10f vs. R 10g and R 10h vs. R 10i and R 10j , R 10k and R 10lEach of the pairs independently, in combination with the carbon atom to which they are respectively attached, forms R x A saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring can be formed spiro-bonded to the ring, wherein the 3-, 4-, 5-, or 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-, 4-, 5-, or 6-membered monocyclic ring is selected from F, Cl, Br, a C1-C6 alkyl group, a C1-C4 haloalkyl group, -OR m , -OC1-C4 haloalkyl group, CN, -NR m R m or oxo; Each R m and R n is independently selected from H or a -C1-C6 alkyl group; or alternatively, R 10a and R 10b vs. R 10c and R 10d vs. R 10e and R 10f vs. R 10g and R 10 h vs. R 10i and R 10j Pair or R 10k and R 10l The opposite is [ka] where Q is a CR Q1 R Q2 and R Q1 and R Q2 are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group.

[0016] In some embodiments, R x teeth, [ka] is.

[0017] In some preferred embodiments, R10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i and R 10j each is H, deuterium, halogen, -CN, -OH, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl group, C1-C6 alkoxy group, and C1-C6 haloalkyl group are optionally substituted with 1 to 5 substituents selected from deuterium, halogen, -OH, -CN, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, and -O-C1-C6 haloalkyl group; and the pair R10a and R10b is [ka] Q forms a CR Q1 R Q2 and R Q1 and R Q2 are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, or R 10a and R 10b The pair, together with the carbon atom to which it is attached, forms a C3-C8 cycloalkyl group spiro-bonded to the Rx ring, and further, the C3-C8 cycloalkyl group is substituted with 0, 1, 2 or 3 groups selected from F, Cl, Br, a C1-C6 alkyl group, a C1-C4 haloalkyl group, -OH, a C1-C6 alkoxy group, -OC1-C4 haloalkyl group, -CN, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl) or oxo.

[0018] In some embodiments, R x teeth, [ka] is selected from Preferably, R x teeth, [ka] is selected from More preferably, R x teeth, [ka] is selected from.

[0019] 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. [ka]

[0020] In some embodiments, R 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)NH-, -C=N(OH)- or -NH(C=O)-; and / or (a)R 12 is H, (b)R 12 is an oxetanyl group, a cyclopropyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F, Cl), and a C1-C6 alkoxy group; or (c)R 12 is a C1-C6 alkyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and a C1-C6 alkoxy group.

[0021] Preferably, the group -ZR 12 is -N=S(=O)-(R 12 )2, where two R12 can alternatively be combined with the sulfur atom to which they are respectively 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; or the group -ZR 12 In the formula, Z is a single bond and R 12 is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are selected from the group consisting of F, Cl, Br, C1-C6 alkyl groups, C1-C6 haloalkyl groups, -OR a , -OC1-C6 haloalkyl group, 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 alkyleneNR 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)NR a R a , -NR a C2-6 alkylene NR a R a , -NR a C2-C6 alkylene OR a , -C1-C6 alkyleneNR a R a , -C1-C6 alkylene OR a , -C1-C6 alkyleneN(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 is independently selected from H and a -C1-C6 alkyl group.

[0022] More preferably, R1 is a group -ZR 12 where Z is -NHSO2- or -SO2NH-, and R 12 is an oxetanyl group, a cyclopropyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and C1-C6 alkoxy groups; or R 12 is a C1-C6 alkyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and a C1-C6 alkoxy group.

[0023] More preferably, R1 is selected from the following groups:

[0024] [Table 1]

[0025] Even more preferably, R1 is selected from the following groups:

[0026] [Table 2]

[0027] Most preferably, R1 is [ka] is selected from.

[0028] 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. [ka]

[0029] Preferably, formula (I) is as shown in formula (I)-1-1, formula (I)-1-2, formula (I)-2-1 or formula (I)-2-2. [ka]

[0030] In some embodiments, each R 3 are independently H, a C1-C4 alkyl group, or a C1-C4 haloalkyl group; Preferably, each R 3 are independently H.

[0031] In some embodiments, X7 is CR7.

[0032] In some embodiments, X7 is N.

[0033] In some embodiments, X8 is CR8.

[0034] In some embodiments, X8 is N.

[0035] In some embodiments, X9 is CR9.

[0036] In some embodiments, X9 is N.

[0037] In some embodiments, X7 is CR7, X8 is CR8, and X9 is CR9.

[0038] In some embodiments, X7 is CR7, X8 is CR8, and X9 is N.

[0039] In some embodiments, X7 is CR7, X8 is N, and X9 is CR9.

[0040] In some embodiments, X7 is CR7, X8 is N, and X9 is N.

[0041] In some embodiments, R7 is H, halogen, a C1-C8 alkyl group, a C1-C6 haloalkyl group, -OH, -OR 8a , -OR 8b or -NR a R a and Preferably, R7 is H, halogen, a C1-C8 alkyl group, -NR a R a and More preferably, R7 is H or -NR a R a and Even more preferably, R7 is H, -NH2 or -NH-C1-C6 alkyl group.

[0042] In some embodiments, R7 is H.

[0043] In some embodiments, R7 is -NR a R a is.

[0044] In some embodiments, R7 is -NH2 or -NH-C1-C6 alkyl group, preferably R7 is -NH2 or -NHCH3.

[0045] In some embodiments, X7 is CR7 and R7 is -NH2 or -NH-C1-C6 alkyl group, X8 is CH, and X9 is CH.

[0046] 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.

[0047] In some embodiments, X7 is N and / or X8 is N.

[0048] In some embodiments, R8 and R9 are independently H, halogen, a C1-C8 alkyl group, a C1-C6 haloalkyl group, -OH, -OR 8a , -OR 8b or -NR a R a and preferably, R and R are independently H, halogen, a C-C alkyl group, —OH, or —NR a R a and more preferably, R8 and R9 are independently H or halogen, and most preferably, R8 and R9 are H.

[0049] In some embodiments, A is selected from a phenyl group, a 5- to 6-membered nitrogen-containing heteroaryl group, a benzomonoheterocyclyl group, a benzobisheterocyclyl group, a 5- to 6-membered nitrogen-containing heteroaryl-fused monoheterocyclyl group, a 5- to 6-membered nitrogen-containing heteroaryl-fused bisheterocyclyl group, a benzomonoheteroaromatic ring group, and a 5- to 6-membered nitrogen-containing heteroaryl-fused monoheteroaromatic ring group; Optionally, the phenyl group, 5- to 6-membered nitrogen-containing heteroaryl group, benzomonoheterocyclyl group, benzobisheterocyclyl group, 5- to 6-membered nitrogen-containing heteroaryl-fused monoheterocyclyl group, 5- to 6-membered nitrogen-containing heteroaryl-fused bisheterocyclyl group, benzomonoheteroaromatic ring group, and 5- to 6-membered nitrogen-containing heteroaryl-fused monoheteroaromatic ring group may be selected from the group consisting of one or more R z is replaced by The monoheterocyclyl group in the benzomonoheterocyclyl and 5- to 6-membered nitrogen-containing heteroaryl-fused monoheterocyclyl contains 0, 1, 2, or 3 atoms selected from N, O, and S; the monoheteroaromatic ring group in the benzomonoheteroaromatic ring group and the 5- to 6-membered nitrogen-containing heteroaryl-fused monoheteroaromatic ring group contains 0, 1, 2 or 3 atoms selected from N, O and S; The bisheterocyclyl group in the benzobisheterocyclyl group and the 5- to 6-membered nitrogen-containing heteroaryl-fused bisheterocyclyl group contains 0, 1, 2 or 3 atoms selected from N, O and S.

[0050] In some embodiments, A is selected from groups A1, A2, and A3; The groups in the A1 group are [ka] and In group A1, R A1 are 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, said monocyclic ring or bicyclic ring optionally substituted with 0, 1, 2, or 3 groups selected from deuterium, halogen, C-C alkyl group, C-C cycloalkyl group, C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R AIare each independently selected from deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, —CN, —O—C-C alkyl group, a C-C alkylene-O—C-C alkyl group, a C-C haloalkoxy group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C 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, and m4 is selected from 0 or 1; The groups in group A2 are [ka] and R in group A2 I and R II are each independently selected from deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, -OH, -CN, a C-C alkoxy group, -NH, -NH-C-C alkyl group, -OC(=O)C-C alkyl group, or -N(C-C alkyl)(C-C alkyl), and two R II may together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, or C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; R A2 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C3-C8 cycloalkyl-C1-C6 alkylene group, -OH, C1-C6 alkoxy group, -NH2, -NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 or -S(O)2-Rz1 wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, and C3-C8 cycloalkyl-C1-C6 alkylene group are optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C1-C4 haloalkyl group; Each R z1 are independently selected from the group consisting of C1-C6 alkyl groups, C1-C6 haloalkyl groups; m5 is selected from 0, 1, 2 or 3, m6 is selected from 0, 1 or 2, n1 is selected from integers of 0 to 4, n2 is selected from integers of 0 to 6, n3 is selected from integers of 0 to 8, n4 is selected from integers of 0 to 2, n5 is selected from 0 or 1, n7 is selected from integers of 0 to 3, q ​​is 0 or 1, s is selected from integers of 0 to 6, t is selected from integers of 0 to 8, and r is selected from 0 or 1.

[0051] The groups in group A3 are: [ka] and In group A3, each G is independently selected from hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, -OH, -CN, a C1-C6 alkoxy group, -NH2, -NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, or -N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, or C1-C6 alkoxy group is optionally substituted with a substituent selected from deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; or two Gs linked on the same carbon atom can form an oxo group (=O); or two Gs linked on the same carbon atom can form a C3-C8 cycloalkyl group together with the carbon atoms to which they are linked; R A3 are independently hydrogen, deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, -OH, -CN, -O-C3-C8 cycloalkyl group, C1-C6 alkoxy group, -NH2, -NH-C1-C6 alkyl group, -C(=O)NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, -C(=O)C3-C8 cycloalkyl group, -N(C1-C6 alkyl)(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl group, 1, a 5- to 6-membered monocyclic heteroaryl group containing 2 or 3 N atoms, and a 5- to 6-membered monocyclic heteroaryl group containing 0, 1, 2 or 3 N atoms and 1 or 2 atoms selected from O, wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group, and 5- to 6-membered monocyclic heteroaryl group are optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; R IIIare independently deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, -OH, -CN, -O-C3-C8 cycloalkyl group, C1-C6 alkoxy group, -NH2, -NH-C1-C6 alkyl group, -C(=O)NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, -C(=O)C3-C8 cycloalkyl group, -N(C1-C6 alkyl)(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl group, -5- to 6-membered monocyclic ring containing 1, 2 or 3 N atoms heteroaryl-C1-C6 alkyl group, a 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 N atoms, and a 5- to 6-membered monocyclic heteroaryl group containing 0, 1, 2 or 3 N atoms and 1 or 2 atoms selected from O, wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group, and 5- to 6-membered monocyclic heteroaryl group are optionally substituted with a substituent selected from deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group, and C1-C4 haloalkyl group; e is selected from 0, 1, 2 or 3; f is selected from 0, 1 or 2;

[0052] In some embodiments, each G is independently selected from hydrogen, deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, —CN, a C-C alkoxy group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), wherein the C-C alkyl group, C-C cycloalkyl group, C-C haloalkyl group, or C-C alkoxy group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C-C alkyl group, a C-C cycloalkyl group, a C-C alkoxy group, or a C-C haloalkyl group; or two Gs linked on the same carbon atom can form an oxo group (═O); or two Gs linked on the same carbon atom can, together with the carbon atoms to which they are linked, form a C-C cycloalkyl group.

[0053] In some embodiments, R A3 and R III are each independently deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, -OH, -CN, -O-C3-C8 cycloalkyl group, C1-C6 alkoxy group, -NH2, -NH-C1-C6 alkyl group, -C(=O)NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, -C(=O)C3-C8 cycloalkyl group, -N(C1-C6 alkyl)(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl group, 1 , a 5- to 6-membered monocyclic heteroaryl group containing 2 or 3 N atoms, and a 5- to 6-membered monocyclic heteroaryl group containing 0, 1, 2 or 3 N atoms and 1 or 2 atoms selected from O, wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group, and 5- to 6-membered monocyclic heteroaryl group may be optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group.

[0054] In some other embodiments, R A3 are independently selected from hydrogen, deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, —CN, a C-C alkoxy group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), wherein the C-C alkyl group, C-C cycloalkyl group, C-C alkyl group, or C-C alkoxy group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C-C alkyl group, a C-C cycloalkyl group, a C-C alkyl group, a C-C alkoxy group, or a C-C haloalkyl group.

[0055] In some embodiments, R A3 and R III are each independently selected from deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, —CN, a C-C alkoxy group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), wherein the C-C alkyl group, C-C cycloalkyl group, C-C alkyl group, or C-C alkoxy group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C-C alkyl group, a C-C cycloalkyl group, a C-C alkyl group, a C-C alkoxy group, or a C-C haloalkyl group.

[0056] In some embodiments, A is selected from groups A1, A2, and A3; The groups in the A1 group are [ka] and In group A1, R A1are 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, said monocyclic ring or bicyclic ring optionally substituted with 0, 1, 2, or 3 groups selected from deuterium, halogen, C-C alkyl group, C-C cycloalkyl group, C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R AI are each independently selected from deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, —CN, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C 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, and m4 is selected from 0 or 1; The groups in group A2 are [ka] TIFF2026508745000028.tif150170, R in group A2 I and R II are each independently selected from deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, -OH, -CN, a C-C alkoxy group, -NH, -NH-C-C alkyl group, -OC(=O)C-C alkyl group, or -N(C-C alkyl)(C-C alkyl), and two R IImay together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, or C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; R A2 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C3-C8 cycloalkyl-C1-C6 alkylene group, -OH, C1-C6 alkoxy group, -NH2, -NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, -N(C1-C6 alkyl)(C1-C6 alkyl), -S(O)-R z1 or -S(O)2-R z1 wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, and C3-C8 cycloalkyl-C1-C6 alkylene group are optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; Each R z1 are independently selected from the group consisting of C1-C6 alkyl groups, C1-C6 haloalkyl groups; m5 is selected from 0, 1, 2 or 3, m6 is selected from 0, 1 or 2, n1 is selected from integers of 0 to 4, n2 is selected from integers of 0 to 6, n3 is selected from integers of 0 to 8, n4 is selected from integers of 0 to 2, n5 is selected from 0 or 1, n7 is selected from integers of 0 to 3, q ​​is 0 or 1, s is selected from integers of 0 to 6, t is selected from integers of 0 to 8, and r is selected from 0 or 1.

[0057] The groups in group A3 are: [ka] and In group A3, G, R A3 and R III are each independently as defined above. For example, in some embodiments, each G is independently selected from hydrogen, deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, -OH, -CN, a C-C alkoxy group, -NH, -NH-C-C alkyl group, -OC(=O)C-C alkyl group, or -N(C-C alkyl)(C-C alkyl), wherein the C-C alkyl group, C-C cycloalkyl group, C-C haloalkyl group, or C-C alkoxy group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C-C alkyl group, a C-C cycloalkyl group, a C-C alkoxy group, or a C-C haloalkyl group, or two Gs linked on the same carbon atom form an oxo group (=O), and / or in some embodiments, R A3 are independently selected from hydrogen, deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, —CN, a C-C alkoxy group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), wherein the C-C alkyl group, C-C cycloalkyl group, or C-C alkoxy group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C-C alkyl group, a C-C cycloalkyl group, a C-C alkoxy group, or a C-C haloalkyl group; and R IIIare independently selected from deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, —CN, a C-C alkoxy group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), wherein the C-C alkyl group, C-C cycloalkyl group, or C-C alkoxy group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C-C alkyl group, a C-C cycloalkyl group, a C-C alkoxy group, or a C-C haloalkyl group; and in some other embodiments, R A3 and R III are each independently selected from deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —CN, a C1-C6 alkoxy group, —NH, —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, or C1-C6 alkoxy group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; e is selected from 0, 1, 2 or 3; f is selected from 0, 1 or 2.

[0058] In some embodiments, A is selected from groups A1, A2, and A3; The groups in the A1 group are [ka] and In group A1, R A1are 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, said monocyclic ring or bicyclic ring optionally substituted with 0, 1, 2, or 3 groups selected from deuterium, halogen, C-C alkyl group, C-C cycloalkyl group, C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R AI are each independently selected from deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C 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, and m4 is selected from 0 or 1; The groups in group A2 are [ka] and R in group A2 I and R II are each independently selected from deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, -OH, -CN, a C-C alkoxy group, -NH, -NH-C-C alkyl group, -OC(=O)C-C alkyl group, or -N(C-C alkyl)(C-C alkyl), and two R IImay together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, or C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; R A2 are each independently selected from hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, —NH, —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl) or a C3-C8 cycloalkyl-C1-C6 alkylene group, wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C3-C8 cycloalkyl-C1-C6 alkylene group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group or a C1-C4 haloalkyl group; m5 is selected from 0, 1, 2 or 3, m6 is selected from 0, 1 or 2, n1 is selected from integers of 0 to 4, n2 is selected from integers of 0 to 6, n3 is selected from integers of 0 to 8, n4 is selected from integers of 0 to 2, n5 is selected from 0 or 1, n7 is selected from integers of 0 to 3, q ​​is 0 or 1, s is selected from integers of 0 to 6, t is selected from integers of 0 to 8, and r is selected from 0 or 1; The groups in group A3 are: [ka] and In group A3, G, R A3 and R IIIare each independently as defined above. For example, in some embodiments, each G is independently selected from hydrogen, deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, a C-C alkoxy group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), wherein the C-C alkyl group, C-C cycloalkyl group, C-C haloalkyl group, or C-C alkoxy group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C-C alkyl group, a C-C cycloalkyl group, a C-C alkoxy group, or a C-C haloalkyl group; and / or in some embodiments, R A3 are independently selected from hydrogen, deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, a C-C alkoxy group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), wherein the C-C alkyl group, C-C cycloalkyl group, C-C alkyl group, or C-C alkoxy group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C-C alkyl group, a C-C cycloalkyl group, a C-C alkoxy group, or a C-C haloalkyl group; and R III are independently selected from deuterium, halogen, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, a C-C alkoxy group, —NH, —NH—C-C alkyl group, —OC(═O)C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), wherein the C-C alkyl group, C-C cycloalkyl group, C-C alkyl group, or C-C alkoxy group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C-C alkyl group, a C-C cycloalkyl group, a C-C alkoxy group, or a C-C haloalkyl group; and in some other embodiments, R A3 and R IIIare each independently selected from deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, —NH, —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkyl group, or C1-C6 alkoxy group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; e is selected from 0, 1, 2 or 3; f is selected from 0, 1 or 2;

[0059] In some embodiments, A is selected from a group in the A1 group, where R A1 are each independently selected from saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic rings containing zero or one N atom, said monocyclic rings being optionally substituted with zero, one, two or three groups selected from deuterium, halogen, —CN, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R AI are each independently selected from deuterium, halogen, —CN, a C-C alkyl group, a C-C haloalkyl group, —OH, —O—C-C alkyl group, —C-C alkylene-O—C-C alkyl group, a C-C haloalkoxy group, —NH, —NH—C-C alkyl group, and —N(C-C alkyl)(C-C 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; and m4 is selected from 0 or 1.

[0060] In some embodiments, A is selected from a group in the A1 group, where R A1are each independently selected from saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic rings containing zero or one N atom, said monocyclic rings being optionally substituted with zero, one, two or three groups selected from deuterium, halogen, —CN, a C-C alkyl group, a C-C cycloalkyl group, a C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R AI are each independently selected from deuterium, halogen, —CN, a C-C alkyl group, a C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, and —N(C-C alkyl)(C-C 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; and m4 is selected from 0 or 1.

[0061] In some embodiments, A is selected from the groups in the A1 group: R in A1 group A1 are each independently selected from saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic rings containing zero or one N atom, said monocyclic rings being optionally substituted with zero, one, two or three groups selected from deuterium, halogen, C-C alkyl group, C-C cycloalkyl group, C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R AI are each independently selected from deuterium, halogen, a C-C alkyl group, a C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, and —N(C-C alkyl)(C-C 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; and m4 is selected from 0 or 1.

[0062] In some embodiments, A is selected from the groups in the A1 group.

[0063] In some embodiments, R A1 are each independently selected from saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic rings containing 0 or 1 N atom, said monocyclic rings being optionally substituted with 0, 1, 2 or 3 groups selected from deuterium, halogen, C-C alkyl group, C-C cycloalkyl group, C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), preferably R A1 are each independently selected from saturated 5- or 6-membered monocyclic rings containing 0 or 1 N atom, said monocyclic rings being optionally substituted with 0, 1, 2, or 3 groups selected from deuterium, halogen, C-C alkyl group, C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl).

[0064] In some embodiments, R AI are each independently selected from deuterium, halogen, a C-C alkyl group, a C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, and —N(C-C alkyl)(C-C alkyl), preferably R AI are each independently selected from deuterium, halogen, a C1-C6 alkyl group, —OH, —O—C1-C6 alkyl group, —NH2, —NH—C1-C6 alkyl group, and —N(C1-C6 alkyl)(C1-C6 alkyl).

[0065] 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.

[0066] In some embodiments, A is selected from a group in the A1 group, where R A1 are each independently selected from saturated 5- or 6-membered monocyclic rings containing 0 or 1 N atom, said monocyclic rings being optionally substituted with 0, 1, 2, or 3 groups selected from deuterium, halogen, C-C alkyl group, C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R AI are each independently selected from deuterium, halogen, —CN, a C1-C6 alkyl group, —OH, —O—C1-C6 alkyl group, —NH2, —NH—C1-C6 alkyl group, and —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; and m4 is selected from 0 or 1.

[0067] In some embodiments, A is selected from a group in the A1 group, where R A1 are each independently selected from saturated 5- or 6-membered monocyclic rings containing 0 or 1 N atom, said monocyclic rings being optionally substituted with 0, 1, 2, or 3 groups selected from deuterium, halogen, C-C alkyl group, C-C haloalkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R AI are each independently selected from deuterium, halogen, a C-C alkyl group, —OH, —O—C-C alkyl group, —NH, —NH—C-C alkyl group, and —N(C-C alkyl)(C-C 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; and m4 is selected from 0 or 1.

[0068] In some embodiments, A is [ka] where R A1 , R AI , m1, m3 are as defined above, and preferably, A is [ka] where R A1 , R AI , m1, and m3 are selectable ranges as defined above.

[0069] In some embodiments, A is [ka] where R A1 , R AI , m1, m3 are as defined above, and preferably, A is [ka] where R A1 , R AI , m1, and m3 are selectable ranges as defined above.

[0070] In some embodiments, A is selected from the groups in the A2 group.

[0071] In some embodiments, A is [ka] where R I , R II , R A2 , n1, n2, n3, m5 are as defined above, and preferably R I and R IIare each independently selected from deuterium, halogen, a C-C alkyl group, a C-C haloalkyl group, —OH, a C-C alkoxy group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), and two R II can form a C3-C6 cycloalkyl group together with the carbon atom to which they are attached, and R A2 are each independently selected from hydrogen, deuterium, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 haloalkyl group, wherein the C1-C6 alkyl group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 alkoxy group; m5 is selected from 0, 1, 2, or 3; n1 is selected from integers of 0 to 2; n2 is selected from integers of 0 to 2; and n3 is selected from integers of 0 to 2.

[0072] In some embodiments, A is [ka] where R I , R II , R A2 , n1, m5 are as defined above, and preferably R I and R II are each independently selected from deuterium, halogen, a C-C alkyl group, a C-C haloalkyl group, —OH, a C-C alkoxy group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), and two R II can form a C3-C6 cycloalkyl group together with the carbon atom to which they are attached, and R A2are each independently selected from hydrogen, deuterium, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 haloalkyl group, wherein the C1-C6 alkyl group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 alkoxy group; m5 is selected from 0, 1, 2, or 3; and n1 is selected from an integer of 0 to 2.

[0073] In some embodiments, A is [ka] where R I , R II , R A2 , n1, m5 are as defined above, and preferably R I and R II are each independently selected from deuterium, halogen, a C-C alkyl group, a C-C haloalkyl group, —OH, a C-C alkoxy group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), and two R II can form a C3-C6 cycloalkyl group together with the carbon atom to which they are attached, and R A2 are each independently selected from hydrogen, deuterium, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 haloalkyl group, wherein the C1-C6 alkyl group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 alkoxy group; m5 is selected from 0, 1, 2, or 3; and n1 is selected from an integer of 0 to 2.

[0074] In some embodiments, A is [ka] where R I , R II , R A2, n4, n5, m5, m6, and q are selectable within the ranges defined above. Preferably, R I and R II are each independently selected from deuterium, halogen, a C-C alkyl group, —OH, —CN, a C-C alkoxy group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R A2 are each independently selected from a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl-C1-C4 alkyl group, wherein said C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 haloalkyl group, and C3-C6 cycloalkyl-C1-C4 alkyl group are optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; 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; and q is selected from 0 or 1; More preferably, R A2 are each independently selected from a C1-C6 alkyl group or a C3-C6 cycloalkyl-C1-C2 alkyl group, and the C1-C6 alkyl group or C3-C6 cycloalkyl-C1-C2 alkyl group is optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, —OH, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, and a C1-C4 haloalkyl group; More preferably, R A2 are each independently a methyl group, [ka] is selected from Even more preferably, R A2 are each independently [ka] is selected from.

[0075] In some embodiments, A is [ka] where R I , R II , R A2 , n4, m5 are selectable ranges as defined above, Preferably, R I and R II are each independently selected from deuterium, halogen, a C-C alkyl group, —OH, —CN, a C-C alkoxy group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R A2 are each independently selected from a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl-C1-C4 alkyl group, wherein the C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 haloalkyl group, and C3-C6 cycloalkyl-C1-C4 alkyl group are optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; m5 is selected from 0 or 1; and n4 is selected from 0 or 1; More preferably, R A2 are each independently selected from a C1-C6 alkyl group or a C3-C6 cycloalkyl-C1-C2 alkyl group, and the C1-C6 alkyl group or C3-C6 cycloalkyl-C1-C2 alkyl group is optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, —OH, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, and a C1-C4 haloalkyl group; More preferably, R A2 are each independently a methyl group, [ka] is selected from Even more preferably, RA2 are each independently [ka] is selected from.

