Kif18a inhibitors and uses thereof

Abstract

The present application relates to the technical field of medicine, in particular to KIF18A inhibitor compound, pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof, pharmaceutical composition and preparation containing the compound, pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof, method for preparing the compound, pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof, and use of the compound, pharmaceutically acceptable salt, ester, deuterium or stereoisomer thereof in preparation of drugs for treating and / or preventing diseases mediated by KIF18A and related diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to KIF18A inhibitors, pharmaceutically acceptable salts, esters, deuterated compounds or stereoisomers thereof, pharmaceutical compositions and formulations containing said compounds, pharmaceutically acceptable salts, esters, deuterated compounds or stereoisomers thereof, methods for preparing said compounds, pharmaceutically acceptable salts, esters, deuterated compounds or stereoisomers thereof, and the use of said compounds, pharmaceutically acceptable salts, esters, deuterated compounds or stereoisomers thereof in the preparation of medicaments for treating and / or preventing KIF18A-mediated diseases and related diseases. Background Technology

[0002] Kinesin molecules are motor proteins that use microtubules as their orbital pathways, playing crucial roles in organelle migration, tissue and organ development, signal transduction, mitosis, and meiosis. Various microtubule-associated proteins (MAPs) of the kinesin-8 family regulate microtubule dynamic instability by influencing microtubule polymerization and depolymerization. The kinesin family has been reported to be closely associated with the invasion, metastasis, and poor prognosis of various cancers. An increasing number of kinesin family members are believed to be involved in tumorigenesis and progression. KIF18A, a member of the kinesin-8 family, is a multifunctional protein that utilizes adenosine triphosphate (ATP) hydrolysis to generate force and move along microtubules. It participates in various cellular functions, including cell division, cell motility, microtubule dynamics, and organelle transport. KIF18A affects cell differentiation and cancer development. Previous studies have shown that KIF18A is associated with tumor behavior and could be used as a potential biomarker for breast cancer, colorectal cancer, and hepatocellular carcinoma.

[0003] Genetic instability is a common characteristic of tumor cells, with a large number of tumor cells exhibiting frequent loss or gain of chromosomes. This chromosomal instability (CIN) is primarily due to defects leading to abnormal interactions between chromosomes and microtubules in the mitotic spindle, thereby increasing chromosome segregation errors. Compared to chromosome-stable cells, CIN cells show increased microtubule aggregation and reduced attachment turnover between microtubules and kinetochores, specialized protein structures assembled in the centromere region of mitotic chromosomes. Therefore, CIN cells may be particularly vulnerable to antimitotic therapies targeting the microtubule cytoskeleton.

[0004] The altered microtubule dynamics in mitotic CIN cells make them particularly dependent on KIF18A to reduce kinetochore-microtubule turnover and limit microtubule growth. In the absence of KIF18A activity, centrosome breakage occurs, and mitotic progress is slowed or stopped. KIF18A is largely dispensable for the proliferation of diploid somatic cells in vivo, but is essential for the proliferation of CIN tumor cells. Inhibition of KIF18A resulted in delayed mitosis, increased multipolar spindle formation, and cell death in CIN tumor cells. Therefore, KIF18A may be an effective target for specifically inhibiting the growth of CIN tumor cells, while exhibiting relatively low toxicity in somatic and diploid cells.

[0005] In conclusion, developing inhibitors targeting KIF18A will provide new ideas and strategies for the treatment of different types of tumors. Summary of the Invention

[0006] The purpose of this invention is to provide a KIF18A inhibitor and its application. The specific technical solution is as follows:

[0007] In some embodiments, the present invention first provides compounds of general formula (I), pharmaceutically acceptable salts, esters, deuterated derivatives thereof, or stereoisomers thereof:

[0008]

[0009] in,

[0010] X1 and X3 are independently selected from N or CR. a ;

[0011] X2 is selected from C(O), S(O)2, S(O), O, S, NR c or CR a R b ;

[0012] X5 is selected from N or CR a ;

[0013] X8 is selected from C(O), O, NR c2 or CR a2 R b2 ;

[0014] X9 is selected from C(O), O, NR c3 or CR a3 R b3 ;

[0015] X 10 Selected from C(O), O, NR c4 or CR a4 R b4 ;

[0016] X 11 Selected from C(O), O, NR c5 or CR a5 R b5 ;

[0017] X6 is selected from C(O), O, NR c6 or CR a6 R b6 ;

[0018] X7 is selected from C(O), O, NR c7 or CR a7 R b7 ;

[0019] X4 is selected from N or CR a8 ;

[0020] R 1 R 2 R 3 R 4 R 5 Each time it appears, it is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH2, -S(O)2-NH2, and -(L1) optionally substituted by one or more substituents Q1. q -C 1-6 Alkyl group, -(L1) q -C 2-6 Alkenyl, -(L1) q -C 2-6 Alkyne group, -(L1) q -C 1-6 Alkoxy, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl group, -(L1) q -3-12 membered cycloalkyl, -(L1) q -3-12-membered heterocyclic group, -(L1) q -6-10 aryl, -(L1) q -5-12 heteroaryl groups, -(L1) q -5-12 spirocyclic group, -(L1) q -5-12 spirocyclic groups, -(L1) q -5-12 Yuan Bridge Ring Foundation, -(L1) q -5-12-element bridged heterocyclic base;

[0021] L and L1 are each independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, and -NR, respectively. c1 -、-CR a1 R b1 -;

[0022] R a R a1 R a2 R a3 R a4 R a5 R a6 R a7 R b R b1 R b2 R b3 R b4 R b5 R b6 R b7 Each time it appears, it is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, and optionally from the C group that has been deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylaminoyl, C 1-6 Alkyl amide, C 1-6 Alkylsulfonamide, C 1-6 alkylaminosulfonyl, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, 6-10 aryl, 5-12 heteroaryl, 3-8 cycloalkyl or -3-8 heterocyclic;

[0023] Or, R a2 With R b2 R a3 With R b3 R a4 With R b4 Or R a5 With R b5 Together with the carbon atom to which it is attached, it forms a 3-8 membered cycloalkyl or a 3-8 membered heterocyclic group, wherein the 3-8 membered cycloalkyl or the 3-8 membered heterocyclic group is optionally substituted by one or more Q2 groups;

[0024] Q1 and Q2 are each independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, and C, respectively. 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino, -C(O)-NH2,C 1-6 Alkyl carbonyl, C 1-6 Alkyloxycarbonyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonamide, optionally substituted with 1-4 substituents p1, of which are 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclic, or 5-12 membered heterocyclic, wherein the substituents p1 are independently selected from halogen, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0025] R a8 Selected from deuterium, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, with C atoms optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylaminoyl, C 1-6 Alkyl amide, C 1-6 Alkylsulfonamide, C 1-6 alkylaminosulfonyl, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl group, -(L1) q -3-12 membered cycloalkyl, -(L1) q -3-12-membered heterocyclic group, wherein -(L1) q -3-12 membered cycloalkyl, -(L1) q -3-12-membered heterocyclic groups can be optionally replaced by halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkyl or halogenated C 1-6 Alkyl substitution;

[0026] R c R c1 R c2 R c3 R c4 R c5 R c6 R c7 Each time it appears, it is independently selected from deuterium, hydrogen, and optionally from C atoms that have been deuterated. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -C(O)-C 1-6 alkyl;

[0027] Each occurrence of m, n, and q is an independent integer between 0 and 6;

[0028] n1 and n2 are independent integers from 0 to 4.

[0029] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives, or stereoisomers thereof, wherein each R 1 R 2 R 3 R 4 R 5 The group is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH2, -S(O)2-NH2, and -(L1) optionally substituted with 1-4 substituents Q1. q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl group, -(L1) q -3-10 membered cycloalkyl groups, -(L1) q -3-10 heterocyclic group, -(L1) q -6-10 aryl, -(L1) q -5-10 grade heteroaryl, -(L1) q -5-11 spirocyclic group, -(L1) q-5-11 spirocyclic group.

[0030] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 R 5 Each group is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group, optionally substituted with 1-4 substituents Q1, -(L1) q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, -(L1) q -3-10 membered cycloalkyl groups, -(L1) q -3-10 heterocyclic group, -(L1) q -6-10 aryl, -(L1) q -5-10 grade heteroaryl, -(L1) q -5-11 spirocyclic group, -(L1) q -5-11 spirocyclic group.

[0031] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 R 5 Each group is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group, optionally substituted with 1-4 substituents Q1, -(L1) q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, -(L1) q -5-10 membered cycloalkyl groups, -(L1) q -5-10 heterocyclic groups, -(L1) q -7-11 spirocyclic group, -(L1) q -7-11 spirocyclic group.

[0032] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 R 5Each group is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, C1 optionally substituted with 1-4 substituents. 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered cycloalkyl, 5-10 membered heterocyclic, 7-11 membered spirocyclic, 7-11 membered spiroheterocyclic.

[0033] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 R 5 Each group is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, optionally substituted with 1-3 substituents Q1, 5-6 membered heterocyclic group, 7-10 membered spirocyclic group.

[0034] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 R 5 Each group is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, optionally substituted with 1-3 substituents Q1, 5-6 member nitrogen-containing heterocyclic group, 7-9 member nitrogen-containing spirocyclic group.

[0035] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 Selected from 8-membered nitrogen-containing spiroheterocyclic groups, optionally substituted with 1-3 substituents Q1; R 5 Selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0036] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 R 5Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy groups, optionally substituted with 1-3 substituents Q1, have the following structures:

[0037]

[0038] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 Selected from -(L1) substituted with 1-4 substituents Q1. q -3-10 membered cycloalkyl groups, -(L1) q -3-10 heterocyclic group, -(L1) q -6-10 aryl, -(L1) q -5-10 grade heteroaryl, -(L1) q -5-11 spirocyclic group, -(L1) q -5-11 spirocyclic group;

[0039] R 5 Selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group, optionally substituted with 1-4 substituents Q1, -(L1) q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, -(L1) q -3-10 membered cycloalkyl groups, -(L1) q -3-10 heterocyclic group, -(L1) q -6-10 aryl, -(L1) q -5-10 grade heteroaryl, -(L1) q -5-11 spirocyclic group, -(L1) q -5-11 spirocyclic group.

