Tricyclic compound and use thereof

Abstract

Provided is a compound represented by formula (I). The compound can modulate a KIF18A protein, thereby affecting a cell cycle and a cell proliferation process to treat cancers and cancer-associated diseases. Further provided are a pharmaceutical composition comprising the compound and a method for treating KIF18A activity-associated conditions.

Description

Tricyclic compounds and uses thereof

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application CN202410383401.3 filed on March 29, 2024, the contents of which are incorporated by reference into this application in their entirety and for all purposes. Technical Field

[0003] The present invention relates to the field of medicinal chemistry, and specifically to a tricyclic compound and its use. Background Art

[0004] Chromosomal instability (CIN), defined as chromosomal instability, is caused by errors in chromosome segregation during mitosis. CIN is a hallmark of recurrent, metastatic, advanced malignancies, occurring in approximately 90% of solid tumors and affecting the genomes of approximately 25% of solid tumor cells. The causes of CIN are diverse, including mitotic errors, replication stress, homologous recombination repair, and breakage-fusion-bridge cycles. CIN is closely associated with cellular transformation, tumor progression and recurrence, chemotherapy resistance, and poor prognosis.

[0005] Kinesins are molecular motors that play important roles in cell division and the transport of intracellular vesicles and organelles. Mitotic kinesins play a role in multiple aspects of spindle assembly, chromosome segregation, centrosome separation, and dynamics. Human kinesins are classified into 14 subfamilies based on sequence homology within the motor domain. KIF18A, a member of the kinesin-8 family, is specifically expressed during the G2 / M phase of mitosis and plays a key role in maintaining bipolar spindle integrity during cell division, thereby regulating chromosome positioning. KIF18A uses energy released by ATP hydrolysis to move along microtubules toward the positive pole within the cell. Localized at the positive end of microtubules, it regulates microtubule dynamic instability, exerting an activity similar to that of a microtubule depolymerase. During mitosis, KIF18A regulates spindle microtubule dynamics and chromosome amplitude, playing a crucial role in the timely alignment of chromosomes during mitosis, maintaining genomic stability, and successfully completing mitosis.

[0006] Studies have shown that the kinesin KIF18A is an important factor affecting the proliferation of CIN tumor cells. After KIF18A knockout, tumor cells with CIN characteristics exhibit mitotic fragility associated with spindle assembly checkpoint (SAC) activation, multipolar spindle formation, and induction of apoptosis, leading to mitotic arrest, cell cycle arrest, and apoptosis. KIF18A is an essential gene for abnormal somatic cell division, but CIN tumor cells are highly sensitive to KIF18A knockout. Therefore, small molecule inhibitors of KIF18A can selectively target tumor cells with CIN characteristics. Compared with other drugs targeting mitotic mechanisms, KIF18A inhibition does not affect the proliferation of normal cells. Currently, there is a lack of effective therapies targeting CIN, and KIF18A is a highly promising new anti-tumor target. Summary of the Invention

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

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

[0009] L is selected from *-NR 2 -CO-, *-CO-NR 2 -、*-NR 2 CONR 2 - or 5-6 membered heteroaryl, * represents connection with ring A;

[0010] R 2 Selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl;

[0011] R x is selected from C3-C12 cycloalkyl, C3-12 cycloalkenyl, 3-14 membered heterocyclic group; the C3-C12 cycloalkyl, C3-12 cycloalkenyl, 3-14 membered heterocyclic group are each independently optionally substituted by one or more R x1 Replace, each R x1independently selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo (O=), thio (S=), -C(O)R x1a 、-C(O)OR x1a 、-OC(O)R x1a 、-NR x1a C(O)R x1a 、-C(O)NR x1b R x1c 、-S(O)R x1a 、-S(O)2R x1a 、-NR x1b R x1c , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R x1 The atoms to which they are attached form a 3-14 membered ring, or two R atoms attached to the same carbon atom x1 Together with the atoms they are connected to form The C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, two R x1 and the atoms to which they are attached form a 3-7 membered ring optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl;

[0012] R x1a Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl;

[0013] R x1b 、R x1c are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, or R x1b 、R x1c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring, wherein the 3-7 membered heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2;

[0014] R x1e 、R x1fEach is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl;

[0015] X1 is selected from NH, S, O or CH2;

[0016] X2, X3, X4 are selected from N or CR 3 ;

[0017] R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, -OR 3a 、-SR 3a 、-NR 3b R 3c 、-C(O)NR 3b R 3c 、-NR 3e C(O)R 3e 、-C(O)R 3e 、-C(O)OR 3e 、-OC(O)R 3e 、-S(O)R 3e 、-S(O)2R 3e , C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R 3 Combined with the atoms to which they are attached to form a 5-10 membered ring;

[0018] R 3a Independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy C1-C6 alkyl;

[0019] R 3b 、R 3c are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, or R 3b 、R 3c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring, wherein the 3-7 membered heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2;

[0020] R 3e Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl;

[0021] R 1 Yes-ZR 1a, wherein Z is a direct bond, -C1-C6 alkylene-, -C2-C8 alkenylene-, -C2-C8 alkynylene-, -C1-C6 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -S=N-, -NR 1b -、-NR 1b SO2-、-SO2NR 1b -、-NR 1b -S(=O)(=NR 1b )-、-S(=O)(=NR 1b )-NR 1b -、-S(=O)(=NR 1b )-、-C1-C6 alkylene-SO2-、-C1-C6 alkylene-SO2R 1b -, -(C=O)-, -(C=O)NR 1b -、-NR 1b (C=O)-, -C=N(OH)-, or -P(=O)R 1b -; or -ZR 1a Yes-N=S(=O)-(R 1b )2, where two R 1b Can combine with the sulfur atom to which they are attached to form a 3-7 membered ring; or -ZR 1a yes Ring E is selected from a 5-6 membered ring optionally containing 0, 1, 2, or 3 N atoms or 0, 1 or 2 O or S atoms; said ring E is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl;

[0022] R 1aEach is independently selected from hydrogen, deuterium, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl is optionally substituted by deuterium, halogen, cyano, amino, hydroxyl, carboxyl, thiol, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) )2, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, -S(O)(C1-C6 alkyl), -S(O)2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NHC(O)(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -OC(O)(C1-C6 alkyl);

[0023] R 1b Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, C3-C8 cycloalkyl or 4-9 membered heterocyclyl;

[0024] R a 、R b each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, -CONH2, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -NHC(=O)(C1-C 6 alkyl), -C(=O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(=O)(C1-C6 alkyl), C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, C3-C8 cycloalkyloxy, C5-C10 cycloalkenyloxy, 5-10 membered heteroaryloxy, C6-C10 aryloxy, 4-9 membered heterocyclyloxy, or two adjacent R aTogether with the atoms to which they are attached, they form a 5-7 membered ring; the C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -NHC(=O)(C1-C6 alkyl), -C( =O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(=O)(C1-C6 alkyl), C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, C3-C8 cycloalkyloxy, C5-C10 cycloalkenyloxy, 5-10 membered heteroaryloxy, C6-C10 aryloxy, 4-9 membered heterocyclyloxy, or two adjacent R a Together with the atoms to which they are attached, they form a 5-7 membered ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, and 4-9 membered heterocyclyl;

[0025] R c R is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -OC(=O)(C1-C6 alkyl), C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, or two R attached to the same carbon atom. c Together with the carbon atoms to which they are attached, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form a 3-8 membered ring, or two R atoms attached to different ring atoms c and the ring atoms to which they are connected together form a 3-8 membered ring; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -OC(=O)(C1-C6 alkyl), C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form a 3-8 membered ring. Two R atoms attached to different ring atomsc Together with the ring atoms to which they are attached, they form a 3-8 membered ring, which is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, and 4-9 membered heterocyclyl;

[0026] R c1 、R c2 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl;

[0027] m is selected from 0, 1, 2, or 3;

[0028] n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0029] Provided that: when L is selected from *-NH-CO- or *-CO-NH-, R x no

[0030] In some embodiments, the present application provides the compound represented by formula (I) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in the structure of formula (I-1) or (I-2):

[0031] Among them, X2, X3, X4, R 1 、R x , L, R a 、R b 、R c , m, n are as defined above.

[0032] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,

[0033] Among them, R xis selected from C3-C8 membered monocyclic cycloalkenyl, C6-C11 spirocyclic cycloalkenyl, C6-C11 fused ring cycloalkenyl, C6-C11 bridged ring cycloalkenyl, 4-7 membered monocyclic heterocyclyl, 6-11 membered spirocyclic heterocyclyl, 6-11 membered fused ring heterocyclyl, 6-11 membered bridged ring heterocyclyl; the C3-C8 membered monocyclic cycloalkenyl, C6-C11 spirocyclic cycloalkenyl, C6-C11 fused ring cycloalkenyl, C6-C11 bridged ring cycloalkenyl, 6-11 membered spirocyclic heterocyclyl, 6-11 membered fused ring heterocyclyl, 6-11 membered bridged ring heterocyclyl are each independently optionally substituted by one or more R x1 Replace, each R x1 independently selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo (O=), thio (S=), -C(O)R x1a 、-C(O)OR x1a 、-OC(O)R x1a 、-NR x1a C(O)R x1a 、-C(O)NR x1b R x1c 、-S(O)R x1a 、-S(O)2R x1a 、-NR x1b R x1c , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R attached to the same carbon atom x1 The atoms to which they are connected form a 3-14 membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 The atoms to which they are connected form a 3-14 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, or two R atoms connected to the same carbon atom x1 Together with the atoms they are connected to form The C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R groups connected to the same carbon atom x1 The atoms to which they are connected form a 3-14 membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 and the atoms to which they are attached form a 3-14 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl; and / or

[0034] R x1a Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl;

[0035] R x1b 、R x1c are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, or R x1b 、R x1c Together with the nitrogen atom to which they are attached, they form a 3-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 3-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2;

[0036] and / or, provided that: when L is selected from 5-6 membered heteroaryl, R X is selected from 4-7 membered monocyclic heterocyclic group, 6-11 membered spirocyclic heterocyclic group;

[0037] R x1e 、R x1f Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl;

[0038] In some embodiments, R x is selected from C3-C8 membered monocyclic cycloalkenyl, C6-C11 spirocyclic cycloalkenyl, C6-C11 fused ring cycloalkenyl, C6-C11 bridged ring cycloalkenyl, 4-7 membered monocyclic heterocyclyl, 6-11 membered spirocyclic heterocyclyl, 6-11 membered fused ring heterocyclyl, 6-11 membered bridged ring heterocyclyl; the C3-C8 membered monocyclic cycloalkenyl, C6-C11 spirocyclic cycloalkenyl, C6-C11 fused ring cycloalkenyl, C6-C11 bridged ring cycloalkenyl, 4-7 membered monocyclic heterocyclyl, 6-11 membered spirocyclic heterocyclyl, 6-11 membered fused ring heterocyclyl, 6-11 membered bridged ring heterocyclyl are each independently optionally substituted by one or more R x1 Replace, each R x1 independently selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo (O=), thio (S=), -C(O)R x1a 、-C(O)OR x1a 、-OC(O)R x1a 、-NR x1a C(O)R x1a 、-C(O)NR x1b R x1c 、-S(O)R x1a 、-S(O)2R x1a 、-NR x1b Rx1c , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R attached to the same carbon atom x1 The atoms to which they are connected form a 3-14 membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 The atoms to which they are connected form a 3-14 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, or two R atoms connected to the same carbon atom x1 Together with the atoms they are connected to form The C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R groups connected to the same carbon atom x1 The atoms to which they are connected form a 3-14 membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 and the atoms to which they are attached form a 3-14 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl; and / or

[0039] R x1a Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl;

[0040] R x1b 、R x1c are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, or R x1b 、R x1c Together with the nitrogen atom to which they are attached, they form a 3-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 3-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2;

[0041] and / or, provided that: when L is selected from 5-6 membered heteroaryl, R X is selected from 4-7 membered monocyclic heterocyclic group, 6-11 membered spirocyclic heterocyclic group;

[0042] R x1e 、Rx1f Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl.

[0043] In some embodiments, R x is selected from C8-C11 spirocyclic cycloalkenyl, C8-C11 fused ring cycloalkenyl, C7-C9 bridged ring cycloalkenyl, 6-9 membered bridged ring heterocyclyl, 6-9 membered spirocyclic heterocyclyl; the 6-9 membered bridged ring heterocyclyl and 6-9 membered spirocyclic heterocyclyl contain at least one N atom; the C8-C11 spirocyclic cycloalkenyl, C8-C11 fused ring cycloalkenyl, C7-C9 bridged ring cycloalkenyl, 6-9 membered bridged ring heterocyclyl and 6-9 membered spirocyclic heterocyclyl are each independently optionally substituted by one or more R x1 Replace, each R x1 independently selected from deuterium, halogen, cyano, hydroxyl, sulfhydryl, oxo, thio, -C(O)R x1a 、-C(O)OR x1a 、-OC(O)R x1a 、-NR x1a C(O)R x1a 、-C(O)NR x1b R x1c 、-S(O)R x1a 、-S(O)2R x1a 、-NR x1b R x1c , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R attached to the same carbon atom x1 The atoms to which they are connected form a 3-7 membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 The atoms to which they are connected form a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, or two R atoms connected to the same carbon atom x1 Together with the atoms they are connected to form The C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R groups connected to the same carbon atom x1 The atoms to which they are connected form a 3-7 membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1and the atoms to which they are attached form a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, or 4-9 membered heterocyclyl;

[0044] R x1a Each is independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl;

[0045] R x1b 、R x1c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl or R x1b 、R x1c The nitrogen atom to which it is attached forms a 3-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 3-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2;

[0046] R x1e 、R x1f Each is independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl;

[0047] In some embodiments, R x is selected from C8-C11 spirocyclic cycloalkenyl, C8-C10 fused ring cycloalkenyl, C7-C9 bridged ring cycloalkenyl, 6-9 membered bridged ring heterocyclyl, 6-9 membered spirocyclic heterocyclyl; the 6-9 membered bridged ring heterocyclyl, 6-9 membered spirocyclic heterocyclyl contains at least one N atom; the cycloalkenyl is connected to ring D through an alkenyl group, and the 6-9 membered bridged ring heterocyclyl, 6-9 membered spirocyclic heterocyclyl is connected to ring D through an N atom; the C8-C11 spirocyclic cycloalkenyl, C8-C10 fused ring cycloalkenyl, C7-C9 bridged ring cycloalkenyl, 6-9 membered bridged ring heterocyclyl, 6-9 membered spirocyclic heterocyclyl are each independently optionally substituted by one or more R x1 Replace, each R x1 are independently selected from deuterium, halogen, cyano, hydroxyl, sulfhydryl, oxo, thioxo, -NR x1b R x1c , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C3-C6 cycloalkyl, 5-6 membered heteroaryl, phenyl, 4-7 membered heterocyclic group, or two R attached to the same carbon atom x1The atoms to which they are connected form a 3-membered, 4-membered, 5-membered, or 6-membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 The atoms to which they are connected form a 3-membered, 4-membered, 5-membered, or 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring, or two R atoms connected to the same carbon atom x1 Together with the atoms they are connected to form The C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C3-C6 cycloalkyl, 5-6 membered heteroaryl, phenyl, 4-7 membered heterocyclic group, two R groups connected to the same carbon atom x1 The atoms to which they are connected form a 3-membered, 4-membered, 5-membered, or 6-membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 The atoms to which they are attached form a 3-membered, 4-membered, 5-membered, 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2;

[0048] R x1b 、R x1c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, or R x1b 、R x1c Together with the nitrogen atom to which they are attached, they form a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocyclic ring, wherein the 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2;

[0049] R x1e 、R x1f Each is independently selected from hydrogen, F, Cl, Br, cyano, C1-C4 alkyl, C1-C4 haloalkyl;

[0050] In some embodiments, R x Selected from C8-C11 spirocyclic cycloalkenyl, 6-9 membered azabridged heterocyclic group, 6-9 membered azaspirocyclic heterocyclic group.