[0076] In some embodiments, A is [ka] where R I , R II , R A2 , n5, m5 are selectable ranges as defined above, Preferably, R I and R II are each independently selected from deuterium, halogen, a C-C alkyl group, —OH, —CN, a C-C alkoxy group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R A2 are each independently a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl-C1-C4 alkyl group, -S(O)-R z1 or -S(O)2-R z1 wherein the C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 haloalkyl group, and C3-C6 cycloalkyl-C1-C4 alkyl group are optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; and each R z1 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, m5 is selected from 0 or 1, and n5 is selected from 0 or 1; More preferably, R A2 are each independently [ka] or —S(O)2—CF3.

[0077] In some embodiments, A is [ka] where R I , R II , R A2 , n5, m5 are selectable ranges as defined above, Preferably, R I and R II are each independently selected from deuterium, halogen, a C-C alkyl group, —OH, —CN, a C-C alkoxy group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl); R A2 are each independently a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl-C1-C4 alkyl group, -S(O)-R z1 or -S(O)2-R z1 wherein the C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 haloalkyl group, and C3-C6 cycloalkyl-C1-C4 alkyl group are optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; and each R z1 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, m5 is selected from 0 or 1, and n5 is selected from 0 or 1; More preferably, R A2 are each independently [ka] or —S(O)2—CF3.

[0078] In some embodiments, A is [ka] where RI , R II , R A2 , n1, m5, and m6 are selectable ranges as defined above.

[0079] In some embodiments, wherein A is [ka] where R I , R II , R A2 , n1, m5, and m6 are selectable ranges as defined above.

[0080] In some embodiments, A is [ka] where R I , m5, m6 are selectable ranges as defined above.

[0081] In some embodiments, A is [ka] where R I , m5, m6 are selectable ranges as defined above.

[0082] In some embodiments, A is selected from the groups in the A3 group.

[0083] In some embodiments, each G is independently selected from hydrogen, deuterium, halogen, a C-C alkyl group, a deuterated C-C alkyl group, a C-C haloalkyl group, —OH, a C-C alkoxy group, a C-C haloalkoxy group, a C-C deuterated alkoxy group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), or two Gs linked on the same carbon atom form an oxo group (═O).

[0084] In some embodiments, R A3 are independently selected from hydrogen, deuterium, halogen, —CN, a C-C alkyl group, a C-C haloalkyl group, a C-C deuterated alkyl group, OH, a C-C alkoxy group, a C-C haloalkoxy group, a C-C deuterated alkoxy group, —O—C3-C8 cycloalkyl group, —NH, —NH—C-C alkyl group, —C(═O)NH—C-C alkyl group, —C(═O)N(C-C alkyl)(C-C alkyl), a phenyl group, a 5- to 6-membered monocyclic heteroarylene-C-C alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, a 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 N atoms, or —N(C-C alkyl)(C-C alkyl).

[0085] In some embodiments, R III are independently selected from deuterium, halogen, —CN, a C-C alkyl group, a C-C haloalkyl group, a C-C deuterated alkyl group, OH, a C-C alkoxy group, a C-C haloalkoxy group, a C-C deuterated alkoxy group, —O—C3-C8 cycloalkyl group, —NH, —NH—C-C alkyl group, —C(═O)NH—C-C alkyl group, —C(═O)N(C-C alkyl)(C-C alkyl), a phenyl group, a 5- to 6-membered monocyclic heteroarylene-C-C alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, a 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 N atoms, or —N(C-C alkyl)(C-C alkyl).

[0086] In some embodiments, R A3 and R IIIare each independently selected from deuterium, halogen, —CN, a C-C alkyl group, a C-C haloalkyl group, a C-C deuterated alkyl group, OH, a C-C alkoxy group, a C-C haloalkoxy group, a C-C deuterated alkoxy group, —O—C3-C8 cycloalkyl group, —NH, —NH—C-C alkyl group, —C(═O)NH—C-C alkyl group, —C(═O)N(C-C alkyl)(C-C alkyl), a phenyl group, a 5- to 6-membered monocyclic heteroarylene-C-C alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, a 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 N atoms, or —N(C-C alkyl)(C-C alkyl).

[0087] In some embodiments, each G is independently selected from hydrogen, deuterium, halogen, a C-C alkyl group, a deuterated C-C alkyl group, a C-C haloalkyl group, —OH, a C-C alkoxy group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), or two Gs linked on the same carbon atom form an oxo group (═O).

[0088] In some embodiments, R A3 are independently selected from hydrogen, deuterium, halogen, a C-C alkyl group, a C-C haloalkyl group, —OH, a C-C alkoxy group, —NH, —NH—C-C alkyl group, or —N(C-C alkyl)(C-C alkyl), and R III are independently selected from deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, —NH2, —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl).

[0089] In some embodiments, R A3 and R IIIare each independently selected from deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, —NH2, —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl).

[0090] In some embodiments, e is selected from 0, 1, or 2.

[0091] In some embodiments, f is selected from 0 or 1.

[0092] In some embodiments, A is [ka] and is selected from any one of the groups A is preferably [ka] is selected from any one of the groups:

[0093] In some embodiments, A is [ka] and is selected from any one of the groups A is preferably [ka] is selected from any one of the groups:

[0094] In some embodiments, A is [ka] and is selected from any one of the groups A is preferably [ka] is selected from any one of the groups:

[0095] In some embodiments, A is [ka] wherein G, R III , R A3 , e can be selected from the ranges defined above.

[0096] In some embodiments, A is [ka] wherein G, R III , R A3 , e can be selected from the ranges defined above.

[0097] In some embodiments, A is [ka] wherein G, R III , the selectable range of e is as defined above, and preferably A is [ka] is selected from.

[0098] In some embodiments, A is [ka] wherein G, R III , the selectable range of e is as defined above, and preferably A is [ka] is.

[0099] In some embodiments, A is [ka] wherein G, R III , R A3 , the selectable range of e is as defined above, and preferably A is [ka] is.

[0100] In some embodiments, each G is independently selected from hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, —OH, a C1-C6 alkoxy group; or two Gs linked on the same carbon atom form a 3- to 6-membered cycloalkyl group, which C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, or 3- to 6-membered cycloalkyl group may optionally be substituted with 1 to 2 substituents selected from deuterium, F, Cl, and Br; Each R III are independently selected from deuterium, halogen, —CN, a C-C alkyl group, a C-C alkoxy group, a C-C haloalkyl group, a C-C deuterated alkyl group, —OH, —O—C3-C8 cycloalkyl group, a C-C haloalkoxy group, a C-C deuterated alkoxy group, —NH, —NH—C-C alkyl group, —C(═O)NH—C-C alkyl group, —C(═O)N(C-C alkyl)(C-C alkyl), a phenyl group, a 5-6 membered monocyclic heteroarylene-C-C alkyl group containing 1, 2 or 3 N atoms, a 5-6 membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, a 5-6 membered monocyclic heteroaryl group containing 1, 2 or 3 N atoms, or —N(C-C alkyl)(C-C alkyl); e is selected from 0, 1 or 2; f is selected from 0 or 1;

[0101] In some embodiments, each G is independently selected from hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, and a C1-C6 alkoxy group, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, and C1-C6 alkoxy group are optionally substituted with 1 to 2 substituents selected from deuterium, F, Cl, and Br; Each R III are independently selected from deuterium, halogen, —CN, a C1-C6 alkyl group, or a C1-C6 alkoxy group; e is selected from 0, 1 or 2; f is selected from 0 or 1;

[0102] In some embodiments, A is [ka] wherein G, R III The selectable ranges of e and f are as defined above, and preferably, each G is independently selected from hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, and a C1-C6 alkoxy group, and the C1-C6 alkyl group, C1-C6 haloalkyl group, and C1-C6 alkoxy group may optionally be substituted with 1 to 2 substituents selected from deuterium, F, Cl, and Br, and each R III is independently selected from deuterium, halogen, —CN, a C1-C6 alkyl group, and a C1-C6 alkoxy group; e is selected from 0, 1, or 2; and f is selected from 0 or 1.

[0103] In some embodiments, A is [ka] wherein G, R IIIThe selectable ranges of e and f are as defined above, and preferably, each G is independently selected from hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, and a C1-C6 alkoxy group, and the C1-C6 alkyl group, C1-C6 haloalkyl group, and C1-C6 alkoxy group may optionally be substituted with 1 to 2 substituents selected from deuterium, F, Cl, and Br, and each R III is independently selected from deuterium, halogen, —CN, a C1-C6 alkyl group, or a C1-C6 alkoxy group; e is selected from 0, 1, or 2; and f is selected from 0 or 1.

[0104] In some embodiments, A is [ka] wherein G, R III The selectable range of e is as defined above, and preferably, each G is independently selected from hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, and a C1-C6 alkoxy group, and the C1-C6 alkyl group, C1-C6 haloalkyl group, and C1-C6 alkoxy group may optionally be substituted with 1 to 2 substituents selected from deuterium, F, Cl, and Br, and each R III is independently selected from deuterium, halogen, —CN, a C1-C6 alkyl group, or a C1-C6 alkoxy group; e is selected from 0, 1, or 2; and f is selected from 0 or 1.

[0105] In some embodiments, A is [ka] wherein G, R IIIThe selectable range of e is as defined above, and preferably, each G is independently selected from hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, and a C1-C6 alkoxy group, and the C1-C6 alkyl group, C1-C6 haloalkyl group, and C1-C6 alkoxy group may optionally be substituted with 1 to 2 substituents selected from deuterium, F, Cl, and Br, and each R III is independently selected from deuterium, halogen, —CN, a C1-C6 alkyl group, or a C1-C6 alkoxy group; e is selected from 0, 1, or 2; and f is selected from 0 or 1.

[0106] In some embodiments, A is [ka] wherein G, R III , e can be selected from the ranges defined above.

[0107] In some embodiments, A is [ka] wherein G, R III , e can be selected from the ranges defined above.

[0108] In some embodiments, A is [ka] wherein G, R III , e can be selected from the ranges defined above.

[0109] In some embodiments, A is [ka] wherein G, R III, e can be selected from the ranges defined above.

[0110] In some embodiments, A is [ka] wherein G, R III , e can be selected from the ranges defined above.

[0111] In some embodiments, A is [ka] wherein G, R III , e can be selected from the ranges defined above.

[0112] In some embodiments, A is [ka] wherein G, R III , e can be selected from the ranges defined above.

[0113] In some embodiments, A is [ka] wherein G, R III , e can be selected from the ranges defined above.

[0114] In some embodiments, A is [ka] wherein G, R III , e can be selected from the ranges defined above.

[0115] In some embodiments, A is [ka] wherein G, R III , e can be selected from the ranges defined above.

[0116] In some embodiments, A is selected from any one of the following groups:

[0117] [Table 3-1] [Table 3-2] In some embodiments, A is selected from any one of the following groups:

[0118] [Table 4-1] [Table 4-2]

[0119] In some embodiments, A is

[0120] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] TIFF2026508745000093.tif238170 [Table 5-8] is selected from any one of the groups:

[0121] In some embodiments, A is

[0122] [Table 6-1] [Table 6-2] [Table 6-3] TIFF2026508745000098.tif226170 [Table 6-4] is selected from any one of the groups:

[0123] In some embodiments, A is

[0124] [Table 7-1] [Table 7-2] is selected from any one of the groups:

[0125] In some embodiments, A is

[0126] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] is selected from any one of the groups:

[0127] In some embodiments, A is

[0128] [Table 9-1] [Table 9-2] [Table 9-3] TIFF2026508745000112.tif229170 [Table 9-4] is selected from any one of the groups:

[0129] In some embodiments, A is

[0130] [Table 10-1] [Table 10-2] [Table 10-3] TIFF2026508745000117.tif225170 [Table 10-4] [Table 10-5] is selected from any one of the groups:

[0131] In some embodiments, A is

[0132] [Table 11] is selected from any one of the groups:

[0133] In some embodiments, A is

[0134] [Table 12-1] [Table 12-2] is selected from any one of the groups:

[0135] In some embodiments, L is —NR 3 CONR 3 and / or X is CR7 and R7 is -NR a R a is.

[0136] In some embodiments, R 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 (a)R 12 is H, (b)R 12is an oxetanyl group, a cyclopropyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F, Cl), and a C1-C6 alkoxy group; or (c)R 12 is a C1-C6 alkyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and a C1-C6 alkoxy group.

[0137] In some embodiments, the group -ZR 12 is -N=S(=O)-(R 12 )2, where two R 12 can alternatively be combined with the sulfur atom to which they are respectively 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; or the group -ZR 12 In the formula, Z is a single bond and R 12 is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are selected from the group consisting of F, Cl, Br, C1-C6 alkyl groups, C1-C6 haloalkyl groups, -OR m , -OC1-C6 haloalkyl group, 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 alkylNR m R m , -OC2-C6 alkyl OR m , -SR m , -S(=O)R n , -S(=O)2R n , -S(=O)2NRm 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)NR m R m , -NR m C2-6 alkyl NR m R m , -NR m C2-C6 alkyl OR m , -C1-C6 alkylNR m R m , -C1-C6 alkyl OR m , -C1-C6 alkylN(R m )C(=O)R n , -C1-C6 alkylOC(=O)R n , -C1-C6 alkylC(=O)NR m R m , -C1-C6 alkylC(=O)OR m and oxo, and R m and R n is independently selected from H and a -C1-C6 alkyl group.

[0138] In some embodiments, R is a group -ZR 12 where Z is -NHSO2- or -SO2NH-, and R 12 is an oxetanyl group, a cyclopropyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and C1-C6 alkoxy groups; or R 12is a C1-C6 alkyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and a C1-C6 alkoxy group.

[0139] In some embodiments, R1 is

[0140] [Table 13] is selected from the group:

[0141] In some embodiments, R x teeth, [ka] is selected from the group consisting of or alternatively, R 10a and R 10b vs. R 10c and R 10d vs. R 10e and R 10f vs. R 10g and R 10 h pair or R 10i and R 10j Each of the pairs independently, in combination with the carbon atom to which they are respectively attached, forms R x A saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring can be formed spiro-bonded to the ring, wherein the 3-, 4-, 5-, or 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-, 4-, 5-, or 6-membered monocyclic ring is selected from F, Cl, Br, a C1-C6 alkyl group, a C1-C4 haloalkyl group, -OR a , -OC1-C4 haloalkyl group, CN, -NR a R a or oxo; R 10kis selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing H, 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, said monocyclic or bicyclic rings being selected from the group consisting of F, Cl, Br, C1-C6 alkyl groups, C1-C6 haloalkyl groups, -OR a , -OC1-C6 haloalkyl group, 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 alkylNR a R a , -OC2-C6 alkyl 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)NR a R a , -NR a C2-6 alkyl NR a R a , -NR a C2-C6 alkyl OR a , -C1-C6 alkylNR a Ra , -C1-C6 alkyl OR a , -C1-C6 alkylN(R a )C(=O)R b , -C1-C6 alkylOC(=O)R b , -C1-C6 alkylC(=O)NR a R a , -C1-C6 alkylC(=O)OR a and oxo, and R a and R b is independently selected from H and a -C1-C6 alkyl group; R 10l is selected from the group consisting of F, Cl, Br, a C1-C6 alkoxy group, an —O—C1-C6 haloalkyl group, or a C1-C6 alkyl group substituted with 0, 1, 2, 3, 4, or 5 groups of CN.

[0142] In some embodiments, R x teeth, [ka] is selected from.

[0143] In some embodiments, the compound of Formula (I) is a compound of Formula (IC-1) or Formula (IC-1′): [ka] where A is selected from the group A1 and R a is H or a C1-C4 alkyl group.

[0144] In some embodiments, the compound of Formula (I) is a compound of Formula (IC-2) or Formula (IC-2′): [ka] where A is selected from the group A1 and R a is H or a C1-C4 alkyl group.

[0145] In some embodiments, the compound of formula (I) is a compound shown in formula (IA-1): [ka] where L, R X , R1, X7, X8, X9, R A2 , R I , R II The selectable ranges of n4 and m5 are as defined above, and preferably, the compound represented by formula (IA-1) is [ka] is.

[0146] In some embodiments, the compound of formula (I) is a compound shown in formula (IA-2): [ka] where L, R X , R1, X7, X8, X9, R A2 , R I , R II The selectable ranges of n5 and m5 are as defined above, and preferably, the compound represented by formula (IA-2) is [ka] is.

[0147] In some embodiments, the compound of formula (I) is a compound shown in formula (IA-3): [ka] where L, R X , R1, X7, X8, X9, R A2 , R I , R II The selectable ranges of n1 and m5 are as defined above, and preferably, the compound represented by formula (IA-3) is [ka] is.

[0148] In some embodiments, the compound of formula (I) is a compound shown in formula (IA-4): [ka] where L, R X , R1, X7, X8, X9, R A2 , R I , R II The selectable ranges of n1 and m6 are as defined above, and preferably, the compound represented by formula (IA-4) is [ka] is.

[0149] In some embodiments, the compound of formula (I) is a compound shown in formula (IA-5): [ka] where L, R X , R1, X7, X8, X9, R A2 , R I , R II The selectable ranges of n1 and m6 are as defined above, and preferably, the compound represented by formula (IA-5) is [ka] is.

[0150] In some embodiments, the compound of formula (I) is a compound shown in formula (IA-6): [ka] where L, R X , R1, X7, X8, X9, R A2 , R I , R II The selectable ranges of n4 and m5 are as defined above, and preferably, the compound represented by formula (IA-6) is [ka] is.

[0151] In some embodiments, the compound of formula (I) is a compound shown in formula (IA-7): [ka] where L, R X , R1, X7, X8, X9, R A2 , R I , R II The selectable ranges of n4 and m6 are as defined above, and preferably, the compound represented by formula (IA-7) is [ka] is.

[0152] In some embodiments, the compound of formula (I) is a compound shown in formula (IA-8): [ka] where L, R X , R1, X7, X8, X9, R A2 , R I , R II The selectable ranges of n4 and m6 are as defined above, and preferably, the compound represented by formula (IA-8) is [ka] is.

[0153] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-1): [ka] where L, R X , R1, X7, X8, X9, G, R IIIThe selectable range of e is as defined above, and preferably, the compound represented by formula (IB-1) is [ka] is.

[0154] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-2): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-2) is [ka] is.

[0155] In some embodiments, the compound of formula (IB-2) is [ka] is.

[0156] In some other embodiments, the compound of formula (IB-2) is [ka] is.

[0157] In some preferred embodiments, the compound of formula (IB-2) is [ka] is.

[0158] In some more preferred embodiments, the compound of formula (IB-2) is [ka] is.

[0159] In some other preferred embodiments, the compound of formula (IB-2) is [ka] is.

[0160] In some more preferred embodiments, the compound of formula (IB-2) is [ka] is.

[0161] In some such embodiments, preferably, R III is a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, or a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms and 1 or 2 atoms selected from O, In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1.

[0162] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-3): [ka] where L, R X , R1, X7, X8, X9, G, R III , R A3 The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-3) is [ka] is.

[0163] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-4): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-4) is [ka] is.

[0164] In some embodiments, the compound of formula (IB-4) is [ka] is.

[0165] In some preferred embodiments, the compound of formula (IB-4) is [ka] is.

[0166] In some more preferred embodiments, the compound of formula (IB-4) is [ka] is.

[0167] In some other embodiments, the compound of formula (IB-4) is [ka] and In some preferred embodiments, the compound of formula (IB-4) is [ka] is.

[0168] In some more preferred embodiments, the compound of formula (IB-4) is [ka] is.

[0169] In some such embodiments, preferably, R IIIis a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, or a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms and 1 or 2 atoms selected from O, In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1.

[0170] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-5): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-5) is [ka] is.

[0171] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-6): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-6) is [ka] is.

[0172] In some embodiments, the compound of formula (IB-6) is [ka] and In some preferred embodiments, the compound of formula (IB-6) is [ka] and In some more preferred embodiments, the compound of formula (IB-6) is [ka] is.

[0173] In some other embodiments, the compound of formula (IB-6) is [ka] is.

[0174] In some preferred embodiments, the compound of formula (IB-6) is [ka] is.

[0175] In some more preferred embodiments, the compound of formula (IB-6) is [ka] is.

[0176] In some such embodiments, preferably, R III is a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, or a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms and 1 or 2 atoms selected from O, In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1. In some preferred embodiments, each e is 1.

[0177] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-7): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-7) is [ka] is.

[0178] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-8): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-8) is [ka] is.

[0179] In some embodiments, the compound of formula (IB-8) is [ka] and In some preferred embodiments, the compound represented by formula (IB-8) is [ka] is.

[0180] In some more preferred embodiments, the compound of formula (IB-8) is [ka] is.

[0181] In some other embodiments, the compound of formula (IB-8) is [ka] is.

[0182] In some preferred embodiments, the compound represented by formula (IB-8) is [ka] is.

[0183] In some more preferred embodiments, the compound of formula (IB-8) is [ka] is.

[0184] In some such embodiments, preferably, R III is a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms, or a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2, or 3 N atoms and 1 or 2 atoms selected from O, a 5- to 6-membered monocyclic heteroaryl group, a 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 N atoms, or -N(C-C alkyl)(C-C alkyl); and / or each G is independently selected from hydrogen, deuterium, halogen, a C-C alkyl group, a C-C deuterated alkyl group, a C-C haloalkyl group, -OH, a C-C alkoxy group, a C-C haloalkoxy group, -NH, -NH-C-C alkyl group, or -N(C-C alkyl)(C-C alkyl); or two Gs linked on the same carbon atom form an oxo group (=O). In a further preferred embodiment, each e is 1.

[0185] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-9): [ka] where L, R X , R1, X7, X8, X9, G, RIII The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-9) is [ka] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-10): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-10) is [ka] is.

[0186] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-11): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-11) is [ka] is.

[0187] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-12): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-12) is [ka] is.

[0188] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-13): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-13) is [ka] is.

[0189] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-14): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-14) is [ka] is.

[0190] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-15): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-15) is [ka] is.

[0191] In some embodiments, the compound of formula (I) is a compound shown in formula (IB-16): [ka] where L, R X , R1, X7, X8, X9, G, R III The selectable range of e is as defined above, and preferably, the compound represented by formula (IB-16) is [ka] is.

[0192] In some embodiments, the compound of formula (I) is

[0193] [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6] [Table 14-7] [Table 14-8] [Table 14-9] [Table 14-10] Table 14-11 Table 14-12 Table 14-13 Table 14-14 Table 14-15 Table 14-16 Table 14-17 Table 14-18 Table 14-19 Table 14-20 Table 14-21 Table 14-22 Table 14-23 Table 14-24 Table 14-25 Table 14-26 [Table 14-27] [Table 14-28] [Table 14-29] [Table 14-30] [Table 14-31] [Table 14-32] [Table 14-33] [Table 14-34] The compound is selected from the group consisting of:

[0194] In some embodiments, the compound of formula (I) is

[0195] [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] [Table 15-7] [Table 15-8] [Table 15-9] [Table 15-10] [Table 15-11] [Table 15-12] [Table 15-13] [Table 15-14] TIFF2026508745000248.tif222170 [Table 15-15] The compound is selected from the group consisting of:

[0196] The present application further provides a pharmaceutical composition, comprising a compound of formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, and a pharmaceutically acceptable diluent or carrier.

[0197] Furthermore, the present application provides a method for treating a disease treatable with a KIF18A inhibitor, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition as described above.

[0198] In some embodiments, the disease is (a) a solid tumor or a blood-borne 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) leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; (c) hematopoietic tumors of the lymphatic system selected from acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) tumors of stromal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) cancers selected from the group consisting of melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, and Kaposi's sarcoma.

[0199] The present application further provides a method of reducing solid tumor size in a subject, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, or a pharmaceutical composition as described above.

[0200] The present application further provides a method of 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 a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, or a pharmaceutical composition as described above.

[0201] Furthermore, said cell proliferation disorder is a cell proliferation disorder, preferably mediating a cell proliferation disorder by affecting the cell cycle and mitosis.

[0202] The present application further provides a method for inhibiting KIF18A in a cell, the method comprising contacting the cell with a compound of formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition as described above.

[0203] Furthermore, the present application provides a use of a compound of formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or said pharmaceutical composition, in the manufacture of a medicament for treating a disease treatable with a KIF18A inhibitor.

[0204] In some embodiments, the disease is (a) a solid tumor or a blood-borne 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) leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; (c) hematopoietic tumors of the lymphatic system selected from acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) tumors of stromal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) cancers selected from the group consisting of melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, and Kaposi's sarcoma.

[0205] Furthermore, the present application provides the use of a compound of formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or said pharmaceutical composition, in the manufacture of a medicament for reducing solid tumor size in a subject.

[0206] Furthermore, the present application provides the use of a compound of formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or said pharmaceutical composition, in the manufacture of a medicament for treating a cell proliferation disorder in a subject.

[0207] Furthermore, the present application provides a use of a compound represented by formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or said pharmaceutical composition, in the manufacture of a drug for inhibiting KIF18A in a cell.

[0208] The compounds of formula (I) according to the present invention have novel structures and good KIF18A inhibitory activity, and can be used for the treatment, prevention, acute or chronic treatment of KIF18A-mediated diseases and disorders (including, but not limited to, cancer). DETAILED DESCRIPTION OF THE INVENTION

[0209] definition Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. References to technology used herein are intended to mean technology as commonly understood in the art, including modifications of the technology or substitution of equivalent technology that would be apparent to those skilled in the art. Although the following terms are believed to be well understood by those skilled in the art, the following definitions are provided to better interpret the present invention.

[0210] The terms "comprising," "including," "having," "containing," or "relating to," and other variations thereof herein, are inclusive or open-ended and do not exclude other elements or method steps not listed (i.e., these terms also cover "consisting essentially of" and "consisting of").

[0211] As used herein, the term "alkyl group" is defined as a straight-chain or branched-chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl group has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "Ci_6 alkyl group" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as halogen (the group is then referred to as a "haloalkyl group") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3). The term "C1-4 alkyl group" refers to a straight or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0212] As used herein, the term "alkylene group" means a divalent linear or branched saturated aliphatic hydrocarbon group obtained after an alkyl group, as defined above, loses one H. In some embodiments, the alkylene group has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "C alkylene group" 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 one or more (e.g., 1 to 3) suitable substituents, such as halogen (the group is then referred to as a "haloalkylene group") (e.g., -CF-, -CF-, -CHF-, -CHCF-, -CHCl-, or -CHCHCF-, etc.). The term "C alkylene" refers to a divalent straight or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene).

[0213] As can be easily understood by those skilled in the art, when an alkyl group is part of a substituent and is connected to another group on both sides, the term "alkyl group" is still used, and the term "alkyl group" is actually the corresponding alkylene group. For example, "-OC-C alkylNR a R a "The "C2-C6 alkyl group" in " is actually a "C2-C6 alkylene group."