[0040] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 Selected from -(L1) substituted with 1-4 substituents Q1. q -5-10 membered cycloalkyl groups, -(L1) q -5-10 heterocyclic groups, -(L1)q -7-11 spirocyclic group, -(L1) q -7-11 spiroheterocyclic group;

[0041] R 5 Selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group, optionally substituted with 1-4 substituents Q1, -(L1) q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, -(L1) q -5-10 membered cycloalkyl groups, -(L1) q -5-10 heterocyclic groups, -(L1) q -7-11 spirocyclic group, -(L1) q -7-11 spirocyclic group.

[0042] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 Selected from 5-6 membered heterocyclic groups and 7-10 membered spirocyclic groups, optionally substituted with 1-3 substituents Q1; R 5 Selected from hydrogen, halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0043] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 Selected from 5-6 member nitrogen-containing heterocyclic groups and 7-9 member nitrogen-containing spirocyclic groups, substituted with 1-3 substituents Q1; R 5 Selected from hydrogen, halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0044] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 2 Selected from 5-6 membered heterocyclic groups and 7-10 membered spirocyclic groups, which are optionally substituted with 1-3 substituents Q1.

[0045] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 5 Selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl.

[0046] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 1 R 4 The -(L1) group is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, cyano, and optionally substituted with 1 to 4 substituents Q1. q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 alkyl.

[0047] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 1 R 4 Each element is independently selected from deuterium, hydrogen, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0048] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 1 R 4 Each of the following is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0049] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein each L and each L1 are independently selected from -C(O)-, -S(O)-, -S(O)2-, -N(R ... c1 )-、-CR a1 R b1 -

[0050] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein each L and each L1 are independently selected from -C(O)-, -S(O)2-, and -N(R)-. c1 )-.

[0051] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein -(L) n -Selected from -N(R) c1 C(O)- or -C(O)N(R) c1 )-.

[0052] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein -(L1) q -Selected from -N(R) c1 )C(O)-、-C(O)N(R c1 )-、-N(R c1 S(O)2-、-S(O)2N(R) c1 -, -S(O)2-, -S(O)N(R) c1 -, -C(O)-, -N(R) c1 )-.

[0053] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein -(L1) q -Selected from -N(R) c1 S(O)2-、-S(O)2N(R) c1 )-、-S(O)2-.

[0054] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 3 Selected from -(L1) substituted with 1-4 substituents Q1. q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, -(L1) q-3-12 membered cycloalkyl, -(L1) q -3-12-membered heterocyclic group, -(L1) q -6-10 aryl, -(L1) q -5-12 membered heteroaryl.

[0055] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 3 Selected from -(L1) cells substituted with 1-3 substituents Q1. q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, -(L1) q -3-6 membered cycloalkyl groups, -(L1) q -3-6-membered heterocyclic group.

[0056] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 3 Selected from -C(O)N(R) groups substituted with 1-4 substituents Q1. c1 )2、-N(R c1 S(O)2-C 1-6 Alkyl, -N(R) c1 S(O)2-3-6-membered cycloalkyl, -N(R c1 S(O)2-3-6-membered heterocyclic group, -S(O)2N(R) c1 )-C 1-6 Alkyl group, -S(O)2N(R) c1 -3-6 membered cycloalkyl, -S(O)2N(R c1 -3-6-membered heterocyclic group, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic, -S(O)N(R c1 )-C 1-6 Alkyl, -S(O)N(R) c1 -3-6 membered cycloalkyl, -S(O)N(R c1 -3-6-membered heterocyclic groups, -N(R) c1 )C(O)-C 1-6 Alkyl, -N(R) c1 )C(O)-3-6 membered cycloalkyl, -N(R c1 )C(O)-3-6-membered heterocyclic group, -C(O)N(R c1 )-C 1-6 Alkyl, -C(O)N(R) c1 -3-6 membered cycloalkyl, -C(O)N(R)c1 -3-6 heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocyclic, -N(R c1 )-C 1-6 alkyl.

[0057] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 3 Selected from -C(O)N(R) groups substituted with 1-4 substituents Q1. c1 )2、-N(R c1 S(O)2-C 1-6 Alkyl, -N(R) c1 S(O)2-3-6-membered cycloalkyl, -N(R c1 S(O)2-3-6-membered heterocyclic group, -S(O)2N(R) c1 )-C 1-6 Alkyl group, -S(O)2N(R) c1 -3-6 membered cycloalkyl, -S(O)2N(R c1 -3-6-membered heterocyclic group, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic, -S(O)N(R c1 )-C 1-6 Alkyl, -S(O)N(R) c1 -3-6 membered cycloalkyl, -S(O)N(R c1 -3-6-membered heterocyclic groups, -N(R) c1 )-C 1-6 alkyl.

[0058] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 3 Selected from -N(R) groups substituted with 1-3 substituents Q1. c1 S(O)2-C 1-6 Alkyl, -N(R) c1 S(O)2-3-6-membered cycloalkyl, -N(R c1 S(O)2-3-6-membered heterocyclic group, -S(O)2N(R) c1 )-C 1-6 Alkyl group, -S(O)2N(R) c1 -3-6 membered cycloalkyl, -S(O)2N(R c1 -3-6-membered heterocyclic group, -S(O)2-C 1-6Alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic, -S(O)N(R c1 )-C 1-6 Alkyl, -N(R) c1 )-C 1-6 alkyl.

[0059] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 3 Selected from -N(R) groups substituted with 1-3 substituents Q1. c1 S(O)2-C 1-6 Alkyl, -N(R) c1 S(O)2-3-6-membered cycloalkyl, -S(O)2N(R c1 )-C 1-6 Alkyl group, -S(O)2N(R) c1 -3-6 membered cycloalkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -N(R c1 )-C 1-6 alkyl.

[0060] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 3 Selected from -N(H)S(O)2-C, which are optionally substituted with 1-3 substituents Q1. 1-4 Alkyl, -N(H)S(O)2-3-6 membered cycloalkyl, -S(O)2N(H)-C 1-4 Alkyl, -S(O)2N(H)-3-6 membered cycloalkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-3-6 membered cycloalkyl, -N(H)-C 1-4 alkyl.

[0061] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 3 Selected from the following structures:

[0062]

[0063] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R 3 Selected from the following structures:

[0064]

[0065] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a R a1 R a2 R a3 R a4 R a5 R a6 R a7 R b R b1 R b2 R b3 R b4 R b5 R b6 R b7 Each time it appears, it is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, and optionally from the C group that has been deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0066] Or, R a2 With R b2 R a3 With R b3 R a4 With R b4 Or R a5 With R b5 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl or a 3-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl or the 3-6 membered heterocyclic group is optionally substituted with 1-3 Q2 atoms.

[0067] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a R a1 R a2 R a3 R a4 R a5 R a6 R a7 R b R b1 R b2 R b3 R b4 Rb5 R b6 R b7 Each time it appears, it is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, and optionally from the C group that has been deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0068] Or, R a2 With R b2 R a3 With R b3 R a4 With R b4 Or R a5 With R b5 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl or a 3-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl or the 3-6 membered heterocyclic group is optionally substituted with 1-3 Q2 atoms.

[0069] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a R a1 R a2 R a3 R a4 R a5 R a6 R a7 R b R b1 R b2 R b3 R b4 R b5 R b6 R b7 Each time it appears, it is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, and optionally from the C group that has been deuterated. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C) 1-4 alkyl)amino, -C(O)-C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy;

[0070] Or, R a2 With R b2 R a3 With R b3 Ra4 With R b4 Or R a5 With R b5 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl or a 3-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl or the 3-6 membered heterocyclic group is optionally substituted with 1-3 Q2 atoms.

[0071] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a R a1 R a2 R a3 R a4 R a5 R a6 R a7 R b R b1 R b2 R b3 R b4 R b5 R b6 R b7 Each time it appears, it is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, formyl, acetyl;

[0072] Or, R a2 With R b2 R a3 With R b3 R a4 With R b4 Or R a5 With R b5 Together with the carbon atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazineyl groups, which are optionally substituted with 1 to 3 Q2 atoms.

[0073] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a R a1 R a2 R a3 R a4 R a5 Ra6 R a7 Each R b Each R b1 R b2 R b3 R b4 R b5 R b6 R b7 Each time it appears, it is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, formyl, acetyl.

[0074] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a R a1 R a2 R a3 R a4 R a5 R a6 R a7 R b R b1 R b2 R b3 R b4 R b5 R b6 R b7 Each time it appears, it is independently selected from deuterium, hydrogen, halogen, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl group. In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated form, or its stereoisomer, wherein R c R c1 R c2 R c3 R c4 R c5 R c6 R c7 Each time it appears, it is independently selected from deuterium, hydrogen, and optionally from C atoms that have been deuterated. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -C(O)-C1-6 alkyl.

[0075] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R c R c1 R c2 R c3 R c4 R c5 R c6 R c7 Each time it appears, it is independently selected from deuterium, hydrogen, and optionally from C atoms that have been deuterated. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, -C(O)-C 1-4 alkyl.

[0076] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R c R c1 R c2 R c3 R c4 R c5 R c6 R c7 Each time it appears, it is independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, formyl, acetyl.

[0077] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a8 Selected from deuterium, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, with C atoms optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -(L1) q -3-8 membered cycloalkyl groups, -(L1) q -3-8 membered heterocyclic group, wherein -(L1)q -3-8 membered cycloalkyl groups, -(L1) q -3-8 membered heterocyclic groups can be halogenated, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkyl-substituted.

[0078] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a8 Selected from deuterium, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, with C atoms optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -(L1) q -3-6 membered cycloalkyl groups, -(L1) q -3-6-membered heterocyclic group, wherein -(L1) q -3-6 membered cycloalkyl groups, -(L1) q -3-6 membered heterocyclic groups can be optionally replaced by halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkyl-substituted.

[0079] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a8 Selected from deuterium, chlorine, bromine, iodine, and optionally deuterated C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -(L1) q -3-6 membered cycloalkyl groups, -(L1) q -3-6-membered heterocyclic group.

[0080] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a8 Selected from deuterium, chlorine, bromine, iodine, and optionally deuterated C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group.

[0081] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a8 Selected from deuterium, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, oxaziridine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl.

