KIF18A inhibitors

Abstract

The invention provides a compound capable of being used as a KIF18A inhibitor, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, and a method for preparing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof. The invention also relates to application of the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof in preparation of medicines for treating and / or preventing KIF18A-mediated diseases and related diseases, and also relates to application of the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof in preparation of medicines for treating and / or preventing KIF18A-mediated diseases and related diseases. # imgabs0 #

Description

KIF18A inhibitors Technical Field

[0001] The present invention relates to the field of medical technology, and specifically to KIF18A inhibitors, pharmaceutically acceptable salts, esters or stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, pharmaceutically acceptable salts, esters or stereoisomers thereof, methods for preparing the compounds, pharmaceutically acceptable salts, esters or stereoisomers thereof, and uses of the compounds, pharmaceutically acceptable salts, esters or stereoisomers thereof in preparing medicaments for treating and / or preventing diseases mediated by KIF18A and related diseases. Background Art

[0002] Kinesins are motor proteins that use microtubules as their tracks and play important roles in organelle migration, tissue and organ development, signal transduction, mitosis, meiosis, and other processes. Various microtubule-associated proteins (MAPs) from the kinesin-8 family regulate microtubule dynamic instability by influencing microtubule polymerization and depolymerization. Kinesins are reported to be closely associated with the invasion, metastasis, and poor prognosis of various cancers. An increasing number of kinesin family members are implicated in tumor development and progression. KIF18A, a member of the kinesin-8 family, is a multifunctional protein that uses adenosine triphosphate (ATP) hydrolysis to generate force and move along microtubules. It participates in a variety of cellular functions, including cell division, cell motility, microtubule dynamics, and organelle transport. KIF18A can influence cell differentiation and cancer development. Studies have shown that KIF18A is associated with tumor behavior and could serve as a potential biomarker for breast, colorectal, and hepatocellular carcinomas.

[0003] Genetic instability is a common feature of tumor cells, with a large number of tumor cells displaying frequent chromosome losses or gains. This chromosomal instability (CIN) is primarily due to defects leading to abnormal interactions between chromosomes and mitotic spindle microtubules, which in turn increase chromosome segregation errors. Compared with chromosomally stable cells, CIN cells display increased spindle microtubule polymerization and reduced turnover of attachments between spindle microtubules and kinetochores, specialized protein structures assembled at the centromeric regions of mitotic chromosomes. Therefore, CIN cells may be particularly susceptible to antimitotic therapies targeting the microtubule cytoskeleton.

[0004] Altered microtubule dynamics in mitotic CIN cells render them particularly dependent on KIF18A to reduce kinetochore-microtubule turnover and restrict microtubule growth. In the absence of KIF18A activity, centrosome fragmentation occurs, and mitotic progression slows or halts. KIF18A is largely dispensable for the proliferation of diploid somatic cells in vivo but is essential for the proliferation of CIN tumor cells. Upon inhibition of KIF18A, CIN tumor cells exhibit mitotic delay, multipolar spindles, and increased cell death. Therefore, KIF18A may be an effective target for specifically inhibiting the growth of CIN tumor cells while having relatively low toxicity in somatic, diploid cells.

[0005] In summary, the development of inhibitors targeting KIF18A will provide new ideas and strategies for the treatment of different types of tumors.

[0006] Summary of the Invention

[0007] The present invention aims to provide a KIF18A inhibitor and its application. The specific technical solution is as follows:

[0008] In certain embodiments, the present invention first provides a compound represented by general formula (I), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof:

[0009] in,

[0010] X 1 、X 4 are independently selected from N or CR a ;

[0011] X 2 、X 3 are independently selected from N or C;

[0012] Ring A is selected from 5-12 membered cycloalkyl, 5-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, 5-12 membered bridged cyclyl or 5-12 membered bridged heterocyclyl;

[0013] Each R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH2, -S(O)2-NH2 or -(L) optionally substituted with 1-4 substituents Q2 m -H, -(L) m -C 1-6 Alkyl, -(L)m -C 2-6 Alkenyl, -(L) m -C 2-6 Alkynyl, - (L) m -C 1-6 Alkoxy, di(C 1-6 Alkyl)amino, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -3-12 membered cycloalkyl, -(L) m -3-12 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -5-12 membered spirocyclic group, -(L) m -5-12 membered spiroheterocyclic group, -(L) m -5-12 membered bridged ring group, -(L) m -5-12 membered bridged heterocyclic group;

[0014] Each Q1 and each Q2 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, hydroxy 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 Alkylcarbonyl, C 1-6 Alkyloxycarbonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, C 1-6 Alkyl-OC 1-4 Alkylene, haloC 1-6 Alkyl-OC 1-4 Alkylene or 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl optionally substituted by 1-4 substituents q, wherein the substituents q are independently selected from halogen, hydroxyl, amino, carboxyl, cyano, C 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0015] Each L is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, -NR c -、-S(O)(NR c )-、-CR a1 R b -;

[0016] Each R a , each R a1 , each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl aminoacyl, C 1-6 Alkyl amido, C 1-6 Alkylsulfonylamino, C 1-6 Alkylaminosulfonyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -3-8 membered cycloalkyl or -(L) m -3-8 membered heterocyclic group;

[0017] Each R c are independently selected from hydrogen, C 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;

[0018] Each m and n are independently an integer from 0 to 6;

[0019] p is selected from 0, 1, 2 or 3.