[0214] As used herein, the term "alkoxy group" refers to an -O-alkyl group, wherein the alkyl group is as defined above. The term "Ci_6 alkoxy group" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentyloxy, or n-hexyloxy), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as halogen (in this case, the group is called a "haloalkoxy group") (e.g., -OCF3, -OC2F5, -OCHF2, -OCH2F, -OCH2CF3, -OCH2Cl, or -OCH2CH2CF3, etc.). The term "C1-4 alkoxy" refers to a linear or branched alkoxy group of 1 to 4 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy).

[0215] As used herein, the term "cycloalkyl group" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (e.g., bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthalenyl, etc.)), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms, suitably 3 to 10 carbon atoms. For example, the term "C cycloalkyl group" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as a cyclopropyl group substituted with a methyl group.

[0216] As used herein, the term "heterocyclyl group" refers to a saturated or partially unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring 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', where Ra' represents a hydrogen atom or a C1-6 alkyl group or a halo-C1-6 alkyl group. The heterocyclyl group may be linked to the remainder of the molecule via any one of the carbon atoms or the nitrogen atom, if present. In particular, a 3- to 10-membered heterocyclyl group is a group having 3 to 10 (e.g., 3 to 7, 4 to 6, or 5 to 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.

[0217] As used herein, the term "heterocyclyl group" includes parallel ring structures, the point of attachment of the parallel ring structure to another group may be at any one of the rings in the parallel ring structure. Therefore, the heterocyclyl group of the present invention further includes, but is not limited to, a heterocyclyl-fused heterocyclyl group, a heterocyclyl-fused cycloalkyl group, a monoheterocyclyl-fused monoheterocyclyl group, a monoheterocyclyl-fused monocycloalkyl group, such as a 3- to 7-membered (mono)heterocyclyl-fused 3- to 7-membered (mono)heterocyclyl group, a 3- to 7-membered (mono)heterocyclyl-fused (mono)cycloalkyl group, a 3- to 7-membered (mono)heterocyclyl-fused C4-6 (mono)cycloalkyl group, and examples thereof include, but are not limited to, a pyrrolidinyl-fused cyclopropyl group, a cyclopentyl-fused aziridinyl group, a pyrrolidinyl-fused cyclobutyl group, a pyrrolidinyl-fused pyrrolidinyl group, a pyrrolidinyl-fused piperidinyl group, a pyrrolidinyl-fused piperazinyl group, a piperidinyl-fused morpholinyl group, [ka] Including, but not limited to:

[0218] As used herein, the term "heterocyclyl group" includes bridged heterocyclyl groups and spiro heterocyclyl groups.

[0219] 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, nitrogen, and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, such as a 7- to 10-membered bridged heterocycle, an 8- to 10-membered bridged heterocycle, a 7- to 10-membered nitrogen-containing bridged heterocycle, a 7- to 10-membered oxygen-containing bridged heterocycle, or a 7- to 10-membered sulfur-containing bridged heterocycle. [ka] 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.

[0220] As used herein, the term "fused heterocyclyl group" refers to a two- or multi-membered heterocyclyl group (e.g., a two-membered heterocyclyl group, a three-membered heterocyclyl group, etc.) that covers a parallel ring structure, and the connection point between the parallel ring structure and another group may be at any one of the rings in the parallel ring structure. Thus, the fused heterocyclyl group of the present invention includes an aromatic ring-fused heterocyclyl group, a heterocyclyl-fused cycloalkyl group, a monoheterocyclyl group-fused monoheterocyclyl group, a monoheterocyclyl-fused monocycloalkyl group, a heteroaromatic ring-fused heterocyclyl group, for example, a 3- to 7-membered (mono)heterocyclyl-fused 3- to 7-membered (mono)heterocyclyl group, and a 3- to 7-membered (mono)heterocyclyl-fused (mono)cycloalkyl group. Further examples include, but are not limited to, a 3- to 7-membered (mono)heterocyclyl-fused C4-6 (mono)cycloalkyl group, a 6- to 10-membered (mono)aromatic ring-fused 3- to 7-membered (mono)heterocyclyl group, a 6- to 10-membered (mono)aromatic ring-fused 6- to 10-membered (bis)heterocyclyl group, a 6- to 10-membered (bis)aromatic ring-fused 6- to 10-membered (mono)heterocyclyl group, and a 6- to 10-membered (bis)aromatic ring-fused 6- to 10-membered (bis)heterocyclyl group.

[0221] As used herein, the term "aryl group" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C aryl group" refers to an aromatic group containing 6 to 14 (e.g., 6 to 12) carbon atoms, such as a phenyl group or a naphthyl group. The aryl group is optionally substituted with one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO, C alkyl group, etc.).

[0222] As used herein, the term "heteroaryl group" 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 has at least one heteroatom, which may be the same or different, such as oxygen, nitrogen or sulfur, and which may further be benzo-fused in each case. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl (1,2,3-triazolyl, 1,2,4-triazolyl), thiadiazolyl, etc., and their benzo derivatives, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.

[0223] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0224] As used herein, the term "haloalkyl group" refers to an alkyl group substituted with one or more (e.g., 1 to 3) of the same or different halogen atoms, wherein said alkyl group is as defined herein. The terms "C1-8 haloalkyl group," "C1-6 haloalkyl group," and "C1-4 haloalkyl group" refer to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0225] The term "substituted" refers to the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with the indicated group selection, provided that the normal valence for the designated atom in its current context is not exceeded and the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0226] When a substituent is described as being "optionally substituted with," the substituent may be (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as being optionally substituted with one or more in a list of substituents, one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be replaced singly and / or together with independently selected optional substituents. When a nitrogen of a substituent is described as being optionally substituted with one or more in a list of substituents, one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may be replaced with each independently selected optional substituent.

[0227] When substituents are described as being "independently selected from" a group, each substituent is selected independently of the others, and therefore each substituent can be the same or different from another (other) substituent.

[0228] As used herein, the term "one or more" means one or more than one, where reasonable, for example, two, three, four, five or ten.

[0229] Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position on the substituent.

[0230] When a substituent bond is shown to pass through a bond connecting two atoms in a ring (a "dangling bond"), unless otherwise stated, such substituent may be bonded to any one ring-forming atom in the substitutable ring. When an available ring member is shown to have a replaceable hydrogen atom, the replaceable hydrogen atom is substantially replaced (i.e., absent) when the dangling bond is attached to the available ring member.

[0231] As used herein, NRaRa groups and the like include substituents in which two Ra groups together with the N to which they are attached form a ring (optionally containing N, O, or S atoms), and include the following groups, e.g. [ka] The group N(Cα-β alkyl)Cα-β alkyl group (where α and β are as defined above and are the number of carbon atoms in the alkyl group) includes substituents in which the two Cα-β alkyl groups together form a ring (optionally containing an N, O or S atom), and includes the following groups, for example: [ka] Includes.

[0232] "Bicyclic" refers to a group having two connected rings. The bicycle may be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (in addition to carbon atoms, the ring atoms contain, for example, one, two, or three heteroatoms, such as N, O, or S). The two rings may either be aliphatic (e.g., decahydronaphthalene and norbornane), aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin).

[0233] Bicycles are (a) spirocyclic compounds, in which the two rings share only one atom (the spiroatom, which is commonly called a quaternary carbon), and examples of spirocyclic compounds are [ka] spirocyclic compounds, including but not limited to: (b) Fused bicyclic compounds, in which the two rings share two adjacent atoms, in other words, the rings share one covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-tiudiene and decahydronaphthalene), and examples of fused bicyclic rings are [ka] and fused bicyclic compounds, including but not limited to: (c) Bridged bicyclic compounds, in which two rings share three or more atoms and a bridge containing at least one atom separates the two bridgehead atoms, such as norbornane, also known as bicyclo[2.2.1]heptane, which is recognized as a pair of cyclopentane rings, each ring sharing three of their five carbon atoms; an example of a bridged bicyclic ring is [ka] and bridged bicyclic compounds, including but not limited to:

[0234] Benzomonoheterocycle refers to a bicyclic ring formed by the fusion of a phenyl group with one (mono)heterocyclyl group.

[0235] A monobenzoheteroaromatic ring refers to a bicyclic ring formed by the fusion of a phenyl group with one (mono)heteroaryl group.

[0236] Benzobisheterocycle refers to a tricyclic ring formed by the fusion of a phenyl group with one bicyclic heterocyclyl group.

[0237] A nitrogen-containing heteroaryl-fused monoheterocycle refers to a bicycle formed by the fusion of a nitrogen-containing heteroaryl group with one (mono)heterocyclyl group.

[0238] A nitrogen-containing heteroaryl-fused monoheteroaromatic ring refers to a bicyclic ring formed by fusing a nitrogen-containing heteroaryl group with one (mono)heteroaryl.

[0239] A nitrogen-containing heteroaryl-fused bis-heterocycle refers to a tricyclic ring formed by the fusion of a nitrogen-containing heteroaryl group with one bicyclic heterocyclyl group.

[0240] The present invention further includes all pharmaceutically acceptable isotopically labeled compounds, which are the same as the compounds of the present invention except that one or more atoms are replaced with atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in 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., C, C, and C), isotopes of chlorine (e.g., Cl), isotopes of fluorine (e.g., F), isotopes of iodine (e.g., I and I), isotopes of nitrogen (e.g., N and N), isotopes of oxygen (e.g., O, O, and O), isotopes of phosphorus (e.g., P), and isotopes of sulfur (e.g., S). Some isotopically labeled compounds of the present invention (e.g., those incorporating a radioactive isotope) can be used in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotopes tritium (i.e., 3H) and carbon-14 (i.e., 14C) are particularly useful for this purpose due to their ease of incorporation and ready detection. Substitution with positron-emitting isotopes (e.g., 11C, 18F, 15O, and 13N) can be used to verify substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by the accompanying routes and / or analogous methods described in the Examples and Preparations, by substituting appropriate isotopically labeled reagents for previously employed unlabeled reagents. Pharmaceutically acceptable solvates of the present invention include those in which the solvent of crystallization may be isotopically substituted, e.g., DO, acetone-d6, or DMSO-d6.

[0241] The term "stereoisomer" refers to an isomer formed by at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. Certain individual molecules may exist in geometric isomers (cis / trans). Similarly, compounds of the present invention may exist in rapidly equilibrating mixtures of two or more structurally distinct forms (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of this application covers all such isomers in any percentage (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0242] In this specification, a solid line [ka] , solid wedge [ka] or dotted wedge [ka] The chemical bonds of the compounds of the present invention can be depicted using the following symbols. Drawing bonds connected to asymmetric carbon atoms using a solid line is intended to include all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.). Drawing bonds connected to asymmetric carbon atoms using a solid or dotted wedge is intended to indicate the existence of the depicted stereoisomer. When present in a racemic mixture, the solid or dotted wedge is used to define relative stereochemistry, rather than absolute stereochemistry. Unless otherwise specified, it is intended that the compounds of the present invention can exist in the form of stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention can exhibit one or more types of isomerization and can be comprised of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0243] It should be further understood that some compounds of the present invention may be present in free form for treatment, or may be present in their pharmaceutically acceptable derivative form, when appropriate. In the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable salt, ester, solvate, metabolite, or prodrug, which, upon administration to a patient in need thereof, can directly or indirectly provide the compound of the present invention or a metabolite or residue thereof. Therefore, when referring to a "compound of the present invention" herein, it is also intended to include the various derivative forms of the compound.

[0244] In this specification, the wavy line [ka] The chemical bonds of the compounds of the present invention can be depicted using the following formula: The use of a wavy line to depict a bond attached to an asymmetric carbon atom includes the absolute configuration at that carbon atom (e.g., R or S configuration).

[0245] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base salts thereof.

[0246] Suitable acid addition salts are formed with acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, hydrogensulfate / sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, and other similar salts.

[0247] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts and other similar salts.

[0248] 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.

[0249] As used herein, the term "ester" refers to an ester derived from a compound of each general formula in this application, including physiologically hydrolyzable esters (compounds of the invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the invention themselves may be esters.

[0250] The present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0251] The compounds of the present invention may exist in the form of solvates, preferably hydrates, in which the compounds of the present invention contain a polar solvent, in particular water, methanol or ethanol, as a structural element of the crystal lattice of said compounds. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0252] Further included within the scope of this invention are metabolites of the compounds of this invention, i.e., substances formed in the body upon administration of a compound of this invention. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of this invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0253] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are derivatives of the compounds of the present invention that themselves have little or no pharmacological activity and can be converted to the compounds of the present invention having the desired activity upon administration to or on the body, for example, by hydrolytic cleavage. Generally, such prodrugs are functional derivatives of the compounds that are readily converted to the desired therapeutically active compound in vivo. For further information regarding the use of prodrugs, see "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. E. B. Roche, 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 pro-moieties known to those skilled in the art (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0254] The present invention further includes compounds of the present invention that contain protecting groups. During any process for preparing compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any relevant molecule, thereby forming a form of chemical protection for the compounds of the present invention. This can be achieved using common protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. The protecting groups can be removed at a suitable subsequent stage using methods known in the art.

[0255] As used herein, the term "about" refers to within ±10% of the numerical value, preferably within ±5%, and more preferably within ±2%.

[0256] The present invention will be further described below with reference to specific examples. It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. Experimental methods for which specific conditions are not specified in the following examples generally follow general conditions.

[0257] Some representative compounds of the present invention can be prepared by the following synthetic methods. In each of the following reaction schemes, the reagents and conditions for each step can be selected from common reagents or conditions used by a person skilled in the art for such preparation methods. After the structure of the compound of the present invention is disclosed, the selection can be made by a person skilled in the art based on his or her knowledge in the art. Example 1: Synthesis of 2-amino-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (1) [ka]

[0258] Step 1: Synthesis of Compound 1-2 Compound 1-1 (2.0 g, 7.967 mmol) and (2,4-dimethoxyphenyl)methylamine (1.20 mL, 7.97 mmol) were dissolved in DMF (10 mL) and Cs2CO3 (5191.62 mg, 15.93 mmol) was added. The reaction mixture was placed in an oil bath at 60 °C and stirred for 1 h. 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 = 40:1 to 20:1) to give compound 1-2.

[0259] Step 2: Synthesis of Compounds 1-3 6-Azaspiro[2.5]octane hydrochloride (714.04 mg, 4.84 mmol) was dissolved in DMSO (10 mL), NaH (338.52 mg, 14.11 mmol) was added, and the mixture was stirred for a while. Compound 1-2 (1.6 g, 4.03 mmol) was then added and the mixture was stirred at 125 °C overnight. After the reaction was complete, the reaction mixture was diluted with EA (60 mL), and the organic layer was washed with brine (80 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 49:1) to give compound 1-3.

[0260] Step 3: Synthesis of Compounds 1-4 To a solution of compound 1-3 (325 mg, 0.66 mmol) in MeOH (2 mL) and HO (0.1 mL), NaOH (79.69 mg, 1.99 mmol) was added and the mixture was stirred at 60 °C overnight. The reaction mixture was diluted with EA (50 mL). The organic layer was washed with brine (80 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 90:10 to 80:20) to give compound 1-4.

[0261] Step 4: Synthesis of Compounds 1-5 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. 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 NaSO, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 100:0 to 95:5 to 90:10) to give compound 1-5.

[0262] Step 5: Synthesis of Compounds 1-6 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 CsCO (110.78 mg, 0.34 mmol) were added to a reaction flask. Anhydrous 1,4-dioxane (2 mL) was added under argon gas protection, and the reaction was stirred at 100 °C for 4 h. The reaction mixture was diluted with EA (12 mL), and the organic layer was washed with brine (180 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 100:0, 90:10, 60:40) to give product compound 1-6.

[0263] Step 6: Synthesis of Compound 1 Compound 1-6 (85 mg, 0.13 mmol) was added to the reaction flask, followed by DCM (1 mL) and CF3COOH (0.3 mL, 0.13 mmol). The mixture 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 separation to give the product compound 1.

[0264] 1H 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). 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) [ka]

[0265] Step 1: Synthesis of compound 3-2 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 mixture of N,N-dimethylformamide (15 mL) and water (15 mL). N,N-diisopropyl-ethylamine (7.72 g, 59.75 mmol) was added, and the reaction mixture was placed in an oil bath at 100 °C and stirred for 6 h. 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. The crude product was purified by column chromatography (PE:EA = 98:2 to 95:5) to obtain compound 3-2.

[0266] Step 2: Synthesis of compound 3-3 Compound 3-2 (5.9 g, 17.24 mmol) was dissolved in a mixed solvent of MeOH (32 mL) and HO (8 mL). NaOH (4.14 g, 103.45 mmol) was added, and the reaction mixture was placed in an oil bath at 60 °C and stirred for 3 hours. After completion of the reaction, 2 M HCl was added to acidify the reaction mixture. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was dried over NaSO, filtered, and concentrated to obtain compound 3-3.

[0267] Step 3: Synthesis of Compound 3-4 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 completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 99:10 to 97:30) to obtain compound 3-4.

[0268] Step 4: Synthesis of Compounds 3-5 Compound 3-4 (159 mg, 0.31 mmol) was dissolved in DCM (2 mL) and the reaction mixture was cooled to 0 °C. Oxalyl chloride (119.78 mg, 0.94 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 0.5 hours. After completion of the reaction, the reaction mixture was directly dried by spin-drying 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 mixture was cooled to 0 °C. NaH (14.57 mg, 0.61 mmol) was added, and the reaction mixture was placed in an oil bath at 60 °C and stirred for 30 minutes. The reaction mixture was then cooled to 0 °C, and the acyl chloride obtained above was added. The reaction mixture was mixed and allowed to react at room temperature for 2 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 NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 97:3 to 95:5) to give compound 3-5.

[0269] Step 5: Synthesis of Compounds 3-6 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. The reaction mixture was placed in an oil bath and stirred at 180 °C for 2 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 97:3) to give compound 3-6.

[0270] Step 6: Synthesis of Compounds 3-7 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). Catalyst CAS: 1599466-83-7 (8.74 mg, 0.01 mmol) and cesium carbonate (30.96 mg, 0.10 mmol) were added. The reaction mixture was placed in an oil bath at 95 °C and stirred for 3 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 90:10 to 80:20) to give compound 3-7.

[0271] Step 7: Synthesis of Compound 3 Compound 3-7 (28 mg, 0.04 mmol) was dissolved in methanol (1 mL), and 10% palladium carbon (0.43 mg) was added thereto. The reaction mixture was placed in a hydrogen gas atmosphere and stirred overnight at room temperature. After completion of the reaction, the reaction mixture 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] + .

[0272] 1 H 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). Example 4: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(2-hydroxyethylsulfonamido)-2-methylamino-6-(6-azaspiro[2.5]octan-6-yl)benzamide (4) [ka]

[0273] Step 1: Synthesis of compound 4-2 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 mixture of DMF (25 mL) and HO (25 mL). CsCO (7.72 g, 59.75 mmol) was added, and the reaction mixture was placed in an oil bath at 100 °C and stirred for 3 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 98:2 to 95:5) to give compound 4-2.

[0274] Step 2: Synthesis of compound 4-3 Compound 4-2 (5.8 g, 16.95 mmol) was dissolved in a mixed solvent of MeOH (32 mL) and HO (8 mL). NaOH (4.07 g, 101.69 mmol) was added, and the reaction mixture was placed in an oil bath at 60 °C and stirred for 3 hours. After completion of the reaction, 2 M HCl was added to acidify the reaction mixture. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was dried over NaSO, filtered, and concentrated to give compound 4-3.

[0275] Step 3: Synthesis of compound 4-4 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 min. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 99:1 to 97:3) to give compound 4-4.

[0276] Step 4: Synthesis of Compounds 4-5 Compound 4-4 (400 mg, 0.93 mmol) was dissolved in DCM (6 mL) and the reaction mixture was cooled to 0 °C. Oxalyl chloride (355 mg, 2.79 mmol) was slowly added, and the reaction mixture was stirred at room temperature for half an hour. After completion of the reaction, the reaction mixture was directly dried by spin-drying and used in the next step. 2-Chloro-6-methylpyrimidin-4-amine (200.63 mg, 1.40 mmol) was dissolved in DMF (4 mL). The reaction mixture was cooled to 0 °C. NaH (33.54 mg, 1.40 mmol) was added, and the reaction mixture was placed in an oil bath at 60 °C and stirred for 30 minutes. The reaction mixture was then cooled to 0 °C, and the acyl chloride obtained above was added. The reaction mixture was mixed and allowed to react 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 NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 97:3) to give compound 4-5.

[0277] Step 5: Synthesis of Compounds 4-6 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). N,N-diisopropylethylamine (97.82 mg, 0.76 mmol) was added, and the reaction mixture was placed in an oil bath and stirred at 180 °C for 2 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 97:3) to give compound 4-6.

[0278] Step 6: Synthesis of Compounds 4-7 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). Catalyst CAS: 1599466-89-3 (22.62 mg, 0.03 mmol) and Cs2CO3 (136.84 mg, 0.42 mmol) were added, and the reaction mixture was placed in an oil bath at 95 °C and stirred for 2 h. 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 (DCM:MeOH = 95:5) to give compound 4-7.

[0279] Step 7: Synthesis of Compound 4 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 thereto. The reaction mixture was placed in a hydrogen gas atmosphere and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture 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 give compound 4. MS (ESI, pos. ion) m / z: 594.3 [M+1] + .

[0280] 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). Example 5: Synthesis of N-(1-(cyclopropylmethyl)indoline-4-(2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (5) [ka]

[0281] Step 1: Synthesis of compound 5-2 To a suspension of compound 5-1 (250 mg, 0.48 mmol) in AcOH (5 mL), NaBHCN (89.93 mg, 1.43 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into NaOH solution (2N, 40 mL) and extracted with EA (80 mL × 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The yellow residue was purified by column chromatography (PE:EA = 95:5 to 90:10) to give compound 5-2.

[0282] Step 2: Synthesis of Compound 5 To a solution of compound 5-2 (100 mg, 0.21 mmol) in DMSO (2 mL) was added copper iodide (79.28 mg, 0.42 mmol), catalyst CAS: 68737-65-5 (29.61 mg, 0.21 mmol), potassium phosphate tripotassium (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 N atmosphere overnight. The reaction mixture was poured into water (10 mL) and extracted with EA (30 mL × 3). The combined organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The crude product was purified to give compound 5.

[0283] 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),7.30 (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). Example 6: Synthesis of 4-(N-(2-hydroxyethyl)sulfonamido)-N-(1-methylindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (6) [ka]

[0284] Step 1: Synthesis of compound 6-2 NaH (125 mg, 3 mmol) was added to a DMF solution of compound 6-1 (500 mg, 3 mmol), and iodomethane (0.2 mL) was added dropwise. 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 give compound 6-2.

[0285] Step 2: Synthesis of compound 6-3 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 overnight under a hydrogen gas atmosphere, filtered, and concentrated under reduced pressure to give compound 6-3.

[0286] Step 3: Synthesis of compound 6-4 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 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.

[0287] Step 4: Synthesis of compound 6-5 Compound 6-4 (350 mg, 0.72 mmol) was stirred in AcOH (1 mL) at room temperature, and NaBHCN (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 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 6-5.

[0288] Step 5: Synthesis of Compound 6 Compound 6-5 (150 mg, 0.31 mmol) and 2-hydroxyethane-1-sulfonamide (154 mg, 1.23 mmol) were dissolved in DMSO (2 mL), potassium phosphate (327 mg, 1.54 mmol), cuprous iodide (30 mg, 0.15 mmol), and sarcosine (14 mg, 0.15 mmol) were added, and the mixture was heated at 120 °C overnight after protecting with nitrogen gas. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3 × 30 mL). The organic solution was removed and concentrated in vacuo. 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] + .

[0289] 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). 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 [ka]

[0290] Step 1: Synthesis of compound 7-2 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) and cooled to -78 °C. After 1 h, 1-chloro-3-iodopropane (16 g, 80.72 mmol) was added dropwise to the solution. After completion, 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 NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to give compound 7-2.

[0291] Step 2: Synthesis of compound 7-3 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 placed in an oil bath at 60 °C under nitrogen gas protection. After 5 h of reaction, the reaction was cooled to room temperature and quenched with cold water and extracted with EtOAc. The organic layer was washed with water, 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 give compound 7-3.

[0292] Step 3: Synthesis of compound 7-4 Compound 7-3 (2.5 g, 9.12 mmol), HNBoc (1.6 g, 13.68 mmol), CsCO (5.95 g, 18.2 mmol), Pd(dba) (0.42 g, 0.46 mmol), and Xantphos (0.8 g, 1.37 mmol) were added to 1,4-dioxane and heated at 110 °C overnight under a N atmosphere. The reaction was cooled to room temperature and quenched with cold water and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to give compound 7-4.

[0293] Step 4: Synthesis of compound 7-5 Compound 7-4 (2 g, 7.6 mmol) was dissolved in HCl-EA (10 mL) solution and stirred at room temperature for 3 h. The HCl-EA was removed by rotary evaporation, and the reaction mixture was adjusted to pH 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 give compound 7-5.

[0294] Step 5: Synthesis of compound 7-6 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) at 0 °C, oxalyl chloride (770 mg, 6 mmol) was added dropwise, and DMF (0.10 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and co-distilled with toluene to give crude 2-(6-azaspiro[2.5]oct-6-yl)-4-iodobenzoyl chloride, which was used in the next step without further purification.

[0295] B: To a solution of compound 7-5 in DMF (5 mL) was added NaH (220 mg, 9.1 mmol) at 0° C., and 2-(6-azaspirocyclo[2.5]oct-6-yl)-4-iodobenzoyl chloride was added at 0° C. The reaction mixture was stirred at room temperature for 3 hours and quenched with cold water, extracted with EtOAc, the organic layer was washed with water, 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 4 / 1) to give compound 7-6.

[0296] Step 6: Synthesis of Compound 7 Compound 7-6 (170 mg, 1.35 mmol) was dissolved in DMSO (2 mL), potassium phosphate (372 mg, 1.75 mmol), cuprous iodide (34 mg, 0.17 mmol), and sarcosine (32 mg, 0.34 mmol) were added, and the mixture was heated at 120 °C overnight after protecting with nitrogen gas. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3 × 30 mL). The organic solution was removed and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to give compound 7.

[0297] MS (ESI,pos.ion) m / z: 500.3[M+1] + . 1 H 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). 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) [ka]

[0298] Step 1: Synthesis of compound 8-2 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 and placed in an oil bath at 60 °C under nitrogen gas protection. After 5 h of reaction, the reaction was cooled to room temperature and quenched with cold water and extracted with EtOAc. The organic layer was washed with water, 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 give compound 8-2.