[0082] In some embodiments, the compound, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer as described above, wherein m, n, n1, n2, q are each independently an integer from 0 to 4 each time they appear.

[0083] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives or their stereoisomers, wherein each m, n, n1, n2, q is independently 0, 1, 2, 3, 4 each time it appears.

[0084] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein at least one of X1, X2, X3, X4, X5 is N.

[0085] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein X1, X3, and X4 are each independently selected from CR a .

[0086] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein X1, X3 and X4 are independently selected from CH or N.

[0087] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein X2 is selected from C(O), NR c or CR a R b .

[0088] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein X2 is selected from C(O), NH or CH2.

[0089] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or stereoisomer thereof, wherein X2 is selected from C(O).

[0090] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated form or its stereoisomer, wherein X5 is selected from N or CH.

[0091] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein,

[0092] X8 is selected from O and NR. c2 or CR a2 R b2 ;

[0093] X9 is selected from O and NR. c3 or CR a3 R b3 ;

[0094] X 10 Selected from O, NR c4 or CR a4 R b4 ;

[0095] X 11 Selected from O, NR c5 or CR a5 R b5 ;

[0096] X6 is selected from C(O), NR c6 or CR a6 R b6 ;

[0097] X7 is selected from C(O), NR c7 or CR a7 R b7 ;

[0098] R a2 R b2 R a3 R b3 R a4 R b4 R a5 R b5 R a6 R b6 R a7 R b7 R c2 R c3 R c4 R c5 R c6 Rc7 The definition is as described in any of the aforementioned technical solutions.

[0099] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a6 R b6 R a7 R b7 The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl.

[0100] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a6 R b6 R a7 R b7 The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0101] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a6 R b6 R a7 R b7 The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C) 1-4 alkyl)amino, -C(O)-C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkyl group.

[0102] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a6 R b6 R a7 R b7 Each group is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, formyl, and acetyl.

[0103] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a6 R b6 R a7 R b7 Each of the following is independently selected from deuterium, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, formyl, and acetyl.

[0104] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R a6 R b6 R a7 R b7 Each element is independently selected from deuterium, hydrogen, halogens, and carbon. 1-6 Alkyl, deuterated C 1-6 alkyl.

[0105] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R c2 R c3 R c4 R c5 R c6 R c7 The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -C(O)-C 1-6 alkyl.

[0106] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R c2 R c3 R c4 R c5 R c6 R c7 The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, -C(O)-C 1-4 alkyl.

[0107] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein R c2 R c3 R c4 R c5 R c6 R c7 Each of the following groups is independently selected from deuterium, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, formyl, and acetyl.

[0108] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein Q1 and Q2, each time appearing, are independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino.

[0109] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product or its stereoisomer, wherein Q1 and Q2 are each independently selected from deuterium, halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 alkyl.

[0110] In some embodiments, the compounds shown in the foregoing scheme, their pharmaceutically acceptable salts, their esters, deuterated derivatives or stereoisomers thereof, wherein Q1 and Q2, each time appearing, are independently selected from deuterium, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl.

[0111] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein,

[0112] X1 and X3 are independently selected from N or CR. a ;

[0113] X2 is selected from C(O), NR c or CR a R b ;

[0114] X5 is selected from N or CR a ;

[0115] X8 is selected from C(O), O, NR c2 or CR a2 R b2 ;

[0116] X9 is selected from C(O), O, NR c3 or CR a3 R b3 ;

[0117] X 10 Selected from C(O), O, NR c4 or CR a4 R b4 ;

[0118] X 11 Selected from C(O), O, NR c5 or CRa5 R b5 ;

[0119] X6 is selected from C(O), O, NR c6 or CR a6 R b6 ;

[0120] X7 is selected from C(O), O, NR c7 or CR a7 R b7 ;

[0121] X4 is selected from N or CR a8 ;

[0122] R 1 R 4 Each occurrence is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, cyano, and optionally substituted with 1-4 substituents Q1 -(L1). q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 alkyl;

[0123] R 2 R 5 The -(L1) group is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and optionally substituted with 1 to 4 substituents Q1. q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, -(L1) q -3-10 membered cycloalkyl groups, -(L1) q -3-10 heterocyclic group, -(L1) q -6-10 aryl, -(L1) q -5-10 grade heteroaryl, -(L1) q -5-11 spirocyclic group, -(L1) q -5-11 spirocyclic group;

[0124] R 3 Selected from -C(O)N(R) groups substituted with 1-4 substituents Q1. c1 )2、-N(R c1 S(O)2-C 1-6 Alkyl, -N(R) c1 S(O)2-3-6-membered cycloalkyl, -N(Rc1 S(O)2-3-6-membered heterocyclic group, -S(O)2N(R) c1 )-C 1-6 Alkyl group, -S(O)2N(R) c1 -3-6 membered cycloalkyl, -S(O)2N(R c1 -3-6-membered heterocyclic group, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic, -S(O)N(R c1 )-C 1-6 Alkyl, -S(O)N(R) c1 -3-6 membered cycloalkyl, -S(O)N(R c1 -3-6-membered heterocyclic groups, -N(R) c1 )C(O)-C 1-6 Alkyl, -N(R) c1 )C(O)-3-6 membered cycloalkyl, -N(R c1 )C(O)-3-6-membered heterocyclic group, -C(O)N(R c1 )-C 1-6 Alkyl, -C(O)N(R) c1 -3-6 membered cycloalkyl, -C(O)N(R) c1 -3-6 heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocyclic, -N(R c1 )-C 1-6 alkyl;

[0125] L and L1 are each independently selected from -C(O)-, -S(O)-, -S(O)2-, and -NR, respectively. c1 -、-CR a1 R b1 -;

[0126] R a R a1 R a2 R a3 R a4 R a5 R a6 R a7 R b R b1 R b2 R b3 R b4 R b5 R b6 R b7 Each time it appears, it is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, and optionally from the C group that has been deuterated.1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0127] Or, R a2 With R b2 R a3 With R b3 R a4 With R b4 Or R a5 With R b5 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl or a 3-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl or the 3-6 membered heterocyclic group is optionally substituted by 1-3 Q2 atoms;

[0128] R a8 Selected from deuterium, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, with C atoms optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -(L1) q -3-8 membered cycloalkyl groups, -(L1) q -3-8 membered heterocyclic group, wherein -(L1) q -3-8 membered cycloalkyl groups, -(L1) q -3-8 membered heterocyclic groups can be halogenated, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution;

[0129] R c R c1 R c2 R c3 R c4 R c5 R c6 R c7 Each time it appears, it is independently selected from deuterium, hydrogen, and optionally from C atoms that have been deuterated. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkyl, Halogenated C 1-6 Alkoxy group, -C(O)-C 1-6 alkyl;

[0130] Q1 and Q2 are each independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino;

[0131] Each occurrence of m, n, n1, n2, and q is an independent integer between 0 and 4.

[0132] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer has the structure shown in formula (II).

[0133]

[0134] Each R 1 R 2 R 3 R 4 R 5 R a8 R c7 X1, X3, X8, X9, X 10 X 11 The definitions of m and n2 are as described in any of the aforementioned technical solutions.

[0135] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer has the structure shown in formula (II).

[0136] Among them, X8 is selected from O and NR. c2 or CR a2 R b2 ;

[0137] X9 is selected from O and NR. c3 or CR a3 R b3 ;

[0138] X 10 Selected from O, NR c4 or CR a4 R b4 ;

[0139] X 11 Selected from O, NR c5 or CR a5 R b5 ;

[0140] R a1 R a2 R b1 R b2 R a3 R b3 R a4 R b4 R a5 R b5 The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0141] Or, R a2 With R b2 R a3 With R b3 R a4 With R b4 Or R a5 With R b5 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl or a 3-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl or the 3-6 membered heterocyclic group is optionally substituted by one or more Q2 groups;

[0142] R 2 R 5 Each group is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group, optionally substituted with 1-4 substituents Q1, -(L1) q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, -(L1) q -5-10 membered cycloalkyl groups, -(L1) q -5-10 heterocyclic groups, -(L1)q -7-11 spirocyclic group, -(L1) q -7-11 spiroheterocyclic group;

[0143] L and L1 are each independently selected from -C(O)-, -S(O)2-, and -N(R)-, respectively. c1 )-、-CR a1 R b1 ;

[0144] R 3 Selected from -N(R) groups substituted with 1-3 substituents Q1. c1 S(O)2-C 1-6 Alkyl, -N(R) c1 S(O)2-3-6-membered cycloalkyl, -N(R c1 S(O)2-3-6-membered heterocyclic group, -S(O)2N(R) c1 )-C 1-6 Alkyl group, -S(O)2N(R) c1 -3-6 membered cycloalkyl, -S(O)2N(R c1 -3-6-membered heterocyclic group, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic, -S(O)N(R c1 )-C 1-6 Alkyl, -N(R) c1 )-C 1-6 alkyl;

[0145] R a8 Selected from deuterium, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, with C atoms optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -(L1) q -3-6 membered cycloalkyl groups, -(L1) q -3-6-membered heterocyclic group, wherein -(L1) q -3-6 membered cycloalkyl groups, -(L1) q -3-6 membered heterocyclic groups can be optionally replaced by halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution;

[0146] R c1 R c2 Rc3 R c4 R c5 R c7 The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -C(O)-C 1-6 alkyl;

[0147] Q1 and Q2 are each independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino; m, n2, and q are each independent integers from 0 to 3 each time they appear.

[0148] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated derivative, or its stereoisomer, has the structure shown in formula (III).

[0149]

[0150] Each R 1 R 2 R 3 R 4 R 5 R a8 R c7 X1, X3, X9, X 10 The definitions of m and n2 are as described in any of the aforementioned technical solutions.

[0151] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated derivative, or its stereoisomer, has the structure shown in formula (III).

[0152] Among them, X9 is selected from O and NR. c3 or CR a3 R b3 ;

[0153] X 10 Selected from O, NRc4 or CR a4 R b4 ;

[0154] R a3 R b3 R a4 R b4 The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0155] Or, R a3 With R b3 Or R a4 With R b4 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl or a 3-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl or the 3-6 membered heterocyclic group is optionally substituted by 1-3 Q2 atoms;

[0156] Each R 1 R 2 R 3 R 4 R 5 R a8 R c3 R c4 R c7 The definitions of each of Q2, X1, and X3 are as described in any of the aforementioned technical solutions.