[0051] In some embodiments, R x Selected from optionally one or more R x1 Substituted with the following groups:

[0052] In some embodiments, R x Selected from

[0053] In some embodiments, R x Selected from

[0054] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,

[0055] Wherein, L is selected from *-NR 2 -CO-, *-CO-NR 2 -、*-NR 2 CONR 2 - or 5-6 membered heteroaryl, * represents connection with ring A;

[0056] R 2 is selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 haloalkyl;

[0057] In some embodiments, L is selected from *-NR 2 -CO- or 5-6 membered heteroaryl, * indicates connection with ring A; and / or

[0058] R 2 is selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 haloalkyl;

[0059] In some embodiments, L is selected from *-NR 2 -CO-, * indicates connection to ring A; and / or

[0060] R 2 Selected from hydrogen or C1-C4 alkyl;

[0061] In some embodiments, L is selected from a 5-membered heteroaryl group having 1, 2, or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from oxygen or sulfur;

[0062] In some embodiments, L is selected from *-NR 2 -CO-, * indicates connection with ring A; represents a 5-membered heteroaryl group, Y1 and Y5 are each independently C or N, and Y2, Y3, and Y4 are each independently N, NH, O, S, or CH; and Y1, Y2, Y3, Y4, and Y5 are connected Each independently represents a single bond or a double bond; two are not double bonds at the same time; when Y2, Y3, Y4 are O, S or NH, the is a single bond;

[0063] In some embodiments, L is selected from *-NR 2 -CO- or * indicates connection with ring A;

[0064] In some embodiments, L is * indicates connection with ring A;

[0065] In some embodiments, L is selected from *-NH-CO-, * indicates connection with ring A;

[0066] In some embodiments, L is selected from *-NH-CO-, * indicates connection to ring A.

[0067] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,

[0068] Wherein, X2, X3, X4 are selected from N or CR 3 ;

[0069] R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, -OR 3a 、-SR 3a 、-NR 3b R 3c 、-C(O)NR 3b R 3c 、-NR 3e C(O)R 3e 、-C(O)R 3e 、-C(O)OR 3e 、-OC(O)R 3e 、-S(O)R 3e 、-S(O)2R 3e , C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclic group, or two R 3and the atoms to which they are attached to form a 5-10 membered ring; and / or

[0070] R 3a Independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy C1-C4 alkyl;

[0071] R 3b 、R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl or R 3b 、R 3c Together with the nitrogen atom to which they are attached, they form a 3-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 3-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2;

[0072] R 3e Each is independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl;

[0073] In some embodiments, X2, X3, X4 are selected from N or CR 3 ;

[0074] R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, -OR 3a 、-SR 3a 、-NR 3b R 3c , C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclic group, or two R 3 and the atoms to which they are attached to form a 5-10 membered ring; and / or

[0075] R 3a Independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy C1-C4 alkyl;

[0076] R 3b 、R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl or R 3b 、R 3cThe nitrogen atom to which it is attached forms together a 3-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 3-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2;

[0077] In some embodiments, X2, X3, X4 are selected from N or CR 3 ;

[0078] R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, -OR 3a 、-SR 3a 、-NR 3b R 3c , C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclic group, or two R 3 and the atoms to which they are attached to form a 5-6 membered ring; and / or

[0079] R 3a Independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy C1-C4 alkyl;

[0080] R 3b 、R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl or R 3b 、R 3c The nitrogen atom to which it is attached forms together a 4-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 4-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2;

[0081] In some embodiments, X2, X3, and X4 are selected from CR 3 ;

[0082] R 3 independently selected from hydrogen, halogen or C1-C4 alkyl;

[0083] In some embodiments, X2, X3, and X4 are selected from CR 3 ;

[0084] R 3 is hydrogen;

[0085] In some embodiments, for # indicates connection with L;

[0086] R 3 Each is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OR 3a 、-NR 3b R 3c , or two R 3 and the atoms to which they are attached form a saturated, partially saturated or unsaturated 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, in which case Has the following structure: G1, G2, G3, G4 represent CH or N, G5, G6, G7, G8 represent NH, O, S or CH2, # represents connection with L;

[0087] R 3a Independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy C1-C4 alkyl;

[0088] R 3b 、R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl or R 3b 、R 3c The nitrogen atom to which it is attached forms together a 4-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 4-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2;

[0089] In some embodiments, for # indicates connected to L; R 3 Selected from hydrogen, halogen or C1-C4 alkyl;

[0090] In some embodiments, for

[0091] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,

[0092] Wherein, in some embodiments, R 1 Yes-ZR 1a , wherein Z is a direct bond, -C1-C6 alkylene-, -C2-C8 alkenylene-, -C2-C8 alkynylene-, -C1-C6 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -S=N-, -NR 1b -、-NR 1b SO2-、-SO2NR 1b -、-NR 1b -S(=O)(=NR 1b )-、-S(=O)(=NR 1b )-NR 1b -、-S(=O)(=NR 1b )-、-C1-C6 alkylene-SO2-、-(C=O)-、-(C=O)NR 1b -、-NR 1b (C=O)-, -C=N-, or -P(=O)R 1b -; or -ZR 1a Yes-N=S(=O)-(R 1b )2, where two R 1b Can combine with the sulfur atom to which they are attached to form a 3-7 membered ring; or -ZR 1a yes Ring E is selected from a 5-6 membered ring optionally containing 0, 1, 2, or 3 N atoms or 0, 1 or 2 O or S atoms; said ring E is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl;

[0093] R 1aEach is independently selected from hydrogen, deuterium, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl is optionally substituted by deuterium, halogen, cyano, amino, hydroxyl, carboxyl, thiol, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) )2, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, -S(O)(C1-C6 alkyl), -S(O)2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NHC(O)(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -OC(O)(C1-C6 alkyl);

[0094] R 1b Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, C3-C8 cycloalkyl or 4-9 membered heterocyclyl.

[0095] In some embodiments, R 1 Yes-ZR 1a , wherein Z is a direct bond, -C1-C4 alkylene-, -C2-C6 alkenylene-, -C2-C6 alkynylene-, -C1-C4 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -S=N-, -NR 1b -、-NR 1b SO2-、-SO2NR 1b -、-NR 1b -S(=O)(=NR 1b )-、-S(=O)(=NR 1b )-NR 1b -、-S(=O)(=NR 1b )-、-C1-C4 alkylene-SO2-、-C1-C4 alkylene-SO2R 1b -, -(C=O)-, -(C=O)NR 1b -、-NR 1b (C=O)-, -C=N(OH)-, or -P(=O)R 1b -; or -ZR 1a Yes-N=S(=O)-(R 1b )2, where two R 1bcan combine with the sulfur atom to which they are attached to form a saturated or partially saturated 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 -ZR 1a yes Ring E is selected from a saturated 5-membered or 6-membered monocyclic ring optionally containing 0, 1, 2, or 3 N atoms or 0, 1 or 2 O or S atoms; said ring E is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl;

[0096] R 1a Each is independently selected from hydrogen, deuterium, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl is optionally substituted by deuterium, halogen, cyano, amino, hydroxyl, carboxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) )2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, -S(O)(C1-C4 alkyl), -S(O)2(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -NHC(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -C(O)O(C1-C4 alkyl), -OC(O)(C1-C4 alkyl);

[0097] R 1b Each is independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl;

[0098] In some embodiments, R 1 Yes-ZR 1a , wherein Z is a direct bond, -C1-C4 alkylene-, -C2-C6 alkenylene-, -C2-C6 alkynylene-, -C1-C4 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -S=N-, -NR 1b -、-NR 1b SO2-、-SO2NR 1b -、-NR1b -S(=O)(=NR 1b )-、-S(=O)(=NR 1b )-NR 1b -、-S(=O)(=NR 1b )-、-C1-C4 alkylene-SO2-、-(C=O)-、-(C=O)NR 1b -、-NR 1b (C=O)-, -C=N-, or -P(=O)R 1b -; or -ZR 1a Yes-N=S(=O)-(R 1b )2, where two R 1b can combine with the sulfur atom to which they are attached to form a saturated or partially saturated 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 -ZR 1a yes Ring E is selected from a saturated 5-membered or 6-membered monocyclic ring optionally containing 0, 1, 2, or 3 N atoms or 0, 1 or 2 O or S atoms; said ring E is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl;

[0099] R 1a Each is independently selected from hydrogen, deuterium, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl is optionally substituted by deuterium, halogen, cyano, amino, hydroxyl, carboxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) )2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, -S(O)(C1-C4 alkyl), -S(O)2(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -NHC(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -C(O)O(C1-C4 alkyl), -OC(O)(C1-C4 alkyl);

[0100] R 1bEach is independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl.

[0101] In some embodiments, R 1 -ZR 1a , wherein Z is a direct bond, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -S=N-, -NH-, -NHSO2-, -SONH-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -C1-C4 alkylene-SO2-, -(C=O)-, -(C=O)NH-, -NH(C=O)-, -C=N(OH)-; and / or

[0102] R 1a Each is independently selected from hydrogen, deuterium, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted with deuterium, halogen, cyano, amino, hydroxy, carboxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy, hydroxyC1-C4 alkyl, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl;

[0103] In some embodiments, R 1 -ZR 1a , wherein Z is a direct bond, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -S=N-, -NH-, -NHSO2-, -SONH-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -C1-C4 alkylene-SO2-, -(C=O)-, -(C=O)NH-, -NH(C=O)-, -C=N-; and / or

[0104] R 1a Each is independently selected from hydrogen, deuterium, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, and the C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted by deuterium, halogen, cyano, amino, hydroxy, carboxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy, hydroxyC1-C4 alkyl, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl.

[0105] In some embodiments, R 1 -ZR 1a , wherein -Z is -NHSO2- or -SO2NH-; and / or

[0106] R 1a Each is independently selected from hydrogen, deuterium, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted with deuterium, halogen, cyano, amino, hydroxy, carboxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy, hydroxyC1-C4 alkyl, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl;

[0107] In some embodiments, R 1 -ZR 1a , wherein Z is -NHSO2-;

[0108] R 1a Each is independently selected from C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with hydroxy.

[0109] In some embodiments, R 1 Selected from the following groups:

[0110] In some embodiments, R 1 Selected from

[0111] In some embodiments, R 1 Selected from

[0112] In some embodiments, R 1a Selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted by halogen, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl.

[0113] In some embodiments, R 1a is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a hydroxy group.

[0114] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,

[0115] Among them, each R a 、R b each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, -CONH2, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -NHC(=O)(C1-C 6 alkyl), -C(=O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(=O)(C1-C6 alkyl), C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, C3-C8 cycloalkyloxy, C5-C10 cycloalkenyloxy, 5-10 membered heteroaryloxy, C6-C10 aryloxy, 4-9 membered heterocyclyloxy, or two adjacent R a Together with the atoms to which they are attached, they form a 5-7 membered ring; the C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -NHC(=O)(C1-C6 alkyl), -C( =O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(=O)(C1-C6 alkyl), C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, C3-C8 cycloalkyloxy, C5-C10 cycloalkenyloxy, 5-10 membered heteroaryloxy, C6-C10 aryloxy, 4-9 membered heterocyclyloxy, or two adjacent R a Together with the atoms to which they are attached, they form a 5-7 membered ring, which is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, and 4-9 membered heterocyclyl.

[0116] In some embodiments, R a 、R beach independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, -CONH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -NHC(=O)(C1-C 4-membered alkyl), -C(=O)N(C1-C4 alkyl)2, -N(C1-C4 alkyl)C(=O)(C1-C4 alkyl), C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10-membered heteroaryl, C6-C10 aryl, 4-7-membered heterocyclyl, C3-C6 cycloalkyloxy, C5-C7 cycloalkenyloxy, 5-10-membered heteroaryloxy, C6-C10 aryloxy, 4-7-membered heterocyclyloxy, or two adjacent R a Together with the atoms to which they are attached, they form a 5-membered, 6-membered or 7-membered ring; the C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -NHC(=O)(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -N(C1-C4 alkyl)C(=O)(C1-C4 alkyl), C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, C3-C6 cycloalkyloxy, C5-C7 cycloalkenyloxy, 5-10 membered heteroaryloxy, C6-C10 aryloxy, 4-7 membered heterocyclyloxy, or two adjacent R a Together with the atoms to which they are attached, they form a 5-, 6-, or 7-membered ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, or 4-7 membered heterocyclyl; and / or

[0117] m is selected from 0, 1, 2 or 3;

[0118] In some embodiments, each R a 、R beach independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, -CONH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -NHC(=O)(C1-C 4-membered alkyl), -C(=O)N(C1-C4 alkyl)2, -N(C1-C4 alkyl)C(=O)(C1-C4 alkyl), C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10-membered heteroaryl, C6-C10 aryl, 4-7-membered heterocyclyl, C3-C6 cycloalkyloxy, C5-C7 cycloalkenyloxy, 5-10-membered heteroaryloxy, C6-C10 aryloxy, 4-7-membered heterocyclyloxy, or two adjacent R a Together with the atoms to which they are attached, they form a 5-membered, 6-membered or 7-membered ring; the C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -NHC(=O)(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -N(C1-C4 alkyl)C(=O)(C1-C4 alkyl), C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, C3-C6 cycloalkyloxy, C5-C7 cycloalkenyloxy, 5-10 membered heteroaryloxy, C6-C10 aryloxy, 4-7 membered heterocyclyloxy, or two adjacent R a Together with the atoms to which they are attached, they form a 5-, 6-, or 7-membered ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, or 4-7 membered heterocyclyl; and / or

[0119] m is selected from 0, 1, 2 or 3;

[0120] In some embodiments, R a 、R bEach is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, 5-6 membered heteroaryl, phenyl; the C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 , C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, 5-6 membered heteroaryl, phenyl are optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-6 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl; and / or

[0121] m is selected from 0 or 1;

[0122] In some embodiments, each R a 、R b Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, 5-6 membered heteroaryl, phenyl; the C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 , C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, 5-6 membered heteroaryl, phenyl are optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-6 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl; and / or

[0123] m is selected from 0 or 1;

[0124] In some embodiments, each R a are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy; and / or

[0125] m is selected from 1;

[0126] In some embodiments, R b Selected from hydrogen, halogen or C1-6 alkyl;

[0127] In some embodiments, R a is selected from hydrogen, fluorine, cyano, methyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy; and / or

[0128] R b selected from hydrogen;

[0129] In some embodiments, each R a are each independently selected from hydrogen, fluorine, cyano, methyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy; and / or

[0130] R b selected from hydrogen;

[0131] In some embodiments, R a Selected from hydrogen, cyano, methoxy, ethoxy, isopropoxy, and / or

[0132] R b Selected from hydrogen.

[0133] In some embodiments, each R a Each independently selected from hydrogen, cyano, methoxy, ethoxy, isopropoxy, and / or

[0134] R b Selected from hydrogen.

[0135] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,

[0136] Among them, each R c R is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -OC(=O)(C1-C6 alkyl), C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, or two R attached to the same carbon atom. cTogether with the carbon atoms to which they are attached, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form a 3-8 membered ring, or two R atoms attached to different ring atoms c and the ring atoms to which they are connected together form a 3-8 membered ring; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -OC(=O)(C1-C6 alkyl), C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form a 3-8 membered ring. Two R atoms attached to different ring atoms c Together with the ring atoms to which they are attached, they form a 3-8 membered ring, which is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, and 4-9 membered heterocyclyl;

[0137] R c1 、R c2 Each is independently selected from hydrogen, halogen, cyano, and C1-C6 alkyl.