[0299] Step 2: Synthesis of compound 8-3 Compound 8-2 (1.1 g, 3.5 mmol), HNBoc (0.65 g, 5.25 mmol), CsCO (2.28 g, 7 mmol), Pd(dba) (0.16 g, 0.18 mmol), and Xantphos (0.31 g, 0.53 mmol) were added to 1,4-dioxane and heated at 110 °C overnight under a N atmosphere. The reaction was cooled to room temperature and quenched with cold water and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to give compound 8-3.

[0300] Step 3: Synthesis of compound 8-4 Compound 8-3 (1.5 g, 4.94 mmol) was dissolved in HCl-EA (10 mL) solution and stirred at room temperature for 3 hours. The HCl-EA was removed by rotary evaporation, and the reaction mixture was adjusted to pH 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 give compound 8-4.

[0301] Step 4: Synthesis of compound 8-5 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) at 0° C., pentafluorophenyl trifluoroacetate (530 mg, 1.89 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 h to give crude perfluorophenyl 4-iodo-2-(6-azaspiro[2.5]octyl)benzoate, which was used in the next step without further purification.

[0302] Step b: To a solution of compound 8-4 in DMF (5 mL) was added NaHMDS (1.44 mL, 3.6 mmol) at 0 °C. After reacting for 10 min, 4-iodo-2-(6-azaspiro[2.5]octyl)perfluorophenyl benzoate was added at 0 °C. The reaction mixture was stirred at 60 °C for 5 h, 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 8-5.

[0303] Step 5: Synthesis of Compound 8 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), tBuXPhos Pd G4 (6 mg, 0.01 mmol) and cesium carbonate (102 mg, 0.31 mmol) were added, and the mixture was heated at 100 °C overnight after protecting with nitrogen gas. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3 × 30 mL). The organic solution was removed and concentrated in vacuo. 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] + .

[0304] 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). Example 9: Synthesis of N-(1-(cyclopropylmethyl)-1H-indole-4-(2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (9) [ka]

[0305] Step 1: Synthesis of compound 9-2 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 a N atmosphere. The reaction mixture was stirred at room temperature for 15 min under a N atmosphere. To the above solution was added (bromomethyl)cyclopropane (0.20 mL, 2.04 mmol). The reaction mixture was stirred at room temperature under a N atmosphere for 2 h. The reaction mixture was poured into water (50 mL) and extracted with EA (100 mL * 2). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 90:10) to give compound 9-2.

[0306] Step 2: Synthesis of compound 9-3 To a solution of compound 9-2 (35 mg, 1.62 mmol) in MeOH (5 mL), Pd / C (40 mg, 0.2 mmol) was added and the mixture was purged with H 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.

[0307] Step 3: Synthesis of compound 9-4 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 * 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 9:1) to give compound 9-4.

[0308] Step 4: Synthesis of Compound 9 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 overnight at 120 °C under a N atmosphere. The reaction mixture was poured into water (10 mL) and extracted with EA (30 mL * 3). The combined organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The crude product was purified to give compound 9.

[0309] 1H NMR (DMSO-d6) δ: 11.18 (s,1H),9.96-10.23 (m,1H),7.94 (d,J=7.8Hz,1H),7.85-7.91 (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). 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) [ka]

[0310] 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 overnight after protecting with nitrogen gas. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3 × 30 mL). The organic solution was removed and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to obtain compound 10. MS (ESI, pos. ion) m / z: 483.2 [M+1] + .

[0311] 1H 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),3.33-3.39 (m,2H),2.97-3.07(m,4H),1.39-1.52 (m,4H),0.23-0.31 (m,4H). 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) [ka]

[0312] Step 1: Synthesis of compound 11-2 Compound 11-1 (4.5 g, 20 mmol) and hydroxylamine hydrochloride (1.32 g, 40 mmol) were dissolved in pyridine (20 mL) and reacted 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 give compound 11-2.

[0313] Step 2: Synthesis of compound 11-3 Under a nitrogen atmosphere, DIBAL-H (5.78 mL) was added to compound 11-2 (3 g, 12.5 mmol) in DCM (20 mL) at 0-5 °C within 10 min. Stirring was continued at 0 °C for 5 min and then at room temperature for 2 h. 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 min. The reaction was cooled to room temperature and quenched with cold water and extracted with EtOAc. The organic layer was washed with water, 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 give compound 11-3.

[0314] Step 3: Synthesis of compound 11-4 Compound 11-3 (700 mg, 3.1 mmol) was dissolved in THF, and NaH (186 mg, 4.64 mmol) was added. After reacting at room temperature for 20 min, iodomethane (660 mg, 4.64 mmol) was added dropwise at 0 °C. The reaction was then allowed to proceed at room temperature for 2 h, 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 give compound 11-4.

[0315] Step 4: Synthesis of compound 11-5 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), t BuONa (280 mg, 2.91 mmol) was added to toluene and 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 × 30 mL). The organic solution was removed and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to give compound 11-5.

[0316] Step 5: Synthesis of compound 11-6 Compound 11-5 (300 mg, 1.09 mmol) was dissolved in HCl-EA (10 mL) solution and stirred at room temperature for 3 h. The HCl-EA was removed by rotary evaporation, and the reaction mixture was adjusted to pH 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 give compound 11-6.

[0317] Step 6: Synthesis of compound 11-7 A mixture of 2-(6-azaspiro[2.5]oct-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 reaction was then quenched with water and 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.

[0318] Step 7: Synthesis of Compound 11 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 mixture was heated at 120 °C overnight after protecting with nitrogen gas. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3 × 30 mL). The organic solution was removed and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to give compound 11. MS m / z (ESI): 513.3 [M+1] + .

[0319] 1H 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),3.21-3.27 (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). 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) [ka]

[0320] Step 1: Synthesis of compound 12-2 Compound 12-1 (1400 mg, 6.19 mmol) was dissolved in DMF, and NaH (496 mg, 12.4 mmol) was added. After reacting at room temperature for 20 min, bromomethylcyclopropane (1254 mg, 9.29 mmol) was added dropwise at 0 °C. The reaction was then continued at 70 °C for 2 h, 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 give compound 12-2.

[0321] Step 2: Synthesis of compound 12-3 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), tBuONa (247 mg, 2.57 mmol) was added to toluene and 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 × 30 mL). The organic solution was removed and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to give compound 12-3.

[0322] Step 3: Synthesis of compound 12-4 Compound 12-3 (310 mg, 0.98 mmol) was dissolved in HCl-EA (10 mL) solution and stirred at room temperature for 3 hours. The HCl-EA was removed by rotary evaporation, and the reaction mixture was adjusted to pH 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 give compound 12-4.

[0323] Step 4: Synthesis of compound 12-5 A mixture of 2-(6-azaspiro[2.5]oct-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 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.

[0324] Step 5: Synthesis of Compound 12 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 mixture was heated at 120 °C overnight after protecting with nitrogen gas. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3 × 30 mL). The organic solution was removed and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to give compound 12. MS m / z (ESI): 553.3 [M+1] + .

[0325] 1 H NMR (DMSO-d6) δ: 11.34-11.51 (m,1H),8.14-8.20 (m,1H),7.32-7.36 (m,1H),7.13-7.25 (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),1.17-1.37 (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). Example 13: Synthesis of N-(2-chloro-1-(cyclopropylmethyl)-1H-indol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (13) [ka]

[0326] Step 1: Synthesis of compound 13-2 Compound 13-1 (450 mg, 1.80 mmol) was added to AcOH (9 mL), cooled to 0 °C, zinc powder (0.35 g, 5.39 mmol) was added, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture 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 give compound 13-2. MS m / z (ESI): 221.0 [M+1] + .

[0327] Step 2: Synthesis of compound 13-3 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 mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was extracted with EA (10 mL × 3). The combined organic phases were washed with water (10 mL × 2) and saturated brine (20 mL × 1), respectively, 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 give compound 13-3. MS m / z (ESI): 512.0 [M+1] + .

[0328] Step 3: Synthesis of compound 13 Compound 13-3 (100 mg, 0.19 mmol), 2-hydroxyethane-1-sulfonamide (29.28 mg, 0.23 mmol), CsCO (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 overnight at 80 °C under N gas protection. The reaction mixture was extracted with EA (5 mL × 3). The combined organic phase was washed with water (5 mL × 2) and saturated brine (5 mL × 1), dried over anhydrous NaSO, concentrated under reduced pressure, and purified to give compound 13. MS m / z (ESI): 557.0 [M+1] +

[0329] 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). Example 14: Synthesis of N-(1-(cyclobutylmethyl)dihydroindol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka]

[0330] Step 1: Synthesis of compound 14-2.

[0331] 14-1 (500 mg, 3.08 mmol) and CsCO (2009.37 mg, 6.17 mmol) were dissolved in DMF (10 mL), and (bromomethyl)cyclobutane (505.50 mg, 3.39 mmol) was added dropwise slowly. The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20 to 1 / 10) to give 14-2.

[0332] Step 2: Synthesis of compound 14-3.

[0333] A solution of 14-2 (700 mg, 3.04 mmol) and Pd / C 10% (70 mg, 0.66 mmol) in MeOH (10 mL) was stirred at room temperature under H for 18 h. The reaction mixture was filtered under suction, and the filtrate was concentrated under reduced pressure to give 14-3.

[0334] Step 3: Synthesis of compound 14-4.

[0335] A solution of 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) in CHCN (5 mL) was added, and a solution of DIEA-ethyldiisopropylamine (563.21 mg, 4.36 mmol) was slowly added dropwise. After stirring at room temperature for 18 h, the reaction mixture was diluted with EA (20 mL). The organic layer was washed with NaCl (60 mL), dried over NaSO, filtered, concentrated, and purified by column chromatography (PE:EA = 4:1) to give 14-4.

[0336] Step 4: Synthesis of compound 14-5.

[0337] Sodium cyanoborohydride (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 h, adjusted to pH 7-8 with aqueous sodium bicarbonate, and diluted with EA (20 mL). The organic layer was washed with NaCl (60 mL), dried over NaSO, filtered, and concentrated to give 14-5.

[0338] Step 5: Synthesis of compound 14.

[0339] 14-5 (200 mg, 0.4 mmol), 2-hydroxyethane-1-sulfonamide (202.46 mg, 1.62 mmol), CsCO (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 h. The reaction mixture was diluted with EA (20 mL). The organic layer was washed with NaCl (60 mL), dried over NaSO, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 20:1) to give compound 14.

[0340] MS m / z (ESI): 539.3 [M+1] + . 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). Example 15: Synthesis of N-(1-(cyclopentylmethyl)dihydroindol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide [ka]

[0341] Step 1: Synthesis of compound 15-2.

[0342] 15-1 (500 mg, 3.08 mmol) and CsCO (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 h, diluted with ethyl acetate (20 mL), washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 15-2.

[0343] Step 2: Synthesis of compound 15-3.

[0344] 15-2 (570 mg, 2.33 mmol) and Pd / C 10% (57 mg, 0.54 mmol) were dissolved in MeOH (10 mL) and stirred at room temperature under H2 for 18 h. The reaction mixture was filtered under suction, and the filtrate was concentrated under reduced pressure to give compound 15-3.

[0345] Step 3: Synthesis of compound 15-4.

[0346] 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), a solution of DIEA (353 mg, 2.71 mmol) was added dropwise. After stirring at room temperature for 18 h, the reaction mixture was diluted with EA (20 mL). The organic layer was washed with NaCl (60 mL), dried over NaSO, filtered, concentrated, and purified by column chromatography (PE:EA = 4:1) to give compound 15-4.

[0347] Step 4: Synthesis of compound 15-5.

[0348] To a solution of 15-4 (400 mg, 0.79 mmol) in acetic acid (8 mL) was added sodium cyanoborohydride (148.88 mg, 2.37 mmol), and the reaction mixture was stirred at room temperature for 3 h. 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 give compound 15-5.

[0349] Step 5: Synthesis of compound 15.

[0350] 15-5 (300 mg, 0.59 mmol), 2-hydroxyethane-1-sulfonamide (295.32 mg, 1.62 mmol), CsCO (576.70 mg, 1.77 mmol), and a 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 h. The reaction mixture was diluted with EA (20 mL). The organic layer was washed with NaCl (60 mL), dried over NaSO, 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] + .

[0351] 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,1H),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). Example 16: Synthesis of N-(1-cyclopropylmethyl)-1H-benzimidazol-4-yl)-4-(2-hydroxyethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (16) [ka]

[0352] Step 1: Synthesis of compound 16-2 Compound 16-1 (1 g, 4.55 mmol) and cyclopropylmethylamine (0.47 mL, 5.45 mmol) were dissolved in 1,4-dioxane (5 mL). Potassium carbonate (1.26 g, 9.09 mmol) was added to the solution, and the reaction mixture was placed in an oil bath at 60 °C and stirred for 4 h. After the reaction was completed, 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 NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 98:2) to give compound 16-2.

[0353] Step 2: Synthesis of compound 16-3 Compound 16-2 (989 mg, 3.65 mmol) was dissolved in ethanol (5 mL) and water (5 mL). Iron powder (1.02 g, 18.24 mmol) and ammonium chloride (975.65 mg, 18.24 mmol) were added, and the reaction mixture was placed in an oil bath at 80 °C and stirred for 3 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 97:3) to give compound 16-3.

[0354] Step 3: Synthesis of compound 16-4 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. The reaction mixture was placed in an oil bath at 70 °C and stirred for 18 h. After completion of the reaction, the reaction mixture 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 to 95:5-80:20) to give compound 16-4.

[0355] Step 4: Synthesis of compound 16-5 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), to which BrettPhos Pd G4 (293.24 mg, 0.32 mmol) and cesium carbonate (2.08 g, 6.37 mmol) were added. The reaction mixture was placed in an oil bath at 95 °C and stirred for 2 h. After completion of the reaction, the reaction mixture 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 to 90:10 to 80:20) to give compound 16-5.

[0356] Step 5: Synthesis of compound 16-6 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. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture 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 to 80:20 to 0:100) to give compound 16-6.

[0357] Step 6: Synthesis of compound 16-7 Compound 16-6 (100 mg, 0.53 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-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. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture 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 to 95:5 to 90:10) to give compound 16-7.

[0358] Step 7: Synthesis of Compound 16 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 the catalyst CAS: 1599466-83-7 (16.90 mg, 0.02 mmol) and cesium carbonate (59.81 mg, 0.18 mmol) were added. The reaction mixture was placed in an oil bath at 95 °C and stirred 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 NaSO, filtered, and concentrated. The crude product was purified by preparative separation to give compound 16. MS (ESI, pos. ion) m / z: 524.2 [M+1] + .

[0359] 1H 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). 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) [ka]

[0360] Step 1: Synthesis of compound 17-2 Compound 17-1 (1 g, 4.72 mmol) was dissolved in ultra-dehydrated tetrahydrofuran (10 mL) and, under nitrogen gas protection, LDA (4.72 mL, 9.44 mmol) was slowly added dropwise to the solution at -78 °C. The mixture was stirred at -78 °C for 1 h. 1,2-dibromoethane (1.22 mL, 14.15 mmol) was then added dropwise, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with ice water, adjusted to pH 5 with 2N HCl, extracted with EA, and 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 10:1) to give compound 17-2. MS (ESI, pos. ion) m / z: 238.0 / 240.0 [M+1] + .

[0361] Step 2: Synthesis of compound 17-3 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 thereto and reacted at 70 °C for 30 min. 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 = 20:1) to give compound 17-3.

[0362] Step 3: Synthesis of compound 17-4 Compound 17-3 (330 mg, 1.13 mmol), NHBoc (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 N2 protection. 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 = 5:1) to give compound 17-4. MS (ESI, pos. ion) m / z: 329.2 [M+1] +

[0363] Step 4: Synthesis of compound 17-5 Compound 17-4 (248 mg, 0.76 mmol) was dissolved in DCM (1 mL), HCl / EA (3 mL) was added, and the mixture was allowed to react at 25 °C overnight. The reaction mixture was quenched with ice water, neutralized with saturated NaHCO3 solution, extracted with EA, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and dried to give compound 17-5. MS (ESI, pos. ion) m / z: 229.1 [M+1] + .

[0364] Step 5: Synthesis of compound 17-6 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (181 mg, 0.58 mmol) was dissolved in DCM (1 mL), oxalyl chloride (0.10 mL, 1.16 mmol) and a catalytic amount of DMF were added, and the mixture was allowed to react at 25 °C for 10 minutes. The reaction mixture was concentrated and dried on an oil pump 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 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 give compound 17-6.

[0365] Step 6: Synthesis of Compound 17 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 a palladium catalyst (CAS: 1599466-89-3, 5 mg) were dissolved in dioxane (2 mL) and reacted at 100 °C for 2 h under N2 protection. 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 to give compound 17. MS (ESI, pos. ion) m / z: 565.3 [M+1] + .

[0366] 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),1.80 - 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). 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]oct-6-yl)benzamide (18) [ka]

[0367] Step 1: Synthesis of compound 18-2 Compound 18-1 (500 mg, 2.34 mmol) and cesium carbonate (1.52 g, 4.68 mmol) were dissolved in ultra-anhydrous DMF (5 mL), and bromomethylcyclopropane (0.27 mL, 2.81 mmol) was added thereto and reacted at 70 °C for 30 min. 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 silica gel column chromatography (PE:EA = 10:1) to give compound 18-2.

[0368] 1H 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).

[0369] Step 2: Synthesis of compound 18-3 Compound 18-2, NHBoc (538 mg, 4.60 mmol), cesium carbonate (2.25 g, 6.89 mmol), and a 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 N protection. 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 18-3.

[0370] Step 3: Synthesis of compound 18-4 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, followed by reaction overnight at 25° C. The reaction solution was filtered and dried to obtain compound 18-4.

[0371] Step 4: Synthesis of compound 18-5 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-dehydrated 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 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 = 10:1) to give compound 18-5. MS (ESI, pos. ion) m / z: 496.1 / 498.1 [M+1] + .

[0372] Step 5: Synthesis of Compound 18 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 a palladium catalyst (CAS: 1599466-87-1, 42 mg, 0.05 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 100 °C for 3 hours under N2 protection. 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 to give compound 18. MS (ESI, pos. ion) m / z: 541.3 [M+1] + .

[0373] 1H 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). 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) [ka]

[0374] Step 1: Synthesis of compound 19-2 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 NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 20 / 1) to give compound 19-2.

[0375] Step 2: Synthesis of compound 19-3 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]oct-6-yl)benzoic acid (995 mg, 3.21 mmol) were added to DMF (5 mL) and reacted overnight at room temperature. The reaction mixture was diluted with EA (20 mL), washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give compound 19-3.

[0376] Step 3: Synthesis of compound 19 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), protected with nitrogen gas, and stirred at 80 °C for 3 hours. 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 give compound 19.

[0377] MS m / z (ESI): 474.6 [M+1] + . 1H 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). Example 22: Synthesis of 2-(cyclohexyloxy)-N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-(2-hydroxyethyl)sulfonamido)benzamide (22) [ka]

[0378] Step 1: Synthesis of compound 22-2 Cyclohexanol (4.5 g, 44.9 mmol) was dissolved in DMF (20 mL) and cooled to 0 °C. NaH (1.8 g, 44.9 mg) was slowly added and stirred at room temperature for 30 min. Compound 22-1 (2 g, 9.13 mmol) was added and the mixture was left overnight at 50 °C under nitrogen gas protection. The reaction mixture was diluted with EA (50 mL), washed with brine (100 mL), dried over anhydrous NaSO, 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 22-2.

[0379] Step 2: Synthesis of compound 22-3 Compound 22-2 (500 mg, 1.67 mmol) was dissolved in DCM (5 mL), protected with nitrogen gas, and oxalyl chloride (350 mg, 2.7 mmol) was added dropwise at 0 °C. The reaction mixture was then reacted at room temperature for 1 hour. The reaction mixture was directly concentrated, dried by spin-drying, and sealed for 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 min under nitrogen gas protection. The crude product was dissolved in DCM (2 mL) and added dropwise to the reaction mixture for 3 h at room temperature. The reaction mixture was diluted with EA (20 mL), washed with brine (30 mL), dried over anhydrous NaSO, 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 22-3.

[0380] Step 3: Synthesis of compound 22 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), protected with nitrogen gas, and reacted at 100 °C overnight. The reaction mixture was diluted with EA (20 mL), washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 20 / 1) to give compound 22.

[0381] MS (ESI,pos.ion) m / z:539.1[M+1] + . 1H 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),4.87-5.03 (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). Example 23: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzamide (23) [ka]

[0382] Step 1: Synthesis of compound 23-2 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 the mixture was 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, 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 = 0-50%) to give compound 23-2.

[0383] Step 2: Synthesis of compound 23-3 Compound 23-2 (280 mg, 0.93 mmol) was dissolved in dichloromethane and oxalyl chloride (0.16 mL, 1.86 mmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 1 hour. After concentrating under reduced pressure, 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) in an ice bath. The mixture was allowed to react at 50 °C for 2 hours. After cooling, the reaction mixture was poured into 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 = 0-30%) to give compound 23-3.

[0384] Step 3: Synthesis of compound 23 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 for 16 h under nitrogen gas protection. After cooling, 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 give compound 23. MS m / z (ESI): 541.2 [M+1] + .

[0385] 1H 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). Example 24: Synthesis of 2-((4,4-difluorocyclohexyl)oxy)-N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (24) [ka]

[0386] Step 1: Synthesis of compound 24-2 Compound 24-1 (1 g, 7.46 mmol) was dissolved in methanol (20 mL), and sodium borohydride (851 mg, 22.39 mmol) was added under ice bath conditions. The mixture was then reacted at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with brine (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 24-2, which was used directly in the next step.

[0387] Step 2: Synthesis of compound 24-3 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 the mixture was 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 the mixture was stirred at 80 °C overnight. After cooling, 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 = 0-50%) to obtain compound 24-3.

[0388] Step 3: Synthesis of compound 24-4 Compound 24-3 (170 mg, 0.445 mmol) was dissolved in dichloromethane and oxalyl chloride (0.08 mL, 0.89 mmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 1 hour. After concentrating under reduced pressure, 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) in an ice bath. The mixture was allowed to react at 50 °C for 2 hours. After cooling, the reaction mixture was poured into 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 = 0-30%) to give compound 24-4.

[0389] Step 4: Synthesis of compound 24 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 for 16 h under nitrogen gas protection. After cooling, 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 give compound 24. MS (ESI) m / z: 575.2 [M+1] + .

[0390] 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). Example 25: Synthesis of N-(1-(cyclopropylmethyl)indolin-4-yl)-8-((2-hydroxyethyl)sulfonamido)-2,3-dihydrobenzo[b][1,4]dioxine-5-formamide (25) [ka]

[0391] Step 1: Synthesis of compound 25-2 2-Methylpropan-2-amine (1.26 mL, 11.90 mmol) was dissolved in toluene (12 mL) and dichloromethane (7 mL) at 25 °C. The mixture was cooled to -78 °C, and bromine (0.37 mL, 7.14 mmol) was slowly added dropwise and stirred for 10 min. Within 20 min, compound 25-2 (1 g, 5.95 mmol) dissolved in dichloromethane (7 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 30 min and then slowly warmed to room temperature. Ethyl acetate (25 mL) was added, followed by 1 M dilute hydrochloric acid (25 mL x 2), and then washed with water. The combined organic phases were 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 high-performance silica gel column chromatography (ethyl acetate / petroleum ether = 5-10%) to obtain compound 25-2. MS m / z (ESI): 246.9 [M + H] +

[0392] Step 2: Synthesis of compound 25-3 Compound 25-2 (190 mg, 0.77 mmol) was dissolved in DMF (3 mL) at 25 °C, and cesium carbonate (1002.30 mg, 3.08 mmol) was added. The mixture was heated to 70 °C and stirred for 1 h. 1,2-Dibromoethane (0.27 mL, 3.08 mmol) was then added, and the reaction mixture was stirred at 110 °C overnight. The mixture was then allowed to cool slowly to room temperature. Ethyl acetate (5 mL) was added, and the mixture was washed with water (5 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the crude product. The crude product was purified by high-performance silica gel column chromatography (ethyl acetate / petroleum ether = 5-10%) to give compound 25-3. MS m / z (ESI): 272.9 [M+H] +

[0393] Step 3: Synthesis of compound 25-4 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. The mixture was stirred at room temperature for 2 hours. 1 M diluted hydrochloric acid was added to adjust the pH to 5. Ethyl acetate (5 mL) was added, and water (5 mL * 2) was added and washed. The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried to obtain compound 25-4, which was used directly in the next step. MS m / z (ESI): 258.9 [M+H] +

[0394] Step 4: Synthesis of compound 25-5 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 h, and then ethyl acetate (5 mL) was added and washed with water (5 mL x 2). The combined organic phases were 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 high-performance silica gel column chromatography (ethyl acetate / petroleum ether = 5-70%) to obtain compound 25-5. MS m / z (ESI): 427.06 [M+H] +

[0395] Step 5: Synthesis of compound 25-6 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, followed by washing 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 dryness to obtain the crude product, which was used directly in the next step. The crude product was purified by high-performance silica gel column chromatography (PE:EA = 20-50%) to obtain compound 25-6. MS m / z (ESI): 429.07 [M+H] +

[0396] Step 6: Synthesis of Compound 25 Compound 25-6 (80 mg, 0.19 mmol) was dissolved in 1,4-dioxane (5 mL) at 25 °C, and 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 mixture was purged with nitrogen gas, heated to 100 °C, and stirred overnight. Ethyl acetate (5 mL) was added, and water (5 mL x 2) was added and washed. The combined organic phase was 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 high-performance silica gel column chromatography (dichloromethane / methanol = 2-5%) to obtain compound 25. MS m / z (ESI): 474.2 [M+H]. + 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). Example 26: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(spiro[3.3]heptan-2-yloxy)benzamide (26) [ka]

[0397] Step 1: Synthesis of compound 26-2 Spiro[3.3]heptan-2-ol (770 mg, 6.88 mmol) was dissolved in DMF (10 mL), sodium hydride (459 mg, 11.5 mmol) was added in an ice bath, and the mixture was allowed to react at room temperature for 1 hour. Compound 26-1 (1 g, 4.59 mmol) was then added in an ice bath and the mixture was allowed to react at room temperature for 16 hours. 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), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / PE = 0-30%) to obtain compound 26-2.

[0398] Step 2: Synthesis of compound 26-3 Compound 26-2 (700 mg, 2.26 mmol) was dissolved in dichloromethane (10 mL) and oxalyl chloride (711 mg, 5.65 mmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 1 hour, then concentrated for further use. 2-Chloro-6-methylpyrimidin-4-amine (387 mg, 2.7 mmol) was dissolved in DMF (10 mL) and sodium hydride (180 mg, 4.5 mmol) was added in an ice bath. The mixture was allowed to react at room temperature for 1 hour, and the previously prepared acyl chloride was added in an ice bath. The 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), 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 = 0-70%) to give compound 26-3.