[0020] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X1 、X 2 、X 3 、X 4 At least one of them is N.

[0021] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 1 、X 2 、X 3 、X 4 There are at least two N.

[0022] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 1 Selected from CR a .

[0023] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 1 is N.

[0024] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 2 For C.

[0025] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 2 is N.

[0026] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 3 For C.

[0027] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 3 is N.

[0028] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 4 Selected from CR a .

[0029] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 4 Selected from N.

[0030] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl.

[0031] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from a 5-6 membered monocycloalkyl, a 5-6 membered monoheterocyclic group, an 8-10 membered fused cyclic group, an 8-10 membered fused heterocyclic group, a phenyl group, a 5-6 membered monoheteroaryl, an 8-10 membered fused aryl or an 8-10 membered fused heteroaryl.

[0032] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from a 5-6 membered single heteroaryl, an 8-10 membered fused heterocyclic group or an 8-10 membered fused heteroaryl group.

[0033] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from a 5-6 membered nitrogen-containing monoheteroaryl, an 8-10 membered nitrogen-containing fused heterocyclic group or an 8-10 membered nitrogen-containing fused heteroaryl group.

[0034] In certain embodiments, the compounds shown in the aforementioned schemes, their pharmaceutically acceptable salts, their esters, or their stereoisomers, wherein ring A is selected from cyclopentanyl, cyclohexanyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, or an 8-10 membered nitrogen-containing fused heterocyclic group.

[0035] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or 8-10 membered nitrogen-containing fused heterocyclic group.

[0036] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein, Selected from the following structures,

[0037] Each R a , each R 1 , every Q 1 , and n are defined as described in any of the aforementioned technical solutions.

[0038] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein, Selected from the following structures,

[0039] Each R a , each R 1 , every Q 1 , and n are defined as described in any of the aforementioned technical solutions.

[0040] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R 1 、R 2 、R 3 、R 4 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, or -(L) optionally substituted with 1 to 4 substituents Q2 m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 alkyl.

[0041] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R 1 、R 2 、R 3 、R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0042] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R 1 、R 2 、R 3 、R 4Each is independently selected from hydrogen, fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0043] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 is selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, or -(L) optionally substituted with 1 to 4 substituents Q2 m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L) m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiroheterocyclyl.

[0044] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 Selected from -(L) optionally substituted with 1 to 4 substituents Q2 m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -5-10 membered cycloalkyl, -(L) m -5-10 membered heterocyclic group, -(L) m -7-11 membered spirocyclic group, -(L) m -7-11 membered spiroheterocyclyl.

[0045] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 It is selected from a 5-6 membered heterocyclyl or a 7-10 membered spiroheterocyclyl group optionally substituted by 1 to 3 substituents Q2.

[0046] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 It is selected from a 5-6 membered nitrogen-containing heterocyclic group or a 7-9 membered nitrogen-containing spiro heterocyclic group optionally substituted by 1 to 3 substituents Q2.

[0047] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 is selected from an 8-membered nitrogen-containing spiro heterocyclic group optionally substituted by 1 to 3 substituents Q2.

[0048] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 Selected from the following structures optionally substituted by 1-3 substituents Q2:

[0049] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 Selected from the following structures optionally substituted by 1-3 substituents Q2:

[0050] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each L is independently selected from -C(O)-, -S(O)-, -S(O)2-, -NR c -、-S(O)(NR c )-、-CR a1 R b -.

[0051] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each L is independently selected from -S(O)2-, -NR c -、-CR a1 R b -.

[0052] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 is selected from -S(O)2H, -C(O)H, -C(O)N(R c )2、-N(R c )S(O)2-C 1-6 Alkyl, -N(R c )-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2N(R c)-3-6 membered cycloalkyl, -S(O)2N(R c )-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 group, -S(O)(NR c )-C 1-6 Alkyl, -S(O)(NR c )-3-6 membered cycloalkyl, -S(O)(NR c )-3-6 membered heterocyclic group, -N(R c )C(O)-C 1-6 Alkyl, -N(R c )C(O)-3-6 membered cycloalkyl, -N(R c )C(O)-3-6 membered heterocyclic group, -C(O)N(R c )-C 1-6 Alkyl, -C(O)N(R c )-3-6 membered cycloalkyl, -C(O)N(R c )-3-6 membered heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocyclic group.

[0053] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 is selected from -S(O)2H, -C(O)H, -C(O)N(R c )2、-N(R c )S(O)2-C 1-6 Alkyl, -N(R c )-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -S(O)2N(R c )-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 group, -S(O)(NR c )-C 1-6 Alkyl, -S(O)(NR c )-3-6 membered cycloalkyl, -S(O)(NR c )-3-6 membered heterocyclic group.

[0054] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 is selected from -S(O)2H, -N(R c )S(O)2-C 1-6 Alkyl, -N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2-C 1-6 alkyl.