[0157] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated derivative, or its stereoisomer has the structure shown in formula (III-1).

[0158]

[0159] Each R 1 R 3 R 4 R 5 R a8 R c3 R c4 R c7 m, n2, X1, X3, X9, X 10 The definition is as described in any of the aforementioned technical solutions.

[0160] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated derivative, or its stereoisomer, has the structure shown in formula (IV).

[0161] Each R 1 R 2 R 3 R 4 R 5 R a8 R c7 m, n2, X1, X3, X 10 The definition is as described in any of the aforementioned technical solutions.

[0162] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, its deuterated derivative, or its stereoisomer, has the structure shown in formula (IV-1).

[0163] Each R 1 R 3 R 4 R 5 R a8 R c7 m, n2, X1, X3, X 10 The definition is as described in any of the aforementioned technical solutions.

[0164] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein,

[0165] Selected from the following structures,

[0166]

[0167] Each R 1 R a R a8 R c7 The definitions of m are as described in any of the aforementioned technical solutions.

[0168] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated derivative, or its stereoisomer, has the structure shown in formula (V).

[0169] Each R 1 R 2 R 3 R 4 R 5 m, n2, R a8 Rc7 The definitions of X1 and X3 are as described in any of the aforementioned technical solutions.

[0170] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, has the structure shown in formula (V-1).

[0171] Each R 1 R 3 R 4 R 5 m, n2, R a8 R c7 Each R a The definition is as described in any of the aforementioned technical solutions.

[0172] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein,

[0173] R 2 Selected from the following structures, which are substituted by 1-3 substituents Q1:

[0174]

[0175] R 3 Selected from the following structures:

[0176]

[0177] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein,

[0178] R 2 R 5 Each group is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group, optionally substituted with 1-4 substituents Q1, -(L1) q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, -(L1) q -5-10 membered cycloalkyl groups, -(L1) q -5-10 heterocyclic groups, -(L1) q -7-11 spirocyclic group, -(L1) q -7-11 spiroheterocyclic group;

[0179] L and L1 are each independently selected from -C(O)-, -S(O)2-, and -N(R)-, respectively. c1 )-;

[0180] R 3 Selected from -N(R) groups substituted with 1-3 substituents Q1. c1 S(O)2-C 1-6 Alkyl, -N(R) c1 S(O)2-3-6-membered cycloalkyl, -N(R c1 S(O)2-3-6-membered heterocyclic group, -S(O)2N(R) c1 )-C 1-6 Alkyl group, -S(O)2N(R) c1 -3-6 membered cycloalkyl, -S(O)2N(R c1 -3-6-membered heterocyclic group, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic, -S(O)N(R c1 )-C 1-6 Alkyl, -N(R) c1 )-C 1-6 alkyl.

[0181] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein,

[0182] X1 and X3 are independently selected from N or CR. a ;

[0183] X2 is selected from C(O), NH or CH2;

[0184] X4 is selected from N or CR a8 ;

[0185] X6 is selected from C(O);

[0186] X7 was selected independently from NR c7 Or CH2;

[0187] X8 is selected from O, NH or CH2;

[0188] X9 is selected from O, NH or CH2;

[0189] X 10 Selected from O, NH or CH2;

[0190] X 11 Selected from O, NH or CH2;

[0191] Each R a Ra8 R c7 The definition is as described in any of the aforementioned technical solutions.

[0192] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, its ester, deuterated product, or its stereoisomer, wherein,

[0193] in, Selected from the following structures,

[0194]

[0195] R 2 Selected from the following structures, which are substituted by 1-3 substituents Q1:

[0196]

[0197]

[0198] R 3 Selected from the following structures:

[0199]

[0200] In some embodiments of the present invention, the structures of the provided compounds, their pharmaceutically acceptable salts, esters, deuterated derivatives, or stereoisomers thereof are shown below:

[0201]

[0202]

[0203] The present invention also provides a pharmaceutical composition comprising a compound represented by the foregoing general formula, a pharmaceutically acceptable salt, ester, deuterated form thereof or a stereoisomer thereof, and one or more second therapeutic agents, optionally, the pharmaceutical composition further comprising one or more pharmaceutical carriers and / or diluents.

[0204] The second therapeutic agent described in this invention includes, but is not limited to, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, antimetabolites, antimitotic agents, angiogenesis inhibitors, biological response modifiers, antihormonal agents, and anticancer drugs.

[0205] The present invention also provides a pharmaceutical formulation comprising a compound represented by the aforementioned general formula, a pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical formulation being any clinically or pharmaceutically acceptable dosage form.

[0206] In some embodiments of the present invention, the above-described pharmaceutical preparations can be administered to patients or subjects requiring such treatment via oral, parenteral, rectal, or pulmonary administration. For oral administration, the pharmaceutical composition can be formulated into oral preparations, such as conventional oral solid dosage forms like tablets, capsules, pills, granules, etc.; or into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When formulating oral preparations, suitable fillers, binders, disintegrants, lubricants, etc., can be added. For parenteral administration, the above-described pharmaceutical preparations can also be formulated into injectable preparations, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When formulating injectable preparations, conventional methods in the existing pharmaceutical field can be used. When preparing injectable preparations, excipients may not be added, or suitable excipients may be added depending on the properties of the drug. For rectal administration, the pharmaceutical composition can be formulated into suppositories, etc. For pulmonary administration, the pharmaceutical composition can be formulated into inhalers or sprays, etc.

[0207] The pharmaceutical carriers and / or diluents used in the pharmaceutical compositions or formulations of the present invention can be any conventional carriers and / or diluents in the field of pharmaceutical formulation. The selection of a specific carrier and / or diluent will depend on the route of administration or the type and state of disease for treating a particular patient. The preparation method of a suitable pharmaceutical composition for a specific route of administration is entirely within the knowledge of those skilled in the art of pharmaceuticals. For example, pharmaceutical carriers and / or diluents may include solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc., conventional in the pharmaceutical field. If necessary, flavoring agents, preservatives, and sweeteners, etc., may also be added to the pharmaceutical composition.

[0208] The present invention also provides the use of the compounds represented by the foregoing general formula, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, the foregoing pharmaceutical preparations or the foregoing pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of KIF18A-mediated diseases and related diseases; wherein the KIF18A-mediated diseases and related diseases are selected from cancer or benign tumors.

[0209] The present invention also provides the use of the compounds represented by the foregoing general formula, their pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, the foregoing pharmaceutical preparations or the foregoing pharmaceutical compositions in the treatment and / or prevention of KIF18A-mediated diseases and related diseases; wherein the KIF18A-mediated diseases and related diseases are selected from cancer or benign tumors.

[0210] The present invention also provides a method for treating a disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound represented by the aforementioned general formula, a pharmaceutically acceptable salt, ester, deuterated form thereof or a stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition, wherein the disease is a KIF18A-mediated disease or related disease; the KIF18A-mediated disease or related disease is selected from cancer or benign tumors.

[0211] The cancers or benign tumors mentioned include, but are not limited to, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, head and neck cancer, thyroid cancer, lung cancer, bronchial cancer, esophageal cancer, stomach cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, colon cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, bone cancer, and hematologic malignancies; the lung cancers mentioned include, but are not limited to, small cell lung cancer and non-small cell lung cancer; the hematologic malignancies mentioned include, but are not limited to, leukemia, lymphoma, and myeloma; the brain cancers mentioned include, but are not limited to, glioma, neuroblastoma, astrocytoma, and meningioma.

[0212] This application provides a method for preparing the above-mentioned compound, but is not limited to the following method. The reaction equations for the preparation method are as follows:

[0213]

[0214] Intermediate 1 and intermediate 2 were reacted to obtain the compound shown in formula (III);

[0215] G is a halogen; each R 1 R 2 R 3 R 4 R 5 m, n2, R a8 R c7 X3, X9, X 10 The definition is as described in any of the aforementioned schemes.

[0216] In some embodiments, the preparation method of formula (III) is as follows:

[0217] Intermediate 1 and intermediate 2 are dissolved in a suitable solvent (e.g., 1,4-dioxane), and a catalyst (e.g., tris(dibenzylacetone)dipalladium, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene)) and a basic reagent (e.g., NaH, potassium carbonate, cesium carbonate, sodium carbonate) are added. Under nitrogen protection, the mixture is heated to 80-120°C and reacted for 1-20 hours. The compound of formula (III) is obtained by a suitable method (e.g., silica gel column chromatography).

[0218] This application also provides an intermediate for preparing the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, deuterated product or stereoisomer thereof, having the following structure:

[0219]

[0220] G is a halogen; each R 1 m, n2, R a8 R c7 X3, X9, X 10 The definition is as described in any of the aforementioned technical solutions.

[0221] In the specification and claims of this application, compounds are named according to their chemical structural formulas. If the name of the compound and its chemical structural formula do not match when referring to the same compound, the chemical structural formula shall prevail.

[0222] In this application, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the invention, definitions of some terms are provided below. When the definitions and interpretations of terms provided in this application differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations provided in this application shall prevail.

[0223] The "halogen" mentioned in this invention refers to fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.

[0224] In this invention, "halogenation" means that any hydrogen in the substituent can be replaced by one or more identical or different halogens. "Halogen" is as defined above.

[0225] The "C" described in this invention 1-6 "Alkyl" refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, "C". 1-5 Alkyl", C 1-4 Alkyl", C 1-3 Alkyl", C 1-2 Alkyl", C 2-6 Alkyl", C 2-5 Alkyl", C 2-4 Alkyl", C 2-3 Alkyl", C 3-6 Alkyl", C 3-5 Alkyl", C 3-4 Alkyl", C 4-6 Alkyl", C 4-5 Alkyl", C 5-6Alkyl groups, etc., specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The "C" in this invention... 1-4 "alkyl" refers to C 1-6 Specific examples of alkyl groups containing 1-4 carbon atoms.