[0399] Step 3: Synthesis of compound 26-4 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 for 5 hours under nitrogen gas protection. After cooling, the reaction mixture was poured into 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 give compound 26-4.

[0400] Step 4: Synthesis of compound 26-5 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 for 16 h under nitrogen gas protection. After cooling, 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 (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 give 26. MS (ESI, pos. ion) m / z: 566.22 [M+1] + .

[0401] 1 H 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). Example 27: Synthesis of 2-(cyclohexyloxy)-N-(1-(cyclopropylmethyl)indolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (27) [ka]

[0402] Step 1: Synthesis of compound 27-2 NaH (752 mg, 18.8 mmol) was added to a DMF solution of cyclohexanol (1.5 g, 15 mmol) and the mixture was allowed to react for 30 min. After that, compound 27-1 (1 g, 3.76 mmol) was added and the mixture was stirred at 80 °C for 3 h. The reaction was cooled to room temperature and quenched with cold water and extracted with EtOAc. The organic layer was washed with water, 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 give compound 27-2.

[0403] Step 2: Synthesis of compound 27-3 A mixture of compound 27-2 (161 mg, 4.51 mmol), 1-(cyclopropylmethyl)indol-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 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 give compound 27-3.

[0404] Step 3: Synthesis of compound 27-4 Compound 27-3 (110 mg, 0.21 mmol) was dissolved in acetic acid (3 mL), NaBHCN (41 mg, 0.64 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The acetic acid was removed by rotary evaporation, and water was added, followed by extraction 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 27-4.

[0405] Step 4: Synthesis of compound 27 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 the catalyst CAS: 1599466-85-9 (2 mg, 0.001 mmol) and cesium carbonate (26 mg, 0.08 mmol) were added. After protecting with nitrogen gas, the mixture was heated at 100 °C overnight. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3 × 30 mL). The organic solution was removed and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to give compound 27. MS m / z (ESI): 514.3 [M+1] + .

[0406] 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,1H),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), Example 28 Synthesis of 2-(cyclopentyloxy)-N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (28) [ka]

[0407] Step 1: Synthesis of compound 28-2 Sodium hydride (601 mg, 15 mmol) was added to a DMF solution of cyclopentanol (972 mg, 11.28 mmol). After 30 min of reaction, compound 28-1 (1 g, 3.76 mmol) was added and the mixture was stirred at 80 °C for 3 h. The reaction was cooled to room temperature and quenched with cold water and extracted with EtOAc. The organic layer was washed with water, 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 give compound 28-2.

[0408] Step 2: Synthesis of compound 28-3 A: To a solution of compound 28-2 (373 mg, 1.3 mmol) in DCM (6 mL) at 0° C., oxalyl chloride (286 mg, 2.25 mmol) was added dropwise, and DMF (0.10 mL) was added. The reaction mixture was stirred at room temperature for 1 h. 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.

[0409] B: To a solution of 2-(4,4-difluorohexahydropyridin-1-yl)pyridin-4-amine (200 mg, 0.94 mmol) in pyridine (2 mL) at 0° C., the product obtained in step A was added, the reaction mixture was stirred at 50° C. overnight, and then quenched with cold water and extracted with EtOAc. The organic layer was washed with water, 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 obtain compound 28-3.

[0410] Step 3: Synthesis of compound 28 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 the catalyst CAS: 1599466-85-9 (12 mg, 0.01 mmol) and cesium carbonate (186 mg, 0.57 mmol) were added. After protecting with nitrogen gas, the mixture was heated at 100 °C overnight. EtOAc (20 mL) and water (5 mL) were added to the system, and the aqueous phase was washed with EtOAc (3 × 30 mL). The organic solution was removed and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to give compound 28. MS m / z (ESI): 525.2 [M+1] + .

[0411] 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). Example 29: Synthesis of N-(1-(cyclopropylmethyl)indolin-4-yl)-2-((4,4-difluorocyclohexyl)oxy)-4-((2-hydroxyethyl)sulfonamido)benzamide (29) [ka]

[0412] Step 1: Synthesis of compound 29-2 Compound 29-1 (2000 mg, 12.33 mmol) was dissolved in N,N-dimethylformamide (20 mL) at 25 °C and cooled to 0 °C. Sodium hydride (986.74 mg, 24.67 mmol) was slowly added, and the mixture was allowed to warm to room temperature and stirred for 0.5 h. Bromomethylcyclopropane (1.33 mL, 13.57 mmol) was added and stirred for 1 h. Water (50 mL) was added, followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were 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 high-performance silica gel column chromatography (ethyl acetate / petroleum ether = 5-10%) to obtain compound 29-2. MS m / z (ESI): 217.09 [M+H] +

[0413] Step 2: Synthesis of compound 29-3 Compound 29-2 (560 mg, 2.59 mmol) was dissolved in methanol (7 mL) at 25 °C, 10% palladium carbon (56 mg, 0.3 mmol) was added, the mixture was purged with hydrogen gas, and the mixture was stirred overnight. The mixture was filtered, concentrated under reduced pressure, and dried to give compound 29-3. MS m / z (ESI): 187.12 [M+H] +

[0414] Step 3: Synthesis of compound 29-4 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, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (992.14 mg, 2.61 mmol) was added. N,N-diisopropylethylamine (421.53 mg, 3.26 mmol) was added dropwise and stirred for 2 hours. Water (20 mL) was added, and ethyl acetate (20 mL*3) was added for extraction. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by high-performance silica gel column chromatography (ethyl acetate / petroleum ether = 5-13%) to give compound 29-4. MS m / z (ESI): 551.09 [M+H] +

[0415] Step 4: Synthesis of compound 29-5 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, and sodium cyanoborohydride (6.17 mg, 0.10 mmol) was added and stirred for 1 hour. Water (2 mL) was added, and sodium carbonate was added to adjust the pH to 8. Ethyl acetate (2 mL*3) was added for extraction. The combined organic phases were washed with saturated brine (2 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 high-performance silica gel column chromatography (ethyl acetate / petroleum ether = 10-15%) to obtain compound 29-5. MS m / z (ESI): 553.11 [M+H] + .

[0416] Step 5: Synthesis of compound 29 Compound 29-5 (108 mg, 0.20 mmol) was dissolved in 1,4-dioxane (2 mL) at 25 °C, and catalyst CAS: 1599466-85-9 (16.63 mg, 0.02 mmol) and cesium carbonate (191.10 mg, 0.59 mmol) were added. The mixture was purged with nitrogen gas, heated to 100 °C under nitrogen gas protection, and stirred overnight. The reaction mixture was cooled to 25 °C, water (5 mL) was added, and ethyl acetate (5 mL x 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 high-performance silica gel column chromatography (ethyl acetate / petroleum ether = 20-50%) to obtain compound 29. MS m / z (ESI): 550.21 [M+H] + .

[0417] 1 H 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). Example 30 Synthesis of 2-(cyclopentyloxy)-N-(1-(cyclopropylmethyl)indolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (30) [ka]

[0418] Step 1: Synthesis of compound 30-2 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. 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 (20 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 95:5 to 90:10). Compound 30-2 was obtained.

[0419] Step 2: Synthesis of compound 30-3 To a solution of compound 30-2 (200 mg, 0.40 mmol) in CH3COOH (5 mL) was added NaBH3CN (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 Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 95:5 to 90:10). Compound 30-3 was obtained.

[0420] Step 3: Synthesis of Compound 30 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). CsCO (64.85 mg, 0.20 mmol) and catalyst CAS:1599466-89-3 (8.89 mg, 0.01 mmol) were added, and the reaction was stirred at 100 °C overnight. The reaction mixture was diluted with EA (90 mL), and the organic layer was washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 100:0 to 90:10 to 60:40). Compound 30 was obtained.

[0421] 1H 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). Example 32 Synthesis of N-(1-(cyclopropylmethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-((2-hydroxyethyl)sulfanilamido)-2-(6-azaspiro[2.5]octan-6-yl)4-benzamide (32) [ka]

[0422] Step 1: Synthesis of compound 32-2 Compound 32-1 (1 g, 6.57 mmol) and cesium carbonate (6.4 g, 19.65 mmol) were dissolved in DMF (10 mL), and bromomethylcyclopropane (0.5 mL, 7.2 mmol) was added at room temperature. The reaction was carried out at 50 °C for 2 hours under N2 protection. The reaction mixture was quenched by adding 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 32-2.

[0423] Step 2: Synthesis of compound 32-3 Compound 32-2 (1 g, 4.85 mmol) was dissolved in glacial acetic acid (5 mL), and sodium cyanoborohydride (1.5 g, 24.25 mmol) was added to the reaction mixture at 0 °C, followed by reaction at 50 °C for 12 h. 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 give compound 32-3.

[0424] Step 3: Synthesis of compound 32-4 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 for 3 h under nitrogen gas protection. The reaction mixture was diluted with EA (10 mL) and washed with saturated NaCl solution (10 mL), dried over anhydrous NaSO, 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 32-4.

[0425] Step 4: Synthesis of compound 32-5 Compound 32-4 (400 mg, 1.38 mmol) was dissolved in a hydrochloric acid-ethyl acetate solution and reacted at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, washed with saturated aqueous sodium bicarbonate until the pH reached 9, extracted with EA (10 mL), and the organic phase was washed with saturated NaCl solution (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 32-5, which was used directly in the next step without further purification.

[0426] Step 5: Synthesis of compound 32-6 4-Bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoic acid (246 mg, 0.79 mmol) was dissolved in DCM (3 mL), and oxalyl chloride (0.13 mL, 1.58 mmol) and a catalytic amount of DMF were added under nitrogen gas protection at 0 °C. The mixture was then cooled to room temperature and reacted 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). The acylated chloride of 4-bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoic acid was added to the reaction mixture at 0 °C and reacted at 80 °C for 24 hours. The reaction mixture was quenched by adding 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.

[0427] Step 6: Synthesis of Compound 32 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 for 3 hours under nitrogen gas 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 2 / 1) to give compound 32. MS (ESI, pos. ion) m / z: 526.3 [M+1] + .

[0428] 1HNMR (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),6.98-7.03 (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).

[0429] Example 33: Synthesis of N-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-((2-hydroxyethyl)sulfanilamido)-2-(6-azaspiro[2.5]octan-6-yl)4-benzamide (33) [ka]

[0430] Step 1: Synthesis of compound 33-2 Compound 33-1 (500 mg, 3.27 mmol) and cesium carbonate (3.2 g, 9.8 mmol) were dissolved in DMF (10 mL), and bromomethylcyclopropane (0.35 mL, 3.6 mmol) was added at room temperature. The reaction was carried out at 50 °C for 2 hours under N2 protection. The reaction mixture was quenched by adding 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 33-2.

[0431] Step 2: Synthesis of compound 33-3 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 for 3 h under nitrogen gas protection. The reaction mixture was diluted with EA (10 mL), washed with saturated NaCl solution (10 mL), dried over anhydrous NaSO, 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 33-3.

[0432] Step 3: Synthesis of compound 33-4 Compound 33-3 (280 mg, 0.97 mmol) was dissolved in a hydrochloric acid-ethyl acetate solution and reacted at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, washed with saturated aqueous sodium bicarbonate until the pH reached 9, extracted with EA (10 mL), and the organic phase was washed with saturated NaCl solution (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 33-4, which was used directly in the next step without further purification.

[0433] Step 4: Synthesis of compound 33-5 4-Bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoic acid (297 mg, 0.96 mmol) was dissolved in DCM (3 mL) and added with oxalyl chloride (0.16 mL, 1.92 mmol) and a catalytic amount of DMF under nitrogen gas protection at 0 °C. The mixture was then cooled to room temperature and reacted for 30 minutes. The mixture was concentrated under reduced pressure and then dissolved in DMF (1 mL). Compound 33-4 (150 mg, 0.8 mmol) was slowly added to NaH (35 mg, 0.8 mmol) under nitrogen gas protection at 0 °C and reacted at 60 °C for 30 minutes. The acylated chloride of 4-bromo-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid was added to the reaction mixture at 0 °C and reacted at 80 °C for 2 hours. The reaction mixture was quenched by adding 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.

[0434] Step 5: Synthesis of Compound 33 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 for 3 hours under nitrogen gas protection. The reaction mixture was quenched by adding 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] + .

[0435] 1HNMR (DMSO-d6) δ: 11.24-11.30 (m,1H),8.19 (d,J=5.5Hz,1H),8.02-8.09 (m,1H),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). 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) [ka]

[0436] Step 1: Synthesis of compound 34-2 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 (3.19 mL, 14.91 mmol) was added in an ice bath and the mixture was reacted at room temperature for 2 hours under N2 protection. The reaction mixture was quenched by adding 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 34-2.

[0437] Step 2: Synthesis of compound 34-3 Compound 34-2 (1 g, 2.3 mmol) was dissolved in methanol (10 mL), saturated aqueous sodium bicarbonate (2.3 mL) was added, and the mixture was reacted at room temperature under N2 protection for 3 hours. The reaction mixture was quenched by adding water (10 mL), and the mixture was 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 34-3.

[0438] Step 3: Synthesis of compound 34-4 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 was carried out at 50 °C for 2 hours under N2 protection. The reaction mixture was quenched by adding 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 34-4.

[0439] Step 4: Synthesis of compound 34-5 Compound 34-4 (670 mg, 1.72 mmol) was dissolved in a hydrochloric acid-ethyl acetate solution and reacted at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, washed with saturated aqueous sodium bicarbonate until the pH reached 9, extracted with EA (10 mL), and the organic phase was washed with saturated NaCl solution (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give compound 34-5, which was used directly in the next step without further purification.

[0440] Step 5: Synthesis of compound 34-6 4-Bromo-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid (297 mg, 0.96 mmol) was dissolved in DCM (3 mL) and added with oxalyl chloride (0.16 mL, 1.92 mmol) and a catalytic amount of DMF under nitrogen gas protection at 0 °C. The mixture was then cooled to room temperature and reacted for 30 minutes. The mixture was then concentrated under reduced pressure and dissolved in DMF (1 mL). Compound 34-5 (150 mg, 0.8 mmol) was slowly added to NaH (35 mg, 0.8 mmol) under nitrogen gas protection at 0 °C and reacted at 60 °C for 30 minutes. The acylated chloride of 4-bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoic acid was added to the reaction mixture at 0 °C and reacted at 80 °C for 2 hours. The reaction mixture was quenched by adding 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.

[0441] Step 6: Synthesis of compound 34 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 for 3 hours under nitrogen gas 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 3 / 1) to give compound 34. MS (ESI, pos. ion) m / z: 525.3 [M+1] + .

[0442] 1HNMR (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). 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]oct-6-yl)benzamide [ka]

[0443] Step 1: Synthesis of compound 37-2 Compound 37-1 (500 mg, 3.00 mmol) and cesium carbonate (1.95 g, 6.00 mmol) were dissolved in DMF (5 mL), and bromomethylcyclopropane (0.35 mL, 3.60 mmol) was added. The mixture was allowed to react at 70 °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 = 20:1 to 10:1) to give compound 37-2. MS (ESI, pos. ion) m / z: 221.0 [M+1] + .

[0444] Step 2: Synthesis of compound 37-3 Compound 37-2 (270 mg, 1.22 mmol), NHBoc (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 gas protection. 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 = 20:1 to 10:1) to give compound 37-3. MS (ESI, pos. ion) m / z: 302.2 [M+1] + .

[0445] Step 3: Synthesis of compound 37-4 Compound 37-3 was dissolved in DCM (1 mL), HCl / EA (5 mL) was added, and the mixture was allowed to react at 25 °C for 2 hours. The reaction mixture was quenched with ice water, neutralized with saturated NaHCO3 solution, extracted with EA, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and dried to give compound 37-4. MS (ESI, pos. ion) m / z: 202.1 [M+1] + .

[0446] Step 4: Synthesis of compound 37-5 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 then reacted at 25 °C for 10 minutes. The reaction mixture was concentrated and dried on 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 then reacted at 60 °C for 30 minutes. 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride was then added and 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 Na2SO4, 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]+.

[0447] Step 5: Synthesis of compound 37 Compound 37-5 (30 mg, 0.06 mmol), 2-hydroxyethanesulfonamide (38 mg, 0.30 mmol), cesium carbonate (59 mg, 0.18 mmol), and a 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 gas protection. 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 to give compound 37. MS (ESI, pos. ion) m / z: 538.3 [M+1]+.

[0448] 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). Example 38: Synthesis of N-(1-(cyclopropylmethyl)-1H-indol-4-yl)-6-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide [ka]

[0449] Step 1: Synthesis of compound 38-2 38-1 (800 mg, 4.93 mmol) and CsCO (3.2 g, 9.87 mmol) were dissolved in DMF (15 mL), and (bromomethyl)cyclobutane (733 mg, 5.43 mmol) was added dropwise slowly. The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated NaCl solution (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20 to 1 / 10) to give 38-2.

[0450] Step 2: Synthesis of compound 38-3 38-2 (800 mg, 3.7 mmol) and Pd / C 10% (80 mg, 0.75 mmol) were dissolved in MeOH (10 mL) and stirred at room temperature under H2 for 18 hours. The reaction mixture was filtered under vacuum, and the filtrate was concentrated under reduced pressure to give 38-3. MS m / z (ESI): 187.1 [M+1]+ .

[0451] Step 3: Synthesis of compound 38-5 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 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated NaCl solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20 to 1 / 10) to give compound 38-5. MS m / z (ESI): 267.0 [M+1] + .

[0452] Step 4: Synthesis of compound 38-6 Compound 38-5 (90 mg, 0.34 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (63, 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 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 to 1 / 5) to give compound 38-6. MS m / z (ESI): 435.2 [M+1] + .

[0453] Step 5: Synthesis of compound 38 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 for 10 h under N2 protection. 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 preparative separation to give compound 38. MS m / z (ESI): 524.3 [M+1] + .

[0454] 1 H 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,4H),1.28 - 1.22 (m,1H),0.55 - 0.47 (m,2H),0.44 - 0.36 (m,2H),0.26 (s,4H). 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) [ka]

[0455] Step 1: Synthesis of compound 39-2 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) and Cs2CO3 (25.96 g, 79.67 mmol) was added. The reaction mixture was placed in an oil bath at 60 °C and stirred for 4 h. 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. The crude product was purified by column chromatography (PE:EA = 100:0 to 98:2 to 95:5) to give compound 39-2.

[0456] Step 2: Synthesis of compound 39-3 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 h. After the reaction was complete, the reaction mixture was diluted with EA (120 mL). The organic layer was washed with brine (180 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 49:1) to give compound 39-3.

[0457] Step 3: Synthesis of compound 39-4 To a solution of compound 39-3 (1.38 g, 2.82 mmol) in methanol (10 mL) and water (2.5 mL), sodium hydroxide (0.68, 16.92 mmol) was added and stirred at 60 °C for 18 h. The reaction mixture was diluted with EA (120 mL). The organic layer was washed with brine (180 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:0 to 90:10 to 80:20) to give compound 39-4.

[0458] Step 4: Synthesis of compound 39-5 Compound 39-4 (1.2 g, 2.52 mmol) and 1-cyclopropylmethyl-1H-indol-4-amine (517.19 mg, 2.78 mmol) were dissolved in DMF (10 mL). Azabenzotriazolyltetramethyluronium hexafluorophosphate (1.15 g, 3.03 mmol) and N,N-diisopropylethylamine (0.84 mL, 5.05 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EA (120 mL). The organic layer was washed with brine (180 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 100:0 to 90:10 to 80:20) to give compound 39-5.

[0459] Step 5: Synthesis of compound 39-6 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 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 NaSO, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 100:0 to 90:10 to 80:20) to give compound 39-6.

[0460] Step 6: Synthesis of compound 39-7 Compound 39-6 (497 mg, 0.76 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL, 40.26 mmol) was added, and 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 NaSO, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 100:0 to 90:10 to 80:20) to give compound 39-7.

[0461] Step 7: Synthesis of Compound 39 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). Catalyst CAS: 1599466-83-7 (30.47 mg, 0.03 mmol) and cesium carbonate (214.44 mg, 0.66 mmol) were added. The reaction mixture was placed in an oil bath at 95 °C and stirred for 1.5 h. The reaction mixture was diluted with EA (100 mL). The organic layer was washed with brine (180 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified to give compound 39. MS (ESI, pos. ion) m / z: 552.3 [M+1] + .

[0462] 1 H 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). Example 40: Synthesis of N-(1-cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2-hydroxyethylsulfonamido)-2-methylamino-6-(6-azaspiro[2.5]octan-6-yl)benzamide (40) [ka]

[0463] Step 1: Synthesis of compound 40-2 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 mixture of DMF (25 mL) and HO (25 mL). CsCO (7.72 g, 59.75 mmol) was added, and the reaction mixture was placed in an oil bath at 100 °C and stirred for 3 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. Compound 40-2 was obtained by column chromatography (PE:EA = 98:2 to 95:5).

[0464] Step 2: Synthesis of compound 40-3 Compound 40-2 (5.8 g, 16.95 mmol) was dissolved in a mixture of MeOH (32 mL) and HO (8 mL), and NaOH (4.07 g, 101.69 mmol) was added. The reaction mixture was placed in an oil bath at 60 °C and stirred for 3 hours. After completion of the reaction, 2 M HCl was added to acidify the reaction mixture. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (30 × 3 mL). The organic layer was dried over NaSO, filtered, and concentrated to give compound 40-3.

[0465] Step 3: Synthesis of compound 40-4 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 min. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. Purification by column chromatography (DCM:MeOH = 99:1 to 97:3) gave compound 40-4.

[0466] Step 4: Synthesis of compound 40-5 Compound 40-4 (300 mg, 0.70 mmol) was dissolved in DCM (6 mL) and cooled to 0 °C. Oxalyl chloride (56.45 mg, 2.10 mmol) was slowly added, and the reaction mixture was stirred at room temperature for half an hour. After completion of the reaction, the reaction mixture was directly dried by spin-drying 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). The reaction mixture was cooled to 0 °C, and NaH (33.54 mg, 1.40 mmol) was added. The reaction mixture was placed in an oil bath at 60 °C and stirred for 30 minutes. The reaction mixture was then cooled to 0 °C, and the acyl chloride obtained above was added. The mixture was mixed and allowed to react 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 NaSO, filtered, and concentrated. Compound 40-5 was obtained by column chromatography (PE:EA = 100:0 to 97:3).

[0467] Step 5: Synthesis of compound 40-6 Compound 40-5 (128 mg, 0.21 mmol) and 2-hydroxyethane-1-sulfonamide (107 mg, 0.86 mmol) were dissolved in dioxane (2 mL). Catalyst CAS: 1599466-89-3 (35 mg, 0.04 mmol) and CsCO (139 mg, 0.43 mmol) were added, and the reaction mixture was placed in an oil bath at 95 °C and stirred for 2 h. 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 NaSO, filtered, and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 95:5) to give compound 40-6.

[0468] Step 6: Synthesis of compound 40 Compound 40-6 (56 mg, 0.09 mmol) was dissolved in methanol (1 mL), and 10% palladium carbon (0.93 mg, 0.01 mmol) was added thereto. The reaction mixture was placed in a hydrogen gas atmosphere and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture 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 separation to give compound 40. MS (ESI, pos. ion) m / z: 553.3 [M+1] + .

[0469] 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). 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) [ka]

[0470] Step 1: Synthesis of compound 41-2 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). Cesium carbonate (12.93 g, 39.68 mmol) was added, and the reaction mixture was placed in an oil bath at 60 °C and stirred for 3 h. After completion of the reaction, the reaction mixture 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. Compound 41-2 was obtained by column chromatography (PE:EA = 98:2 to 95:5).

[0471] Step 2: Synthesis of compound 41-3 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 41-2 (2.78 g, 6.98 mmol) was then added thereto, and the reaction mixture was placed in an oil bath at 125 °C and stirred 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 NaSO, filtered, and concentrated to give compound 41-3.

[0472] Step 3: Synthesis of compound 41-4 Compound 41-3 (498 mg, 1.02 mmol) was dissolved in methanol (4 mL) and water (0.4 mL), and LiOH (74 mg, 3.06 mmol) was added. The reaction mixture was placed in an oil bath at 60 °C and stirred for 7 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. Purification by column chromatography (PE:EA = 100:0 to 90:10 to 80:20) gave compound 41-4.

[0473] Step 4: Synthesis of compound 41-5 Compound 41-4 (170 mg, 0.36 mmol) and 1-cyclopropylmethyl-1H-indol-4-amine (66.61 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (3 mL). Azabenzotriazolyltetramethyluronium hexafluorophosphate (135.98 mg, 0.36 mmol) and N,N-diisopropylethylamine (46.22 mg, 0.36 mmol) were added, and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture 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 41-5 was obtained by column chromatography (PE:EA = 100:0 to 90:10 to 80:20).

[0474] Step 5: Synthesis of compound 41-6 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). Catalyst CAS: 1599466-89-3 (7.41 mg, 0.01 mmol) and CsCO (119.47 mg, 0.37 mmol) were added, and the reaction mixture was placed in an oil bath at 95 °C and stirred for 3 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. Compound 41-6 was obtained by column chromatography (PE:EA = 100:0 to 90:10 to 80:20).

[0475] Step 6: Synthesis of compound 41 Compound 41-6 (40 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL, 13.42 mmol) was added, and the reaction mixture was stirred at room temperature for 6 minutes. After completion of the reaction, the reaction mixture 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 NaSO, filtered, concentrated, and purified by HPLC to give compound 41. MS (ESI, pos. ion) m / z: 538.3 [M+1]+.

[0476] 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). 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) [ka]

[0477] Step 1: Synthesis of compound 42-2 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). Cesium carbonate (12.93 g, 39.68 mmol) was added, and the reaction mixture was placed in an oil bath at 60 °C and stirred for 3 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. Compound 42-2 was obtained by column chromatography (PE:EA = 98:2 to 95:5).

[0478] Step 2: Synthesis of compound 42-3 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 placed in an oil bath at 125 °C and stirred 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 NaSO, filtered, and concentrated to give compound 42-3.

[0479] Step 3: Synthesis of compound 42-4 Compound 42-3 (498 mg, 1.02 mmol) was dissolved in methanol (4 mL) and water (0.4 mL). The reaction mixture was placed in an oil bath at 60 °C and stirred for 7 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. Purification by column chromatography (PE:EA = 100:0 to 90:10 to 80:20) gave compound 42-4.