[0138] In some embodiments, R c R is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, oxo, thio, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OC(=O)(C1-C4 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form a 3-8 membered saturated or partially unsaturated ring, or two R atoms attached to different ring atoms cand the ring atoms to which they are connected together form a 3-8 membered saturated or partially unsaturated ring; the C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OC(=O)(C1-C4 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, two R c Together with the carbon atoms to which they are connected, they form a 3-8 membered saturated or partially unsaturated ring. Two R atoms connected to different ring atoms c Together with the ring atoms to which they are attached, they form a 3-8 membered saturated or partially unsaturated ring, which is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, and 4-7 membered heterocyclyl;

[0139] R c1 、R c2 Each is independently selected from hydrogen, halogen, cyano, C1-C4 alkyl;

[0140] n is selected from 0, 1, 2, 3, 4, 5 or 6;

[0141] In some embodiments, each R c R is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, oxo, thio, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OC(=O)(C1-C4 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form a 3-8 membered saturated or partially unsaturated ring, or two R atoms attached to different ring atoms cand the ring atoms to which they are connected together form a 3-8 membered saturated or partially unsaturated ring; the C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OC(=O)(C1-C4 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, two R c Together with the carbon atoms to which they are connected, they form a 3-8 membered saturated or partially unsaturated ring. Two R atoms connected to different ring atoms c Together with the ring atoms to which they are attached, they form a 3-8 membered saturated or partially unsaturated ring, which is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, and 4-7 membered heterocyclyl;

[0142] R c1 、R c2 Each is independently selected from hydrogen, halogen, cyano, C1-C4 alkyl;

[0143] n is selected from 0, 1, 2, 3, 4, 5 or 6;

[0144] In some embodiments, R c Each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, oxo, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, or two R attached to the same carbon atom c Together with the carbon atoms to which they are connected, they form a 3-6 membered saturated or partially unsaturated ring; the C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, two R c Together with the carbon atoms to which they are attached, they form a 3-6 membered saturated or partially unsaturated ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, and C1-C4 alkyl;

[0145] n is selected from 0, 1, 2, 3 or 4;

[0146] In some embodiments, each R c Each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, oxo, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, or two R attached to the same carbon atom cTogether with the carbon atoms to which they are connected, they form a 3-6 membered saturated or partially unsaturated ring; the C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, two R c Together with the carbon atoms to which they are attached, they form a 3-6 membered saturated or partially unsaturated ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, and C1-C4 alkyl;

[0147] n is selected from 0, 1, 2, 3 or 4;

[0148] In some embodiments, each R c Each is independently selected from hydrogen, halogen (e.g., F), C1-C6 alkyl, or C1-C6 haloalkyl;

[0149] n is selected from 0, 1 or 2;

[0150] In some embodiments, R c Each R is independently selected from hydrogen, deuterium, fluorine, hydroxyl, oxo, methyl, ethyl, methoxy, ethoxy, deuterated methyl, difluoromethyl, trifluoromethyl, deuterated methoxy, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form cyclopropyl, cyclobutyl, oxetane, and azetidine;

[0151] n is selected from 0, 1, 2, 3 or 4.

[0152] In some embodiments, each R c Each R is independently selected from hydrogen, deuterium, fluorine, hydroxyl, oxo, methyl, ethyl, methoxy, ethoxy, deuterated methyl, difluoromethyl, trifluoromethyl, deuterated methoxy, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form cyclopropyl, cyclobutyl, oxetane, and azetidine;

[0153] n is selected from 0, 1, 2, 3 or 4.

[0154] In some embodiments, each R c are each independently selected from hydrogen, fluorine or methyl;

[0155] n is selected from 0, 1 or 2.

[0156] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,

[0157] in for

[0158] In some embodiments, for

[0159] In some embodiments, for and / or

[0160] R a Selected from hydrogen, halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C4 alkyl)2, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, 5-6 membered heteroaryl, phenyl; the C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C4 alkyl)2, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, 5-6 membered heteroaryl, phenyl are optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl; the 5-6 membered heteroaryl contains 1, 2 or 3 N atoms, or contains 1 or 2 N atoms and 1 or 2 atoms selected from O, S;

[0161] In some embodiments, R a is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy; and / or

[0162] R c Each is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2; the C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 are optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, C1-C6 alkyl;

[0163] In some embodiments, R c is selected from hydrogen, halogen (e.g. F) or C1-C6 alkyl;

[0164] In some embodiments, for

[0165] In some embodiments, the present application provides the compound or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystal form, ester, metabolite, pharmaceutically acceptable salt or prodrug, which is shown in the structure of formula (II) or formula (III):

[0166] in, represents a 5-membered heteroaryl group, Y1 and Y5 are each independently C, N, Y2, Y3, and Y4 are each independently N, NH, O, S, or CH; and Y1, Y2, Y3, Y4, and Y5 are connected Each independently represents a single bond or a double bond; two are not double bonds at the same time; when Y2, Y3, Y4 are O, S or NH, the is a single bond;

[0167] Among them, X2, X3, X4, R 1 、R x 、R a 、R b 、R c , m, n are as defined above.

[0168] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of formulas (II-1), (II-2), (III-1) and (III-2):

[0169] Among them, Y1, Y2, Y3, Y4, Y5, X2, X3, X4, R 1 、R x 、R a 、R b 、R c , m, n are as defined above.

[0170] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of formula (II-1-1), (II-1-2), (II-1-3), (II-2-1), (II-2-2), and (II-2-3):

[0171] Among them, Y1, Y2, Y3, Y4, Y5, X2, X3, X4, R 1 、R a 、R b 、R c , m, n are as defined above.

[0172] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of formula (II-1-1'), (II-1-2'), (II-1-3'), (II-2-1'), (II-2-2'), and (II-2-3'):

[0173] Among them, Y1, Y2, Y3, Y4, Y5, X2, X3, X4, R 1 、R a 、R c As defined above.

[0174] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of formula (II-1-1"), (II-1-2"), (II-1-3"), (II-2-1"), (II-2-2"), and (II-2-3"):

[0175] Among them, Y1, Y2, Y3, Y4, Y5, X2, X3, X4, R 1a 、R a 、R c As defined above.

[0176] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of Formula (IV-1), (IV-2), (V-1), (V-2), (VI-1) or (VI-2):

[0177] Among them, X 1、X2, X3, X4, R 1 、R 2 、R a 、R b 、R c , m, n are as defined above.

[0178] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of Formula (IV-1-1), (IV-1-2), (IV-2-1), (IV-2-2), (V-1-1), (V-1-2), (V-2-1), (V-2-2), (VI-1-1), (VI-1-2), (VI-2-1) or (VI-2-2):

[0179] Among them, X2, X3, X4, R 1 、R 2 、R a 、R b 、R c , m, n are as defined above.

[0180] In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of Formula (IV-1-1'), (IV-1-2'), (IV-2-1'), (IV-2-2'), (V-1-1'), (V-1-2'), (V-2-1'), (V-2-2'), (VI-1-1'), (VI-1-2'), (VI-2-1') or (VI-2-2'):

[0181] Among them, X2, X3, X4, R 1a 、R 2 、R a 、R c As defined above. In some embodiments, the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein the compound is selected from the group consisting of the following compounds:

[0182] Furthermore, the present application provides a pharmaceutical composition comprising a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable diluent or carrier.

[0183] Furthermore, the present application provides a method for treating a condition that can be treated with a KIF18A inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition as described above.

[0184] In some embodiments, the condition is a cancer selected from the group consisting of: (a) a solid tumor or a hematogenic tumor selected from the group consisting of bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkett lymphoma; (c) a hematopoietic neoplasm of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, a xeroderma pigmentosum, a keratoacanthoma, a follicular thyroid carcinoma, or a Kaposi's sarcoma.

[0185] Furthermore, the present application provides a method for reducing the size of a solid tumor in a subject, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition as described above.

[0186] Furthermore, the present application provides a method for treating a cell proliferation disorder in a subject, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition as described above.

[0187] Furthermore, the cell proliferation disorder, ie, abnormal cell proliferation, preferably mediates abnormal cell proliferation by affecting the cell cycle and mitosis.

[0188] Furthermore, the present application provides a method for inhibiting KIF18A in cells, comprising contacting the cells with a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions as described above.

[0189] Furthermore, the present application provides a use of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or said pharmaceutical composition in the preparation of a medicament for treating a disease that can be treated with a KIF18A inhibitor.

[0190] In some embodiments, the condition is a cancer selected from the group consisting of: (a) a solid tumor or a hematogenic tumor selected from the group consisting of bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkett lymphoma; (c) a hematopoietic neoplasm of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, a xeroderma pigmentosum, a keratoacanthoma, a follicular thyroid carcinoma, or a Kaposi's sarcoma.

[0191] Furthermore, the present application provides a use of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition thereof in the preparation of a drug for reducing the size of a solid tumor in a subject.

[0192] Furthermore, the present application provides a use of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition thereof in the preparation of a drug for treating a cell proliferation disorder in a subject.

[0193] Furthermore, the present application provides a use of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition thereof in the preparation of a drug for inhibiting KIF18A in cells.

[0194] The compound represented by formula (I) provided by the present invention has a novel structure and good KIF18A inhibitory activity, and can be used for therapeutic, preventive, acute or chronic treatment of KIF18A-mediated diseases and disorders (including but not limited to cancer). DETAILED DESCRIPTION

[0195] definition

[0196] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0197] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of and "consisting of").

[0198] The term "substituted" or "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O) or a thio group (=S), it means that two hydrogen atoms are replaced. Oxo groups and / or thio groups will not occur on aromatic groups.

[0199] The term "optional" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, a 3-7 membered heterocyclic ring is optionally substituted with one or more deuterium groups, which means that the 3-7 membered heterocyclic ring may be unsubstituted, monosubstituted, polysubstituted, or fully substituted. It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and / or cannot be synthesized will be introduced.

[0200] As used herein, the term "one or more" means one or more than one, such as two, three, four, five, or ten, as appropriate. When a group is substituted with "one or more" substituents, it means that one or more hydrogen atoms on the group are replaced with one or more substituents from the specified group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., substituents, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds.

[0201] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0202] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0203] When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such substituent may be bonded to any ring atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown as carrying a substitutable hydrogen atom, the substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is to the available ring member.

[0204] As used herein, the term "alkyl" is defined as a straight or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C1-6 alkyl" refers to a linear or branched group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl) of 1 to 6 carbon atoms. The term "C1-4 alkyl" refers to a straight or branched aliphatic hydrocarbon chain (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) of 1 to 4 carbon atoms.

[0205] As used herein, the term "alkylene" means a divalent straight or branched saturated aliphatic hydrocarbon group obtained by losing 1 H from an alkyl group as defined above. In some embodiments, the alkylene group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C1-6 alkylene" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene or n-hexylene). The term "C1-4 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).

[0206] Those skilled in the art will readily understand that, in the case where an alkyl group is part of a substituent and is connected to another group on both sides thereof, if the term "alkyl" is still used, the term "alkyl" is actually the corresponding alkylene group. For example, the "C1-C6 alkyl" in "hydroxy C1-C6 alkyl-" is actually "C1-C6 alkylene".

[0207] As used herein, the term "alkoxy" refers to -O-alkyl, wherein the alkyl group is as defined above. The term "C1-6 alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy, or n-hexyloxy). The term "C1-4 alkoxy" refers to a linear or branched alkoxy group having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy).

[0208] As used herein, the term "alkylthio" refers to -S-alkyl, wherein the alkyl group is as defined above. The term "C1-6alkylthio" refers to a linear or branched alkylthio group having 1 to 6 carbon atoms (e.g., methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio, or n-hexylthio).

[0209] As used herein, the term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The term "C2-C10 alkenyl" is understood to mean a linear or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. "C2-C10 alkenyl" may include "C2-C8 alkenyl," "C2-C6 alkenyl," and "C2-C4 alkenyl." It is understood that when the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

[0210] As used herein, the term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond. The term "C2-C10 alkynyl" may be understood to mean a straight or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C10 alkynyl" may include "C2-C8 alkynyl", "C2-C6 alkynyl", "C2-C4 alkynyl". Examples of "C2-C10 alkynyl" include, but are not limited to, ethynyl, propynyl, but-1-ynyl, but-2-ynyl or but-3-ynyl, etc.

[0211] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.). The cycloalkyl group has 3 to 15 carbon atoms, suitably 3 to 10 carbon atoms. For example, the term "C3-6 cycloalkyl" refers to a saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

[0212] As used herein, the term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic group having at least one carbon-carbon double bond and existing in the form of a monocyclic, fused, bridged, or spirocyclic ring, and having 3, 4, 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms. Specific examples of the cycloalkenyl group include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, wait.

[0213] As used herein, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic, fused, spirocyclic or bridged ring group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more (e.g., one, two, three or four) selected from C(=O), O, S, S(=O), S(=O)2 and NR a’ A heteroatom-containing group, wherein R a’ "heterocyclic radical" refers to a group having 3 to 11 carbon atoms and heteroatoms, such as, but not limited to, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl. In some embodiments, the heteroatoms of the heterocyclyl group are selected from nitrogen, oxygen, or sulfur. In some embodiments, the heteroatoms of the heterocyclyl group are selected from nitrogen or oxygen. In some embodiments, the heteroatoms of the heterocyclyl group are selected from nitrogen. In some embodiments, the number of heteroatoms of the heterocyclyl group is 1 or 2. In some embodiments, the heteroatoms of the heterocyclyl group are selected from nitrogen, and the number of heteroatoms is selected from 1; in some embodiments, the heterocyclyl group is selected from 6-11 membered (e.g., 6, 7, 8, 9, 10, or 11 membered) saturated bridged or spirocyclic heterocyclyl groups, including 7-8 membered saturated bridged heterocyclyl groups and 7-9 membered saturated spirocyclic heterocyclyl groups.

[0214] As used herein, the term "aryl" 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 "C6-10 aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.

[0215] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case, may be benzo-fused. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), thiadiazolyl and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof.

[0216] As used herein, the term "ring" includes any of the cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl groups described above, for example, "3-7 membered ring", "5-7 membered ring", "3-8 membered ring", "5-10 membered ring" refers to cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl groups having 3-7 (3, 4, 5, 6, or 7), 5-7 (5, 6, or 7), 3-8 (3, 4, 5, 6, 7, or 8), or 5-10 (5, 6, 7, 8, 9, or 10) ring atoms.

[0217] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0218] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) identical or different halogen atoms, as defined herein. The terms "C1-8haloalkyl", "C1-6haloalkyl" and "C1-4haloalkyl" refer to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0219] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2H), tritium (T, 3H)); isotopes of carbon (e.g., 11C, 13C, and 14C); isotopes of chlorine (e.g., 36Cl); isotopes of fluorine (e.g., 18F); isotopes of iodine (e.g., 123I and 125I); isotopes of nitrogen (e.g., 13N and 15N); isotopes of oxygen (e.g., 15O, 17O, and 18O); isotopes of phosphorus (e.g., 32P); and isotopes of sulfur (e.g., 35S). Certain isotopically labeled compounds of the present invention (e.g., those incorporating radioisotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). The radioisotopes tritium (i.e., 3H) and carbon-14 (i.e., 14C) are particularly useful for this purpose because they are easily incorporated and easily detected. Substitution with positron-emitting isotopes (e.g., 11C, 18F, 15O, and 13N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0220] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0221] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0222] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0223] Wavy lines may be used in this article Depicting chemical bonds of compounds of the invention. The use of wavy lines to depict bonds to asymmetric carbon atoms is intended to indicate that the absolute configuration (eg, R or S) at that carbon atom is included.

[0224] When a substituent crosses the bond connecting two ring atoms in a ring, it means that the substituent can be bonded to any atom in the ring (e.g. The substituent F is cross-linked to the bond connecting the 2-carbon atom and the 3-carbon atom on the piperidine ring, indicating that F can be bonded to the 1-nitrogen, 2-carbon, 3-carbon, 4-carbon, 5-carbon, or 6-carbon. When the cross-link is connected to a bicyclic or higher ring system, any bondable position of the ring to which the cross-link extends can be bonded to the substituent indicated by the cross-link, for example The cross bond extends from the furan ring to the benzene ring, indicating that the substituent cyano group indicated by the cross bond can be bonded to any bondable position on the furan ring and the benzene ring. The cross bond only extends to the furan ring, not to the benzene ring, indicating that the substituent cyano group indicated by the cross bond can only be bonded to any bondable position on the furan ring. Represents the substituent R cIt can be bonded to any bondable ring atom of ring C, and the substituent R a It may be bonded to any bondable ring atom of Ring A.