[0226] The "C" described in this invention 2-6 "Alkenyl" refers to a straight-chain, branched, or cyclic alkenyl group containing at least one double bond and having 2-6 carbon atoms, including, for example, "C". 2-5 "alkenyl", "C" 2-4 "alkenyl", "C" 2-3 "Alkenyl", etc., specific examples include but are not limited to: vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl -1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-1-butenyl, 2-ethyl-1-butenyl, 2-ethyl-3-butenyl, etc.

[0227] The "C" described in this invention 2-6 "Alkyne group" refers to a straight-chain or branched alkynyl group containing 2-6 carbon atoms with a triple bond, including, for example, "C". 2-5 "Alkyne", "C" 2-4 "Alkyne", "C" 2-3"Alynyl", etc., specific examples include but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, etc.

[0228] The “C” mentioned in this article 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylaminoyl, C 1-6 Alkyl amide, C 1-6 alkylsulfonyl, C 1-6 Alkylsulfonamide, C 1-6 Alkylaminosulfonyl, C 1-6 "alkyl carbonyl" refers to a group with C 1-6 Alkyl-O-, C 1-6 Alkyl-NH-, (C 1-6 Alkyl)2-N-, C 1-6 Alkyl-NH-C(O)-, C 1-6 Alkyl-C(O)-NH-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl-S(O)2-NH-, C 1-6 Alkyl-NH-S(O)2-, C 1-6 Alkyl-C(O)-- groups, wherein "C" is formed in the manner of alkyl-C(O)-- 1-6 The definition of "alkyl" is as described above.

[0229] The “C” mentioned in this article 1-4 Alkoxy, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 1-4 Alkylaminoyl, C 1-4 Alkyl amide, C 1-4 alkylsulfonyl, C 1-4 Alkylsulfonamide, C 1-4 Alkylaminosulfonyl, C 1-4 "alkyl carbonyl" refers to a group with C 1-4 Alkyl-O-, C 1-4 Alkyl-NH-, (C 1-4 Alkyl)2-N-, C 1-4 Alkyl-NH-C(O)-, C 1-4 Alkyl-C(O)-NH-, C 1-4 Alkyl-S(O)2-, C1-4 Alkyl-S(O)2-NH-, C 1-4 Alkyl-NH-S(O)2-, C 1-4 A group formed in the alkyl-C(O)- manner, wherein "C" 1-4 The definition of "alkyl" is as described above.

[0230] The "halogenated C" mentioned in this article 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, Halogenated C 1-6 "Alkoxy" refers to one or more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl, amino, and carboxyl groups that respectively replace C. 1-6 Alkyl, C 1-6 A group formed by the hydrogen atom in an alkoxy group.

[0231] The "halogenated C" mentioned in this article 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, Halogenated C 1-4 "Alkoxy" refers to one or more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl groups, and amino groups that have substituted C for C. 1-4 Alkyl, C 1-4 A group formed by the hydrogen atom in an alkoxy group.

[0232] The “3-12 membered cycloalkyl” mentioned in this invention refers to a saturated or partially saturated cycloalkyl group containing 3-12 carbon atoms that is not aromatic, including “monocycloalkyl” and “fused cycloalkyl”.

[0233] The term "monocyclic alkyl" as used in this invention refers to a saturated or partially saturated monocyclic cyclic alkyl group that is non-aromatic. It can be "3-10 membered cycloalkyl", "3-8 membered saturated cycloalkyl", "3-8 membered partially saturated cycloalkyl", "3-4 membered cycloalkyl", "3-5 membered cycloalkyl", "3-6 membered cycloalkyl", "3-7 membered cycloalkyl", "4-5 membered cycloalkyl", "4-6 membered cycloalkyl", "4-7 membered cycloalkyl", "4-8 membered cycloalkyl", "5-6 membered cycloalkyl", "5-7 membered cycloalkyl", "5-8 membered cycloalkyl", "6-7 membered cycloalkyl", "6-8 membered cycloalkyl", "7-8 membered cycloalkyl", "3-6 membered saturated cycloalkyl", "4-7 membered saturated cycloalkyl", "4-8 membered saturated cycloalkyl", "5-8 membered saturated cycloalkyl", "5-7 membered saturated cycloalkyl", "5-6 membered saturated cycloalkyl", "3-6 membered partially saturated cycloalkyl", or "4-7 membered partially saturated cycloalkyl". The terms "4-8 member partially saturated cycloalkyl", "5-8 member partially saturated cycloalkyl", "5-7 member partially saturated cycloalkyl", and "5-6 member partially saturated cycloalkyl" are used. Specific examples of "3-8 member partially saturated cycloalkyl" include, but are not limited to: cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), and cyclooctane (cyclooctyl), etc. Specific examples of "alkyl" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptenyl, cycloheptenyl-1,3-diene, cycloheptenyl-1,4-diene, cycloheptenyl-1,3,5-trienyl, cyclooctenyl, cyclooctyl-1,3-diene, cyclooctyl-1,4-diene, cyclooctyl-1,5-diene, cyclooctyl-1,3,5-trienyl, cyclooctatetraenyl, etc.

[0234] The "fused cyclic alkyl" as described in this invention refers to a saturated or partially saturated non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms. One ring in the fused ring may be an aromatic ring, but the fused ring as a whole does not possess aromaticity. Examples include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, octahydrocyclopentadienyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthrene, bicyclo[ [3.1.0] Hex-2-enyl, bicyclo[4.1.0] hept-3-enyl, bicyclo[3.2.0] hept-3-enyl, bicyclo[4.2.0] oct-3-enyl, 1,2,3,3a-tetrahydrocyclopentadienyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydronaphthyl, 1,2,3,4,5,6,8a-decahydrophenanthrene, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl, etc.

[0235] The "3-12 membered heterocyclic group" described in this invention refers to a saturated or partially saturated monocyclic or fused-ring group containing at least one heteroatom (e.g., 1, 2, 3, 4, or 5) of 3-12 ring atoms, and lacking aromaticity. The heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Optionally, the ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure can be substituted with oxygen. The "3-12 membered heterocyclic group" described in this invention includes "3-12 membered saturated heterocyclic groups" and "3-12 membered partially saturated heterocyclic groups." Preferably, the "3-12 membered heterocyclic group" described in this invention contains 1-3 heteroatoms; more preferably, the "3-12 membered heterocyclic group" described in this invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms. The “3-12 membered heterocyclic group” is preferably a “3-10 membered heterocyclic group”, a “3-8 membered heterocyclic group”, a “4-8 membered heterocyclic group”, a “3-6 membered heterocyclic group”, a “3-6 membered saturated heterocyclic group”, a “3-6 membered nitrogen-containing heterocyclic group”, a “3-6 membered saturated nitrogen-containing heterocyclic group”, a “4-6 membered heterocyclic group”, a “4-6 membered nitrogen-containing heterocyclic group”, a “5-6 membered heterocyclic group”, or a “5-6 membered saturated heterocyclic group”.Specific examples of “3-12 membered heterocyclic groups” include, but are not limited to: aziridine, 2H-aziridine, diaziridine, 3H-diazacyclopropenyl, aziridinebutyl, 1,4-dioxanehexyl, 1,3-dioxanehexyl, 1,3-dioxanepentyl, 1,4-dioxanehexadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrroleyl, pyrroleyl, imidazolyl, 4,5-dihydroimidazolyl, pyrazolyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, 2-piperidinoneyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisooxazolyl, 2,3-dihydroisooxazolyl, 2H- 1,2-Oxazinyl, 6H-1,3-Oxazinyl, 4H-1,3-Thiazinyl, 6H-1,3-Thiazinyl, 2H-Pyranyl, 2H-Pyran-2-one, 3,4-Dihydro-2H-Pyranyl, Pyrrolidinylcyclopropyl, Cyclopentylaziryl, Pyrrolidinylcyclobutyl, Pyrrolidinylpyrrylalkyl, Pyrrolidinylpiperidinyl, Pyrrolidinylpiperazinyl, Pyrrolidinylmorpholinyl, Piperidinylmorpholinyl, Benzopyrrolidinyl, Benzocyclopentyl, Benzocyclohexyl, Benzotetrahydrofuranyl, Benzopyrrolidinyl, Benzoimidazoalkyl, Benzooxazolidinyl, Benzothiazoalkyl, Benzoisooxazolidinyl, Benzoisothiazoalkyl, Benzopiperidinyl, Benzomorpholinyl, Benzopiperazinyl, Benzotetrahydropyranyl, Pyridinylcyclopentyl pyridocyclohexyl, pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridoimidazolyl, pyridooxazolyl, pyridothiazolyl, pyridoisooxazolyl, pyridoisothiazolyl, pyridopiperidinyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolyl, pyrimidooxazolyl, pyrimidoisothiazolyl, pyrimidopiperidinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidotetrahydropyranyl; tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalolinyl, benzo[d][1,3]pyridinyl Dioxacyclopentenyl, 2H-chromenyl, 2H-chromenyl-2-one, 4H-chromenyl, 4H-chromenyl-4-one, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furano[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H-furano[3,4-d]imidazolyl, 4,6-dihydro-1H- Thiophene[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d]imidazolyl, decahydroquinolinyl, hexahydrothieneno[imidazolyl, hexahydrofuran[imidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenten[c]pyrrolel, 4H-1,3-benzoxazinyl, etc.

[0236] The "6-10 aryl" mentioned in this invention refers to an aromatic cyclic group containing 6-10 cyclic carbon atoms, including "6-8 membered monocyclic aryl" and "8-10 membered fused-ring aryl". Examples include, but are not limited to, phenyl, cyclooctatetraenyl, naphthyl, etc.

[0237] The "5-12-membered heteroaryl" as described in this invention refers to an aromatic cyclic group containing 5-12 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom), including "mono-heteroaryl" and "fused heteroaryl". Optionally, the ring atom (e.g., a carbon atom, nitrogen atom, or sulfur atom) in the cyclic structure can be oxidized. For example, it can be a 5-12-membered nitrogen-containing heteroaryl, a 5-12-membered oxygen-containing heteroaryl, a 5-12-membered sulfur-containing heteroaryl, a 5-10-membered heteroaryl, a 5-8-membered heteroaryl, a 5-6-membered heteroaryl, a 5-6-membered nitrogen-containing heteroaryl, a 5-membered nitrogen-containing heteroaryl, an 8-10-membered fused heteroaryl, a 9-10-membered fused heteroaryl, an 8-9-membered fused heteroaryl, etc. Specific examples include, but are not limited to, furanyl, thiopheneyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazoleyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridoneyl, 4-pyridoneyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, and 1,2,4,5-tetraazinyl. Aza-heptatrienyl, 1,3-diaza-heptatrienyl, aza-octatetraenyl, pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanothiophene, pyrazolooxazole, benzofuranyl, benzoisofuranyl, benzothiopheneyl, indolyl, isoindolyl, benzooxazolyl, benzoimidazolyl, indazole, benzotriazolyl, quinolinyl, 2-quinolinoneyl, 4-quinolinoneyl, 1-isoquinolinoneyl, isoquinolinyl, acridineyl, phenanthridineyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthidyl, etc.