[0480] Step 4: Synthesis of compound 42-5 Compound 42-4 (160 mg, 0.34 mmol) and 1-cyclopropylmethyl-1H-indol-4-amine (63.37 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (3 mL). Azabenzotriazolyltetramethyluronium hexafluorophosphate (153.57 mg, 0.40 mmol) and N,N-diisopropylethylamine (87.00 mg, 0.67 mmol) were added, and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture 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 42-5 was obtained by column chromatography (PE:EA = 100:0 to 90:10 to 80:20).

[0481] Step 5: Synthesis of compound 42-6 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). Catalyst CAS: 1599466-89-3 (6.07 mg, 0.01 mmol) and CsCO (97.90 mg, 0.30 mmol) were added. The reaction mixture was placed in an oil bath at 95 °C and stirred for 3 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, and concentrated. Compound 42-6 was obtained by column chromatography (PE:EA = 100:0 to 90:10 to 80:20).

[0482] Step 6: Synthesis of compound 42 Compound 42-6 (70 mg, 0.10 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.6 mL, 8.05 mmol) was added, and the reaction mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction mixture 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, concentrated, and purified to give compound 42. MS (ESI, pos. ion) m / z: 540.3 [M+1] + .

[0483] 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 - 6.43 (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). Example 44: Synthesis of N-(1-(cyclopropylmethyl)-1H-indol-4-yl)-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (44) [ka]

[0484] Step 1: Synthesis of compound 44-2 Compound 44-1 (150 mg, 0.81 mmol), 4-iodo-2-(6-azaspiro[2.5]oct-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 for 2 hours under nitrogen gas protection at 0 °C. The reaction mixture was quenched by adding water (10 mL) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 20 / 1) to give compound 44-2.

[0485] Step 2: Synthesis of compound 44 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 for 1 hour under a N2 atmosphere. After the reaction was complete, the mixture was cooled to room temperature, and 3-methyloxetan-3-amine (0.1 mL, 1.14 mmol) and aqueous sodium hypochlorite solution (0.3 mL, 3.8 mmol) were added. The mixture was then reacted at room temperature overnight. The reaction mixture was quenched by adding 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 give compound 44. MS (ESI, pos. ion) m / z: 549.3 [M+1] + .

[0486] 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),1.42-1.48 (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). 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) [ka]

[0487] Step 1: Synthesis of compound 50-2 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 placed in an oil bath at 70 °C and stirred for 1.5 h. 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 NaSO, filtered, concentrated, and purified by column chromatography (PE:EA = 100:0 to 90:10) to give compound 50-2.

[0488] Step 2: Synthesis of compound 50-3 Compound 50-2 (260 mg, 0.97 mmol) and NHBoc (227 mg, 1.94 mmol) were dissolved in 1,4-dioxane (5 mL), and the catalyst CAS: 1599466-83-7 (179 mg, 0.19 mmol) and cesium carbonate (948 mg, 2.91 mmol) were added. The reaction mixture was placed in an oil bath at 95 °C and stirred for 1.5 h. After completion of the reaction, the reaction mixture 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 NaSO, filtered, concentrated, and purified by column chromatography (PE:EA = 100:0 to 90:10 to 80:20) to give compound 50-3.

[0489] Step 3: Synthesis of compound 50-4 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 thereto. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture 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 NaSO, filtered, concentrated, and purified by column chromatography (PE:EA = 100:0 to 90:10 to 80:20) to give compound 50-4.

[0490] Step 4: Synthesis of compound 50-5 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 azabenzotriazolyltetramethyluronium hexafluorophosphate (134 mg, 0.35 mmol) and N,N-diisopropylethylamine (76 mg, 0.59 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 h. After completion of the reaction, the reaction mixture 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 to 95:5 to 90:10) to give compound 50-5.

[0491] Step 5: Synthesis of Compound 50 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. The reaction mixture was placed in an oil bath at 95 °C and stirred 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 NaSO, filtered, and concentrated. Purification afforded compound 50. MS (ESI, pos. ion) m / z: 541.2 [M+1] + 1H 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). Example 56: Synthesis of N-(1-(cyclopropylmethyl)-7-fluoro-1H-indol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (56) [ka]

[0492] Step 1: Synthesis of compound 56-2 Compound 56-1 (300 mg, 1.40 mmol) and cesium carbonate (913 mg, 2.80 mmol) were dissolved in DMF (4 mL), and (bromomethyl)cyclopropane (0.16 mL, 1.68 mmol) was added. The mixture was allowed to react at 70 °C for 30 minutes. 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 = 1 / 20 to 1 / 10) to give compound 56-2. MS (ESI, pos. ion) m / z: 267.9 / 269.9 [M+1] + .

[0493] Step 2: Synthesis of compound 56-3 Compound 56-2 (350 mg, 1.31 mmol), NHBoc (306 mg, 2.62 mmol), and cesium carbonate (1.28 g, 3.93 mmol) were dissolved in dioxane (5 mL), and the catalyst CAS: 1599466-83-7 (241 mg, 0.26 mmol) was added. The reaction was allowed to proceed at 90 °C for 3 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 NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20 to 1 / 10) to give compound 56-3.

[0494] Step 3: Synthesis of compound 56-4 Compound 56-3 (369 mg, 1.21 mmol) was dissolved in dichloromethane (2 mL), and a hydrogen chloride-dioxane solution (3 mL) was added thereto, followed by reaction at 25° C. for 2 hours. The reaction mixture was filtered and dried to obtain the hydrochloride salt of compound 56-4. MS (ESI, pos. ion) m / z: 205.0 [M+1-HCl] + .

[0495] Step 4: Synthesis of compound 56-5 Compound 56-4 hydrochloride (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-dehydrated DMF (2 mL). DIEA (0.43 mL, 2.58 mmol) was added and the mixture was reacted 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 NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to give compound 56-5.

[0496] Step 5: Synthesis of Compound 56 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 for 2 h under N2 protection. 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 to give compound 56. MS (ESI, pos. ion) m / z: 541.3 [M+1] + .

[0497] 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). Example 68: Synthesis of N-(1-(cyclopropylmethyl)-1H-indol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide [ka]

[0498] Step 1: Synthesis of compound 68-2 68-1 (1 g, 4.63 mmol) was dissolved in methanol (10 mL), palladium carbon (200 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen gas atmosphere. The reaction solution was filtered and concentrated under reduced pressure to give 68-2.

[0499] Step 2: Synthesis of compound 68-3 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]oct-6-yl)benzoic acid (1.33 g, 4.3 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for 2 h. The reaction mixture was poured into 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 give 68-3.

[0500] Step 3: Synthesis of compound 68 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 for 16 h under nitrogen gas protection. After cooling, the reaction mixture was poured into 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 give 68.

[0501] MS (ESI,pos.ion) m / z: 523.2[M+1] + . 1H 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),7.20 (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=3.0Hz,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). Example 126: Synthesis of 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6,7,8,9-tetrahydropyridine[1,2-a]indole-1)benzamide (126) [ka]

[0502] Step 1: Synthesis of compound 126-2 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 under a hydrogen atmosphere for 16 hours. The palladium on carbon was removed by filtration, and the organic phase was concentrated under reduced pressure to give compound 126-2.

[0503] Step 2: Synthesis of compound 126-3 Compound 126-2 (95 mg, 0.33 mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrochloric acid in ethyl acetate (0.5 mL, 1.98 mmol) was added dropwise under ice bath. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to give compound 126-3.

[0504] Step 3: Synthesis of compound 126-4 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 2 h. The reaction mixture was poured into 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 give compound 126-4.

[0505] Step 4: Synthesis of Compound 126 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 for 16 h under nitrogen gas protection. After cooling, 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 give compound 126. MS (ESI, pos. ion) m / z: 525.2 [M+1] + .

[0506] 1H NMR (DMSO-d6) δ: 10.71-10.79 (m,1H),7.76-7.84 (m,1H),7.11-7.20 (m,2H),6.93-7.03 (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). Example 127: Synthesis of N-(1-(cyclopropylmethyl)-1H-indol-4-yl)-4-methoxy-2-(6-azaspiro[2.5]octan-6-yl)benzamide (127) [ka]

[0507] Step 1: Synthesis of compound 127-2 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 2 hours. The reaction mixture was poured into 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 give compound 127-2.

[0508] Step 2: Synthesis of compound 127-3 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 2 hours. The reaction mixture was poured into ice water, extracted three times with ethyl acetate (30 mL), washed twice with brine (30 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 give compound 127-3.

[0509] Step 3: Synthesis of compound 127-4 Compound 127-3 (3.7 g, 11.01 mmol) was dissolved in ethanol (30 mL), concentrated hydrochloric acid (35 mL) was added under ice bath, and the mixture was refluxed at 80 °C for 2 h. After the reaction mixture was cooled, a solid precipitated. The crude product 127-4 was obtained by filtration and used directly in the next step.

[0510] Step 4: Synthesis of compound 127-5 Compound 127-4 (1 g, 3.79 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of borane in tetrahydrofuran (11.36 mL, 11.36 mmol) was added under ice bath. The reaction mixture was stirred at 70 °C overnight. After cooling, the reaction mixture was quenched with dilute hydrochloric acid under ice bath. The mixture was 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 = 0-10%) to give 127-5.

[0511] Step 5: Synthesis of compound 127-6 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 for 2 h under nitrogen gas protection. After cooling, the reaction mixture was poured into 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 give compound 127-6.

[0512] Step 6: Synthesis of compound 127-7 Compound 127-6 (110 mg, 11.01 mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrochloric acid in ethyl acetate (1.92 mL, 3.85 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 2 hours. A solid precipitated in the reaction mixture, and the reaction mixture was concentrated to give crude product 127-7, which was used directly in the next step.

[0513] Step 7: Synthesis of compound 127-8 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 2 h. The reaction mixture was poured into 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 give compound 127-8.

[0514] Step 8: Synthesis of Compound 127 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 for 16 hours under nitrogen gas protection. After cooling, 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 give compound 127. MS (ESI) m / z: 523.2 [M+1] + .

[0515] 1 H 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). Example 128: Synthesis of 2-(6-azaspiro[2.5]oct-6-yl)-N-(8,8-difluoro-6,7,8,9-tetrahydropyridine[1,2-a]indol-1-yl)-4-{[(2-hydroxyethyl)sulfonamide]}benzamide (128) [ka]

[0516] Step 1: Synthesis of compound 128-2 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 thereto, followed by a reaction at 95° C. for 2 h. The reaction mixture 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 silica gel column chromatography (PE:EA = 1 / 10 to 1 / 5) to give compound 128-2.

[0517] Step 2: Synthesis of compound 128-3 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 allowed to react at room temperature for 20 min to give a reaction mixture containing compound 128-3, which was used directly in the next step.

[0518] Step 3: Synthesis of compound 128-4 To the reaction mixture in Step 2, sodium hydride (0.22 g, 5.43 mmol) was added 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 NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA=1 / 20 to 1 / 10) to give compound 128-4.

[0519] Step 4: Synthesis of compound 128-5 Compound 128-4 (560 mg, 1.94 mmol) was dissolved in 1,2-dichloroethane (5 mL), DDQ (883.03 mg, 3.89 mmol) was added, and 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 NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1 / 20 to 1 / 10) to give compound 128-5.

[0520] Step 5: Synthesis of compound 128-6 Compound 128-5 (672 mg, 2.35 mmol), NHBoc (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 for 4 h under N2 protection. 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 to 1 / 5) to give compound 128-6.

[0521] Step 6: Synthesis of compound 128-7.

[0522] Compound 128-6 (800 mg, 1.72 mmol) was dissolved in DCM (5 mL), and hydrochloric acid-1,4-dioxane (5 mL) was added. The mixture was reacted at room temperature for 0.5 h. The mixture was concentrated under reduced pressure to give the hydrochloride salt of compound 128-7, which was used directly in the next step.

[0523] Step 7: Synthesis of compound 128-8.

[0524] Compound 128-7 hydrochloride (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 the mixture was allowed to react at room temperature for 4 h. The reaction mixture 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 silica gel column chromatography (PE:EA = 1 / 10 to 1 / 5) to give compound 128-8.

[0525] Step 8: Synthesis of Compound 128 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 for 4 h under N2 protection. 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 preparative liquid phase to give compound 128. MS m / z (ESI): 559.2 [M+1] + .

[0526] 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 (dd,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). Example 129: Synthesis of N-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-8-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (129) [ka]

[0527] Step 1: Synthesis of compound 129-2 Compound 129-1 (3 g, 11.81 mmol) was dissolved in toluene (15 mL), potassium tert-butoxide (0.88 g, 11.81 mmol) and ethyl acrylate (2.57 mL, 23.61 mmol) were added, and the mixture was allowed to react overnight at 110 °C. 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 to 1 / 10) to give compound 129-2. MS m / z (ESI): 322.0 [M+1] + .

[0528] Step 2: Synthesis of compound 129-3 Compound 129-2 (2.28 g, 7.08 mmol) was dissolved in ultra-dehydrated ethanol (30 mL), and 12 mol / L hydrochloric acid (20 mL) was added thereto and reacted at 80 °C for 1 h. The reaction solution was concentrated and slowly poured into ice water, causing the solid to precipitate. After filtration and drying, compound 129-3 was obtained and used directly in the next step.

[0529] Step 3: Synthesis of compound 129-4 Compound 129-3 (1.7 g, 6.8 mmol) was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (3.25 mL, 20.39 mmol) and trifluoromethanesulfonic acid (0.18 mL, 2.04 mmol) were added to the solution in an ice bath under N2 protection, and the mixture was reacted at 25 °C for 2 h. The reaction mixture was quenched with ice water, neutralized with saturated NaHCO3 solution, extracted with EA, and 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 give compound 129-4.

[0530] Step 4: Synthesis of compound 129-5 Compound 129-4 (300 mg, 1.27 mmol), NHBoc (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 N2 protection. 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 to 1 / 10) to give compound 129-5. MS m / z (ESI): 273.2 [M+1] + .

[0531] Step 5: Synthesis of compound 129-6 Compound 129-5 (260 mg, 0.95 mmol) was dissolved in DCM (1 mL), and HCl / EA (2 mL) was added thereto, followed by reaction at 25° C. for 2 h. The solid precipitated was filtered and dried to obtain the hydrochloride salt of compound 129-6, which was used directly in the next step.

[0532] Step 6: Synthesis of compound 129-7 Compound 129-6 hydrochloride (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 to 1 / 5) to give compound 129-7. MS m / z (ESI): 464.1 / 466.1 [M+1]. + .

[0533] Step 7: Synthesis of Compound 129 Compound 129-7 (198 mg, 0.43...

Claims

1. A compound of formula (I) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, 【Chemistry 1】 A is a monocyclic aryl group, a monocyclic heteroaryl group, a bicyclic aryl group, a bicyclic heteroaryl group, or a fused heterocyclyl group, and optionally the monocyclic aryl group, the monocyclic heteroaryl group, the bicyclic aryl group, the bicyclic heteroaryl group, or the fused heterocyclyl group optionally comprises one or more R ｚ is replaced by L is -NR ３ —CO— or —NR ３ CONR ３ -, and each R ３ are independently H, deuterium, a C1-C6 alkylene group, or a C1-C6 haloalkylene group; R ｘ is -OR ４ or -NR ５ R ６ where R ４ is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group, the 3- to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S, and N; R ５ is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group; R ６ is selected from H or a C1-C6 alkyl group, or R ５ and R ６ together with the N atom to which they are attached form a 4- to 8-membered heterocyclyl group, wherein said 3- to 8-membered cycloalkyl group, 3- to 8-membered cycloalkenyl group, 3- to 8-membered heterocyclyl group and 4- to 8-membered heterocyclyl group contain 0, 1, 2 or 3 heteroatoms selected from O, S and N and optionally one or more R ｚ is replaced by R １ is -CN or -Z-R １２ wherein Z is a direct bond, —C1-C6 alkylene-, —C1-C6 alkylene-O—, —O—, —S—, —S(═O)—, or —SO ２ -, -NR １１ -, -NR １１ SO ２ -, -SO ２ NR １１ -, -NR １１ -S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C6 alkylene-SO ２ -, -C1-C6 alkylene-SO ２ R １１ -, -(C=O)-, -(C=O)NR １１ -, -C=N(OH)- or -NR １１ (C═O)—, or —Z—R １２ is -N=S(=O)-(R １２ ) ２ where two R １２ can combine with the sulfur atom to which they are each 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; X ７ is N or CR ７ and X ８ is N or CR ８ and X ９ is N or CR ９ and R ７ , R ８ and R ９ are independently H, halogen, C1-C8 alkyl group, C1-C6 haloalkyl group, —OH, —O—R ８ａ , -O-R ８ｂ or -NR ａ R ａ and R ７ and R ８ When both exist simultaneously, R ７ and R ８ can combine with the atoms to which they are each 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 ｘ and R ９ When both exist simultaneously, R ｘ and R ９ can combine with the atoms to which they are each 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 is H, R １１ａ or R １１ｂ and R １２ is H, R １２ａ or R １２ｂ and R ８ａ , R １１ａ and R １２ａ is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are selected from the group consisting of F, Cl, Br, a C1-C6 alkyl group, a C1-C6 haloalkyl group, -OR ａ , —OC1-C6 haloalkyl group, 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 alkyleneNR ａ R ａ , —OC2-C6 alkylene OR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR 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) ２ R ｂ , -N(R ａ ) S(=O) ２ NR ａ R ａ , -NR ａ C2-6 alkylene NR ａ R ａ , -NR ａ C2-C6 alkylene OR ａ , —C1-C6 alkyleneNR ａ R ａ , —C1-C6 alkylene OR ａ , —C1-C6 alkyleneN(R ａ ) C(=O)R ｂ , —C1-C6 alkylene OC(═O)R ｂ , —C1-C6 alkyleneC(═O)NR ａ R ａ , —C1-C6 alkylene C(═O)OR ａ , R １４ and oxo; R ８ｂ , R １１ｂ and R １２ｂ are independently F, Cl, Br, -OR ａ , —OC1-C6 haloalkyl, or C1-C6 alkyl substituted with 0, 1, 2, 3, 4, or 5 groups selected from CN; R １４ is, in each occurrence, independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which are selected from the group consisting of F, Cl, Br, a C1-C6 alkyl group, -OR ａ , —OC1-C6 haloalkyl group, 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 alkyleneNR ａ R ａ , —OC2-6 alkylene OR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR 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) ２ R ｂ , -N(R ａ ) S(=O) ２ NR ａ R ａ , -NR ａ C2-C6 alkylene NR ａ R ａ , -NR ａ C2-C6 alkylene OR ａ , —C1-C6 alkyleneNR ａ R ａ , —C1-C6 alkylene OR ａ , —C1-C6 alkyleneN(R ａ ) C(=O)R ｂ , —C1-C6 alkylene OC(═O)R ｂ , —C1-C6 alkyleneC(═O)NR ａ R ａ , —C1-C6 alkylene C(═O)OR ａ and oxo; Each R ａ are each independently H or R ｂ and Each R ｂ are each independently a C1-C6 alkyl group, a phenyl group, or a benzyl group, and the C1-C6 alkyl group is selected from halogen, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and the phenyl or benzyl group is substituted by 0, 1, 2, or 3 substituents selected from halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl); Each R ｚ are independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, —C1-C6 alkylene-O—C1-C6 alkyl group, a C3-C8 cycloalkyl-C1-C6 alkylene group, —OH, —CN, —O—C1-C6 alkyl group, —O—C3-C8 cycloalkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, —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 phenyl group, a 5- to 6-membered monocyclic heteroaryl group containing 0, 1, 2 or 3 N atoms, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 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 said monocyclic or bicyclic ring is selected from the group consisting of deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and two R ｚ teeth, 【Chemistry 2】 or two R ｚ may together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and said C1-C6 alkyl group, C3-C8 cycloalkyl group, —C1-C6 alkylene-O—C1-C6 alkyl group, —O—C1-C6 alkyl group, and C3-C8 cycloalkyl-C1-C6 alkylene group may optionally be substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, a C1-C4 haloalkyl group, and a C3-C8 halocycloalkyl group; Each R ｚ１ are independently selected from the group consisting of H, C1-C6 alkyl groups, and C1-C6 haloalkyl groups; Each R ｚ２ are independently selected from the group consisting of H, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 deuterated alkyl groups, and C3-C8 cycloalkyl groups; Q is O or CR Ｑ１ R Ｑ２ and R Ｑ１ and R Ｑ２ are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl group, and C1-C6 haloalkyl group, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

2. A is a monocyclic aryl group, a monocyclic heteroaryl group, a bicyclic aryl group, a bicyclic heteroaryl group, or a fused heterocyclyl group, and optionally the monocyclic aryl group, the monocyclic heteroaryl group, the bicyclic aryl group, the bicyclic heteroaryl group, or the fused heterocyclyl group optionally comprises one or more R ｚ is replaced by L is -NR ３ —CO— or —NR ３ CONR ３ -, and each R ３ are independently H, deuterium, a C1-C6 alkylene group, or a C1-C6 haloalkylene group; R ｘ is -OR ４ or -NR ５ R ６ where R ４ is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group, the 3- to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S, and N; R ５ is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group; R ６ is selected from H or a C1-C6 alkyl group, or R ５ and R ６ together with the N atom to which they are attached form a 4- to 8-membered heterocyclyl group, wherein said 3- to 8-membered cycloalkyl group, 3- to 8-membered cycloalkenyl group, 3- to 8-membered heterocyclyl group and 4- to 8-membered heterocyclyl group contain 0, 1, 2 or 3 heteroatoms selected from O, S and N and optionally one or more R ｚ is replaced by R １ is -CN or -Z-R １２ wherein Z is a direct bond, —C1-C6 alkylene-, —C1-C6 alkylene-O—, —O—, —S—, —S(═O)—, or —SO ２ -, -NR １１ -, -NR １１ SO ２ -, -SO ２ NR １１ -, -NR １１ -S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C6 alkylene-SO ２ -, -C1-C6 alkylene-SO ２ R １１ -, -(C=O)-, -(C=O)NR １１ -, -C=N(OH)- or -NR １１ (C═O)—, or —Z—R １２ is -N=S(=O)-(R １２ ) ２ where two R １２ can combine with the sulfur atom to which they are each 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; X ７ is N or CR ７ and X ８ is N or CR ８ and X ９ is N or CR ９ and R ７ , R ８ and R ９ are independently H, halogen, C1-C8 alkyl group, C1-C6 haloalkyl group, —OH, —O—R ８ａ , -O-R ８ｂ or -NR ａ R ａ and R ７ and R ８ When both exist simultaneously, R ７ and R ８ can combine with the atoms to which they are each 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 ｘ and R ９ When both exist simultaneously, R ｘ and R ９ can combine with the atoms to which they are each 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 is H, R １１ａ or R １１ｂ and R １２ is H, R １２ａ or R １２ｂ and R ８ａ , R １１ａ and R １２ａ is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are selected from the group consisting of F, Cl, Br, a C1-C6 alkyl group, a C1-C6 haloalkyl group, -OR ａ , —OC1-C6 haloalkyl group, 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 alkyleneNR ａ R ａ , —OC2-C6 alkylene OR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR 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) ２ R ｂ , -N(R ａ ) S(=O) ２ NR ａ R ａ , -NR ａ C2-6 alkylene NR ａ R ａ , -NR ａ C2-C6 alkylene OR ａ , —C1-C6 alkyleneNR ａ R ａ , —C1-C6 alkylene OR ａ , —C1-C6 alkyleneN(R ａ ) C(=O)R ｂ , —C1-C6 alkylene OC(═O)R ｂ , —C1-C6 alkyleneC(═O)NR ａ R ａ , —C1-C6 alkylene C(═O)OR ａ , R １４ and oxo; R ８ｂ , R １１ｂ and R １２ｂ are independently F, Cl, Br, -OR ａ , —OC1-C6 haloalkyl, or C1-C6 alkyl substituted with 0, 1, 2, 3, 4, or 5 groups selected from CN; R １４ is, in each occurrence, independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which are selected from the group consisting of F, Cl, Br, a C1-C6 alkyl group, -OR ａ , —OC1-C6 haloalkyl group, 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 alkyleneNR ａ R ａ , —OC2-6 alkylene OR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR 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) ２ R ｂ , -N(R ａ ) S(=O) ２ NR ａ R ａ , -NR ａ C2-C6 alkylene NR ａ R ａ , -NR ａ C2-C6 alkylene OR ａ , —C1-C6 alkyleneNR ａ R ａ , —C1-C6 alkylene OR ａ , —C1-C6 alkyleneN(R ａ ) C(=O)R ｂ , —C1-C6 alkylene OC(═O)R ｂ , —C1-C6 alkyleneC(═O)NR ａ R ａ , —C1-C6 alkylene C(═O)OR ａ and oxo; Each R ａ are each independently H or R ｂ and Each R ｂ are each independently a C1-C6 alkyl group, a phenyl group, or a benzyl group, and the C1-C6 alkyl group is selected from halogen, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and the phenyl or benzyl group is substituted by 0, 1, 2, or 3 substituents selected from halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl); Each R ｚ are independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, —C1-C6 alkylene-O—C1-C6 alkyl group, a C3-C8 cycloalkyl-C1-C6 alkylene group, —OH, —CN, —O—C1-C6 alkyl group, —O—C3-C8 cycloalkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, —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 group containing 0, 1, 2 or 3 N atoms, a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 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 said monocyclic or bicyclic ring is selected from the group consisting of deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and two R ｚ teeth, 【Transformation 3】 or two R ｚ may together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and said C1-C6 alkyl group, C3-C8 cycloalkyl group, —C1-C6 alkylene-O—C1-C6 alkyl group, —O—C1-C6 alkyl group, and C3-C8 cycloalkyl-C1-C6 alkylene group may optionally be substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, a C1-C4 haloalkyl group, and a C3-C8 halocycloalkyl group; Each R ｚ１ are independently selected from the group consisting of H, C1-C6 alkyl groups, and C1-C6 haloalkyl groups; Each R ｚ２ are independently selected from the group consisting of H, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 deuterated alkyl groups, and C3-C8 cycloalkyl groups; Q is O or CR Ｑ１ R Ｑ２ and R Ｑ１ and R Ｑ２ are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl group, and C1-C6 haloalkyl group, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