[0225] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0226] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

[0227] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

[0228] 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.

[0229] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0230] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0231] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0232] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0233] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0234] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0235] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0236] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally based on conventional conditions.

[0237] Some representative compounds of the present invention can be prepared by the following synthetic methods. In the following reaction formulas, the reagents and conditions of each step can be selected from conventional reagents or conditions for such preparation methods in the art. After the structure of the compound of the present invention is disclosed, the above selection can be made by those skilled in the art based on the knowledge in the art. Unless otherwise specified, the raw materials in the preparation examples of this application were purchased from Bid Pharmaceuticals.

[0238] Synthesis of intermediates

[0239] Example 1A Synthesis of Intermediate M1

[0240] Step 1: Compound M1-1 (1 g, 4.93 mmol) and potassium carbonate (1.7 g, 12.31 mmol) were dissolved in DMSO (8 mL), and 4,4-difluoropiperidine hydrochloride (930 mg, 5.91 mmol) was added. The mixture was reacted at 95°C for 5 hours. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound M1-2.

[0241] Step 2: Dissolve compound M1-2 (400 mg, 1.32 mmol) in toluene (8 mL), add p-toluenesulfonylhydrazide (295 mg, 1.58 mmol), and react at room temperature for 10 minutes. The reaction solution is quenched with ice water, extracted with EA, and the organic phase is washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound M1-3.

[0242] Step 3: Compound M1-3 (1.3 g, 2.75 mmol) was dissolved in toluene (60 mL). NaH (120 mg, 3.03 mmol) was slowly added at 0°C. After stirring for 30 minutes, the mixture was reacted at 135°C for 10 minutes. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound M1-4.

[0243] Step 4: Dissolve compound M1-4 (505 mg, 1.75 mmol) in DCM (10 mL) and add manganese dioxide (1.52 g, 17.50 mmol). React at room temperature for 24 hours. Filter the reaction mixture and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound M1-5.

[0244] Step 5: Compound M1-5 (190 mg, 0.66 mmol), NH2Boc (156 mg, 1.33 mmol), cesium carbonate (649 mg, 1.99 mmol), and a fourth-generation palladium catalyst (CAS: 1599466-85-9, 63 mg, 0.07 mmol) were dissolved in 1,4-dioxane (3 mL) and reacted at 90°C under nitrogen for 1 h. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound M1-6.

[0245] Step 6: Dissolve compound M1-6 (164 mg, 0.51 mmol) in DCM (2 mL), add HCl\EA (3 mL), and react at 25°C for 1 hour. Filter the reaction solution, neutralize the solid with sodium bicarbonate solution, extract, and dry to obtain compound M1. 1 H NMR (400MHz, DMSO-d6) δ = 7.55 (d, J = 8.9Hz, 1H), 6.97 (d, J = 8.0Hz, 1H), 6.80 (d, J = 8.3Hz, 1H) ,6.45(s,1H),5.60(s,2H),4.61(t,J=6.5Hz,2H),3.81(t,J=14.6Hz,2H),2.78-2.59(m,2H).

[0246] Example 2A Synthesis of Intermediate M2

[0247] Step 1: Compound M2-1 (5 g, 22.83 mmol) and potassium carbonate (3.16 g, 22.83 mmol) were dissolved in DMF (32 mL) and water (8 mL). Sodium 2-chloro-2,2-difluoroacetate (6.96 g, 45.66 mmol) was added and the mixture was reacted at 100°C overnight. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound M2-2.

[0248] Step 2: Compound M2-2 (893 mg, 3.32 mmol) and 4,4-difluoropiperidine hydrochloride (628 mg, 3.98 mmol) were dissolved in NMP (8 mL), and DIEA (1.65 mL, 9.96 mmol) was added. The mixture was reacted at 100°C overnight. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound M2-3.

[0249] Step 3: Dissolve compound M2-3 (954 mg, 2.58 mmol) in toluene (8 mL), add p-toluenesulfonylhydrazide (528 mg, 2.84 mmol), and react at room temperature for 20 minutes. The reaction solution is quenched with ice water, extracted with EA, and the organic phase is washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound M2-4.

[0250] Step 4: Compound M2-4 (1387 mg, 2.58 mmol) was dissolved in toluene (20 mL). NaH (114 mg, 2.83 mmol) was slowly added to the mixture at 0°C. After stirring for 30 minutes, the mixture was sealed and reacted at 135°C for 20 minutes. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound M2-5.

[0251] Step 5: Dissolve compound M2-5 (600 mg, 1.69 mmol) in DCM (10 mL) and add manganese dioxide (1.48 g, 16.90 mmol). Allow to react overnight at room temperature. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound M2-6.

[0252] Step 6: Compound M2-6 (470 mg, 1.33 mmol), NH2Boc (312 mg, 2.66 mmol), cesium carbonate (1.30 g, 3.99 mmol), and a fourth-generation palladium catalyst (CAS: 1599466-83-7, 245 mg, 0.27 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 95°C for 1 h under nitrogen. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound M2-7.

[0253] Step 7: Compound M2-7 (352 mg, 0.91 mmol) was dissolved in DCM (2 mL), and a hydrochloric acid-dioxane solution (3 mL) was added. The mixture was reacted at 25°C for 1 hour. The reaction mixture was filtered, the solid dissolved, neutralized, extracted, dried, and concentrated to obtain compound M2. MS (ESI, pos.ion) m / z: 289.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 7.25 (d, J = 8.4Hz, 1H), 6.87 (d, J = 8.5Hz, 1H), 6.35 (s, 1H), 6.2 2(s,1H)5.65(s,2H),4.51(t,J=6.5Hz,2H),3.61(t,J=14.6Hz,2H),2.68-2.58(m,2H).

[0254] Example 3A Synthesis of Intermediate M3

[0255] Step 1: Dissolve compound M3-1 (2000 mg, 8.5 mmol), 4,4-difluoropiperidine (1.25 g, 10.3 mmol), and N,N-diisopropylethylamine (2.21 g, 17.16 mmol) in NMP (10 mL) and react at 100°C under nitrogen for 12 hours. The reaction mixture was quenched with water (20 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 (SiO2, PE / EA = 1 / 0 to 20 / 1) to obtain compound M3-2.

[0256] Step 2: Dissolve compound M3-2 (1100 mg, 3.29 mmol) and N-amino-4-toluenesulfonamide (613 mg, 3.29 mmol) in toluene (10 mL) and react at room temperature for 0.5 h. 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 to obtain the crude product of compound M3-3, which was used in the next step without purification.

[0257] Step 3: Compound M3-3 (1653 mg, 3.29 mmol) and sodium hydride (158 mg, 3.95 mmol) were dissolved in toluene (40 mL). The mixture was reacted at room temperature for 0.5 hour and then at 135°C for 25 minutes. After completion of the reaction as determined by TLC, the reaction solution was quenched with water (10 mL) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified to afford compound M3-4.

[0258] Step 4: Dissolve compound M3-4 (480 mg, 1.51 mmol) and manganese dioxide (1311 mg, 15.1 mmol) in DCM (15 mL) and react at room temperature for 12 hours. After TLC, filter and quench the filtrate with water (6 mL). Separate the layers and wash the organic phase with saturated brine (10 mL), dry over anhydrous Na2SO4, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (SiO2, PE / EA = 1 / 0 to 20 / 1) to obtain compound M3-5.

[0259] Step 5: Compound M3-5 (330 mg, 1.04 mmol), tert-butyl carbamate (244 mg, 2.08 mmol), cesium carbonate (1000 mg, 3.13 mmol), and palladium catalyst (CAS: 1599466-85-9; 88 mg, 0.1 mmol) were dissolved in 1,4-dioxane (8 mL) and reacted at 90°C under nitrogen for 12 hours. The reaction solution was quenched with water (10 mL) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (SiO2, PE / EA = 1 / 0 to 10 / 1) to obtain compound M3-6.

[0260] Step 6: Dissolve compound M3-6 (160 mg, 0.32 mmol) in hydrochloric acid-dioxane (2 mL) and react at room temperature for 3 hours. Concentrate the reaction mixture under reduced pressure, neutralize it with saturated sodium bicarbonate solution, extract, dry, and concentrate to obtain compound M3. 1 H NMR (400MHz, DMSO-d6) δ = 7.04 (d, J = 8.3Hz, 1H), 6.70 (d, J = 8.3Hz, 1H), 6.45 (s, 1H), 6.16 (s, 2H), 4.58 (t, J = 6.5Hz, 2H), 3.90 (s, 3H), 3.58 (br t,J=14.5Hz,2H),2.65-2.53(m,2H).

[0261] Referring to the synthesis method of compound M3, the starting materials were replaced to synthesize the following intermediate compounds:

[0262] Example 9A Synthesis of Intermediate M9

[0263] Step 1: Compound M9-1 (9.7 g, 41.62 mmol) and potassium carbonate (7.48 g, 54.11 mmol) were dissolved in DMSO (60 mL), and 2,2-dimethylmorpholine (5.75 g, 49.95 mmol) was added. The mixture was reacted at 60°C for 3 hours. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound M9-2.

[0264] Step 2: Dissolve compound M9-2 (950 mg, 2.89 mmol) in toluene (10 mL), add p-toluenesulfonylhydrazide (647 mg, 3.47 mmol), and react at room temperature for 20 minutes. The reaction solution is quenched with ice water, extracted with EA, and the organic phase is washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound M9-3.

[0265] Step 3: Compound M9-3 (1.43 g, 2.88 mmol) was dissolved in toluene (20 mL). NaH (130 mg, 3.17 mmol) was slowly added at 0°C. After stirring for 30 minutes, the mixture was reacted at 135°C for 30 minutes. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound M9-4.

[0266] Step 4: Compound M9-4 (366 mg, 1.17 mmol) was dissolved in DCM (5 mL), and MnO2 (1.02 g, 11.70 mmol) was added. The mixture was reacted at 25°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound M9-5. 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.04 (d, J = 8.3Hz, 1H), 6.37 (d, J = 8.4Hz, 1H), 6.14 (s, 1H), 4.93 (s, 2H), 4.20 (s, 2H), 3.82 (s, 3H), 1.33-1.30 (m, 6H).

[0267] Step 5: Compound M9-5 (180 mg, 0.58 mmol), NH2Boc (136 mg, 1.16 mmol), cesium carbonate (567 mg, 1.74 mmol), and a fourth-generation palladium catalyst (CAS: 1599466-83-7, 107 mg, 0.12 mmol) were dissolved in 1,4-dioxane (3 mL) and reacted at 90°C under nitrogen for 1 h. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound M9-6. MS (ESI, pos. ion) m / z: 347.1 [M+1] + .

[0268] Step 6: Compound M9-6 (146 mg, 0.42 mmol) was dissolved in DCM (2 mL), and hydrochloric acid-dioxane (2 mL) was added. The mixture was reacted at 25°C for 1 hour. The reaction solution was filtered, neutralized, extracted, dried, and concentrated to obtain compound M9. MS (ESI, pos.ion) m / z: 247.0 [M+1] + . 1 H NMR(400MHz,CHLOROFORM-d)δ=7.04(d,J=8.3Hz,1H),6.37(d,J=8.4Hz,1H),6.1 4(s,1H),5.54(s,2H),4.93(s,2H),4.20(s,2H),3.82(s,3H),1.33-1.30(m,6H).

[0269] Example 10A Synthesis of Intermediate M10

[0270] Step 1: Compound M10-1 (6 g, 29.56 mmol) and 2,2-dimethyl-1,4-oxazinane (4.09 g, 35.47 mmol) were dissolved in N-methylpyrrolidone (30 mL). N,N-diisopropylethylamine (7.64 g, 59.12 mmol) was added and the mixture was reacted at 100°C overnight. The reaction solution was quenched with water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 97:3-90:10) to obtain compound M10-2.

[0271] Step 2: Dissolve compound M10-2 (4.10 g, 13.75 mmol) in ultra-dry toluene (24 mL), add N-amino-4-methylbenzenesulfonamide (3.07 g, 16.50 mmol), and react at room temperature for 1 h. The reaction mixture is used directly in the next reaction.

[0272] Step 3: Ultra-dry toluene (24 mL) was added to the reaction solution of the previous step (M10-3 reaction solution), and sodium hydride (0.71 g, 25.59 mmol) was added thereto in an ice bath and N2 protection conditions. The mixture was stirred at 25°C for 0.5 h, and then reacted at 135°C for 10 minutes. The reaction solution was diluted with ice water, 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 prepared and purified to obtain compound M10-4.

[0273] Step 4: Dissolve compound M10-4 (500 mg, 1.77 mmol) and manganese dioxide (1.54 g, 17.70 mmol) in dioxane (10 mL) and react at room temperature for 1.5 h. Filter, dilute the filtrate with water, extract with EA, wash the organic phase with saturated NaCl solution, dry over anhydrous Na2SO4, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (PE:EA = 97:3-90:10) to obtain compound M10-5.

[0274] Step 5: Compound M10-5 (427 mg, 1.52 mmol), 2-methylpropan-2-ylcarbamate (357.09 mg, 3.09 mmol), cesium carbonate (1.49 g, 4.57 mmol), and palladium catalyst (CAS: 1599466-81-5, 65.57 mg, 0.08 mmol) were dissolved in 1,4-dioxane (8 mL) and reacted at 95°C under nitrogen for 1.5 h. The reaction solution was diluted 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 = 90:10) to provide compound M10-6.

[0275] Step 6: Compound M10-6 (450 mg, 1.42 mmol) was dissolved in 6 mL of ethyl acetate (2 M) hydrochloric acid and allowed to react at room temperature for 1 h. The reaction mixture was quenched with icy sodium bicarbonate solution, extracted with EA, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound M10. MS m / z (ESI): 217.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 7.43 (d, J = 8.1Hz, 1H), 7.26 (d, J = 7.5Hz, 1H), 7.03 (t, J = 7 .9Hz,1H),6.21(s,1H),5.43(s,2H),4.99-4.95(m,2H),3.95(s,2H),1.33(s,6H).

[0276] Referring to the synthesis method of compound M10, the starting materials were replaced to synthesize the following compounds

[0277] Example 16A Synthesis of Intermediate M16

[0278] Step 1: Compound M16-1 (500 mg, 1.47 mmol), 4,4,5,5-tetramethyl-2-(spiro[2.5]-5-octen-6-yl)-1,3,2-dioxaborolane (345 mg, 1.47 mmol), cesium carbonate (956 mg, 2.98 mmol), and tetrakistriphenylphosphine palladium (170 mg, 0.3 mmol) were dissolved in 1,4-dioxane (10 mL) and water (3 mL) and reacted at 70°C under nitrogen for 6 h. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound M16-2.

[0279] Step 2: Compound M16-2 (240 mg, 0.74 mmol) and LiOH (54 mg, 2.24 mmol) were added to a single-necked flask, followed by the addition of tetrahydrofuran / water (2 mL / 2 mL). The reaction mixture was reacted at 45°C for 4 hours. After the reaction was complete, the reaction solution was concentrated and the pH was adjusted to approximately 3 with dilute hydrochloric acid. The precipitated solid was filtered and dried to obtain compound M16. 1 HNMR (400MHz, DMSO-d6) δ = 7.52 (d, J = 1.9 Hz, 1H), 7.21 ( d, J = 8.2 Hz, 1H), 6.71 ( d, J = 8.0 Hz, 1H), d 6.69-6.58(m,1H),2.42-2.13(m,2H),1.90-1.97(m,2H),1.35-1.32(m,2H),0.35(s,4H).