[0238] The "5-12-membered bridged ring group" described in this invention refers to a structure containing 5-12 carbon atoms formed by any two rings sharing two non-directly connected atoms. The "5-12-membered bridged ring group" includes 5-12-membered saturated bridged ring groups and 5-12-membered partially saturated bridged ring groups. Preferably, it includes 5-11-membered, 5-10-membered, 5-8-membered, 6-10-membered, 7-11-membered, and 7-12-membered bridged ring groups. Specific examples include, but are not limited to, 5-12-membered bridged ring groups.

[0239] The "5-12-membered bridged heterocyclic group" described in this invention refers to a 5-12-membered bridged heterocyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1-4 heteroatoms. This also includes cases where carbon, nitrogen, and sulfur atoms can be substituted with oxygen. Preferably, it includes 5-11-membered bridged heterocyclic groups, 5-10-membered bridged heterocyclic groups, and 5-8-membered bridged heterocyclic groups. Specific examples include, but are not limited to:

[0240]

[0241] The "5-12 membered spirocyclic group" described in this invention refers to a structure containing 5-12 carbon atoms formed by at least two rings sharing a single atom. It includes 5-12 membered saturated spirocyclic groups and 5-12 membered partially saturated spirocyclic groups, preferably 5-11 membered spirocyclic groups, 5-10 membered spirocyclic groups, 5-8 membered spirocyclic groups, 6-8 membered spirocyclic groups, 7-12 membered spirocyclic groups, 7-11 membered spirocyclic groups, 7-10 membered spirocyclic groups, 7-9 membered spirocyclic groups, 8-10 membered spirocyclic groups, 8-11 membered spirocyclic groups, and 8-12 membered spirocyclic groups. Specific examples include, but are not limited to: Groups formed by substituting any substituted hydrogen atoms with cyclic structures. 5-12 member partially saturated spirocyclic groups refer to groups in which at least one ring is unsaturated. Specific examples include, but are not limited to:

[0242] Groups formed by replacing any substituted hydrogen atoms with cyclic structures.

[0243] The "5-12-membered spiroheterocyclic group" described in this invention refers to a 5-12-membered spirocyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1-4 heteroatoms, and includes cases where the carbon atom, nitrogen atom, and sulfur atom can be substituted with oxygen. Examples include, for instance, 5-11-membered spiroheterocyclic groups, 5-10-membered spiroheterocyclic groups, 5-8-membered spiroheterocyclic groups, 5-6-membered spiroheterocyclic groups, 7-12-membered spiroheterocyclic groups, 7-11-membered spiroheterocyclic groups, 7-10-membered spiroheterocyclic groups, 7-9-membered spiroheterocyclic groups, 7-8-membered spiroheterocyclic groups, 8-12-membered spiroheterocyclic groups, 8-10-membered spiroheterocyclic groups, 8-10-membered nitrogen-containing spiroheterocyclic groups, and 7-11-membered nitrogen-containing spiroheterocyclic groups. Specific examples include, but are not limited to:

[0244]

[0245] The phrase "optionally replaced by..." as described in this invention includes both "replaced" and "not replaced".

[0246] In this invention, "deuteration" refers to the substitution of one or more hydrogen atoms on a deuterated group by one or more deuterium atoms. This can be partial or complete deuteration. For example, a deuterated compound may contain only one deuterium atom. In some embodiments, the deuterated compound contains only two deuterium atoms. In some embodiments, the deuterated compound contains only three deuterium atoms. In some embodiments, the deuterated compound contains four deuterium atoms.

[0247] The "optionally deuterated" in this invention includes two cases: the group is deuterated and the group is not deuterated, wherein "deuterated" is as defined above.

[0248] The "pharmaceutically acceptable salt" as described in this invention refers to the addition salt of pharmaceutically usable acids and bases, such as metal salts, ammonium salts, salts formed with organic acids, salts formed with organic bases, salts formed with inorganic acids, and salts formed with acidic or basic amino acids.

[0249] The term "ester" as used in this invention refers to a pharmaceutically acceptable ester, particularly esters that are hydrolyzed in vivo and include esters that readily decompose in the human body, leaving behind a parent compound (the compound of general formula (I)) or its salt. The term "ester" as used in this invention may, for example, be selected from the following group: (1) carboxylic acid esters obtained by esterification with carboxylic acid compounds, wherein the non-carbonyl portion of the carboxylic acid compound is selected, for example, C 1-20 Straight-chain or branched alkyl groups, C 1-12 Straight-chain or branched alkyl groups, C 1-8 Straight-chain or branched alkyl groups, C 1-6 Straight-chain or branched alkyl groups (e.g., methyl, ethyl, n-propyl, tert-butyl, or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g., methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (e.g., benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g., phenoxymethyl), C 6-10 Aryl (e.g., phenyl, optionally replaced by, for example, halogen, C) 1-4 Alkyl or C 1-4 (1) Alkoxy or amino substituted); (2) sulfonates, such as alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) amino acid esters (e.g., L-valine or L-isoleucyl); and (4) mono-, di-, or triphosphate esters, etc.; (4) esters obtained by esterification with alcohols, wherein the non-hydroxyl portion of the alcohol is selected from, for example, C 1-20 Straight-chain or branched alkyl groups, C 1-12 Straight-chain or branched alkyl groups, C 1-8 Straight-chain or branched alkyl groups, C 1-6Straight-chain or branched alkyl groups (e.g., methyl, ethyl, n-propyl, tert-butyl, or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g., methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (e.g., benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g., phenoxymethyl), C 6-10 Aryl (e.g., phenyl, optionally replaced by, for example, halogen, C) 1-4 Alkyl or C 1-4 (alkoxy or amino substitution).

[0250] The term "stereoisomer" as used in this invention refers to compounds containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. Compounds of this invention may have asymmetric centers, each of which independently produces two optical isomers. The scope of this invention includes all possible optical isomers and mixtures thereof. If the compounds of this invention contain an alkene double bond, unless otherwise specified, they include cis and trans isomers. Compounds of this invention may exist as tautomers (a type of functional group isomer) having different hydrogen connection points through one or more double bond shifts; for example, ketones and their enol forms are keto-enol tautomers. All tautomers and mixtures thereof are included within the scope of this invention. All enantiomers, diastereomers, racemic mixtures, mesomixes, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of this invention.

[0251] The "therapeutic effective amount" as described in this invention refers to the amount of the aforementioned compound, pharmaceutical preparation, or pharmaceutical composition that, when administered to a patient, at least alleviates the patient's symptoms. The actual amount comprising the "therapeutic effective amount" can vary depending on various factors, including but not limited to the specific condition being treated, the severity of the condition, the patient's physical and health condition, and the route of administration. Skilled medical practitioners can easily determine the appropriate amount using methods known in the medical field.

[0252] Beneficial effects of the invention

[0253] (1) The compounds of the present invention, their pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof have excellent KIF18A inhibitory activity and can treat and / or prevent KIF18A-mediated diseases and related diseases.

[0254] (2) The compounds of the present invention, their pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof have good inhibitory effects on tumor cells;

[0255] (3) The compounds of the present invention, their pharmaceutically acceptable salts, esters, deuterated derivatives or their stereoisomers have good pharmacokinetic properties, longer duration of action and high bioavailability;

[0256] (4) The compounds of the present invention, their pharmaceutically acceptable salts, esters, deuterated derivatives or their stereoisomers have good safety;

[0257] (5) The compound of the present invention has a simple preparation process, high drug purity, stable quality, and is easy to carry out large-scale industrial production.

[0258] The following experiments further illustrate the beneficial effects of the compounds provided in the embodiments of the present invention, but this should not be construed as the compounds provided in the embodiments of the present invention having only the following beneficial effects.

[0259] Experimental Example 1: In vitro cellular activity of the compounds of the present invention

[0260] Test samples: Some of the compounds of this invention, the chemical names and structures of which are given in the preparation examples.

[0261] The cell lines used in the following experiments are as follows:

[0262] OVCAR3: TP53-mutated human ovarian cancer cells; MDA-MB-157: TP53-mutated human breast cancer cells.

[0263] Experimental Method (CelltiterGlo assay)

[0264] 1. Prepare cells

[0265] 1.1 Cell Culture:

[0266] All cells were adherent cells. OVCAR3 cells were cultured in RPMI Medium 1640 + 20% FBS + 1% PS, and MDA-MB-157 cells were cultured in DMEM Medium + 10% FBS + 1% PS. The cells were tested during the logarithmic growth phase.

[0267] 1.2 Preparation of cell suspension:

[0268] Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was assessed using the trypan blue rejection assay to ensure it was above 90%. The concentration was adjusted, and 90 μL of cell suspension was added to each well of a 96-well plate.

[0269] Table 1. Number of cells seeded

[0270]

[0271] 2. Preparation of test compounds

[0272] 2.1 Prepare a DMSO stock solution for the test compound. The concentration of the stock solution for the test compound is 10 mM.

[0273] 2.2 Preparation of working stock solution for test compounds

[0274] The test compound stock solution was 10 mM, serially diluted 10-fold to 1 mM, and then serially diluted 3-fold, for a total of 8 concentrations. Then, 2 L of each serially diluted compound in DMSO was added to 198 L of culture medium to prepare the working stock solution of the test compound (the compound concentration was 10 times the final concentration, with the highest concentration being 10 μM).

[0275] 2.3 Compound Treatment

[0276] Add 10 μL of the compound working stock solution (10-fold dilution, final DMSO concentration 0.1%) to each well of a 96-well plate seeded with cells.