3. A is a monocyclic aryl group, a monocyclic heteroaryl group, a bicyclic aryl group, a bicyclic heteroaryl group, or a fused heterocyclyl group, and optionally the monocyclic aryl group, the monocyclic heteroaryl group, the bicyclic aryl group, the bicyclic heteroaryl group, or the fused heterocyclyl group optionally comprises one or more R ｚ is replaced by L is -NR ３ —CO— or —NR ３ CONR ３ -, and each R ３ are independently H, deuterium, a C1-C6 alkylene group, or a C1-C6 haloalkylene group; R ｘ is -OR ４ or -NR ５ R ６ where R ４ is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group, the 3- to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S, and N; R ５ is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkenyl group, or a 3- to 8-membered heterocyclyl group; R ６ is selected from H or a C1-C6 alkyl group, or R ５ and R ６ together with the N atom to which they are attached form a 4- to 8-membered heterocyclyl group, wherein said 3- to 8-membered cycloalkyl group, 3- to 8-membered cycloalkenyl group, 3- to 8-membered heterocyclyl group and 4- to 8-membered heterocyclyl group contain 0, 1, 2 or 3 heteroatoms selected from O, S and N and optionally one or more R ｚ is replaced by R １ is -CN or -Z-R １２ wherein Z is a direct bond, —C1-C6 alkylene-, —C1-C6 alkylene-O—, —O—, —S—, —S(═O)—, or —SO ２ -, -NR １１ -, -NR １１ SO ２ -, -SO ２ NR １１ -, -NR １１ -S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C6 alkylene-SO ２ -, -C1-C6 alkylene-SO ２ R １１ -, -(C=O)-, -(C=O)NR １１ -, -C=N(OH)- or -NR １１ (C═O)—, or —Z—R １２ is -N=S(=O)-(R １２ ) ２ where two R １２ can combine with the sulfur atom to which they are each 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; X ７ is N or CR ７ and X ８ is N or CR ８ and X ９ is N or CR ９ and R ７ , R ８ and R ９ are independently H, halogen, C1-C8 alkyl group, C1-C6 haloalkyl group, —OH, —O—R ８ａ , -O-R ８ｂ or -NR ａ R ａ and R ７ and R ８ When both exist simultaneously, R ７ and R ８ can combine with the atoms to which they are each 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 ｘ and R ９ When both exist simultaneously, R ｘ and R ９ can combine with the atoms to which they are each 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 is H, R １１ａ or R １１ｂ and R １２ is H, R １２ａ or R １２ｂ and R ８ａ , R １１ａ and R １２ａ is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are selected from the group consisting of F, Cl, Br, a C1-C6 alkyl group, a C1-C6 haloalkyl group, -OR ａ , —OC1-C6 haloalkyl group, 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 alkyleneNR ａ R ａ , —OC2-C6 alkylene OR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR 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) ２ R ｂ , -N(R ａ ) S(=O) ２ NR ａ R ａ , -NR ａ C2-6 alkylene NR ａ R ａ , -NR ａ C2-C6 alkylene OR ａ , —C1-C6 alkyleneNR ａ R ａ , —C1-C6 alkylene OR ａ , —C1-C6 alkyleneN(R ａ ) C(=O)R ｂ , —C1-C6 alkylene OC(═O)R ｂ , —C1-C6 alkyleneC(═O)NR ａ R ａ , —C1-C6 alkylene C(═O)OR ａ , R １４ and oxo; R ８ｂ , R １１ｂ and R １２ｂ are independently F, Cl, Br, -OR ａ , —OC1-C6 haloalkyl, or C1-C6 alkyl substituted with 0, 1, 2, 3, 4, or 5 groups selected from CN; R １４ is, in each occurrence, independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which are selected from the group consisting of F, Cl, Br, a C1-C6 alkyl group, -OR ａ , —OC1-C6 haloalkyl group, 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 alkyleneNR ａ R ａ , —OC2-6 alkylene OR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR 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) ２ R ｂ , -N(R ａ ) S(=O) ２ NR ａ R ａ , -NR ａ C2-C6 alkylene NR ａ R ａ , -NR ａ C2-C6 alkylene OR ａ , —C1-C6 alkyleneNR ａ R ａ , —C1-C6 alkylene OR ａ , —C1-C6 alkyleneN(R ａ ) C(=O)R ｂ , —C1-C6 alkylene OC(═O)R ｂ , —C1-C6 alkyleneC(═O)NR ａ R ａ , —C1-C6 alkylene C(═O)OR ａ and oxo; Each R ａ are each independently H or R ｂ and Each R ｂ are each independently a C1-C6 alkyl group, a phenyl group, or a benzyl group, and the C1-C6 alkyl group is selected from halogen, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and the phenyl or benzyl group is substituted by 0, 1, 2, or 3 substituents selected from halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl); Each R ｚ are independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, a C3-C8 cycloalkyl-C1-C6 alkylene group, —OH, —CN, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl), —S(O)—R ｚ１ , -S(O) ２ -R ｚ１ , saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, said monocyclic or bicyclic rings being preferably selected from the group consisting of deuterium, halogen, C1-C6 alkyl groups, C3-C8 cycloalkyl groups, C1-C6 haloalkyl groups, —OH, —O—C1-C6 alkyl groups, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and two R ｚ teeth, 【Chemistry 4】 or two R ｚ may together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, —O—C1-C6 alkyl group, and C3-C8 cycloalkyl-C1-C6 alkylene group may optionally be substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, a C1-C4 haloalkyl group, and a C3-C8 halocycloalkyl group; Each R ｚ１ are independently selected from the group consisting of C1-C6 alkyl groups, C1-C6 haloalkyl groups; Q is O or CR Ｑ１ R Ｑ２ and R Ｑ１ and R Ｑ２ are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl group, and C1-C6 haloalkyl group, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

4. Each R ｚ are independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group 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 said monocyclic or bicyclic ring is selected from the group consisting of deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and two or more of said substituents together with the carbon atom to which they are attached can form a C3-C8 cycloalkyl group, and said C1-C6 alkyl group, C3-C8 cycloalkyl group, or —O—C1-C6 alkyl group may be optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

5. Formula (I) is as shown in formula (I)-1, formula (I)-2 or formula (I)-3, 【Transformation 5】 The compounds according to any one of claims 1 to 4, wherein each symbol in formula (I)-1 to formula (I)-3 is as defined in any one of claims 1 to 4, or stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs thereof.

6. R ｘ teeth, 【Transformation 6】 is 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 represents H, deuterium, halogen, —CN, —OH, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C3-C8 cycloalkyl group, —NH ２ , —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), N, O, S, wherein the C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C3-C8 cycloalkyl group are optionally substituted by 1 to 5 substituents selected from deuterium, halogen, —OH, —CN, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, and —O-C1-C6 haloalkyl group, and the monocyclic or bicyclic ring is optionally substituted by 1 to 5 substituents selected from F, Cl, Br, C1-C6 alkyl group, C1-C6 haloalkyl group, —OR ｍ , —OC1-C6 haloalkyl group, 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 alkyleneNR ｍ R ｍ , —OC2-C6 alkylene OR ｍ , -SR ｍ , -S(=O)R ｎ , -S(=O) ２ R ｎ , -S(=O) ２ NR 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) ２ R ｎ , -N(R ｍ ) S(=O) ２ NR ｍ R ｍ , -NR ｍ C2-6 alkylene NR ｍ R ｍ , -NR ｍ C2-C6 alkylene OR ｍ , —C1-C6 alkyleneNR ｍ R ｍ , —C1-C6 alkylene OR ｍ , —C1-C6 alkyleneN(R ｍ ) C(=O)R ｎ , —C1-C6 alkylene OC(═O)R ｎ , —C1-C6 alkyleneC(═O)NR ｍ R ｍ , —C1-C6 alkylene C(═O)OR ｍ and oxo; Or alternatively, R １０ａ and R １０ｂ Against R １０ｃ and R １０ｄ Against R １０ｅ and R １０ｆ Against R １０ｇ and R １０ｈ Against R １０ｉ and R １０ｊ , R １０ｋ and R １０ｌ Each of the pairs independently, in combination with the carbon atom to which they are each attached, represents R ｘ and a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring spiro-bonded to the ring, wherein the 3-, 4-, 5-, or 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-, 4-, 5-, or 6-membered monocyclic ring is selected from F, Cl, Br, a C1-C6 alkyl group, a C1-C4 haloalkyl group, -OR ｍ , —OC1-C4 haloalkyl group, CN, —NR ｍ R ｍ or oxo; Each R ｍ and R ｎ is independently selected from H or a —C1-C6 alkyl group; Or alternatively, R １０ａ and R １０ｂ Against R １０ｃ and R １０ｄ Against R １０ｅ and R １０ｆ Against R １０ｇ and R １０ h vs. R １０ｉ and R １０ｊ Pair or R １０ｋ and R １０ｌ The opposite is 【Transformation 7】 where Q is CR Ｑ１ R Ｑ２ and R Ｑ１ and R Ｑ２ are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl group, and C1-C6 haloalkyl group, 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.

7. R ｘ teeth, 【Transformation 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, according to any one of claims 1 to 6,

8. R １０ｃ , R １０ｄ , R １０ｅ , R １０ｆ , R １０ｇ , R １０ｈ , R １０ｉ and R １０ｊ are each H, deuterium, halogen, —CN, —OH, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, —NH ２ , —NH(C1-C6 alkyl) or —N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl group, C1-C6 alkoxy group, and C1-C6 haloalkyl group are optionally substituted with 1 to 5 substituents selected from deuterium, halogen, —OH, —CN, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, and —O—C1-C6 haloalkyl group; R １０ａ and R １０ｂ The opposite is 【Chemistry 9】 and Q is CR Ｑ１ R Ｑ２ and R Ｑ１ and R Ｑ２ are independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, or R １０ａ and R １０ｂ The pair, together with the carbon atom to which it is attached, is R ｘ forming a C3-C8 cycloalkyl group spiro-bonded to the ring, and further, the C3-C8 cycloalkyl group is selected from the group consisting of F, Cl, Br, a C1-C6 alkyl group, a C1-C4 haloalkyl group, —OH, a C1-C6 alkoxy group, —OC1-C4 haloalkyl group, —CN, —NH ２ 8. The compound of any one of claims 1 to 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, wherein the compound is substituted with 0, 1, 2 or 3 groups selected from -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl) or oxo.

9. R ｘ teeth, 【Chemistry 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, selected from the group consisting of:

10. Formula (I) is as 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: 【Chemistry 11】 10. The compound of any one of claims 1 to 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.

11. R １ is the group -Z-R １２ wherein -Z is a single bond, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-, -S-, -S(═O)-, or -SO ２ -, -NH-, -NHSO ２ -, -SO ２ NH-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C4 alkylene-SO ２ -, -(C=O)-, -(C=O)NH-, -C=N(OH)- or -NH(C=O)-, and / or (a) R １２ is H, (b) R １２ is an oxetanyl group, a cyclopropyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F, Cl), and C1-C6 alkoxy groups; or (c) R １２ is a C1-C6 alkyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and a C1-C6 alkoxy group; 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.

12. The group -Z-R １２ is -N=S(=O)-(R １２ ) ２ where two R １２ can alternatively be combined with the sulfur atom to which they are respectively 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; or the group -Z-R １２ In the formula, Z is a single bond, and R １２ is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are selected from the group consisting of F, Cl, Br, a C1-C6 alkyl group, a C1-C6 haloalkyl group, -OR ａ , —OC1-C6 haloalkyl group, 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 alkyleneNR ａ R ａ , —OC2-C6 alkylene OR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR 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) ２ R ｂ , -N(R ａ ) S(=O) ２ NR ａ R ａ , -NR ａ C2-6 alkylene NR ａ R ａ , -NR ａ C2-C6 alkylene OR ａ , —C1-C6 alkyleneNR ａ R ａ , —C1-C6 alkylene OR ａ , —C1-C6 alkyleneN(R ａ ) C(=O)R ｂ , —C1-C6 alkylene OC(═O)R ｂ , —C1-C6 alkyleneC(═O)NR ａ R ａ , —C1-C6 alkylene C(═O)OR ａ and oxo, and R ａ and R ｂ are independently selected from H and —C1-C6 alkyl groups, 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.

13. R １ is the group -Z-R １２ where Z is —NHSO ２ -or-SO ２ NH— and R １２ is an oxetanyl group, a cyclopropyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and C1-C6 alkoxy groups, or R １２ is a C1-C6 alkyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and a C1-C6 alkoxy group; 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.

14. R １ teeth, Table 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, selected from the group consisting of:

15. 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: 【Chemistry 12】 15. The compound of 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.

16. Each R ３ are independently H, a C1-C4 alkyl group, or a C1-C4 haloalkyl group, 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.

17. Each R ３ are independently H, 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.

18. X ７ is CR 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, according to any one of claims 1 to 17,

19. R ７ is -NR ａ R ａ 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, according to any one of claims 1 to 18,

20. R ７ is -NH ２ or -NH-C1-C6 alkyl group, 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.

21. X ７ is CR ７ and X ８ is CR ８ and X ９ is CR 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, according to any one of claims 1 to 20,

22. X ７ is CR ７ and R ７ is -NH ２ or —NH—C1-C6 alkyl group, and X ８ is CH, and X ９ is CH or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

23. X ７ is CH, and X ８ is N or CR ８ and X ９ is N or CR ９ and preferably, X ７ is CH, and X ８ is CR ８ and X ９ is CR ９ and more preferably, X ７ is CH, and X ８ is CH and X ９ is CH; or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

24. X ９ is N, 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.

25. X ７ is N, and / or X ８ is N, 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.

26. A is selected from a phenyl group, a 5- to 6-membered nitrogen-containing heteroaryl group, a benzomonoheterocyclyl group, a benzobisheterocyclyl group, a 5- to 6-membered nitrogen-containing heteroaryl-fused monoheterocyclyl group, a 5- to 6-membered nitrogen-containing heteroaryl-fused bisheterocyclyl group, a benzomonoheteroaromatic ring group, and a 5- to 6-membered nitrogen-containing heteroaryl-fused monoheteroaromatic ring group; Optionally, the phenyl group, 5- to 6-membered nitrogen-containing heteroaryl group, benzomonoheterocyclyl group, benzobisheterocyclyl group, 5- to 6-membered nitrogen-containing heteroaryl-fused monoheterocyclyl group, 5- to 6-membered nitrogen-containing heteroaryl-fused bisheterocyclyl group, benzomonoheteroaromatic ring group, 5- to 6-membered nitrogen-containing heteroaryl-fused monoheteroaromatic ring group may be selected from the group consisting of one or more R ｚ is replaced by The monoheterocyclyl group in the benzomonoheterocyclyl and 5- to 6-membered nitrogen-containing heteroaryl-fused monoheterocyclyl contains 0, 1, 2, or 3 atoms selected from N, O, and S; the monoheteroaromatic ring group in the benzomonoheteroaromatic ring group and the 5- to 6-membered nitrogen-containing heteroaryl-fused monoheteroaromatic ring group contains 0, 1, 2 or 3 atoms selected from N, O and S; The compound according to any one of claims 1 to 25, wherein the bisheterocyclyl group in the benzobisheterocyclyl group and the 5- to 6-membered nitrogen-containing heteroaryl-fused bisheterocyclyl group contains 0, 1, 2, or 3 atoms selected from N, O, and S, 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.

27. A is selected from the groups A1, A2 and A3; Groups A1 include: 【Chemistry 13】 and In the A1 group, R Ａ１ are each independently selected from saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, said monocyclic rings or bicyclic rings optionally containing deuterium, halogen, C1-C6 alkyl groups, C3-C8 cycloalkyl groups, C1-C6 haloalkyl groups, —OH, —O—C1-C6 alkyl groups, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and R ＡＩ are each independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —CN, —O—C1-C6 alkyl group, a C1-C6 alkylene-O—C1-C6 alkyl group, a C1-C6 haloalkoxy group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, 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, and m4 is selected from 0 or 1; Group A2 is 【Chemistry 14】 and R in A2 group Ｉ and R ＩＩ are each independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —CN, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and two R ＩＩ may together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, or C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; R Ａ２ are each independently hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, a C3-C8 cycloalkyl-C1-C6 alkylene group, —OH, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl), —S(O)—R ｚ１ or -S(O) ２ -R ｚ１ wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, and C3-C8 cycloalkyl-C1-C6 alkylene group are optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C1-C4 haloalkyl group; Each R ｚ１ are independently selected from the group consisting of C1-C6 alkyl groups, C1-C6 haloalkyl groups; m5 is selected from 0, 1, 2 or 3, m6 is selected from 0, 1 or 2, n1 is selected from integers of 0 to 4, n2 is selected from integers of 0 to 6, n3 is selected from integers of 0 to 8, n4 is selected from integers of 0 to 2, n5 is selected from 0 or 1, n7 is selected from integers of 0 to 3, q ​​is 0 or 1, s is selected from integers of 0 to 6, t is selected from integers of 0 to 8, and r is selected from 0 or 1; Groups A3 include: 【Chemistry 15】 and In group A3, Each G is independently hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —CN, a C1-C6 alkoxy group, or —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, or C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; or two Gs linked to the same carbon atom may form an oxo group (═O); or two Gs linked to the same carbon atom may, together with the carbon atoms to which they are linked, form a C3-C8 cycloalkyl group; R Ａ３ are independently H, deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —CN, —O—C3-C8 cycloalkyl group, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group, —C(═O)NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, —C(═O)C3-C8 cycloalkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl group, 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 N atoms, 0, 1, 2 or 3 N atoms and O and a 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 atoms selected from the group consisting of a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, and a 5- to 6-membered monocyclic heteroaryl group, which may be optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; R ＩＩＩ are independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —CN, —O—C3-C8 cycloalkyl group, a C1-C6 alkoxy group, —NH ２ , -NH-C1-C6 alkyl group, -C(=O)NH-C1-C6 alkyl group, -OC(=O)C1-C6 alkyl group, -C(=O)C3-C8 cycloalkyl group, -N(C1-C6 alkyl)(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl group, -5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2 or 3 N atoms, 5- to 6-membered monocyclic heteroaryl containing 1, 2 or 3 N atoms a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, a 5- to 6-membered monocyclic heteroaryl group containing 0, 1, 2 or 3 N atoms and 1 or 2 atoms selected from O, wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxy group, and the 5- to 6-membered monocyclic heteroaryl group are optionally substituted with a substituent selected from deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; 27. The compound of any one of claims 1 to 26, wherein e is selected from 0, 1, 2 or 3, and f is selected from 0, 1 or 2, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

28. A is selected from the groups A1, A2 and A3; Groups A1 include: 【Chemistry 16】 In the A1 group, R Ａ１ are each independently selected from saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, said monocyclic rings or bicyclic rings optionally containing deuterium, halogen, C1-C6 alkyl groups, C3-C8 cycloalkyl groups, C1-C6 haloalkyl groups, —OH, —O—C1-C6 alkyl groups, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and R ＡＩ are each independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —CN, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, 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, and m4 is selected from 0 or 1; Group A2 is 【Chemistry 17】 and R in A2 group Ｉ and R ＩＩ are each independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —CN, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and two R ＩＩ may together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, or C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; R Ａ２ are each independently hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, a C3-C8 cycloalkyl-C1-C6 alkylene group, —OH, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl), —S(O)—R ｚ１ or -S(O) ２ -R ｚ１ wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, and C3-C8 cycloalkyl-C1-C6 alkylene group are optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, and a C1-C4 haloalkyl group; Each R ｚ１ are independently selected from the group consisting of C1-C6 alkyl groups, C1-C6 haloalkyl groups; m5 is selected from 0, 1, 2 or 3, m6 is selected from 0, 1 or 2, n1 is selected from integers of 0 to 4, n2 is selected from integers of 0 to 6, n3 is selected from integers of 0 to 8, n4 is selected from integers of 0 to 2, n5 is selected from 0 or 1, n7 is selected from integers of 0 to 3, q ​​is 0 or 1, s is selected from integers of 0 to 6, t is selected from integers of 0 to 8, and r is selected from 0 or 1; Group A3 is [Chemistry 18] and In group A3, G, R Ａ３ and R ＩＩＩ are each independently as defined in claim 27; 28. The compound of any one of claims 1 to 27, wherein e is selected from 0, 1, 2 or 3, and f is selected from 0, 1 or 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.

29. A is selected from the groups A1, A2 and A3; Groups A1 include: 【Chemistry 19】 and In the A1 group, R Ａ１ are each independently selected from saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, said monocyclic rings or bicyclic rings optionally containing deuterium, halogen, C1-C6 alkyl groups, C3-C8 cycloalkyl groups, C1-C6 haloalkyl groups, —OH, —O—C1-C6 alkyl groups, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and R ＡＩ are each independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —CN, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, 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, and m4 is selected from 0 or 1; Group A2 is 【Chemistry 20】 and R in A2 group Ｉ and R ＩＩ are each independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —CN, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and two R ＩＩ may together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, or C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; R Ａ２ are each independently hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, a C3-C8 cycloalkyl-C1-C6 alkylene group, —OH, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl), —S(O)—R ｚ１ or -S(O) ２ -R ｚ１ wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, and C3-C8 cycloalkyl-C1-C6 alkylene group are optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, and a C1-C4 haloalkyl group; Each R ｚ１ are independently selected from the group consisting of C1-C6 alkyl groups, C1-C6 haloalkyl groups; m5 is selected from 0, 1, 2 or 3, m6 is selected from 0, 1 or 2, n1 is selected from integers of 0 to 4, n2 is selected from integers of 0 to 6, n3 is selected from integers of 0 to 8, n4 is selected from integers of 0 to 2, n5 is selected from 0 or 1, n7 is selected from integers of 0 to 3, q ​​is 0 or 1, s is selected from integers of 0 to 6, t is selected from integers of 0 to 8, and r is selected from 0 or 1; Group A3 is 【Chemistry 21】 and In group A3, G, R Ａ３ and R ＩＩＩ are each independently as defined in claim 27, e is selected from 0, 1, 2 or 3, and f is selected from 0, 1 or 2; or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof.

30. A is selected from the groups A1, A2 and A3; Groups A1 include: 【Chemistry 22】 and In the A1 group, R Ａ１ are each independently selected from saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, said monocyclic rings or bicyclic rings optionally containing deuterium, halogen, C1-C6 alkyl groups, C3-C8 cycloalkyl groups, C1-C6 haloalkyl groups, —OH, —O—C1-C6 alkyl groups, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and R ＡＩ are each independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, 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, and m4 is selected from 0 or 1; Group A2 is 【Chemistry 23】 and R in A2 group Ｉ and R ＩＩ are each independently deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —CN, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and two R ＩＩ may together with the carbon atom to which they are attached form a C3-C8 cycloalkyl group, and the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, or C1-C6 alkoxy group may optionally be substituted with a substituent selected from deuterium, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; R Ａ２ are each independently hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group, —OC(═O)C1-C6 alkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl) or a C3-C8 cycloalkyl-C1-C6 alkylene group, wherein the C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, or C3-C8 cycloalkyl-C1-C6 alkylene group may be optionally substituted with a substituent selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; m5 is selected from 0, 1, 2 or 3, m6 is selected from 0, 1 or 2, n1 is selected from integers of 0 to 4, n2 is selected from integers of 0 to 6, n3 is selected from integers of 0 to 8, n4 is selected from integers of 0 to 2, n5 is selected from 0 or 1, n7 is selected from integers of 0 to 3, q ​​is 0 or 1, s is selected from integers of 0 to 6, t is selected from integers of 0 to 8, and r is selected from 0 or 1; Group A3 is 【Chemistry 24】 and In group A3, G, R Ａ３ and R ＩＩＩ are each independently as defined in claim 27, e is selected from 0, 1, 2 or 3, and f is selected from 0, 1 or 2; or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

31. A is selected from the groups in the A1 group, and in the A1 group, R Ａ１ are each independently selected from saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic rings containing 0 or 1 N atom, said monocyclic rings optionally containing deuterium, halogen, —CN, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl); R ＡＩ are each independently deuterium, halogen, —CN, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —C1-C6 alkylene-O—C1-C6 alkyl group, a C1-C6 haloalkoxy group, —NH ２ , —NH—C1-C6 alkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl); 31. The compound of any one of claims 27 to 30, wherein 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, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

32. A is selected from the groups in the A1 group, and in the A1 group, R Ａ１ are each independently selected from saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic rings containing 0 or 1 N atom, said monocyclic rings optionally containing deuterium, halogen, —CN, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl); R ＡＩ are each independently deuterium, halogen, —CN, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl); 31. The compound of any one of claims 27 to 30, wherein 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, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

33. A is selected from the groups in the A1 group, and in the A1 group, R Ａ１ are each independently selected from saturated, partially saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic rings containing 0 or 1 N atom, said monocyclic rings optionally containing deuterium, halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl); R ＡＩ are each independently deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl); 30. The compound of any one of claims 26 to 29, wherein 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, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

34. A is selected from the groups in the A1 group, and in the A1 group, R Ａ１ are each independently selected from saturated 5- or 6-membered monocyclic rings containing 0 or 1 N atom, said monocyclic rings optionally containing deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and R ＡＩ are each independently deuterium, halogen, —CN, a C1-C6 alkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl); 31. The compound of any one of claims 27 to 30, wherein 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, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

35. A is selected from the groups in the A1 group, and in the A1 group, R Ａ１ are each independently selected from saturated 5- or 6-membered monocyclic rings containing 0 or 1 N atom, said monocyclic rings optionally containing deuterium, halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and R ＡＩ are each independently deuterium, halogen, a C1-C6 alkyl group, —OH, —O—C1-C6 alkyl group, —NH ２ , —NH—C1-C6 alkyl group, —N(C1-C6 alkyl)(C1-C6 alkyl); 31. The compound of any one of claims 27 to 30, wherein 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, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

36. A is, 【Chemistry 25】 36. The compound of 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, selected from:

37. A is, 【Chemistry 26】 37. The compound of 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, selected from:

38. A is, 【Chemistry 27】 38. The compound of 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, selected from:

39. A is, 【Chemistry 28】 39. The compound of 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, selected from:

40. A is selected from the group A2, 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 according to any one of claims 27 to 30.

41. A is, 【Chemistry 29】 41. The compound of claim 40, 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, selected from:

42. A is, 【Transformation 30】 42. The compound of claim 41, 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, selected from:

43. A is, 【Chemistry 31】 43. The compound of claim 42, 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, selected from:

44. R Ｉ and R ＩＩ are each independently deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), and two R ＩＩ can together with the carbon atom to which they are attached form a C3-C6 cycloalkyl group; R Ａ２ are each independently selected from hydrogen, deuterium, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 haloalkyl group, wherein the C1-C6 alkyl group is optionally substituted with a substituent selected from deuterium, F, Cl, Br, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 alkoxy group; 44. The compound of any one of claims 41 to 43, wherein m5 is selected from 0, 1, 2 or 3, n1 is selected from an integer from 0 to 2, n2 is selected from an integer from 0 to 2, and n3 is selected from an integer from 0 to 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.