[0055] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 Selected from the following structures:

[0056] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each Q1 and each Q2 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-4 Alkyl-OC 1-3 Alkylene, haloC 1-4 Alkyl-OC 1-3 Alkylene or 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl which is optionally substituted by 1-3 substituents q.

[0057] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each Q1 and each Q2 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1- 6 alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-3 Alkyl-OC 1-2 Alkylene, haloC1-3 Alkyl-OC 1-2 Alkylene or 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted by 1 to 3 substituents q.

[0058] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each Q1 and each Q2 are independently selected from 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, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxy Methyl, hydroxyethyl, methylamino, ethylamino, dimethylamino, methyl-O-methylene, methyl-O-ethylene, monofluoromethyl-O-methylene, monofluoromethyl-O-ethylene, difluoromethyl-O-methylene, difluoromethyl-O-ethylene, trifluoromethyl-O-methylene, trifluoromethyl-O-ethylene, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl optionally substituted with 1-3 q.

[0059] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each q is independently selected from halogen, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0060] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each q is independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0061] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R a , each R a1 , each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or carboxyl C 1-6 alkyl.

[0062] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R a , each R a1 , each R b are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0063] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R a , each R a1 , each R b Each of the following groups is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0064] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R a , each R a1 , each R b Each is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0065] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R a , each R a1 , each R b are independently selected from hydrogen or methyl.

[0066] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R c are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl or carboxyl C 1-4 alkyl.

[0067] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R c Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0068] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each m is independently an integer of 0-4.

[0069] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each m is independently selected from 0, 1, 2 or 3.

[0070] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each n is independently an integer of 0-4.

[0071] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each n is independently selected from 0, 1, 2, 3.

[0072] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein p is selected from 0 or 1.

[0073] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0074] Ring A is selected from a 5-6 membered monocycloalkyl group, a 5-6 membered monoheterocyclic group, an 8-10 membered fused cyclic group, an 8-10 membered fused heterocyclic group, a phenyl group, a 5-6 membered monoheteroaryl group, an 8-10 membered fused aryl group or an 8-10 membered fused heteroaryl group;

[0075] Each R 1 、R 2 、R 3 、R 4 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro or -(L) optionally substituted with 1 to 4 substituents Q2 m -C 1-6 Alkyl, -(L)m -C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1- 6-alkyl;

[0076] R 5 is selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro or -(L) optionally substituted with 1 to 4 substituents Q2 m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L) m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiroheterocyclyl;

[0077] Each L is independently selected from -S(O)2-, -NR c -、-CR a1 R b -;

[0078] R 6 is selected from -S(O)2H, -C(O)H, -C(O)N(R c )2、-N(R c )S(O)2-C 1-6 Alkyl, -N(R c )-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -S(O)2N(R c )-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 group, -S(O)(NR c )-C 1-6 Alkyl, -S(O)(NR c )-3-6 membered cycloalkyl, -S(O)(NR c)-3-6 membered heterocyclic group, -N(R c )C(O)-C 1-6 Alkyl, -N(R c )C(O)-3-6 membered cycloalkyl, -N(R c )C(O)-3-6 membered heterocyclic group, -C(O)N(R c )-C 1-6 Alkyl, -C(O)N(R c )-3-6 membered cycloalkyl, -C(O)N(R c )-3-6 membered heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocyclyl;

[0079] Each R a , each R a1 , each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 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, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or carboxyl C 1-6 alkyl;

[0080] Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0081] Each Q1 and each Q2 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-4 Alkyl-OC 1-3 Alkylene, haloC 1-4 Alkyl-OC 1-3Alkylene or 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl optionally substituted by 1-3 substituents q; each q is independently selected from halogen, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy;

[0082] Each m and n are independently an integer from 0 to 4;

[0083] p is selected from 0 or 1.

[0084] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0085] Ring A is selected from a 5-6 membered monoheteroaryl, an 8-10 membered fused heterocyclic group or an 8-10 membered fused heteroaryl group;

[0086] Each R 1 、R 2 、R 3 、R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0087] R 5 Selected from -(L) optionally substituted with 1 to 4 substituents Q2 m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -5-10 membered cycloalkyl, -(L) m -5-10 membered heterocyclic group, -(L) m -7-11 membered spirocyclic group, -(L) m -7-11 membered spiroheterocyclyl;

[0088] Each L is independently selected from -S(O)2-, -NR c -、-CR a1 R b -;

[0089] R 6 is selected from -S(O)2H, -N(R c )S(O)2-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c)-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -S(O)2N(R c )-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 heterocyclyl.

[0090] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0091] Ring A is selected from cyclopentanyl, cyclohexanyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl or an 8-10 membered nitrogen-containing fused heterocyclic ring;

[0092] Each R 1 、R 2 、R 3 、R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0093] R 5 is selected from a 5-6 membered heterocyclyl or a 7-10 membered spiroheterocyclyl group optionally substituted by 1-3 substituents Q2;

[0094] R 6 is selected from -S(O)2H, -N(R c )S(O)2-C 1-6 Alkyl, -N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2-C 1-6 alkyl;

[0095] Each R a , each R b are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0096] Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0097] Each Q1 and each Q2 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, haloC 1-3 Alkyl-OC 1-2 Alkylene or 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted by 1-3 substituents q; each q is independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy;

[0098] n is selected from 0, 1 or 2;

[0099] p is selected from 0 or 1.