[0277] The final concentrations of the tested compounds were: 1000.0 nM, 333.3 nM, 111.1 nM, 37.0 nM, 12.3 nM, 4.1 nM, 1.4 nM, and 0.5 nM.

[0278] 2.4 Setting of reference holes

[0279] Solvent control: 0.1% DMSO.

[0280] Blank control: Culture medium

[0281] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 4 days.

[0282] 3. Testing

[0283] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Gloassay kit) to each well, shake for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal value using a multi-functional microplate reader.

[0284] 4. Data Processing

[0285] 1) Inhibition rate (%) = 1 - (test sample well reading - blank control well reading) / (DMSO solvent control well reading - blank control well reading) × 100%;

[0286] 2) Input the data into GraphPad Prism to plot the curve and obtain the IC. 50 .

[0287] Experimental Results and Conclusions

[0288] IC50 of the inhibitory activity of the compounds of this invention against OVCAR3 50 Values, 1 nM to 50 nM are represented by A, 50 nM to 100 nM by B, and 100 nM to 500 nM by C; IC50 values ​​for the inhibitory activity of the compounds of this invention against MDA-MB-157. 50 Values ​​are represented as follows: 1 nM to 50 nM is represented by A, 50 nM to 100 nM by B, and 100 nM to 500 nM by C.

[0289] Table 2. In vitro cellular activities (IC50) of the compounds of the present invention 50 ,nM)

[0290]

[0291] This demonstrates that the compounds of the present invention can effectively inhibit the proliferation of OVCAR3 and MDA-MB-157 cells, indicating that the compounds of the present invention have clinical application potential in treating TP53-mutant cancers. Detailed Implementation

[0292] The technical solution of the present invention will now be described with reference to specific embodiments. These embodiments are merely some, not all, of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0293] Example 1 Preparation of 4-(cyclopropylsulfonyl)-N-(4,4-difluoro-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-6'-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (Compound 1)

[0294]

[0295] (1) Preparation of 6'-bromo-4,4-difluoro-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione

[0296] 5-Bromo-6-hydroxy-3-methylpyridine amide (3.0 g, 12.9 mmol) and 4,4-difluorocyclohexanone (6.9 g, 51.5 mmol) were dissolved in 1,4-dioxane (35 mL). Concentrated sulfuric acid (1.3 g) was added dropwise to the system. The reaction mixture was stirred at 95 °C for 3 hours. The mixture was then concentrated, and the residue was slurried in n-hexane and filtered to give 3.1 g of the target compound, yield: 69%.

[0297] (2) Preparation of 4-(cyclopropylsulfonyl)-N-(4,4-difluoro-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-6'-yl)-2-(6-azaspiro[2,5]oct-6-yl)benzamide

[0298] 4-(cyclopropylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (50 mg, 0.15 mmol) and 6'-bromo-4,4-difluoro-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (50 mg, 0.15 mmol) were dissolved in 1,4-dioxane (15 mL), along with 4,5-bis(diphenylphosphine). 9,9-Dimethyloxanthracene (11 mg, 0.019 mmol), cesium carbonate (100 mg, 0.31 mmol), and tris(dibenzylacetone)dipalladium (8 mg, 0.009 mmol) were reacted under nitrogen protection. The reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction system was then concentrated, and the residue was subjected to column chromatography (dichloromethane:methanol = 10:1) to give 20 mg of the target compound, yield: 22%.

[0299] 1 H-NMR (400MHz, DMSO) δ: 12.02 (s, 1H), 10.38 (s, 1H), 8.50 (s, 1H), 8.14 (d, J = 7.8Hz, 1H), 7.71-7.65 (m, 2H), 3.10-2.95 (m, 4 H),2.65-2.10(m,7H),1.75-1.55(m,6H),1.40-1.01(m,6H),0.90-0.60(m,1H),0.30-0.10(m,4H).LC-MS(m / z):601.2(M+H) + ).

[0300] Example 2 Preparation of 4-(cyclopropylsulfonyl)-N-(3,3-difluoro-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclobutane-1,3'-imidazo[1,5-a]pyridine]-6'-yl)-2-(6-azaspiro[2,5]oct-6-yl)benzamide (Compound 2)

[0301] (1) Preparation of 1-oxide of 5-bromo-2-(ethoxycarbonyl)-3-methylpyridine

[0302] Ethyl 5-bromo-3-methylpyridinecarboxylate (4.6 g, 18.8 mmol) was dissolved in dichloromethane (100 mL). At 0 °C, trifluoroacetic anhydride (8.4 g, 40.0 mol) and urea peroxide (3.8 g, 40.1 mol) were added. After the reaction was continued at 20 °C for 16 hours, 150 mL of water was added to the reaction solution. The aqueous phase was extracted with dichloromethane, and the organic phases were combined. The organic phases were washed successively with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and the filtrate was collected. The solvent was removed under reduced pressure to obtain 4.4 g of crude product, which was directly added to the next reaction step.

[0303] (2) Preparation of ethyl 5-bromo-6-hydroxy-3-methylpyridinecarboxylate

[0304] The crude product (4.4 g) obtained in the previous step was dissolved in N,N-dimethylformamide (40 mL), and trifluoroacetic anhydride (7.4 g, 35.2 mmol) was added. The reaction mixture was heated to 50 °C and reacted for 4 hours. The reaction mixture was then cooled to 20 °C, and water was added to the reaction solution. A solid precipitated, and the solid was filtered to obtain 3.0 g of the target compound. The yield of the two steps was 61.2%.

[0305] (3) Preparation of 5-bromo-6-hydroxy-3-methylpyridine amide

[0306] Ethyl 5-bromo-6-hydroxy-3-methylpyridinecarboxylate (3.0 g, 11.5 mmol) was dissolved in anhydrous ethanol (35 mL), and concentrated ammonia (35 g, 25%-28%) was added. The reaction mixture was heated to 45 °C, and after reacting in a sealed tube for 16 hours, the reaction mixture was concentrated under reduced pressure. The residue was slurried with a dichloromethane / methanol mixture and filtered to give 2.0 g of product, yield: 75.0%.

[0307] (4) Preparation of 6'-bromo-3,3-difluoro-8'-methyl-2'H-spiro[cyclobutane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione

[0308] 5-Bromo-6-hydroxy-3-methylpyridine amide (500 mg, 2.2 mmol) and 3,3-difluorocyclobutane-1-one (700 mg, 6.6 mmol) were dissolved in 1,4-dioxane (10 mL). Concentrated sulfuric acid (220 mg, 2.2 mmol) was added dropwise to the system. The reaction solution was microwaved at 150 °C for 1 hour. After cooling to 20 °C, the pH of the system was adjusted to 6-7 with diisopropylethylamine. The mixture was concentrated, and the residue was mixed with silica gel. The target compound was prepared in normal phase using n-heptane / ethyl acetate as the mobile phase (ethyl acetate ratio from 0% to 60%), yielding 300 mg in 43.4%.

[0309] (5) Preparation of 4-(cyclopropylsulfonyl)-N-(3,3-difluoro-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclobutane-1,3'-imidazo[1,5-a]pyridine]-6'-yl)-2-(6-azaspiro[2,5]oct-6-yl)benzamide

[0310] 4-(cyclopropylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (48 mg, 0.15 mmol) and 6'-bromo-3,3-difluoro-8'-methyl-2'H-spiro[cyclobutane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (50 mg, 0.15 mmol) were dissolved in 1,4-dioxane (10 mL), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (15 mg, 0.15 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was prepared by heating the reaction mixture to 100°C under nitrogen protection. After reacting for 14 hours, the pH of the system was adjusted to 5-6 with hydrogen chloride-dioxane. The reaction mixture was then concentrated, and the residue was subjected to column chromatography (using n-heptane-ethyl acetate as the mobile phase, with the ethyl acetate ratio ranging from 0% to 60%) to give 40 mg of the target compound, with a yield of 46.6%.

[0311] 1 H-NMR (400MHz, DMSO) δ: 12.24 (s, 1H), 10.33 (s, 1H), 8.51 (s, 1H), 8.15 (d, J = 8.4Hz, 1H), 7.78-7.30 (m, 2H), 4.25-4.0 5(m,2H),3.12-2.92(m,7H),2.43(s,3H),1.80-1.66(m,4H),1.30-1.00(m,4H),0.29(s,4H).LC-MS(m / z):573.2(M+H + ).

[0312] The KIF18A inhibitor and its applications provided by this invention have been described in detail above. Specific embodiments have been used to illustrate the principles and implementation methods of this invention. These embodiments are merely illustrative and are intended to help understand the method and central ideas of this invention. It should be noted that those skilled in the art can make various improvements and modifications to this invention without departing from its principles, and these improvements and modifications also fall under the protection of the claims of this invention.