[0280] Example 17A Synthesis of Intermediate M17

[0281] Compound M17-1 (180 mg, 0.82 mmol), 3-azabicyclo[3.2.1]octane hydrochloride (182.77 mg, 1.64 mmol), and Cs2CO3 (799.50 mg, 2.46 mmol) were added to a DMSO (4 mL) solution. The reaction mixture was stirred in an oil bath at 135°C for 24 hours. After monitoring the reaction completion, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 × 3 mL). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (PE:EA = 3:1) to yield compound M17. 1 H NMR (400MHz, DMSO-d6) δ = 7.33 (d, J = 2.1Hz, 1H), 6.94 (d, J = 2.0, 8.0Hz, 1H), 6.65 (d, J = 8.2Hz, 1H ),3.10(d,J=3.1,10.6Hz,2H),2.81(d,J=10.3Hz,2H),2.65-2.55(m,2H),1.67(m,2H),1.47(br s,2H),1.42-1.34(m,2H).

[0282] Referring to the synthesis method of compound M17, the starting materials were replaced to synthesize the following compounds

[0283] Example 20A Synthesis of Intermediate 26-0

[0284] Step 1: Compound 26-0-1 (1.0 g, 4.55 mmol), 6-aza-spiro[2.5]octane hydrochloride (1.01 g, 6.81 mmol), and Cs2CO3 (2.95 g, 9.09 mmol) were added to a DMSO (15 mL) solution. The reaction mixture was stirred in an 85°C oil bath for 10 hours. After monitoring the reaction completion, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 × 2 mL). The mixture was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (PE:EA = 3:1) to afford compound 26-0-2.

[0285] Step 2: Compound 26-0-2 (1.2 g, 3.21 mmol), iron powder (0.5 g, 9.63 mmol), and ammonium chloride (0.51 g, 9.63 mmol) were added to a solution of ethanol (10 mL) and water (10 mL). The reaction mixture was stirred in an 80°C oil bath for 2 hours. After monitoring the reaction, the reaction solution was filtered, the filtrate was concentrated, and the mixture was extracted with ethyl acetate (15 × 3 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (PE:EA = 3:1) to obtain compound 26-0-3.

[0286] Step 3: Compound 26-0-3 (600 mg, 2.13 mmol) was dissolved in acetonitrile (18 mL). Azidotrimethylsilane (491.65 mg, 4.27 mmol) was added in an ice-water bath and allowed to react for 30 minutes. Tert-butyl nitrite (440.06 mg, 4.27 mmol) was then slowly added to the mixture. The reaction mixture was warmed to room temperature and allowed to react overnight. The reaction mixture was quenched with aqueous sodium hypochlorite and diluted with water. The mixture was extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure until a small amount of solvent remained to obtain the crude product of compound 26-0, which was used directly in the next step.

[0287] Example 1 Synthesis of Compound 1

[0288] Step 1: Compound M17 (90 mg, 0.29 mmol), HATU (220.51 mg, 0.58 mmol), and compound M3 (73.19 mg, 0.29 mmol) were added to DMF (5 mL), and DIEA (112.29 mg, 0.87 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with water (6 mL), extracted with EA (15 mL), 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=10 / 1-5 / 1) to obtain compound 1-2.

[0289] Step 2: Compound 1-2 (90 mg, 0.17 mmol), 2-hydroxyethanesulfonamide (41.37 mg, 0.33 mmol), potassium carbonate (45.69 mg, 0.33 mmol), and palladium catalyst (CAS: 1599466-89-3, 13.37 mg, 0.02 mmol) were added to 1,4-dioxane (4 mL) and reacted at 90°C under nitrogen protection for 1 hour. The reaction solution was quenched with water and extracted with EA (20 mL). The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20 / 1 to 10 / 1) to provide compound 1. MS m / z (ESI): 589.2 [M+1] + . 1HNMR (400MHz, DMSO-d6) δ = 10.38 (s, 1H), 7.56 (d, J = 8.3Hz, 1H), 7.37 (d, J = 8.3Hz, 1H), 7 .09(d,J=2.0Hz,1H),6.94(dd,J=2.0,8.3Hz,1H),6.65(d,J=8.5Hz,1H),6.44(s,1H),4 .56(t,J=6.4Hz,2H),3.89(s,3H),3.77(t,J=6.6Hz,2H),3.50(s,2H),3.30(t,J=6.8Hz ,2H),3.10(dd,J=3.1,10.6Hz,2H),2.81(d,J=10.3Hz,2H),2.65-2.53(m,2H),2.19(br s,2H),1.62(br d,J=7.3Hz,2H),1.47(br s,2H),1.42-1.34(m,2H).

[0290] Example 2 Synthesis of Compound 2

[0291] Step 1: Compound M17 (90 mg, 0.29 mmol), HATU (220.51 mg, 0.58 mmol), and compound M10 (94.13 mg, 0.44 mmol) were added to DMF (5 mL), and DIEA (112.29 mg, 0.87 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with water (6 mL) and extracted with EA (15 mL). 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 / 1-5 / 1) to obtain compound 2-1.

[0292] Step 2: Compound 2-1 (70 mg, 0.14 mmol), 2-hydroxyethanesulfonamide (25.84 mg, 0.21 mmol), cesium carbonate (89.71 mg, 0.28 mmol), and palladium catalyst (CAS: 1599466-89-3, 11.13 mg, 0.01 mmol) were added to 1,4-dioxane (4 mL) and reacted at 90°C under nitrogen protection for 1 hour. The reaction solution was quenched with water and extracted with EA (20 mL). The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20 / 1 to 10 / 1) to obtain compound 2. MS m / z (ESI): 553.5 [M+1] + . 1HNMR (400MHz, DMSO-d6) δ = 10.30 (s, 1H), 7.64 (d, J = 7.5Hz, 1H), 7.51 (d, J = 8.5Hz, 1H), 7.19 (d, J = 8.0Hz, 1H), 7.12-7.01 (m, 2H), 6.93 (br d,J=8.3Hz,1H),6.49(s,1H),4.94(s,2H),3.93(s,2H),3.77(t,J=6.6Hz,2H),3.34-3.28(m,2H),3.13(br d,J=7.8Hz,2H),2.80(br d,J=10.3Hz,2H),2.17(br s,2H),1.64(br d,J=7.3Hz,2H),1.45(br s,2H),1.34(s,8H).

[0293] Referring to the synthesis method of Example Compound 2, fragments 1 and 2 in the following table were used as raw materials to synthesize the compounds in the following table:

[0294] Example 26 Synthesis of Compound 26

[0295] Step 1: Compound M10-5 (500 mg, 31.48 mmol) and ethynyltrimethylsilane (1.75 g, 17.85 mmol) were dissolved in N,N-dimethylformamide (8 mL). Palladium acetate (80.85 mg, 0.36 mmol), cuprous iodide (33.99 mg, 0.18 mmol), potassium carbonate (739.91 g, 5.35 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (98.94 mg, 0.18 mmol) were added and reacted at 90°C overnight. The reaction mixture was quenched with water, filtered after addition of EA, and the filter cake was washed with EA. The filtrate was separated, 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 = 100:0-90:10-80:20) to obtain compound 26-2. MS m / z(ESI):298.2[M+1] + .

[0296] Step 2: Dissolve compound 26-2 (325 mg, 1.09 mmol) in methanol (5 mL) and add potassium carbonate (301.98 mg, 2.19 mmol). Allow to react at room temperature for 1 hour. Dilute the reaction solution with aqueous solution, extract with EA, and wash the organic phase with saturated NaCl solution, dry over anhydrous Na2SO4, and concentrate under reduced pressure. The crude product is used directly in the next step.

[0297] Step 3: Dissolve the crude product 26-3, compound 26-0 (199.08 mg, 0.65 mmol), sodium ascorbate (166.90 mg, 0.84 mmol), and copper sulfate pentahydrate (80.90 mg, 0.32 mmol) in dichloromethane (4 mL) and water (2 mL) and react at room temperature for 1 h. The reaction solution was diluted 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 = 100:0-90:10-80:20) to obtain compound 26-4.

[0298] Step 4: Compound 26-4 (175 mg, 0.33 mmol), 2-hydroxyethanesulfonamide (164.51 mg, 1.31 mmol), cesium carbonate (214.16 mg, 0.66 mmol), and palladium catalyst (CAS: 1599466-83-7, 30.24 mg, 0.03 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 95°C under nitrogen protection for 1 h. The reaction solution was quenched with water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified to afford compound 26. MS m / z (ESI): 577.3 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ = 9.00 (s, 1H), 7.67 (d, J = 7.3Hz, 1H), 7.52 (d, J = 8.5Hz, 1H), 7 .43(d,J=8.1Hz,1H),7.22(t,J=7.8Hz,1H),7.13(d,J=2.3Hz,1H),7.03(dd,J=2.3,8 .5Hz,1H),6.89(s,1H),6.34(s,1H),5.01(s,2H),3.99(s,2H),3.79(t,J=6.6Hz,2H) ,3.36-3.33(m,2H),2.75-2.63(m,4H),1.37(s,6H),1.28-1.24(m,4H),0.21(s,4H).

[0299] Example 27 Synthesis of Compound 27

[0300] Step 1: Compound M9-5 (800 mg, 2.58 mmol), Pd(OAc)2 (116 mg, 0.52 mmol), dppf (143 mg, 0.26 mmol), CuI (49 mg, 0.26 mmol), and K2CO3 (1.07 g, 7.74 mmol) were dissolved in DMF (8 mL). Trimethylsilylene (3.12 mL, 25.79 mmol) was added and the mixture was reacted at 90°C under N2 protection overnight. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 99:1) to obtain compound 27-2.

[0301] Step 2: Dissolve compound 27-2 (200 mg, 0.61 mmol) in MeOH (2 mL), add K2CO3 (169 mg, 1.22 mmol), and react at room temperature for 2 h. The reaction solution is quenched with ice water, extracted with EA, and the organic phase is washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 27-3.

[0302] Step 3: Compound 27-3 (140 mg, 0.55 mmol), compound 26-0 (168 mg, 0.55 mmol), anhydrous copper sulfate (18 mg, 0.11 mmol), and sodium L-ascorbate (141 mg, 0.71 mmol) were dissolved in DCM (2 mL) and water (2 mL) and reacted overnight at 25°C. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 27-4.

[0303] Step 4: Compound 27-4 (210 mg, 0.37 mmol), 2-hydroxyethanesulfonamide (187 mg, 1.49 mmol), cesium carbonate (365 mg, 1.12 mmol), and a fourth-generation palladium catalyst (CAS: 1599466-89-3, 30 mg, 0.04 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 95°C under nitrogen for 1 h. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified to yield compound 27. MS (ESI, pos. ion) m / z: 607.3 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ = 8.87 (s, 1H), 7.54 (br d,J=8.1Hz,1H),7.51(d,J=8.5Hz,1H),7.13(d,J=2.1Hz,1H),7.02(dd,J=2.3,8.5Hz,1H),6.85(s,1H),6.77(d,J=8.3Hz,1H),6.27(m,1H)4.9 7(s,2H),4.29(s,2H),3.93(s,3H),3.79(t,J=6.6Hz,2H),3.36-3.33( m,2H),2.71-2.65(m,4H),1.35(s,6H),1.29-1.24(m,4H),0.22(s,4H).

[0304] Example 28 Synthesis of Compound 28

[0305] Step 1: Compound M1-5 (800 mg, 2.8 mmol), trimethylethynylsilane (3.98 ml, 28 mmol), N,N-diisopropylethylamine (1.46 ml, 8.39 mmol), cuprous iodide (53 mg, 0.28 mmol), 1,1'-bis(diphenylphosphino)ferrocene (157 mg, 0.28 mmol), and palladium catalyst (CAS: 3375-31-3; 62.77 mg, 0.28 mmol) were dissolved in DMF (10 mL) and reacted at 120°C under nitrogen for 3 hours. The reaction mixture was quenched with water (10 mL) and separated with EA (40 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 20 / 1) to obtain compound 28-2.

[0306] Step 2: Dissolve compound 28-2 (500 mg, 1.65 mmol) and potassium carbonate (456 mg, 3.3 mmol) in methanol (8 ml) and react at room temperature for 2 hours. The reaction mixture was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 28-3.

[0307] Step 3: Compound 28-3 (350 mg, 1.51 mmol), compound 26-0 (465 mg, 1.51 mmol), anhydrous copper sulfate (48 mg, 0.3 mmol), and sodium L-ascorbate (389 mg, 1.97 mmol) were dissolved in DCM (3 ml) and H2O (3 ml) and reacted at room temperature for 4 hours. The reaction solution was quenched with water (10 ml) and separated with EA (40 mL). The organic phase was washed with saturated 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 obtain compound 28-4.

[0308] Step 4: Compound 28-4 (400 mg, 0.74 mmol), 2-hydroxyethylsulfonamide (186 mg, 1.5 mmol), potassium carbonate (308 mg, 2.23 mmol), and palladium catalyst (CAS: 1599466-89-3; 60 mg, 0.07 mmol) were dissolved in 1,4-dioxane (6 mL) and reacted at 90°C under nitrogen for 3 hours. The reaction mixture was quenched with water (10 mL) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to give compound 28. MS (ESI, pos. ion) m / z: 583.2 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ:9.00(s,1H),7.68(d,J=7.3Hz,1H),7.53(d,J=8.5Hz,1H), 7.47(d,J=8.1Hz,1H),7.25(t,J=7.8Hz,1H),7.14(d,J=2.1Hz,1H),7.03(dd,J=8.6, 2.2Hz,1H),6.96(s,1H),6.36(s,1H),4.29(t,J=6.4Hz,2H),3.79(t,J=6.6Hz,2H), 3.56-3.67(m,2H),3.34-3.36(m,1H),3.33-3.37(m,1H),2.62-2.73(m,6H),1.26(br s,4H),0.21(s,4H).

[0309] Example 29 Synthesis of Compound 29

[0310] Step 1: Compound M3-5 (200 mg, 0.63 mmol), Pd(OAc)2 (28 mg, 0.13 mmol), dppf (35 mg, 0.06 mmol), CuI (12 mg, 0.06 mmol), and NaHCO3 (159 mg, 1.90 mmol) were dissolved in DMF (5 mL). Trimethylsilylene (0.77 mL, 6.33 mmol) was added and the mixture was reacted at 100°C under N2 protection overnight. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 99:1) to obtain compound 29-2.

[0311] Step 2: Dissolve compound 29-2 (159 mg, 0.48 mmol) in MeOH (3 mL), add K2CO3 (132 mg, 0.96 mmol), and react at room temperature for 1 h. The reaction solution is quenched with ice water, extracted with EA, and the organic phase is washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 29-3.

[0312] Step 3: Compound 29-3 (65 mg, 0.25 mmol), compound 26-0 (76 mg, 0.25 mmol), anhydrous copper sulfate (8 mg, 0.05 mmol), and sodium L-ascorbate (64 mg, 0.32 mmol) were dissolved in DCM (2 mL) and water (1 mL) and reacted at 25°C for 2 h. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 29-4.

[0313] Step 4: Compound 29-4 (98 mg, 0.17 mmol), 2-hydroxyethanesulfonamide (86 mg, 0.69 mmol), potassium carbonate (72 mg, 0.52 mmol), and a fourth-generation palladium catalyst (CAS: 1599466-89-3, 14 mg, 0.02 mmol) were dissolved in 1,4-dioxane (3 mL) and reacted at 90°C under nitrogen for 1 h. The reaction solution was quenched with ice water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified to afford compound 29. MS (ESI, pos. ion) m / z: 613.3 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ = 8.87 (s, 1H), 7.55 (d, J = 8.1Hz, 1H), 7.51 (d, J = 8.5Hz, 1H), 7.13 (d, J = 2.1Hz, 1H), 7.02 (dd, J = 2.1, 8. 5Hz,1H),6.92(s,1H),6.80(d,J=8.3Hz,1H),6.20(m,1H),4.61(t,J=6.3Hz,2H),3.94(s,3H),3.79(t,J=6.6Hz,2H),3.56(br t,J=14.5Hz,2H),3.35(br s,2H),2.68(br t,J=4.8Hz,4H),2.65-2.56(m,2H),1.25(br d,J=4.6Hz,4H),0.21(s,4H).