[0100] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0101] Selected from the following structures:

[0102] Each R 1 、R 2 、R 3 、R 4 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0103] Each R a are independently selected from hydrogen, halogen, C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0104] R 5 Selected from the following structures optionally substituted by 1-3 substituents Q2:

[0105] R 6 Selected from the following structures:

[0106] Each Q1 is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, haloC 1-3 Alkyl-OC 1-2 Alkylene or 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted by 1-3 substituents q; each q is independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy;

[0107] Each Q2 is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0108] n is selected from 0, 1 or 2.

[0109] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (II),

[0110] Among them, X 5 is selected from N or CH; t is selected from 0, 1 or 2;

[0111] Ring A, X 1 、X 2 、X 3 、X 4 、R 1 、R 2 、R 3 、R 4 、R 6, each Q1, each Q2, n, and p are defined as described in any of the aforementioned schemes.

[0112] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0113] X 5 is N;

[0114] Each R 1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0115] R 2 、R 3 、R 4 are each independently hydrogen;

[0116] R 6 Selected from the following structures:

[0117] Preferably, R 6 Selected from the following structures:

[0118] Selected from the following structures:

[0119] Preferably, Selected from the following structures:

[0120] Each Q1 is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, haloC 1-3 Alkyl-OC 1-2 Alkylene or 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted by 1-3 substituents q; each q is independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy;

[0121] Each Q2 is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkyl or halogenated C 1-6 alkoxy;

[0122] Each R a are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0123] n is selected from 0, 1 or 2.

[0124] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (III),

[0125] Among them, X 5 is selected from N or CH; t is selected from 0, 1 or 2;

[0126] Ring A, X 1 、X 2 、X 3 、X 4 、R 1 、R 6 , each Q1, each Q2, n, and p are defined as described in any of the aforementioned schemes.

[0127] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (III'),

[0128] wherein t is selected from 0, 1 or 2;

[0129] Ring A, X 2 、X 3 、X 4 、R 1 、R 6 , each Q1, each Q2, n, and p are defined as described in any of the aforementioned schemes.

[0130] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure shown in Formula (III-1), Formula (III-2), Formula (III-3) or Formula (III-4),

[0131] Among them, ring A, X 1 、X 2 、X 3 、X 4 、R 1, each Q1, each Q2, n, p, and t are defined as described in any of the preceding schemes.

[0132] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV),

[0133] wherein t is selected from 0, 1 or 2;

[0134] Ring A, X 3 、R 1 、R a 、R 6 , each Q1, each Q2, and n are defined as described in any of the aforementioned schemes.

[0135] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-1),

[0136] wherein t is selected from 0, 1 or 2;

[0137] R 1 、R a 、R 6 , each Q1, each Q2, and n are defined as described in any of the aforementioned schemes.

[0138] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-2),

[0139] wherein t is selected from 0, 1 or 2;

[0140] R 1 、R a 、R 6 , each Q1, each Q2, and n are defined as described in any of the aforementioned schemes.

[0141] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-3),

[0142] wherein t is selected from 0, 1 or 2;

[0143] R 1 、R a 、R 6 , each Q1, each Q2, and n are defined as described in any of the aforementioned schemes.

[0144] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-4),

[0145] wherein t is selected from 0, 1 or 2;

[0146] R 1 、R a 、R 6 , Q1, and each Q2 are defined as described in any of the aforementioned schemes.

[0147] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-5),

[0148] Among them, R 1 、R a 、R 6 , each Q1, n is defined as described in any of the above schemes.

[0149] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-5),

[0150] Among them, R 6 Selected from the following structures:

[0151] R 1 、R a , each Q1, n is defined as described in any of the above schemes.

[0152] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-6),

[0153] Among them, R 1 、R a 、R 6 , each Q1, n is defined as described in any of the above schemes.

[0154] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-6),

[0155] Among them, R 6 Selected from the following structures:

[0156] R 1 、R a, each Q1, n is defined as described in any of the above schemes.

[0157] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-7),

[0158] Among them, R 1 、R a 、R 6 , each Q1, n is defined as described in any of the above schemes.

[0159] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-7),

[0160] Among them, R 6 Selected from the following structures:

[0161] R 1 、R a , each Q1, n is defined as described in any of the above schemes.

[0162] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-8),

[0163] Among them, R 1 、R a 、R 6 , Q1 is defined as described in any of the above schemes.

[0164] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-8),

[0165] Among them, R 6 Selected from the following structures:

[0166] R 1 、R a , Q1 is defined as described in any of the above schemes.

[0167] In some embodiments of the present invention, the structure of the provided compound, its pharmaceutically acceptable salt or its stereoisomer is as follows:

[0168] The present invention also provides a pharmaceutical composition comprising the aforementioned compound, its pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more second therapeutically active agents. Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or diluents.

[0169] The second therapeutic agent of the present invention includes but is not limited to growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, antimetabolites, antimitotics, angiogenesis inhibitors, biological response modifiers, antihormones, and anticancer drugs.