Claims

1. A compound of general formula (I), its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, in, X1 and X3 are independently selected from N or CR. a ; X2 is selected from C(O), S(O)2, S(O), O, S, NR c or CR a R b ; X5 is selected from N or CR a ; X8 is selected from C(O), O, NR c2 or CR a2 R b2 ; X9 is selected from C(O), O, NR c3 or CR a3 R b3 ; X 10 Selected from C(O), O, NR c4 or CR a4 R b4 ; X 11 Selected from C(O), O, NR c5 or CR a5 R b5 ; X6 is selected from C(O), O, NR c6 or CR a6 R b6 ; X7 is selected from C(O), O, NR c7 or CR a7 R b7 ; X4 is selected from N or CR a8 ; R 1 R 2 R 3 R 4 R 5 Each time it appears, it is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH2, -S(O)2-NH2, and -(L1) optionally substituted by one or more substituents Q1. q -C 1-6 Alkyl group, -(L1) q -C 2-6 Alkenyl, -(L1) q -C 2-6 Alkyne group, -(L1) q -C 1-6 Alkoxy, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl group, -(L1) q -3-12 membered cycloalkyl, -(L1) q -3-12-membered heterocyclic group, -(L1) q -6-10 aryl, -(L1) q -5-12 heteroaryl groups, -(L1) q -5-12 spirocyclic group, -(L1) q -5-12 spirocyclic groups, -(L1) q -5-12 Yuan Bridge Ring Foundation, -(L1) q -5-12-element bridged heterocyclic base; L and L1 are each independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, and -NR, respectively. c1 -、-CR a1 R b1 -; R a R a1 R a2 R a3 R a4 R a5 R a6 R a7 R b R b1 R b2 R b3 R b4 R b5 R b6 R b7 Each time it appears, it is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, and optionally from the C group that has been deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylaminoyl, C 1-6 Alkyl amide, C 1-6 Alkylsulfonamide, C 1-6 alkylaminosulfonyl, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, 6-10 aryl, 5-12 heteroaryl, 3-8 cycloalkyl or -3-8 heterocyclic; Or, R a2 With R b2 R a3 With R b3 R a4 With R b4 Or R a5 With R b5 Together with the carbon atom to which it is attached, it forms a 3-8 membered cycloalkyl or a 3-8 membered heterocyclic group, wherein the 3-8 membered cycloalkyl or the 3-8 membered heterocyclic group is optionally substituted by one or more Q2 groups; Q1 and Q2 are each independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, and C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino, -C(O)-NH2,C 1-6 Alkyl carbonyl, C 1-6 Alkyloxycarbonyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonamide, optionally substituted with 1-4 substituents p1, of which are 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclic, or 5-12 membered heterocyclic, wherein the substituents p1 are independently selected from halogen, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; R a8 Selected from deuterium, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, with C atoms optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylaminoyl, C 1-6 Alkyl amide, C 1-6 Alkylsulfonamide, C 1-6 alkylaminosulfonyl, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl group, -(L1) q -3-12 membered cycloalkyl, -(L1) q -3-12-membered heterocyclic group, wherein -(L1) q -3-12 membered cycloalkyl, -(L1) q -3-12-membered heterocyclic groups can be optionally replaced by halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution; R c R c1 R c2 R c3 R c4 R c5 R c6 R c7 Each time it appears, it is independently selected from deuterium, hydrogen, and optionally from C atoms that have been deuterated. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -C(O)-C 1-6 alkyl; Each occurrence of m, n, and q is an independent integer between 0 and 6; n1 and n2 are independent integers from 0 to 4.

2. The compound of claim 1, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, in, X1 and X3 are independently selected from N or CR. a ; X2 is selected from C(O), NR c or CR a R b ; X5is selected from N or CR a ; X8is selected from C(O), O, NR c2 or CR a2 R b2 ; X9is selected from C(O), O, NR c3 or CR a3 R b3 ; X 10 selected from C(O), O, NR c4 or CR a4 R b4 ; X 11 selected from C(O), O, NR c5 or CR a5 R b5 ; X6is selected from C(O), O, NR c6 or CR a6 R b6 ; X7is selected from C(O), O, NR c7 or CR a7 R b7 ; X4is selected from N or CR a8 ; R 1 , R 4 each occurrence is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, cyano, -(L1) q -C 1-6 alkyl, -(L1) q -C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl; R 2 , R 5 are each independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -(L1) q -C 1-6 alkyl, -(L1) q -C 1-6 alkoxy, -(L1) q -3-10 membered cycloalkyl, -(L1) q -3-10 membered heterocyclyl, -(L1) q -6-10 membered aryl, -(L1) q -5-10 membered heteroaryl, -(L1) q -5-11 membered spirocyclyl, -(L1) q -5-11 membered spiroheterocyclyl; R 3 Selected from -C(O)N(R) groups substituted with 1-4 substituents Q1. c1 )2、-N(R c1 S(O)2-C 1-6 Alkyl, -N(R) c1 S(O)2-3-6-membered cycloalkyl, -N(R c1 S(O)2-3-6-membered heterocyclic group, -S(O)2N(R) c1 )-C 1-6 Alkyl group, -S(O)2N(R) c1 -3-6 membered cycloalkyl, -S(O)2N(R c1 -3-6-membered heterocyclic group, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic, -S(O)N(R c1 )-C 1-6 Alkyl, -S(O)N(R) c1 -3-6 membered cycloalkyl, -S(O)N(R c1 -3-6-membered heterocyclic groups, -N(R) c1 )C(O)-C 1-6 Alkyl, -N(R) c1 )C(O)-3-6 membered cycloalkyl, -N(R c1 )C(O)-3-6-membered heterocyclic group, -C(O)N(R c1 )-C 1-6 Alkyl, -C(O)N(R) c1 -3-6 membered cycloalkyl, -C(O)N(R) c1 -3-6 heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocyclic, -N(R c1 )-C 1-6 alkyl; L, L1are each independently at each occurrence selected from the group consisting of -C(O)-, -S(O)-, -S(O)2-, -NR c1 -; -CR a1 R b1 -; R a R a1 R a2 R a3 R a4 R a5 R a6 R a7 R b R b1 R b2 R b3 R b4 R b5 R b6 R b7 Each time it appears, it is independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, and optionally from the C group that has been deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl; Or, R a2 With R b2 R a3 With R b3 R a4 With R b4 Or R a5 With R b5 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl or a 3-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl or the 3-6 membered heterocyclic group is optionally substituted by 1-3 Q2 atoms; R a8 Selected from deuterium, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, with C atoms optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -(L1) q -3-8 membered cycloalkyl groups, -(L1) q -3-8 membered heterocyclic group, wherein -(L1) q -3-8 membered cycloalkyl groups, -(L1) q -3-8 membered heterocyclic groups can be halogenated, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution; R c R c1 R c2 R c3 R c4 R c5 R c6 R c7 Each time it appears, it is independently selected from deuterium, hydrogen, and optionally from C atoms that have been deuterated. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, -C(O)-C 1-6 alkyl; Q1 and Q2 are each independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino; Each occurrence of m, n, n1, n2, and q is an independent integer between 0 and 4.

3. The compound of claim 1 or 2, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in formula (II), in, X8 is selected from O and NR. c2 or CR a2 R b2 ; X9 is selected from O and NR. c3 or CR a3 R b3 ; X 10 Selected from O, NR c4 or CR a4 R b4 ; X 11 Selected from O, NR c5 or CR a5 R b5 ; R a1 R a2 R b1 R b2 R a3 R b3 R a4 R b4 R a5 R b5 The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl; Or, R a2 With R b2 R a3 With R b3 R a4 With R b4 Or R a5 With R b5 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl or a 3-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl or the 3-6 membered heterocyclic group is optionally substituted by one or more Q2 groups; R 2 R 5 Each group is independently selected from deuterium, hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group, optionally substituted with 1-4 substituents Q1, -(L1) q -C 1-6 Alkyl group, -(L1) q -C 1-6 Alkoxy, -(L1) q -5-10 membered cycloalkyl groups, -(L1) q -5-10 heterocyclic groups, -(L1) q -7-11 spirocyclic group, -(L1) q -7-11 spiroheterocyclic group; L and L1 are each independently selected from -C(O)-, -S(O)2-, and -N(R)-, respectively. c1 )-、-CR a1 R b1 ; R 3 Selected from -N(R) groups substituted with 1-3 substituents Q1. c1 S(O)2-C 1-6 Alkyl, -N(R) c1 S(O)2-3-6-membered cycloalkyl, -N(R c1 S(O)2-3-6-membered heterocyclic group, -S(O)2N(R) c1 )-C 1-6 Alkyl group, -S(O)2N(R) c1 -3-6 membered cycloalkyl, -S(O)2N(R c1 -3-6-membered heterocyclic group, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic, -S(O)N(R c1 )-C 1-6 Alkyl, -N(R) c1 )-C 1-6 alkyl; R a8 Selected from deuterium, chlorine, bromine, iodine, amino, hydroxyl, carboxyl, cyano, with C atoms optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -(L1) q -3-6 membered cycloalkyl groups, -(L1) q -3-6-membered heterocyclic group, wherein -(L1) q -3-6 membered cycloalkyl groups, -(L1) q -3-6 membered heterocyclic groups can be optionally replaced by halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution; R c1 R c2 R c3 R c4 R c5 R c7 The C atoms are independently selected from deuterium and hydrogen, respectively, and are optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -C(O)-C 1-6 alkyl; Q1 and Q2 are each independently selected from deuterium, halogen, carboxyl, hydroxyl, cyano, nitro, amino, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino; Each occurrence of m, n2, and q is an independent integer between 0 and 3.

4. The compound according to any one of claims 1-3, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in formula (III), in, X9 is selected from O and NR. c3 or CR a3 R b3 ; X 10 Selected from O, NR c4 or CR a4 R b4 ; R a3 R b3 R a4 R b4 The C groups are independently selected from deuterium, hydrogen, halogen, amino, hydroxyl, carboxyl, and cyano groups, with the C group optionally deuterated. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; Or, R a3 With R b3 Or R a4 With R b4 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl or a 3-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl or the 3-6 membered heterocyclic group is optionally substituted by 1-3 Q2 atoms; Each R 1 R 2 R 3 R 4 R 5 R a8 R c3 R c4 R c7 The definitions of m, n2, and each Q2, X1, X3 are as described in any one of claims 1-3.

5. The compound according to any one of claims 1-4, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, wherein, Selected from the following structures, 6. The compound according to any one of claims 1-5, its pharmaceutically acceptable salt, ester, deuterated derivative or stereoisomer thereof, having the structure shown in formula (V-1), Each R 1 R 3 R 4 R 5 m, n2, R a8 R c7 Each R a The definition is as described in any one of claims 1-5.

7. A compound, its pharmaceutically acceptable salt, ester, deuterated derivative, or stereoisomer thereof, having the following structure:

8. A pharmaceutical preparation comprising the compound of any one of claims 1-7, a pharmaceutically acceptable salt, ester, deuterated form or stereoisomer thereof, and one or more pharmaceutical carriers and / or diluents; said pharmaceutical preparation being any clinically or pharmaceutically acceptable dosage form.

9. A pharmaceutical composition comprising the compound of any one of claims 1-7, a pharmaceutically acceptable salt, ester, deuterated form or stereoisomer thereof, and one or more second therapeutic agents; optionally, the pharmaceutical composition further comprising one or more pharmaceutical carriers and / or diluents.

10. Use of the compound of any one of claims 1-7, its pharmaceutically acceptable salt, ester, deuterated form or stereoisomer thereof, or the pharmaceutical formulation of claim 10, or the pharmaceutical composition of claim 11, in the preparation of a medicament for the treatment and / or prevention of KIF18A-mediated diseases and related diseases.

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