45. A is, 【Chemistry 32】 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, selected from the group consisting of:

46. A is, 【Transformation 33】 46. ​​The compound of claim 45, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, selected from:

47. R Ｉ and R ＩＩ are each independently deuterium, halogen, a C1-C6 alkyl group, —OH, —CN, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group or —N(C1-C6 alkyl)(C1-C6 alkyl); R Ａ２ are each independently selected from a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 haloalkyl group, and a C3-C6 cycloalkyl-C1-C4 alkyl group, wherein the C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 haloalkyl group, and C3-C6 cycloalkyl-C1-C4 alkyl group are optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; 47. The compound of claim 45 or 46, wherein 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, and q is selected from 0 or 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.

48. R Ａ２ are each independently selected from a C1-C6 alkyl group or a C3-C6 cycloalkyl-C1-C2 alkyl group, and the C1-C6 alkyl group, C3-C6 cycloalkyl-C1-C2 alkyl group is optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, —OH, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, and a C1-C4 haloalkyl group, 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.

49. R Ａ２ are each independently a methyl group, 【Transformation 34】 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, selected from:

50. R Ａ２ are each independently 【Chemistry 35】 50. The compound of claim 49, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, selected from:

51. A is, 【Transformation 36】 51. The compound of 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, selected from:

52. A is, 【Chemistry 37】 52. The compound of claim 51, 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, selected from:

53. R Ｉ and R ＩＩ are each independently deuterium, halogen, a C1-C6 alkyl group, —OH, —CN, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group or —N(C1-C6 alkyl)(C1-C6 alkyl); R Ａ２ are each independently a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl-C1-C4 alkyl group, or —S(O)—R ｚ１ or -S(O) ２ -R ｚ１ wherein the C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 haloalkyl group, and C3-C6 cycloalkyl-C1-C4 alkyl group are optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, I, —OH, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, or a C1-C4 haloalkyl group; and each R ｚ１ are independently selected from a C1-C6 alkyl group and a C1-C6 haloalkyl group; m5 is selected from 0 or 1; and n5 is selected from 0 or 1. 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.

54. R Ａ２ are each independently 【Transformation 38】 or -S(O) ２ -CF ３ 54. The compound of claim 53, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, selected from:

55. A is, 【Chemistry 39】 51. The compound of 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, selected from:

56. A is, 【Chemistry 40】 56. The compound of claim 55, 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, selected from:

57. A is, 【Chemistry 41】 51. The compound of 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, selected from:

58. A is, 【Chemistry 42】 58. The compound of claim 57, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, selected from:

59. A is selected from the group A3, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 27 to 30.

60. A is selected from the groups of group A3, and each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl group, deuterated C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C1-C6 deuterated alkoxy group, —NH ２ , —NH—C1-C6 alkyl group or —N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs linked on the same carbon atom form an oxo group (═O); R Ａ３ are independently hydrogen, deuterium, halogen, —CN, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, OH, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 deuterated alkoxy group, —O—C3-C8 cycloalkyl group, —NH ２ , -NH-C1-C6 alkyl group, -C(=O)NH-C1-C6 alkyl group, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl group, -5- to 6-membered monocyclic heteroarylene-C1-C6 alkyl group containing 1, 2 or 3 N atoms, 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl), R ＩＩＩ are independently deuterium, halogen, —CN, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, OH, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 deuterated alkoxy group, —O—C3-C8 cycloalkyl group, —NH ２ , -NH-C1-C6 alkyl group, -C(=O)NH-C1-C6 alkyl group, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl group, -5- to 6-membered monocyclic heteroarylene-C1-C6 alkyl group containing 1, 2 or 3 N atoms, 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl), 60. The compound of claim 59, wherein e is selected from 0, 1, or 2 and f is selected from 0 or 1, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

61. A is selected from the groups of group A3, and each G is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl group, deuterated C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C1-C6 deuterated alkoxy group, —NH ２ , —NH—C1-C6 alkyl group or —N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs linked on the same carbon atom form an oxo group (═O); R Ａ３ and R ＩＩＩ are each independently deuterium, halogen, —CN, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, OH, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 deuterated alkoxy group, —O—C3-C8 cycloalkyl group, —NH ２ , -NH-C1-C6 alkyl group, -C(=O)NH-C1-C6 alkyl group, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl group, -5- to 6-membered monocyclic heteroarylene-C1-C6 alkyl group containing 1, 2 or 3 N atoms, 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl), 61. The compound of claim 60, wherein e is selected from 0, 1 or 2 and f is selected from 0 or 1, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

62. A is selected from the groups of group A3, and wherein each G is independently hydrogen, deuterium, halogen, C1-C6 alkyl group, deuterated C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group or —N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs linked on the same carbon atom form an oxo group (═O); R Ａ３ are independently H, deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group or —N(C1-C6 alkyl)(C1-C6 alkyl); R ＩＩＩ are independently deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group or —N(C1-C6 alkyl)(C1-C6 alkyl); 62. The compound of claim 61, wherein e is selected from 0, 1 or 2 and f is selected from 0 or 1, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

63. A is selected from the groups of group A3, and wherein each G is independently hydrogen, deuterium, halogen, C1-C6 alkyl group, deuterated C1-C6 alkyl group, C1-C6 haloalkyl group, —OH, C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group or —N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs linked on the same carbon atom form an oxo group (═O); R Ａ３ and R ＩＩＩ are each independently deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, —NH ２ , —NH—C1-C6 alkyl group or —N(C1-C6 alkyl)(C1-C6 alkyl); 63. The compound of claim 62, wherein e is selected from 0, 1, or 2 and f is selected from 0 or 1, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

64. A is, 【Chemistry 43】 and is selected from any one of the groups A is preferably 【Chemistry 44】 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, selected from any one of the groups:

65. A is, 【Chemistry 45】 and is selected from any one of the groups A is preferably 【Chemistry 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, selected from any one of the groups:

66. A is, 【Chemistry 47】 and is selected from any one of the groups A is preferably 【Chemistry 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, selected from any one of the groups:

67. A is, 【Chemistry 49】 and is selected from any one of the groups A is preferably [Transformation 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, selected from any one of the groups:

68. A is, 【Chemistry 51】 and preferably selected from the group 【Chemistry 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, according to any one of claims 27 to 30,

69. A is, 【Chemistry 53】 and preferably selected from the group 【Chemistry 54】 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, according to any one of claims 27 to 30,

70. A is, 【Transformation 55】 and preferably selected from the group 【Transformation 56】 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, according to any one of claims 27 to 30,

71. A is, 【Chemistry 57】 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, selected from the group consisting of:

72. A is, 【Transformation 58】 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, selected from the group:

73. A is, 【Chemistry 59】 and preferably selected from the group 【Transformation 60】 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, according to any one of claims 27 to 30,

74. each G is independently selected from hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, —OH, a C1-C6 alkoxy group; or two Gs linked on the same carbon atom form a 3- to 6-membered cycloalkyl group, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, or 3- to 6-membered cycloalkyl group may optionally be substituted with 1 to 2 substituents selected from deuterium, F, Cl, and Br; Each R ＩＩＩ are independently deuterium, halogen, —CN, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, —OH, —O—C3-C8 cycloalkyl group, a C1-C6 haloalkoxy group, a C1-C6 deuterated alkoxy group, —NH ２ , -NH-C1-C6 alkyl group, -C(=O)NH-C1-C6 alkyl group, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), phenyl group, -5- to 6-membered monocyclic heteroarylene-C1-C6 alkyl group containing 1, 2 or 3 N atoms, 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 N atoms or -N(C1-C6 alkyl)(C1-C6 alkyl), 74. The compound of any one of claims 62 to 73, wherein e is selected from 0, 1 or 2 and f is selected from 0 or 1, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

75. each G is independently selected from hydrogen, deuterium, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, —OH, and a C1-C6 alkoxy group, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, and C1-C6 alkoxy group are optionally substituted with 1 to 2 substituents selected from deuterium, F, Cl, and Br; Each R ＩＩＩ are independently selected from deuterium, halogen, —CN, a C1-C6 alkyl group, or a C1-C6 alkoxy group; 75. The compound of any one of claims 62 to 74, wherein e is selected from 0, 1 or 2 and f is selected from 0 or 1, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

76. A is, 【Chemistry 61】 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, selected from the group consisting of:

77. A is, 【Transformation 62】 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, selected from the group consisting of:

78. A is, 【Transformation 63】 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, selected from the group consisting of:

79. A is, 【Chemistry 64】 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, selected from the group consisting of:

80. A is, 【Transformation 65】 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, selected from the group consisting of:

81. A is, 【Chemical Formula 66】 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, selected from the group consisting of:

82. A is, 【Transformation 67】 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, selected from the group consisting of:

83. A is, 【Transformation 68】 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, selected from the group consisting of:

84. A is, 【Transformation 69】 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, selected from the group consisting of:

85. A is, 【Transformation 70】 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, selected from the group consisting of:

86. A is, Table 2-1 Table 2-2 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, selected from any one of the groups:

87. A is, Table 3-1 Table 3-2 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, selected from any one of the groups:

88. A is, Table 4-1 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 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, selected from any one of the groups:

89. A is, Table 5-1 Table 5-2 Table 5-3 Table 5-4 Table 5-5 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, selected from any one of the groups:

90. A is, Table 6-1 Table 6-2 Table 6-3 Table 6-4 Table 6-5 Table 6-6 Table 6-7 Table 6-8 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, selected from any one of the groups:

91. A is, Table 7-1 Table 7-2 Table 7-3 Table 7-4 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, selected from any one of the groups:

92. A is, Table 8-1 Table 8-2 Table 8-3 Table 8-4 Table 8-5 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, selected from any one of the groups:

93. A is, Table 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, selected from any one of the groups:

94. A is, Table 10-1 Table 10-2 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, selected from any one of the groups:

95. L is -NR ３ CONR ３ - and / or X ７ is CR ７ and R ７ is -NR ａ R ａ 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, of any one of claims 1 to 94,

96. R １ is the group -Z-R １２ wherein -Z is a single bond, -C1-C4 alkyl-, -C1-C4 alkylene-O-, -O-, -S-, -S(=O)-, or -SO ２ -, -NH-, -NHSO ２ -, -SO ２ NH-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-, -C1-C4 alkylene-SO ２ -, -(C=O)-, -(C=O)NH-, -C=N(OH)- or -NH(C=O)-, and / or (a) R １２ is H, (b) R １２ is an oxetanyl group, a cyclopropyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F, Cl), and C1-C6 alkoxy groups; or (c) R １２ is a C1-C6 alkyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and a C1-C6 alkoxy group; 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.

97. The group -Z-R １２ is -N=S(=O)-(R １２ ) ２ where two R １２ can alternatively be combined with the sulfur atom to which they are respectively 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; or the group -Z-R １２ In the formula, Z is a single bond, and R １２ is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are selected from the group consisting of F, Cl, Br, a C1-C6 alkyl group, a C1-C6 haloalkyl group, -OR ｍ , —OC1-C6 haloalkyl group, 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 alkyleneNR ｍ R ｍ , —OC2-C6 alkylene OR ｍ , -SR ｍ , -S(=O)R ｎ , -S(=O) ２ R ｎ , -S(=O) ２ NR 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) ２ R ｎ , -N(R ｍ ) S(=O) ２ NR ｍ R ｍ , -NR ｍ C2-6 alkylene NR ｍ R ｍ , -NR ｍ C2-C6 alkylene OR ｍ , —C1-C6 alkyleneNR ｍ R ｍ , —C1-C6 alkylene OR ｍ , —C1-C6 alkyleneN(R ｍ ) C(=O)R ｎ , —C1-C6 alkylene OC(═O)R ｎ , —C1-C6 alkyleneC(═O)NR ｍ R ｍ , —C1-C6 alkylene C(═O)OR ｍ and oxo, and R ｍ and R ｎ are independently selected from H and —C1-C6 alkyl groups, 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.

98. R １ is the group -Z-R １２ where Z is —NHSO ２ -or-SO ２ NH— and R １２ is an oxetanyl group, a cyclopropyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and C1-C6 alkoxy groups, or R １２ is a C1-C6 alkyl group substituted with 0, 1, 2 or 3 groups selected from OH, halogen (e.g., F), and a C1-C6 alkoxy group; 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.

99. R １ teeth, Table 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, selected from the group consisting of:

100. R ｘ teeth, 【Chemistry 71】 is selected from the group consisting of Or alternatively, R １０ａ and R １０ｂ Against R １０ｃ and R １０ｄ Against R １０ｅ and R １０ｆ Against R １０ｇ and R １０ h pair or R １０ｉ and R １０ｊ Each of the pairs independently, in combination with the carbon atom to which they are each attached, represents R ｘ and a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring spiro-bonded to the ring, wherein the 3-, 4-, 5-, or 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-, 4-, 5-, or 6-membered monocyclic ring is selected from F, Cl, Br, a C1-C6 alkyl group, a C1-C4 haloalkyl group, -OR ａ , —OC1-C4 haloalkyl group, CN, —NR ａ R ａ or oxo; R １０ｋ is selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing H, 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, said monocyclic or bicyclic rings being selected from the group consisting of F, Cl, Br, C1-C6 alkyl groups, C1-C6 haloalkyl groups, -OR ａ , —OC1-C6 haloalkyl group, 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 alkylNR ａ R ａ , —OC2-C6 alkyl OR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR 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) ２ R ｂ , -N(R ａ ) S(=O) ２ NR ａ R ａ , -NR ａ C2-C6 alkylene NR ａ R ａ , -NR ａ C2-C6 alkylene OR ａ , —C1-C6 alkyleneNR ａ R ａ , —C1-C6 alkylene OR ａ , —C1-C6 alkyleneN(R ａ ) C(=O)R ｂ , —C1-C6 alkylene OC(═O)R ｂ , —C1-C6 alkyleneC(═O)NR ａ R ａ , —C1-C6 alkylene C(═O)OR ａ and oxo, and R ａ and R ｂ is independently selected from H and a —C1-C6 alkyl group; R １０ｌ is selected from the group consisting of F, Cl, Br, a C1-C6 alkoxy group, —O—C1-C6 haloalkyl group, or a C1-C6 alkyl group substituted with 0, 1, 2, 3, 4, or 5 groups of CN, 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.

101. R ｘ teeth, 【Chemistry 72】 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, selected from the group consisting of:

102. A compound of formula (IC-1) or formula (IC-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, 【Transformation 73】 A is selected from the groups A1 of any one of claims 27 to 30, R ａ is H or a C1-C4 alkyl group, 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.

103. A compound of formula (I-C-2) or formula (I-C-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, 【Chemistry 74】 A is selected from the groups A1 in any one of claims 27 to 30, R ａ is H or a C1-C4 alkyl group, 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.

104. A compound of formula (I-A-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, 【Chemistry 75】 L, R Ｘ , R １ , X ７ , X ８ , X ９ is as defined in any one of claims 1 to 26, and R Ａ２ , R Ｉ , R ＩＩ , n4, m5 are as defined in any one of claims 27 to 30, 47 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.

105. The compound is 【Transformation 76】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof according to claim 104,

106. A compound represented by formula (I-A-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, 【Chemical 77】 L, R Ｘ , R １ , X ７ , X ８ , X ９ is as defined in any one of claims 1 to 26, and R Ａ２ , R Ｉ , R ＩＩ , n5, m5 are as defined in any one of claims 27 to 30, 53 to 54, 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.

107. The compound is 【Transformation 78】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof according to claim 106,

108. A compound represented by formula (I-A-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, 【Chemistry 79】 L, R Ｘ , R １ , X ７ , X ８ , X ９ is as defined in any one of claims 1 to 26, and R Ａ２ , R Ｉ , R ＩＩ , n1, m5 are as defined in 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.

109. The compound is 【Chemistry 80】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof according to claim 108,

110. A compound represented by formula (I-A-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, 【Chemistry 81】 L, R Ｘ , R １ , X ７ , X ８ , X ９ is as defined in any one of claims 1 to 26, and R Ａ２ , R Ｉ , R ＩＩ , n1, m6 are as defined in 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.

111. The compound is 【Chemistry 82】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof according to claim 110,

112. A compound represented by formula (I-A-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, 【Chemistry 83】 L, R Ｘ , R １ , X ７ , X ８ , X ９ is as defined in any one of claims 1 to 26, and R Ａ２ , R Ｉ , R ＩＩ , n1, m6 are as defined in 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.

113. The compound is 【Chemical 84】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof of formula (IA-5) according to claim 112,

114. A compound represented by formula (I-A-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, 【Chemical 85】 L, R Ｘ , R １ , X ７ , X ８ , X ９ is as defined in any one of claims 1 to 26, and R Ａ２ , R Ｉ , R ＩＩ , n4, m5 are as defined in 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.

115. The compound is 【Chemical 86】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof.

116. A compound represented by formula (I-A-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, 【Chemistry 87】 L, R Ｘ , R １ , X ７ , X ８ , X ９ is as defined in any one of claims 1 to 26, and R Ａ２ , R Ｉ , R ＩＩ , n4, m6 are as defined in 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.

117. The compound is 【Chemical 88】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof of formula (IA-7) according to claim 116,

118. A compound represented by formula (I-A-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, 【Chemical 89】 L, R Ｘ , R １ , X ７ , X ８ , X ９ is as defined in any one of claims 1 to 26, and R Ａ２ , R Ｉ , R ＩＩ , n4, m6 are as defined in 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.

119. The compound is 【Chemistry 90】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof of formula (I-A-8) according to claim 118,

120. A compound represented by 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, 【Chemistry 91】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

121. The compound is 【Chemistry 92】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof according to claim 120,

122. A compound represented by 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, 【Chemistry 93】 L, R Ｘ , R １ , X ７ , X ８ , X ９ is as defined in any one of claims 1 to 26, and R ＩＩＩ , G, e are as defined in 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.

123. The compound is 【Chemical 94】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof.

124. The compound is 【Chemical 95】 or The compound is 【Chemistry 96】 and Preferably, the compound is 【Chemistry 97】 and More preferably, the compound is 【Chem.98】 or Preferably, the compound is 【Chem.99】 and More preferably, the compound is 【Chemistry 100】 and More preferably, each R ＩＩＩ are independently selected from deuterium, halogen, —CN, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, —OH, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 deuterated alkoxy group, —O—C3-C8 cycloalkyl group, —NH2, —NH—C1-C6 alkyl group, —C(═O)NH—C1-C6 alkyl group, —C(═O)N(C1-C6 alkyl)(C1-C6 alkyl), a phenyl group, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2 or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, a 5- to 6-membered monocyclic heteroaryl group 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, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, —NH2, —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs linked on the same carbon atom form an oxo group (═O); More preferably, each e is 1. 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.

125. A compound represented by 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, 【Chemistry 101】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , R Ａ３ , e is as defined in 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.

126. The compound is 【Chemical Engineering 102】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof.

127. A compound represented by formula (IB-4) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, 【Chemistry 103】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

128. The compound is 【Chemical 104】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof.

129. The compound is 【Chemistry 105】 and Preferably, the compound is 【Chemistry 106】 and More preferably, the compound is 【Chemistry 107】 and Or, The compound is 【Chemistry 108】 and Preferably, the compound is 【Chemistry 109】 and More preferably, the compound is 【Chemical 110】 and More preferably, each R ＩＩＩ are independently selected from deuterium, halogen, —CN, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, —OH, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 deuterated alkoxy group, —O—C3-C8 cycloalkyl group, —NH2, —NH—C1-C6 alkyl group, —C(═O)NH—C1-C6 alkyl group, —C(═O)N(C1-C6 alkyl)(C1-C6 alkyl), a phenyl group, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2 or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, a 5- to 6-membered monocyclic heteroaryl group 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, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, —NH2, —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs linked on the same carbon atom form an oxo group (═O); More preferably, each e is 1. 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.

130. A compound represented by 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, 【Chemistry 111】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

131. The compound is 【Chemistry 112】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof of formula (IB-5) according to claim 130,

132. A compound represented by 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, 【Chemistry 113】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

133. The compound is 【Chemistry 114】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof of formula (IB-6) according to claim 132,

134. The compound is 【Chemical 115】 and Preferably, the compound is 【Chemistry 116】 and More preferably, the compound is 【Chemistry 117】 and Or, The compound is 【Chemistry 118】 and Preferably, the compound is 【Chemical 119】 and More preferably, the compound is 【Chemical 120】 and More preferably, each R ＩＩＩ are independently selected from deuterium, halogen, —CN, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, —OH, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 deuterated alkoxy group, —O—C3-C8 cycloalkyl group, —NH2, —NH—C1-C6 alkyl group, —C(═O)NH—C1-C6 alkyl group, —C(═O)N(C1-C6 alkyl)(C1-C6 alkyl), a phenyl group, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2 or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, a 5- to 6-membered monocyclic heteroaryl group 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, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, —NH2, —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs linked on the same carbon atom form an oxo group (═O); More preferably, each e is 1. The compound of formula (IB-6) according to claim 133, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof.

135. A compound represented by 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, 【Chemistry 121】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

136. The compound is 【Chemistry 122】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof.

137. A compound represented by 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, [Chemical 123] L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

138. The compound is 【Chemistry 124】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof.

139. The compound is 【Chemistry 125】 and Preferably, the compound is 【Chemistry 126】 and More preferably, the compound is 【Chemistry 127】 and Or, The compound is 【Chemistry 128】 and Preferably, the compound is 【Chemistry 129】 and More preferably, the compound is 【Chemistry 130】 and More preferably, each R ＩＩＩ are independently selected from deuterium, halogen, —CN, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, —OH, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 deuterated alkoxy group, —O—C3-C8 cycloalkyl group, —NH2, —NH—C1-C6 alkyl group, —C(═O)NH—C1-C6 alkyl group, —C(═O)N(C1-C6 alkyl)(C1-C6 alkyl), a phenyl group, a 5- to 6-membered monocyclic heteroaryl-C1-C6 alkyl group containing 1, 2 or 3 N atoms, a 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 N atoms and 1 or 2 atoms selected from O, a 5- to 6-membered monocyclic heteroaryl group 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, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 haloalkyl group, —OH, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, —NH2, —NH—C1-C6 alkyl group, or —N(C1-C6 alkyl)(C1-C6 alkyl), or two Gs linked on the same carbon atom form an oxo group (═O); More preferably, each e is 1. 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.

140. A compound represented by formula (IB-9) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, 【Chemistry 131】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

141. The compound is 【Chemistry 132】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof of formula (IB-9) according to claim 140,

142. A compound represented by 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, 【Chemistry 133】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

143. The compound is 【Chemistry 134】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof of formula (IB-10) according to claim 142,

144. A compound represented by 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, 【Chemistry 135】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

145. The compound is 【Transformation 136】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof.

146. A compound represented by 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, 【Chemistry 137】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

147. The compound is 【Chemistry 138】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof of formula (IB-12) according to claim 146,

148. A compound represented by formula (IB-13) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, 【Chemistry 139】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

149. The compound is [Chemical 140] or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof of formula (IB-13) according to claim 148,

150. A compound represented by 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, 【Chemistry 141】 L, R Ｘ , R １ , X ７ , X ８ , X ９ is as defined in any one of claims 1 to 26, and R ＩＩＩ , G, e are as defined in 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.

151. The compound is 【Chemistry 142】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof of formula (IB-14) according to claim 150,

152. A compound represented by formula (IB-15) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, 【Chemistry 143】 L, R Ｘ , R １ , X ７ , X ８ , X ９ is as defined in any one of claims 1 to 26, and R ＩＩＩ , G, e are as defined in 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.

153. The compound is 【Chemistry 144】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof of formula (IB-15) according to claim 152,

154. A compound represented by 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, 【Chemistry 145】 L, R Ｘ , R １ , X ７ , X ８ , X ９ are as defined in any one of claims 1 to 26, and G, R ＩＩＩ , e is as defined in 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.

155. The compound is 【Chemistry 146】 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof.

156. The compound is Table 12-1 Table 12-2 Table 12-3 Table 12-4 Table 12-5 Table 12-6 Table 12-7 Table 12-8 Table 12-9 Table 12-10 Table 12-11 Table 12-12 Table 12-13 Table 12-14 Table 12-15 Table 12-16 Table 12-17 Table 12-18 Table 12-19 Table 12-20 Table 12-21 Table 12-22 Table 12-23 Table 12-24 Table 12-25 Table 12-26 Table 12-27 Table 12-28 Table 12-29 Table 12-30 Table 12-31 Table 12-32 Table 12-33 Table 12-34 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, selected from the group consisting of compounds of

157. The compound is Table 13-1 Table 13-2 Table 13-3 Table 13-4 Table 13-5 Table 13-6 Table 13-7 Table 13-8 Table 13-9 Table 13-10 Table 13-11 Table 13-12 Table 13-13 Table 13-14 Table 13-15 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, selected from the group consisting of compounds of

158. 158. A pharmaceutical composition comprising a compound of any one of claims 1 to 157 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, and a pharmaceutically acceptable diluent or carrier.

159. A method for treating a disease treatable with a KIF18A inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 157 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition of claim 158.

160. The disease is (a) a solid tumor or a blood-borne 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 lymphoma selected from the group consisting of leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma. The method of claim 159, wherein the cancer is selected from the group consisting of (a) hematopoietic tumors of the myeloid system, (b) hematopoietic tumors of the myeloid system selected from acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia, (c) tumors of the stromal system selected from fibrosarcoma and rhabdomyosarcoma, (d) tumors of stromal origin selected from fibrosarcoma and rhabdomyosarcoma, (e) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma, or (f) melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

161. 158. A method of reducing solid tumor size in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 157 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition of claim 158.

162. 158. A method of treating a cell proliferation disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 157 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition of claim 158.

163. 158. A method of inhibiting KIF18A in a cell, comprising contacting the cell with a compound of any one of claims 1 to 157 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition of 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, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 158, in the manufacture of a medicament for treating a disease treatable with a KIF18A inhibitor.

165. The disease is (a) a solid tumor or a blood-borne 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 lymphoma selected from the group consisting of leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma. (c) hematopoietic tumors of the myeloid system selected from acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; (d) tumors of stromal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) cancer selected from the group consisting of melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, and Kaposi's sarcoma.

166. Use of a compound of any one of claims 1 to 157 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition of claim 158, in the manufacture of a medicament for reducing solid tumor size in a subject.

167. 158. Use of a compound of any one of claims 1 to 157 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition of claim 158, in the manufacture of a medicament for treating a cell proliferation disorder in a subject.

168. Use of a compound of any one of claims 1 to 157 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, nitroxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition of claim 158, in the manufacture of a medicament for inhibiting KIF18A in a cell.

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