[0170] The present invention also provides a pharmaceutical preparation containing the aforementioned compound, its pharmaceutically acceptable salt, ester or stereoisomer, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical preparation is in any clinically or pharmaceutically acceptable dosage form.

[0171] In some embodiments of the present invention, the pharmaceutical preparations described above can be administered to patients or subjects requiring such treatment orally, parenterally, rectally, or transpulmonaryly. For oral administration, the pharmaceutical composition can be formulated into oral preparations, such as conventional oral solid preparations such as tablets, capsules, pills, granules, or oral liquid preparations such as oral solutions, oral suspensions, and syrups. Suitable fillers, binders, disintegrants, lubricants, and the like can be added to these oral preparations. For parenteral administration, the pharmaceutical preparations described above can also be formulated into injectables, including injections, sterile powders for injection, and concentrated solutions for injection. Injectables can be produced using conventional methods in the pharmaceutical field. Additives may be omitted or added depending on the properties of the drug. For rectal administration, the pharmaceutical composition can be formulated into suppositories. For transpulmonary administration, the pharmaceutical composition can be formulated into inhalers or sprays.

[0172] Available pharmaceutical carrier and / or diluent in pharmaceutical composition of the present invention or pharmaceutical preparation can be any conventional carrier and / or diluent in pharmaceutical preparation field, and the selection of specific carrier and / or diluent will depend on the mode of administration or disease type and state that are used to treat specific patient.The preparation method of the suitable pharmaceutical composition that is used for specific administration mode is fully within the knowledge scope of pharmaceutical field technicians.For example, pharmaceutical carrier and / or diluent can comprise the conventional solvent, diluent, dispersant, suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, adhesive, lubricant, stabilizer, hydrating agent, emulsification accelerator, buffer, absorbent, coloring agent, ion exchanger, releasing agent, coating agent, flavoring agent and antioxidant etc. in pharmaceutical composition.If desired, flavoring agent, preservative and sweetening agent etc. can also be added in pharmaceutical composition.

[0173] The present invention also provides the use of the aforementioned compound, its pharmaceutically acceptable salt, ester or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing KIF18A-mediated diseases and related diseases; the KIF18A-mediated diseases and related diseases are selected from cancer or benign tumors.

[0174] The present invention also provides the use of the aforementioned compound, its pharmaceutically acceptable salt, ester or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in treating and / or preventing KIF18A-mediated diseases and related diseases; the KIF18A-mediated diseases and related diseases are selected from cancer or benign tumors.

[0175] The present invention also provides a method for treating a disease, comprising administering a therapeutically effective amount of the aforementioned compound, its pharmaceutically acceptable salt or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition to a patient in need thereof, wherein the disease is a KIF18A-mediated disease and related diseases; the KIF18A-mediated disease and related diseases are selected from cancer or benign tumors.

[0176] The cancer or benign tumor includes but is not limited to melanoma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, head and neck cancer, thyroid cancer, lung cancer, bronchial cancer, esophageal cancer, gastric cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, colon cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, bone cancer and blood tumor; the lung cancer includes but is not limited to small cell lung cancer and non-small cell lung cancer; the blood tumor includes but is not limited to leukemia, lymphoma, myeloma; the brain cancer includes but is not limited to glioma, neuroblastoma, astrocytoma, meningioma.

[0177] In the specification and claims of this application, compounds are named according to their chemical structural formulas. If the name of the compound and the chemical structural formula do not match when referring to the same compound, the chemical structural formula shall prevail.

[0178] In this application, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, definitions of some terms are provided below. In the event that the definitions and explanations of terms provided in this application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided in this application shall prevail.

[0179] The "halogen" described in the present invention refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

[0180] The term "halo" as used herein means that any hydrogen atom in a substituent group may be replaced by one or more halogen atoms, which may be the same or different. "Halogen" is as defined above.

[0181] The "C 1-6 "Alkyl" means a straight or branched chain alkyl group containing 1 to 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 5-6 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 1- 4 alkyl" refers to C 1-6 Specific examples of alkyl groups contain 1 to 4 carbon atoms.

[0182] The "C 1-6 "Alkylene" refers to the above-mentioned C 1-6 The group formed by removing a hydrogen atom from an alkyl group includes, for example, "C 1-5 Alkylene", "C 1-4 Alkylene", "C 1-3 Alkylene", "C 1-2 Alkylene", "C 2-6 Alkylene", "C 2-5 Alkylene", "C 2-4 Alkylene", "C 2-3 Alkylene", "C 3-6 Alkylene", "C 3-5 Alkylene", "C 3-4 Alkylene", "C 4-6 Alkylene", "C 4-5 Alkylene", "C 5-6 Specific examples include but are not limited to methylene, ethylene, propylene, butylene, pentylene, hexylene, etc. The "C 1-4 "Alkylene" refers to C1-6 Specific examples of the alkylene group include those containing 1 to 4 carbon atoms.

[0183] The "C 2-6 "Alkenyl" refers to a linear, branched or cyclic alkenyl group with 2 to 6 carbon atoms containing at least one double bond, including, for example, "C 2-5 Alkenyl", "C 2-4 Alkenyl", "C 2-3 Specific examples include, but are not limited to, ethenyl, 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, and the like.