[0314] Referring to the synthesis method of compound 29, the following compounds were synthesized:

[0315] Test Example 1: In vitro KIF18A inhibition assay of the compounds of the present invention (ADP-Glo ​​assay)

[0316] 1. Test Purpose

[0317] In this experiment, the inhibitory effect of the compound on the KIF18A target was evaluated based on the IC50 value by detecting the KIF18A ATPase activity of the compound under tubulin stimulation.

[0318] 2. Test methods

[0319] 1. Prepare 30 mL of reaction buffer:

[0320] (1) 450 μL 1M Tris-HCl (pH=7.5) + 300 μL 1M MgCl2 + 30 μL 10% Pluronic F-68 (ThermoFisher, 24040032-100ml);

[0321] (2) Adjust the pH to 7.5 and add water to make up to 30 mL.

[0322] 2. Prepare 5 mg / mL pig microtubules (Microtubules; MT) (Cytoskeleton Inc, MT002) stock solution:

[0323] (1) 10 mL PM buffer = 150 μL 1 M PIPES (pH 7.0) + 20 μL 0.5 mM MgCl2 + 100 μL 2 mM Taxol (Cytoskeleton Inc, TXD01) + 9730 μL water.

[0324] (2) MT (500 μg / tube): Add 100 μL PM buffer to prepare a 5 mg / mL stock solution. Place MT (Cytoskeleton Inc, MT002) at room temperature for 10-15 minutes, mix gently, and store at -80°C.

[0325] 3. Prepare 2 mL of kinase buffer: 2 mL of reaction buffer + 1 μL of 2 mM Taxol (Cytoskeleton Inc, TXD01) + 12 μL of 5 mg / mL MT (Cytoskeleton Inc, MT002).

[0326] 4. Prepare 2×KIF18A (30 nM) (ChemPartner, CPB-P22-31645) working solution: 2.4 μL 10 μM KIF18A (ChemPartner, CPB-P22-31645) + 800 μL 1× kinase buffer.

[0327] 5. Prepare 2×ATP (150 μM) (Promega, G9101) working solution: 12 μL 10 mM ATP + 800 μL 1× kinase buffer.

[0328] 6. Use Echo650 to transfer 25 nL of compound to a 384-well plate.

[0329] 7. Add 2.5 μL of 2X KIF18A (final concentration 30 nM) from step 4 to the 384-well plate and incubate at 25°C for 15 minutes.

[0330] 8. Add 2.5 μL of 2X ATP (final concentration 150 μM) from step 5 to the 384-well plate and incubate at 25°C for 15 minutes.

[0331] 9. Add 5 μL ADP-Glo™ Reagent (Promega, G9101) to a 384-well plate and incubate at 25°C for 40 minutes.

[0332] 10. Add 10 μL of kinase assay reagent (Promega, G9101) to the 384-well plate and incubate at 25°C for 40 minutes.

[0333] 11. Measure the luminescence value using an EnVision Xcite Multilabel Reader (PerkinElmer, 2105-0020).

[0334] III. Data Analysis

[0335] Calculate the IC50 value of the compound inhibitory activity using Graphpad Prism software. The test results of some compounds are shown in Table 1 below.

[0336] Conclusion: The compounds of the present invention have good KIF18A inhibitory activity. The test results of some compounds are shown in Table 1.

[0337] Among the IC50 values for ADP-Glo in Table 1, A indicates IC50 ≤ 100 nM; B indicates 100 nM < IC50 ≤ 500 nM; C indicates 500 nM < IC50 ≤ 5000 nM; D indicates IC50 > 5000 nM.

[0338] Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on the proliferation of Ovcar-3 cells

[0339] I. Test Purpose

[0340] Evaluate the inhibitory effect of the compounds of the present invention on the KIF18A target by testing the inhibitory effect of the compounds of the present invention on the proliferation of OVCAR-3 cells.

[0341] II. Experimental Method

[0342] The following method is used to determine the effect of the compounds of the present invention on the proliferation of human ovarian cancer cells Ovcar-3 (HTB-161, ATCC). The cells are cultured in RPMI-1640 complete medium containing 20% fetal bovine serum, 0.01 mg / mL bovine insulin, 100 U penicillin and 100 μg / mL streptomycin. This method uses a Promega kit Cell Titer-Glo (product number: G7572) for testing.

[0343] For the specific operation steps, refer to the instruction manual of the reagent kit. The process is briefly described as follows: Dissolve the test compound in DMSO to prepare a 10 mM stock solution, dilute the stock solution according to the set test concentrations, and use ECHO to add different concentrations of the test compound into the cell test 384-well plate. Inoculate 400 Ovcar-3 cells in the logarithmic growth phase into each well of the plate that has already added the test compound, so that the final concentration of the test compound in the reaction system is between 0.12 nM and 10 μM, and co-culture in the cell incubator for 10 days. Before the test, equilibrate the cell culture plate at room temperature for 10 minutes, add 25 μL of Cell Titer-Glo to each well, mix well by oscillation and then let it stand for 5 minutes. Read the luminescence value of each well sample in the luminescence mode using a microplate reader.

[0344] III. Data Analysis

[0345] By comparing with the values of the control group (0.1% DMSO), calculate the percentage inhibition rate of the test compound on cell proliferation at each concentration. Perform non-linear regression analysis of the concentration-inhibition rate of the test compound in GraphPad Prism 9 to obtain the IC50 value of the compound.

[0346] Conclusion: The compounds of the present invention have obvious inhibitory effects on the proliferation of Ovcar-3 cells. The test results of some compounds are shown in Table 1.

[0347] Among the IC50 values for OVCAR-3 in Table 1, A represents IC50 ≤ 100 nM; B represents 100 nM < IC50 ≤ 500 nM; C represents 500 nM < IC50 ≤ 5000 nM; D represents IC50 > 5000 nM.

[0348] Table 1

[0349] Test Example 3: Determination of the inhibitory effect of the compounds of the present invention on the proliferation of HCC1954 and HCC1395 cells

[0350] I. Test Purpose

[0351] By testing the inhibitory effect of the disclosed compounds on the proliferation of HCC1954 and HCC1395 cells, evaluate the inhibitory effect of the compounds of the present invention on the KIF18A target.

[0352] II. Experimental Method

[0353] HCC1954 (ATCC, CRL-2388) and HCC1395 (ATCC, CRL-2324) cells were cultured in RPMI-1640 complete medium (Gibco, A1049101) supplemented with 20% fetal bovine serum (Gibco, 10099141C), 100 U penicillin, and 100 μg / mL streptomycin (Gibco, 15140-122). This method was tested using the Promega Cell Titer-Glo kit (Promega: G7572).

[0354] 1. HCC1954 cells (tumor cells sensitive to KIF18A) and HCC1395 cells (tumor cells insensitive to KIF18A) were cultured separately in T75 cell culture flasks (Corning, 430641) and the culture medium was placed in a 37°C, 5% CO2 incubator.

[0355] 2. When the cell density reaches 70-80% (about 2-3 times a week), subculture the cells using trypsin (0.25% EDTA).

[0356] 3. Remove the cell culture flask and add 2 mL of trypsin (0.25% EDTA source) to detach the cells for 5 minutes.

[0357] 4. Add 8 mL of RPMI-1640 medium to terminate digestion, transfer the cell suspension to a centrifuge tube, and centrifuge at 1000 rpm for 5 minutes.

[0358] 5. Resuspend the cells in 5 mL of RPMI-1640 medium. Adjust the cell density to 5 × 10 3 cells / mL(HCC1954),2.5×10 4 cells / mL (HCC1395).

[0359] 6. Add 40 μL of cell solution to a 384-well plate (Corning, 3765).

[0360] 7. Centrifuge the 384-well plate at 1000 rpm for 1 minute.

[0361] 8. Culture the cells in a 37°C, 5% CO2 incubator overnight.

[0362] 9. The next day, 40 nL of compound solution was added to the 384-well plate using Echo650. The plate was then placed in a 37°C, 5% CO2 incubator for 6 days.

[0363] 10. After 6 days, add 20 μL of Cell-Titer-Glo (Promega, G7572) reagent to each well.

[0364] 11. Measure the luminescence value using EnVision Xcite Multilabel Reader (PerkinElmer, 2105-0020).

[0365] 3. Data Analysis

[0366] The percentage inhibition rate of cell proliferation at each concentration of the test compound was calculated by comparing with the values ​​of the control group (0.1% DMSO). The data were subjected to concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC50 value of the compound.

[0367] Conclusion: At least some of the compounds of the present invention have a significant inhibitory effect on the proliferation of HCC1954 cells.

[0368] Test Example 4: PK Study

[0369] 1. Experimental Animals

[0370] Six ICR mice (male / female) were divided into two groups: oral administration and intravenous administration, with three mice in each group. The mice were fasted for 10-14 hours before administration and had free access to water.

[0371] 2. Preparation of drug preparations

[0372] The test compound was weighed according to the dosage and prepared into a dosage formulation of appropriate concentration (5 mL / kg and 10 mL / kg for intravenous and oral administration in mice and rats, respectively). The intravenous injection was a clear solution, and the oral dosage was a clear solution or a homogeneous suspension.

[0373] 3. Animal Medication and Blood Sample Collection

[0374] Animals were dosed via intravenous injection and oral gavage. Blood samples were collected at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. Whole blood was centrifuged at 6800 g for 6 minutes at 4°C, and the supernatant plasma was stored at -80°C until analysis.

[0375] 4. Plasma sample testing

[0376] Dilute the DMSO stock solution of the analyte with methanol or acetonitrile to create a series of working solutions. Add these solutions to blank plasma matrix to prepare a standard curve and quality control samples. Prepare an appropriate volume of plasma sample and, depending on the response, add methanol or acetonitrile containing the internal standard to precipitate the protein. Centrifuge all samples at 18,000 g for 10 minutes at 4°C. Remove the supernatant for LC-MS / MS analysis.

[0377] 5. Parameter calculation

[0378] The plasma drug concentration-time curve was drawn according to the test concentration, and the pharmacokinetic parameters including half-life (T1 / 2), area under the concentration-time curve (AUC0-t), clearance (CL), steady-state volume of distribution (Vss), and bioavailability (F) were calculated using WinNonlin software according to the non-compartmental model.

[0379] Conclusion: At least some of the compounds disclosed herein have good pharmacokinetic properties.

[0380] Test Example 5. Liver microsome stability test

[0381] I. Experimental Methods: Acetonitrile solutions of various liver microsomes and compounds were prepared in 100 mM phosphate buffer (pH 7.4) to prepare a reaction stock solution, achieving a final concentration of 1 μM. After mixing, 30 μL of each aliquot was dispensed into a new 96-well plate to set up reaction groups with NADPH for 0, 5, 15, 30, and 45 min (n=2), and controls without NADPH for 0 and 45 min (n=1). These samples were pre-incubated in a 37°C waterbath with shaking for 5 min. The reactions were initiated by adding 15 μL of NADPH to a final NADPH concentration of 2 mM. The no-NADPH control group was incubated with 15 μL of phosphate buffer, mixed, and incubated for the appropriate time. The reactions were terminated with 200 μL of glacial acetonitrile containing an internal standard. The mixture was vortexed and centrifuged at 4000 rpm at 4°C for 50 min. The supernatant was diluted with ultrapure water and analyzed by UPLC-MS / MS.

[0382] 2. Data Analysis

[0383] The logarithm of the remaining percentage of the test substance was plotted against the incubation time, and the elimination half-life of the test substance was calculated using T1 / 2 = 0.693 / K.

[0384] Conclusion: At least some of the compounds disclosed herein have good stability in liver microsomes.

[0385] Test Example 6. hERG Test

[0386] 1. Test method:

[0387] The cells used in this experiment were HEK293 cell lines transfected with hERG cDNA and stably expressing hERG channels (#60187, provided by BPS, with passages P3-P23 used for experimental studies). Cells were cultured in a medium containing the following components: MEM medium, 10% (v / v) inactivated fetal bovine serum, 1mM sodium pyruvate, 500μg / ml geneticin, 0.1mM non-essential amino acids, and 100U / ml penicillin-streptomycin. HEK293 hERG cells were grown in culture dishes containing the above culture medium and cultured in an incubator at 37°C and 5% CO2. They were passaged approximately three times a week and the cell confluence was maintained between 40% and 80%. 24 to 48 hours before the electrophysiological experiment, HEK293 hERG cells were transferred to glass slides pretreated with 0.05mg / ml PDL and plated at 1×10 4 HEK293 hERG cells were plated in 48-well plates and grown under the same culture medium and conditions. The density of HEK293 hERG cells per round slide was sufficient to ensure that the majority of cells were independent and single. The extracellular solution used in the hERG assay contained the following components (mM): 145 μM NaCl, 4 μM KCl, 2 μM CaCl₂, 1 μM MgCl₂, 10 μglucose, and 10 μM HEPES (pH adjusted to 7.40 with NaOH). The intracellular solution contained the following components (mM): 130 μM KCl, 2 μM MgCl₂, 5 μM EGTA, 10 μM HEPES, and 5 μM Na₂ATP (pH adjusted to 7.25 with KOH). Compounds were tested at the following concentrations (30, 10, 3, 1, 0.3, and 0.1 μM) to determine their IC₅₀ values ​​(if the compound exhibits a strong effect, the test concentration may be adjusted appropriately). Prior to the assay, stock solutions were serially diluted in DMSO to 10, 3, 1, 0.3, and 0.1 mM, and then diluted in extracellular fluid to the final μM test concentration. The final DMSO concentration in each compound solution ranged from 0.1% to 0.3%. All compound solutions were routinely sonicated and thoroughly shaken for 5 to 10 minutes to ensure complete dissolution. All test solutions were then mixed by rotation for at least 10 minutes.

[0388] Electrophysiological experiments were performed using a manual patch-clamp system (HEKA EPC-10 signal amplifier and digital converter, HEKA Electronics, Germany) for whole-cell current recording. The specific testing method is as follows: A circular slide containing CHO hERG cells was placed in an electrophysiological recording chamber under an inverted microscope. Extracellular solution was continuously perfused into the recording chamber (approximately 1 ml per minute). Conventional whole-cell patch-clamp current recording techniques were used. Unless otherwise specified, experiments were performed at room temperature (~25°C). Cells were clamped at -80 mV. The clamping voltage was depolarized to +30 mV to activate hERG potassium channels, and then clamped back to -50 mV after 5 seconds to eliminate inactivation and generate a tail current. The peak tail current was used as the hERG current magnitude. Once the hERG potassium current recorded in the above steps stabilized under continuous perfusion of extracellular solution into the recording chamber, the drug to be tested was continuously perfused until the inhibitory effect on the hERG current reached a steady state. Generally, the coincidence of the three most recent consecutive current recording lines is used as the criterion for judging whether the state is stable.

[0389] 2. Data Analysis

[0390] The dose response curve of the test compound was plotted with % hERG inhibition as the vertical axis and the concentration of the test compound as the horizontal axis, and IC50 was calculated.

[0391] Conclusion: The compounds of the present invention have no obvious hERG inhibitory effect.

[0392] Test Example 7: Determination of the Inhibitory Effect of the Compounds of the Invention on HT-29 Cell Proliferation

[0393] 1. Test Purpose

[0394] The inhibitory effect of the compounds of the present invention on the KIF18A target was evaluated by testing the inhibitory effect of the compounds of the present invention on the proliferation of HT-29 cells.