[0184] The "C 2-6 "Alkynyl" refers to a straight or branched chain alkynyl group with 2 to 8 carbon atoms containing a triple bond, including, for example, "C 2-5 Alkynyl", "C 2-4 Alkynyl", "C 2-3 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, and the like.

[0185] The “C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl aminoacyl, C 1-6 Alkyl amido, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylamino, C 1-6Alkylaminosulfonyl, C 1-6 Alkylcarbonyl, C 1-6 "Alkoxycarbonyl" refers to a 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)-, C 1-6 Alkyl-OC(O)-formed groups, wherein "C 1-6 "Alkyl" is as defined above.

[0186] The “C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-4 Alkyl aminoacyl, C 1-4 Alkyl amido, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfonylamino, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylcarbonyl, C 1-4 "Alkoxycarbonyl" refers to a 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-, C 1-4 Alkyl-S(O)2-NH-, C 1-4 Alkyl-NH-S(O)2-, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-OC(O)-formed groups, wherein "C 1-4 "Alkyl" is as defined above.

[0187] The "halogenated C 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 groups, amino groups, carboxyl groups, etc. 1-6 Alkyl, C 1-6 Alkylene, C 1-6 A group formed by the hydrogen atoms in an alkoxy group.

[0188] The "halogenated C 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, amino groups substituted with C 1-4 Alkyl, C 1-4 A group formed by the hydrogen atoms in an alkoxy group.

[0189] The "3-12 membered cycloalkyl group" mentioned in the present invention includes "3-8 membered cycloalkyl group" and "7-12 membered condensed cycloalkyl group".

[0190] The "3-8 membered cycloalkyl" described in the present invention refers to a saturated or partially saturated monocyclic alkyl group containing 3-8 carbon atoms and not aromatic, including "3-8 membered saturated cycloalkyl" and "3-8 membered partially saturated cycloalkyl"; preferably "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", "5-8 membered saturated cycloalkyl", "5-7 membered saturated cycloalkyl", "5-6 membered saturated cycloalkyl" and the like. Specific examples of the “3-8 membered saturated cycloalkyl” include, but are not limited to, cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), cyclooctane (cyclooctyl), etc.; specific examples of the “3-8 membered partially saturated cycloalkyl” include, but are not limited to, cyclopropane, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexa-1,3-diene, cyclohex-1,4-diene, cycloheptenyl, cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5-trienyl, cyclooctenyl, cyclooct-1,3-dienyl, cyclooct-1,4-dienyl, cyclooct-1,5-dienyl, cyclooct-1,3,5-trienyl, cyclooctatetraenyl, etc.

[0191] The "7-12 membered fused heterocyclic group" described in the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 7-12 ring atoms 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 have aromaticity; it includes "7-9 membered fused heterocyclic group", "9-10 membered fused heterocyclic group", etc., and its fusion mode can be: 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo 5-6 membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl, etc. Examples include, but are not limited to, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octanyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthrenyl, 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-tetrahydropentalenyl, 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, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthryl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl and the like.

[0192] The "3-12 membered heterocyclic group" described in the present invention includes "3-8 membered heterocyclic group" and "7-12 membered fused heterocyclic group".

[0193] The "3-8 membered heterocyclic group" of the present invention refers to a saturated or partially saturated monocyclic group that is not aromatic and contains at least one heteroatom (e.g., 1, 2, 3, 4, or 5) and 3-8 ring atoms, wherein the heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms, or sulfur atoms) in the ring structure may be oxo-substituted. The "3-8 membered heterocyclic group" of the present invention includes "3-8 membered saturated heterocyclic groups" and "3-8 membered partially saturated heterocyclic groups." Preferably, the "3-8 membered heterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-8 membered heterocyclic group" of the present invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3-8 membered heterocyclic group" of the present invention contains 1 nitrogen atom. The “3-8 membered heterocyclic group” is preferably a “3-7 membered heterocyclic group”, “3-6 membered heterocyclic group”, “4-7 membered heterocyclic group”, “4-6 membered heterocyclic group”, “6-8 membered heterocyclic group”, “5-7 membered heterocyclic group”, “5-6 membered heterocyclic group”, “3-6 membered saturated heterocyclic group”, “5-6 membered saturated heterocyclic group”, “3-6 membered nitrogen-containing heterocyclic group”, “3-6 membered saturated nitrogen-containing heterocyclic group”, “5-6 membered nitrogen-containing heterocyclic group”, “5-6 membered saturated nitrogen-containing heterocyclic group”, etc. For example, it contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and other 1 or 2 heteroatoms (such as oxygen atoms and / or sulfur atoms). Specific examples of "3-8 membered heterocyclic group" include, but are not limited to, aziridine, 2H-aziridine, diaziridine, 3H-diazirinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolane, 1,4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, oxazolyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3,4-dihydro-2H-pyranyl, etc.