[0395] 2. Experimental Methods

[0396] HT-29 (ATCC, HTB-38) cells were cultured in McCoy's 5a complete medium (Gibco, 12330-031) supplemented with 10% fetal bovine serum (Gibco, 10099-141C), 100 U penicillin, and 100 μL streptomycin (Gibco, 15140-122). This method was tested using the Promega Cell Titer-Glo kit (Promega: G7572).

[0397] 1. Culture HT-29 cells in T75 cell culture flasks (Corning, 430641) in a 37°C, 5% CO2 incubator. When the cell density reaches 70-80%, passage the cells approximately twice a week.

[0398] 2. When conducting the experiment, the test compound was dissolved in DMSO to prepare a 10 mM stock solution, and the test compound was added to a cell test 384-well plate (Corning, 3765) at a set concentration using ECHO.

[0399] 3. Remove the cell culture flask, remove the culture medium, rinse the cells with PBS, then add 2 mL of trypsin (containing 0.25% EDTA) and place in the incubator for digestion for 4 minutes.

[0400] 4. Add 4 mL of complete culture medium to terminate digestion, transfer the cell suspension to a centrifuge tube, and centrifuge at 1000 rpm for 4 minutes.

[0401] 5. Resuspend the cells in 6 mL of complete culture medium, count the cells, adjust the cell density to 4170 cells / mL, and add 60 μL to each well of a 384-well plate.

[0402] 6. Centrifuge the 384-well plate at 500 rpm for 1 minute and place in a 37°C, 5% CO2 incubator for 6 days.

[0403] 7. After 6 days, equilibrate the cell culture plate at room temperature for 10 minutes. Add 25 μL of Cell Titer-Glo to each well, vortex to mix, and let stand for 5 minutes. Read the luminescence value of each well using a microplate reader in luminescence mode.

[0404] 3. Data Analysis

[0405] The percentage inhibition rate of cell proliferation at each concentration of the test compound was calculated by comparing the values ​​with those of the control group (0.3% DMSO). The data were analyzed by concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC50 value of the compound. The results are shown in Table 1.

[0406] Conclusion: At least some of the compounds of the present invention have a significant inhibitory effect on the proliferation of HT-29 cells.

[0407] Test Example 8: HCT116 cell anti-proliferation experimental method

[0408] HCT116 (ATCC, CCL-247) cells were cultured in McCoy's 5a complete medium (Gibco, 12330-031) supplemented with 10% fetal bovine serum (Gibco, 10099-141C), 100 U penicillin, and 100 μg / mL streptomycin (Gibco, 15140-122). This method was tested using the Promega Cell Titer-Glo kit (Promega: G7572).

[0409] HCT116 was cultured in a T75 cell culture flask (Corning, 430641) and the cells were placed in a 37°C, 5% CO2 incubator. When the cell density reached 70-80%, passage was performed, about twice a week. During the experiment, the test compound was dissolved in DMSO to prepare a 10mM mother solution, and the test compound was added to a cell test 384-well plate (Corning, 3765) at a set concentration (19.5nM-10mM) using ECHO. HCT1169 cells were digested and 150 cells (60μL culture medium) were seeded into each well of the test plate. The 384-well plate was then centrifuged at 500rpm for 1 minute and then placed in a 37°C, 5% CO2 incubator for 6 days. After 6 days, the cell culture plate was equilibrated at room temperature for 10 minutes, and 25μL of Cell Titer-Glo was added to each well, shaken and mixed, and allowed to stand for 5 minutes. The luminescence value of each well sample was read using a microplate reader in luminescence mode.

[0410] The percentage inhibition rate of the test compound on cell proliferation at each concentration was calculated by comparing the values ​​with those of the control group (0.2% DMSO). The data were subjected to concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC value of the compound. 50 value.

[0411] Conclusion: The compounds of the present invention have no antiproliferative effect on HCT116 cells.

[0412] Test Example 9: A2780 cell anti-proliferation experiment

[0413] A2780 (ECACC) cells were cultured in RPMI-1640 complete medium (Gibco, A1049101) supplemented with 10% fetal bovine serum (Gibco, 10099-141C), 100 U penicillin, and 100 μg / mL streptomycin (Gibco, 15140-122). This method was tested using the Promega Cell Titer-Glo kit (Promega: G7572).

[0414] A2780 was cultured in a T75 cell culture flask (Corning, 430641) and the cells were placed in a 37°C, 5% CO2 incubator. When the cell density reached 70-80%, passage was performed once every 5 days. During the experiment, the test compound was dissolved in DMSO to prepare a 10mM mother solution, and the test compound was added to a cell test 384-well plate (Corning, 3765) at a set concentration (19.5nM-10mM) using ECHO. A2780 cells were digested and 4000 cells (60μL culture medium) were seeded into each well of the test plate. The 384-well plate was then centrifuged at 500rpm for 1 minute and placed in a 37°C, 5% CO2 incubator for 6 days. After 6 days, the cell culture plate was equilibrated at room temperature for 10 minutes, and 25μL of Cell Titer-Glo was added to each well, shaken and mixed, and allowed to stand for 5 minutes. The luminescence value of each well sample was read using a microplate reader in luminescence mode.

[0415] The percentage inhibition rate of the test compound on A2780 cell proliferation at each concentration was calculated by comparing the values ​​with those of the control group (0.2% DMSO). The data were subjected to concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC value of the compound. 50 value.

[0416] Conclusion: The compounds of the present invention have no antiproliferative effect on A2780 cells.

[0417] Test Example 10: In vivo pharmacodynamic study in the OVCAR3 human ovarian cancer subcutaneous transplant model

[0418] 1. Experimental purpose: To evaluate the pharmacological effects of the control compound and the compound of the present invention in the OVCAR3 human ovarian cancer subcutaneous transplant tumor model.

[0419] 2. Experimental Materials: Female BALB / c nude mice, 6-8 weeks old or 18-20 g, were provided by Weitonglihua Laboratory Animal Technology Co., Ltd.

[0420] 3. Experimental Methods: All experimental animals were housed in a barrier-free animal room free of specific pathogens. Experiments were started after the animals had adapted for 3 days. Human ovarian cancer OVCAR3 tumor cells were cultured in RPMI 1640 complete medium (supplemented with a final concentration of 20% fetal bovine serum, 1% penicillin and streptomycin, and 0.01 mg / ml insulin) at 37°C in an atmosphere containing 5% CO2 for monolayer culture. Tumor cells were routinely subcultured 2-3 times a week, and cells in the exponential growth phase were collected and counted for tumor cell inoculation. 10x10 6OVCAR3 tumor cells were resuspended in 0.1 ml PBS and mixed with 0.1 ml matrigel, and then inoculated subcutaneously on the right side of each mouse to form tumors. 3 Around 24 hours after administration, suitable tumor-bearing mice were randomly divided into the following groups: a blank control group, a control compound group, and a compound of the present invention group. The blank control group was orally administered with a vehicle, while the other groups were orally administered with the corresponding compound for 28 days. During the experimental period, the tumor volume and animal weight of each group were monitored twice a week. This experiment was conducted by monitoring the tumor volume of each group after administration of the compound, and statistical analysis was performed to test the inhibitory effect of the control compound and the compound of the present invention on the growth of OVCAR3 human ovarian cancer.

[0421] Conclusion: At least some of the compounds of the present invention showed certain anti-tumor efficacy in vivo.

[0422] The above test examples show that the compounds of the present invention have excellent KIF18A inhibitory activity and in vivo anti-tumor efficacy. In addition, the compounds of the present invention have better physicochemical properties (such as solubility, physical and / or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (such as reduced cardiotoxicity and / or fewer side effects), less prone to drug resistance, and other excellent properties.

[0423] Although some exemplary embodiments of the present application have been illustrated and described, the present application is not limited to the disclosed embodiments. On the contrary, those skilled in the art will recognize that some modifications and changes may be made to the described embodiments without departing from the spirit and scope of the present application as described in the appended claims.

Claims

1. A compound represented by formula (I) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, L is selected from *-NR 2 -CO-, *-CO-NR 2 -、*-NR 2 CONR 2 - or 5-6 membered heteroaryl, * represents connection with ring A; R 2 Selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl; R x is selected from C3-C12 cycloalkyl, C3-12 cycloalkenyl, 3-14 membered heterocyclic group; the C3-C12 cycloalkyl, C3-12 cycloalkenyl, 3-14 membered heterocyclic group are each independently optionally substituted by one or more R x1 Replace, each R x1 independently selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo (O=), thio (S=), -C(O)R x1a 、-C(O)OR x1a 、-OC(O)R x1a 、-NR x1a C(O)R x1a 、-C(O)NR x1b R x1c 、-S(O)R x1a 、-S(O)2R x1a 、-NR x1b R x1c , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R x1 The atoms to which they are attached form a 3-14 membered ring, or two R atoms attached to the same carbon atom x1 Together with the atoms they are connected to form The C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, two R x1 and the atoms to which they are attached form a 3-14 membered ring optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, thiol, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl; R x1a Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl; R x1b 、R x1c are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, or R x1b 、R x1c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring, wherein the 3-7 membered heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2; R x1e 、R x1f Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl; X1 is selected from NH, S, O or CH2; X2, X3, X4 are selected from N or CR 3 ; R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, -OR 3a 、-SR 3a 、-NR 3b R 3c 、-C(O)NR 3b R 3c 、-NR 3e C(O)R 3e 、-C(O)R 3e 、-C(O)OR 3e 、-OC(O)R 3e 、-S(O)R 3e 、-S(O)2R 3e , C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R 3 Combined with the atoms to which they are attached to form a 5-10 membered ring; R 3a Independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy C1-C6 alkyl; R 3b 、R 3c are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, or R 3b 、R 3c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring, wherein the 3-7 membered heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2; R 3e Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl; R 1 Yes-ZR 1a , wherein Z is a direct bond, -C1-C6 alkylene-, -C2-C8 alkenylene-, -C2-C8 alkynylene-, -C1-C6 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -S=N-, -NR 1b -、-NR 1b SO2-、-SO2NR 1b -、-NR 1b -S(=O)(=NR 1b )-、-S(=O)(=NR 1b )-NR 1b -、-S(=O)(=NR 1b )-、-C1-C6 alkylene-SO2-、-C1-C6 alkylene-SO2R 1b -, -(C=O)-, -(C=O)NR 1b -、-NR 1b (C=O)-, -C=N(OH)-, or -P(=O)R 1b -; or -ZR 1a Yes-N=S(=O)-(R 1b )2, where two R 1b Can combine with the sulfur atom to which they are attached to form a 3-7 membered ring; or -ZR 1a yes Ring E is selected from a 5-6 membered ring optionally containing 0, 1, 2, or 3 N atoms or 0, 1 or 2 O or S atoms; said ring E is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl; R 1a Each is independently selected from hydrogen, deuterium, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl is optionally substituted by deuterium, halogen, cyano, amino, hydroxyl, carboxyl, thiol, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) )2, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, -S(O)(C1-C6 alkyl), -S(O)2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NHC(O)(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -OC(O)(C1-C6 alkyl); R 1b Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyC1-C6 alkyl, C3-C8 cycloalkyl or 4-9 membered heterocyclyl; R a 、R b each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, -CONH2, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -NHC(=O)(C1-C 6 alkyl), -C(=O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(=O)(C1-C6 alkyl), C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, C3-C8 cycloalkyloxy, C5-C10 cycloalkenyloxy, 5-10 membered heteroaryloxy, C6-C10 aryloxy, 4-9 membered heterocyclyloxy, or two adjacent R a Together with the atoms to which they are attached, they form a 5-7 membered ring; the C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -NHC(=O)(C1-C6 alkyl), -C( =O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(=O)(C1-C6 alkyl), C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, C3-C8 cycloalkyloxy, C5-C10 cycloalkenyloxy, 5-10 membered heteroaryloxy, C6-C10 aryloxy, 4-9 membered heterocyclyloxy, or two adjacent R a Together with the atoms to which they are attached, they form a 5-7 membered ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, and 4-9 membered heterocyclyl; R c R is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -OC(=O)(C1-C6 alkyl), C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, or two R attached to the same carbon atom. c Together with the carbon atoms to which they are attached, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form a 3-8 membered ring, or two R atoms attached to different ring atoms c and the ring atoms to which they are connected together form a 3-8 membered ring; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -OC(=O)(C1-C6 alkyl), C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C10 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form a 3-8 membered ring. Two R atoms attached to different ring atoms c Together with the ring atoms to which they are attached, they form a 3-8 membered ring, which is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, and 4-9 membered heterocyclyl; R c1 、R c2 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; The conditions are: When L is selected from *-NH-CO- or *-CO-NH-, R x no 2. The compound of formula (I) according to claim 1 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in the structure of formula (I-1) or (I-2): in, X2, X3, X4, R 1 、R x , L, R a 、R b 、R c , m, n as defined in claim 1.

3. A compound according to any one of claims 1 to 2, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, in, R x is selected from C3-C8 membered monocyclic cycloalkenyl, C6-C11 spirocyclic cycloalkenyl, C6-C11 fused ring cycloalkenyl, C6-C11 bridged ring cycloalkenyl, 4-7 membered monocyclic heterocyclyl, 6-11 membered spirocyclic heterocyclyl, 6-11 membered fused ring heterocyclyl, 6-11 membered bridged ring heterocyclyl; the C3-C8 membered monocyclic cycloalkenyl, C6-C11 spirocyclic cycloalkenyl, C6-C11 fused ring cycloalkenyl, C6-C11 bridged ring cycloalkenyl, 6-11 membered spirocyclic heterocyclyl, 6-11 membered fused ring heterocyclyl, 6-11 membered bridged ring heterocyclyl are each independently optionally substituted by one or more R x1 Replace, each R x1 independently selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo (O=), thio (S=), -C(O)R x1a 、-C(O)OR x1a 、-OC(O)R x1a 、-NR x1a C(O)R x1a 、-C(O)NR x1b R x1c 、-S(O)R x1a 、-S(O)2R x1a 、-NR x1b R x1c , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R attached to the same carbon atom x1 The atoms to which they are connected form a 3-14 membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 The atoms to which they are connected form a 3-14 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, or two R atoms connected to the same carbon atom x1 Together with the atoms they are connected to form The C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R groups connected to the same carbon atom x1 The atoms to which they are connected form a 3-14 membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 and the atoms to which they are attached form a 3-14 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl; and / or R x1a Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl; R x1b 、R x1c are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, or R x1b 、R x1c Together with the nitrogen atom to which they are attached, they form a 3-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 3-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2; and / or, provided that: when L is selected from 5-6 membered heteroaryl, R X is selected from 4-7 membered monocyclic heterocyclic group, 6-11 membered spirocyclic heterocyclic group; R x1e 、R x1f Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl; Preferably, R x is selected from C8-C11 spirocyclic cycloalkenyl, C8-C11 fused ring cycloalkenyl, C7-C9 bridged ring cycloalkenyl, 6-9 membered bridged ring heterocyclyl, 6-9 membered spirocyclic heterocyclyl; the 6-9 membered bridged ring heterocyclyl and 6-9 membered spirocyclic heterocyclyl contain at least one N atom; the C8-C11 spirocyclic cycloalkenyl, C8-C11 fused ring cycloalkenyl, C7-C9 bridged ring cycloalkenyl, 6-9 membered bridged ring heterocyclyl and 6-9 membered spirocyclic heterocyclyl are each independently optionally substituted by one or more R x1 Replace, each R x1 independently selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thio, -C(O)R x1a 、-C(O)OR x1a 、-OC(O)R x1a 、-NR x1a C(O)R x1a 、-C(O)NR x1b R x1c 、-S(O)R x1a 、-S(O)2R x1a 、-NR x1b R x1c , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R attached to the same carbon atom x1 The atoms to which they are connected form a 3-7 membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 The atoms to which they are connected form a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, or two R atoms connected to the same carbon atom x1 Together with the atoms they are connected to form The C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclic group, or two R groups connected to the same carbon atom x1 The atoms to which they are connected form a 3-7 membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 and the atoms to which they are attached form a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, or 4-9 membered heterocyclyl; R x1a Each is independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl; R x1b 、R x1c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, or R x1b 、R x1c The nitrogen atom to which it is attached forms a 3-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 3-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2; R x1e 、R x1f Each is independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl; Preferably, R x is selected from C8-C11 spirocyclic cycloalkenyl, C8-C10 fused ring cycloalkenyl, C7-C9 bridged ring cycloalkenyl, 6-9 membered bridged ring heterocyclyl, 6-9 membered spirocyclic heterocyclyl; the 6-9 membered bridged ring heterocyclyl, 6-9 membered spirocyclic heterocyclyl contains at least one N atom; the cycloalkenyl is connected to ring D through an alkenyl group, and the 6-9 membered bridged ring heterocyclyl, 6-9 membered spirocyclic heterocyclyl is connected to ring D through an N atom; the C8-C11 spirocyclic cycloalkenyl, C8-C10 fused ring cycloalkenyl, C7-C9 bridged ring cycloalkenyl, 6-9 membered bridged ring heterocyclyl, 6-9 membered spirocyclic heterocyclyl are each independently optionally substituted by one or more R x1 Replace, each R x1 are independently selected from deuterium, halogen, cyano, hydroxyl, sulfhydryl, oxo, thioxo, -NR x1b R x1c , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C3-C6 cycloalkyl, 5-6 membered heteroaryl, phenyl, 4-7 membered heterocyclic group, or two R attached to the same carbon atom x1 The atoms to which they are connected form a 3-membered, 4-membered, 5-membered, or 6-membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 The atoms to which they are connected form a 3-membered, 4-membered, 5-membered, or 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring, or two R atoms connected to the same carbon atom x1 Together with the atoms they are connected to form The C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C3-C6 cycloalkyl, 5-6 membered heteroaryl, phenyl, 4-7 membered heterocyclic group, two R groups connected to the same carbon atom x1 The atoms to which they are connected form a 3-membered, 4-membered, 5-membered, or 6-membered saturated or partially unsaturated carbon or heterocyclic ring, or two R atoms connected to different atoms x1 The atoms to which they are attached form a 3-membered, 4-membered, 5-membered, 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2; R x1b 、R x1c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, or R x1b 、R x1c Together with the nitrogen atom to which they are attached, they form a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocyclic ring, wherein the 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2; R x1e 、R x1f Each is independently selected from hydrogen, F, Cl, Br, cyano, C1-C4 alkyl, C1-C4 haloalkyl; Preferably, R x Selected from optionally one or more R x1 Substituted with the following groups: Preferably, R x Selected from Preferably, R x Selected from 4. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, in, R 2 is selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 haloalkyl; Preferably, L is selected from *-NR 2 -CO- or 5-6 membered heteroaryl, * indicates connection with ring A; and / or R 2 is selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 haloalkyl; Preferably, L is selected from *-NH-CO-, * indicates connection with ring A; Preferably, L is selected from *-NH-CO-, * indicates connection to ring A.

5. A compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, in, X2, X3, X4 are selected from N or CR 3 ; R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, -OR 3a 、-SR 3a 、-NR 3b R 3c 、-C(O)NR 3b R 3c 、-NR 3e C(O)R 3e 、-C(O)R 3e 、-C(O)OR 3e 、-OC(O)R 3e 、-S(O)R 3e 、-S(O)2R 3e , C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclic group, or two R 3 and the atoms to which they are attached to form a 5-10 membered ring; and / or R 3a Independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy C1-C4 alkyl; R 3b 、R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, or R 3b 、R 3c Together with the nitrogen atom to which they are attached, they form a 3-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 3-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2; R 3e Each is independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl; Preferably, X2, X3, X4 are selected from N or CR 3 ; R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, -OR 3a 、-SR 3a 、-NR 3b R 3c , C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclic group, or two R 3 and the atoms to which they are attached to form a 5-10 membered ring; and / or R 3a Independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy C1-C4 alkyl; R 3b 、R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, or R 3b 、R 3c The nitrogen atom to which it is attached forms together a 3-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 3-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2; Preferably, X2, X3, X4 are selected from N or CR 3 ; R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, -OR 3a 、-SR 3a 、-NR 3b R 3c , C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclic group, or two R 3 and the atoms to which they are attached to form a 5-6 membered ring; and / or R 3a Independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy C1-C4 alkyl; R 3b 、R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, or R 3b 、R 3c The nitrogen atom to which it is attached forms together a 4-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 4-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2; Preferably, for # indicates connection with L; R 3 Each is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OR 3a 、-NR 3b R 3c , or two R 3 and the atoms to which they are attached form a saturated, partially saturated or unsaturated 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, in which case Has the following structure: G1, G2, G3, G4 represent CH or N, G5, G6, G7, G8 represent NH, O, S or CH2, # represents connection with L; R 3a Independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy C1-C4 alkyl; R 3b 、R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, or R 3b 、R 3c The nitrogen atom connected thereto forms a 4-7 membered saturated or partially unsaturated heterocyclic ring, and the 4-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, mercapto, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2.

6. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, in, R 1 Yes-ZR 1a , wherein Z is a direct bond, -C1-C4 alkylene-, -C2-C6 alkenylene-, -C2-C6 alkynylene-, -C1-C4 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -S=N-, -NR 1b -、-NR 1b SO2-、-SO2NR 1b -、-NR 1b -S(=O)(=NR 1b )-、-S(=O)(=NR 1b )-NR 1b -、-S(=O)(=NR 1b )-、-C1-C4 alkylene-SO2-、-C1-C4 alkylene-SO2R 1b -, -(C=O)-, -(C=O)NR 1b -、-NR 1b (C=O)-, -C=N(OH)-, or -P(=O)R 1b -; or -ZR 1a Yes-N=S(=O)-(R 1b )2, where two R 1b can combine with the sulfur atom to which they are attached to form a saturated or partially saturated 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 -ZR 1a yes Ring E is selected from a saturated 5-membered or 6-membered monocyclic ring optionally containing 0, 1, 2, or 3 N atoms or 0, 1 or 2 O or S atoms; said ring E is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, thiol, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl; R 1a Each is independently selected from hydrogen, deuterium, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl is optionally substituted by deuterium, halogen, cyano, amino, hydroxyl, carboxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) )2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, -S(O)(C1-C4 alkyl), -S(O)2(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -NHC(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -C(O)O(C1-C4 alkyl), -OC(O)(C1-C4 alkyl); R 1b Each is independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl; Preferably, R 1 -ZR 1a , wherein Z is a direct bond, -C1-C4 alkylene-, -C1-C4 alkylene-O-, -O-, -S-, -S(=O)-, -SO2-, -S=N-, -NH-, -NHSO2-, -SONH-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -C1-C4 alkylene-SO2-, -(C=O)-, -(C=O)NH-, -NH(C=O)-, -C=N(OH)-; and / or R 1a Each is independently selected from hydrogen, deuterium, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted with deuterium, halogen, cyano, amino, hydroxy, carboxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy, hydroxyC1-C4 alkyl, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl; Preferably, R 1 -ZR 1a , wherein Z is -NHSO2- or -SO2NH-; and / or R 1a Each is independently selected from hydrogen, deuterium, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted with deuterium, halogen, cyano, amino, hydroxy, carboxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy, hydroxyC1-C4 alkyl, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl; Preferably, R 1 Selected from the following groups: Preferably, R 1 Selected from 7. A compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, in, R a 、R b each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, -CONH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -NHC(=O)(C1-C 4-membered alkyl), -C(=O)N(C1-C4 alkyl)2, -N(C1-C4 alkyl)C(=O)(C1-C4 alkyl), C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10-membered heteroaryl, C6-C10 aryl, 4-7-membered heterocyclyl, C3-C6 cycloalkyloxy, C5-C7 cycloalkenyloxy, 5-10-membered heteroaryloxy, C6-C10 aryloxy, 4-7-membered heterocyclyloxy, or two adjacent R a Together with the atoms to which they are attached, they form a 5-membered, 6-membered or 7-membered ring; the C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -NHC(=O)(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -N(C1-C4 alkyl)C(=O)(C1-C4 alkyl), C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, C3-C6 cycloalkyloxy, C5-C7 cycloalkenyloxy, 5-10 membered heteroaryloxy, C6-C10 aryloxy, 4-7 membered heterocyclyloxy, or two adjacent R a Together with the atoms to which they are attached, they form a 5-, 6-, or 7-membered ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, or 4-7 membered heterocyclyl; and / or m is selected from 0, 1, 2 or 3; Preferably, R a 、R b Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, 5-6 membered heteroaryl, phenyl; the C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 , C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, 5-6 membered heteroaryl, phenyl are optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-6 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl; and / or m is selected from 0 or 1; Preferably, R a is selected from hydrogen, fluorine, cyano, methyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy; and / or R b selected from hydrogen; Preferably, R a Selected from hydrogen, cyano, methoxy, ethoxy, isopropoxy, and / or R b Selected from hydrogen.

8. A compound according to any one of claims 1 to 7, 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, in, R c is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, carboxyl, oxo, thio, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OC(=O)(C1-C4 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form a 3-8 membered saturated or partially unsaturated ring, or two R atoms attached to different ring atoms c and the ring atoms to which they are connected together form a 3-8 membered saturated or partially unsaturated ring; the C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OC(=O)(C1-C4 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, two R c Together with the carbon atoms to which they are connected, they form a 3-8 membered saturated or partially unsaturated ring. Two R atoms connected to different ring atoms c Together with the ring atoms to which they are attached, they form a 3-8 membered saturated or partially unsaturated ring, which is optionally substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, and 4-7 membered heterocyclyl; R c1 、R c2 Each is independently selected from hydrogen, halogen, cyano, C1-C4 alkyl; n is selected from 0, 1, 2, 3, 4, 5 or 6; Preferably, R c Each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, oxo, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, or two R attached to the same carbon atom c Together with the carbon atoms to which they are connected, they form a 3-6 membered saturated or partially unsaturated ring; the C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, two R c Together with the carbon atoms to which they are attached, they form a 3-6 membered saturated or partially unsaturated ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, and C1-C4 alkyl; n is selected from 0, 1, 2, 3 or 4; Preferably, R c Each R is independently selected from hydrogen, deuterium, fluorine, hydroxyl, oxo, methyl, ethyl, methoxy, ethoxy, deuterated methyl, difluoromethyl, trifluoromethyl, deuterated methoxy, or two R attached to the same carbon atom c Together with the carbon atoms to which they are attached, they form cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; n is selected from 0, 1, 2, 3 or 4.

9. A compound according to any one of claims 1 to 8, 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, in for Preferably, for and / or R a is selected from hydrogen, halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C4 alkyl)2, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, 5-6 membered heteroaryl, phenyl; the C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C4 alkyl)2, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, 5-6 membered heteroaryl, phenyl; (C1-C6 alkyl) 2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C4 alkyl) 2, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, 5-6 membered heteroaryl, phenyl are optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl; the 5-6 membered heteroaryl contains 1, 2 or 3 N atoms, or contains 1 or 2 N atoms and 1 or 2 atoms selected from O, S; and / or R c Each is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2; the C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 are optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, C1-C6 alkyl; Preferably, for 10. The compound according to any one of claims 1 to 9, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in the structure of formula (II) or formula (III): in, represents a 5-membered heteroaryl group, Y1 and Y5 are each independently C, N, Y2, Y3, and Y4 are each independently N, NH, O, S, or CH; and Y1, Y2, Y3, Y4, and Y5 are connected Each independently represents a single bond or a double bond; two are not double bonds at the same time; when Y2, Y3, Y4 are O, S or NH, the is a single bond; Among them, X2, X3, X4, R 1 、R x 、R a 、R b 、R c , m, n are as defined in any one of claims 1-9.

11. The compound according to claim 10 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of formula (II-1), (II-2), (III-1) and (III-2): in, Y1, Y2, Y3, Y4, Y5, X2, X3, X4, R 1 、R x 、R a 、R b 、R c , m, n are as defined in any one of claims 1-9.

12. The compound according to claim 11 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of formula (II-1-1), (II-1-2), (II-1-3), (II-2-1), (II-2-2) and (II-2-3): in, Y1, Y2, Y3, Y4, Y5, X2, X3, X4, R 1 、R a 、R b 、R c , m, n are as defined in any one of claims 1-9.

13. The compound according to claim 12 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the following structures: (II-1-1'), (II-1-2'), (II-1-3'), (II-2-1'), (II-2-2'), (II-2-3'): in, Y1, Y2, Y3, Y4, Y5, X2, X3, X4, R 1 、R a 、R c As defined in any one of claims 1 to 9.

14. The compound according to claim 13 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the following structures: (II-1-1"), (II-1-2"), (II-1-3"), (II-2-1"), (II-2-2"), (II-2-3"): in, Y1, Y2, Y3, Y4, Y5, X2, X3, X4, R 1a 、R a 、R c As defined in any one of claims 1 to 9.

15. A compound according to any one of claims 1 to 9, 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, as represented by any one of the structures of formula (IV-1), (IV-2), (V-1), (V-2), (VI-1) or (VI-2): in, X 1、 X2, X3, X4, R 1 、R 2 、R a 、R b 、R c , m, n are as defined in any one of claims 1-9.

16. The compound according to claim 15 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of formula (IV-1-1), (IV-1-2), (IV-2-1), (IV-2-2), (V-1-1), (V-1-2), (V-2-1), (V-2-2), (VI-1-1), (VI-1-2), (VI-2-1) or (VI-2-2): in, X2, X3, X4, R 1 、R 2 、R a 、R b 、R c , m, n are as defined in any one of claims 1-9.

17. The compound according to claim 16 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the following structures: (IV-1-1'), (IV-1-2'), (IV-2-1'), (IV-2-2'), (V-1-1'), (V-1-2'), (V-2-1'), (V-2-2'), (VI-1-1'), (VI-1-2'), (VI-2-1') or (VI-2-2'): in, X2, X3, X4, R 1a 、R 2 、R a 、R c As defined in any one of claims 1 to 9.

18. The compound according to any one of claims 1 to 17, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: The compound is selected from the group consisting of the following compounds:

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable diluent or carrier.

20. A method for treating a condition treatable with a KIF18A inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 19.

21. The method of claim 20, wherein the condition is a cancer selected from the group consisting of: (a) a solid tumor or a hematogenic tumor selected from the group consisting of bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, and leukemia. (c) a hematopoietic neoplasm of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, a xeroderma pigmentosum, a keratoacanthoma, a follicular thyroid carcinoma, or a Kaposi's sarcoma.

22. A method of reducing the size of a solid tumor in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, or a composition according to claim 19.

23. A method of treating a cell proliferative disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt, or prodrug thereof, or a composition according to claim 19.

24. A method of inhibiting KIF18A in a cell, the method comprising contacting the cell with a compound according to any one of claims 1 to 18, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 19.

25. Use of a compound according to any one of claims 1 to 18 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, N-oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, or a composition according to claim 19 in the preparation of a medicament for treating a condition treatable with a KIF18A inhibitor.

26. The method of claim 25, wherein the disease is a cancer selected from the group consisting of: (a) a solid tumor or a hematogenic tumor selected from the group consisting of bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, and leukemia. (c) a hematopoietic neoplasm of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, a xeroderma pigmentosum, a keratoacanthoma, a follicular thyroid carcinoma, or a Kaposi's sarcoma.

27. Use of a compound according to any one of claims 1 to 18, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 19, in the preparation of a medicament for reducing the size of a solid tumor in a subject.

28. Use of a compound according to any one of claims 1 to 18, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound, N-oxide, solvate, hydrate, crystalline form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, or the composition according to claim 19, in the preparation of a medicament for treating a cell proliferative disorder in a subject.

29. Use of a compound according to any one of claims 1 to 18 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, or the composition according to claim 19 in the preparation of a medicament for inhibiting KIF18A in a cell.

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