[0194] The "7-12 membered fused heterocyclic group" of the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 7-12 ring atoms formed by two or more cyclic structures sharing two adjacent atoms, and at least one ring atom is a heteroatom, wherein one of the rings in the fused ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity, and the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom, and optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure may be oxo-substituted, including but not limited to "7-12 membered heterocyclic group". The condensed heterocyclic group includes, but is not limited to, 5-6-membered heterocyclic group, 5-6-membered heterocyclic group, 5-6-membered heterocyclic group, 5-6-membered cycloalkyl group, benzo-5-6-membered heterocyclic group, benzo-5-6-membered saturated heterocyclic group, 5-6-membered heteroaryl-5-6-membered heterocyclic group, 5-6-membered heteroaryl-5-6-membered saturated heterocyclic group; 5-6-membered heteroaryl is as defined above; specific examples of the "7-12-membered condensed heterocyclic group" include, but are not limited to, pyrazolyl-cyclohexyl, pyrrolidinyl-cyclopropyl, cyclopentyl aziridinyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinylmorpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridocyclopentyl, pyridocyclohexyl, pyridotetrahydrofuranyl pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidooxazolidinyl, pyrimidothiazolidinyl, pyrimidothiazolidinyl, pyrimidoisoxazolidinyl, pyrimidoisothiazolidinyl, pyrimidopiperidinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidooxazolidinyl, pyrimidothiazolidinyl, pyrimidoisoxazolidinyl, pyrimidoisothiazolidinyl, pyrimidopiperidinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidotetrahydropyranyl;Tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxolyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H- Furo[3,4-d]imidazolyl, 4,6-dihydro-1H-thieno[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d]imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenta[c]pyrrolyl, 4H-1,3-benzoxazinyl, etc.;

[0195] The "5-10 membered cycloalkyl group" described in the present invention is an example of a "3-12 membered cycloalkyl group" containing 5 to 10 ring atoms.

[0196] The "5-10 membered heterocycloalkyl" described in the present invention is an example of a "3-12 membered heterocycloalkyl" containing 5 to 10 ring atoms.

[0197] The "6-10 membered aryl group" described in the present invention refers to an aromatic cyclic group containing 6-10 ring carbon atoms, including "6-8 membered monocyclic aryl groups" and "8-10 membered condensed ring aryl groups".

[0198] The "6-8 membered monocyclic aromatic group" described in the present invention refers to a monocyclic aromatic group containing 6-8 ring carbon atoms, examples of which include but are not limited to phenyl, cyclooctatetraenyl, etc.; preferably phenyl.

[0199] The "8-10 membered fused ring aromatic group" described in the present invention refers to an unsaturated aromatic cyclic group containing 8-10 ring carbon atoms, which is formed by two or more cyclic structures sharing two adjacent atoms. It is preferably a "9-10 membered fused ring aromatic group", and specific examples include naphthyl.

[0200] The "5-12 membered heteroaryl group" described in the present 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, an oxygen atom, or a sulfur atom), and can include, for example, a 5-12 membered nitrogen-containing heteroaryl group, a 5-12 membered oxygen-containing heteroaryl group, or a 5-12 membered sulfur-containing heteroaryl group. It includes "5-8 membered single heteroaryl groups" and "7-12 membered fused heteroaryl groups."

[0201] The "5-8 membered monoheteroaryl" of the present invention refers to a monocyclic cyclic group having aromaticity and containing 5-8 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms, or sulfur atoms) in the ring structure may be oxo-substituted. The "5-8 membered monoheteroaryl" includes, for example, "5-7 membered monoheteroaryl", "5-6 membered monoheteroaryl", "5-6 membered nitrogen-containing monoheteroaryl", "5 membered nitrogen-containing monoheteroaryl", etc. Specific examples of “5-8 membered monocyclic heteroaryl” include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, 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-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azacycloheptatrienyl, 1,3-diazacycloheptatrienyl, azacyclooctatetraenyl, and the like. The "5- to 6-membered heteroaryl" refers to a specific example of a 5- to 8-membered heteroaryl containing 5 to 6 ring atoms.

[0202] The "7-12-membered fused heteroaryl" herein refers to an unsaturated aromatic cyclic structure containing 7-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms. Optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms, or sulfur atoms) in the cyclic structure may be oxo-substituted. Including "8-10 membered fused heteroaryl", "7-9 membered fused heteroaryl", etc., and the fusion mode can be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furathiophene, pyrazolooxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinonyl, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, etc.

[0203] The "5-12 membered bridged ring group" of the present invention refers to a structure containing 5-12 carbon atoms formed by any two rings sharing two atoms that are not directly connected. The "5-12 membered bridged ring" includes a 5-12 membered saturated bridged ring group and a 5-12 membered partially saturated bridged ring group. Preferred are a 5-10 membered bridged ring group, a 5-8 membered bridged ring group, a 5-10 membered saturated bridged ring group, a 5-8 membered saturated bridged ring group, a 6-10 membered saturated bridged ring group, and a 7-12 membered partially saturated bridged ring group. Specific examples include but are not limited to

[0204] The "5-12-membered bridged heterocyclic group" of the present 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 1-3 heteroatoms, and also includes the case where the carbon atoms, nitrogen atoms, and sulfur atoms may be oxo-substituted. Preferably, the 5-10-membered bridged heterocyclic group or the 5-8-membered bridged heterocyclic group is used. Specific examples include, but are not limited to:

[0205] The "5-12 membered spirocyclyl" of the present invention refers to a structure containing 5-12 carbon atoms formed by at least two rings sharing one atom. It comprises a 5-12 membered saturated spirocyclyl and a 5-12 membered partially saturated spirocyclyl, including, for example, a "5-10 membered saturated spirocyclyl", "5-10 membered unsaturated spirocyclyl", "5-8 membered spirocyclyl", "5-8 membered saturated spirocyclyl", "5-8 membered unsaturated spirocyclyl", "7-11 membered spirocyclyl", "7-10 membered spirocyclyl", "7-9 membered spirocyclyl", "8-10 membered spirocyclyl", "8-11 membered spirocyclyl", and specific examples of the 5-12 membered saturated spirocyclyl include but are not limited to: A group formed by replacing any substitutable hydrogen atom with a cyclic structure such as 5-12. A 5-12 membered partially saturated spirocyclic group refers to a cyclic group in which at least one ring is unsaturated. Specific examples include but are not limited to: A group formed by replacing any substitutable hydrogen atom with a cyclic structure.

[0206] The "5-12 membered spiro heterocyclyl" of the present invention refers to a 5-12 membered spiro heterocyclyl in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, or N, preferably 1 to 3 heteroatoms, and includes a case where the carbon atom, nitrogen atom, and sulfur atom may be oxoed. Examples include, but are not limited to, 5-10 membered spiro heterocyclyl, 5-8 membered spiro heterocyclyl, 5-6 membered spiro heterocyclyl, 7-12 membered spiro heterocyclyl, 7-11 membered spiro heterocyclyl, 7-11 membered nitrogen-containing spiro heterocyclyl, 7-10 membered spiro heterocyclyl, 7-10 membered nitrogen-containing spiro heterocyclyl, 7-9 membered spiro heterocyclyl, 7-9 membered nitrogen-containing spiro heterocyclyl, and 8 membered nitrogen-containing spiro heterocyclyl. Specific examples include, but are not limited to:

[0207] The "optionally substituted by..." mentioned in the present invention includes two situations: "substituted" and "unsubstituted".

[0208] The "pharmaceutically acceptable salts" described in the present invention refer to pharmaceutically acceptable acid and base addition salts, such as metal salts, ammonium salts, salts formed with organic acids, salts formed with organic bases, salts formed with inorganic acids, salts formed with acidic amino acids or basic amino acids, etc.

[0209] The "ester" of the present invention refers to a pharmaceutically acceptable ester, in particular to an ester that is hydrolyzed in vivo and includes esters that are easily decomposed in the human body to leave the parent compound (the compound of formula (I)) or its salt. The "ester" of the present invention can be selected from the following groups: (1) carboxylic acid esters obtained by esterification with carboxylic acid compounds, wherein the non-carbonyl portion of the carboxylic acid compound is selected from, for example, C 1-20 Straight-chain or branched alkyl, C 1-12 Straight-chain or branched alkyl, C 1-8 Straight-chain or branched alkyl, C 1-6 Straight-chain or branched alkyl (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 (such as benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g. phenoxymethyl), C 6-10 Aryl (e.g. phenyl, optionally substituted with, for example, halogen, C 1-4 Alkyl or C 1-4 (2) sulfonates, such as alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); and (4) mono-, di-, or triphosphates, etc.; (5) 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, C 1-12 Straight-chain or branched alkyl, C 1-8 Straight-chain or branched alkyl, C 1-6 Straight-chain or branched alkyl (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 (such as benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g. phenoxymethyl), C6-10 Aryl (e.g. phenyl, optionally substituted with, for example, halogen, C 1-4 Alkyl or C 1-4 substituted with alkoxy or amino groups).

[0210] As used herein, "stereoisomers" refer to compounds of the present invention that contain one or more asymmetric centers and can therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. Compounds of the present invention may have asymmetric centers, each of which independently gives rise to two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures. Compounds of the present invention that contain olefinic double bonds include cis- and trans-isomers, unless otherwise specified. Compounds of the present invention may exist as tautomers (a type of functional group isomer) that have different points of hydrogen attachment due to the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and their mixtures are included within the scope of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis- and trans-isomers, tautomers, geometric isomers, epimers, and mixtures thereof of all compounds are included within the scope of the present invention.

[0211] As used herein, a "therapeutically effective amount" refers to an amount of the aforementioned compound, pharmaceutical formulation, or pharmaceutical composition that, when administered to a patient, at least alleviates the symptoms of the patient's condition. The actual amount comprising a "therapeutically effective amount" will vary depending on a variety of circumstances, including, but not limited to, the specific condition being treated, the severity of the condition, the patient's physical condition and health, and the route of administration. Skilled medical practitioners can readily determine the appropriate amount using methods known in the medical field.

[0212] Advantageous Effects of the Invention

[0213] (1) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have excellent KIF18A inhibitory activity and can treat and / or prevent KIF18A-mediated diseases and related diseases;

[0214] (2) The compounds of the present invention have a good inhibitory effect on tumor cells;

[0215] (3) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have good pharmacokinetic properties, longer-lasting effects and high bioavailability;

[0216] (4) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have good safety;

[0217] (5) The compound of the present invention has a simple preparation process, high pharmaceutical purity, stable quality, and is easy to carry out large-scale industrial production.

[0218] The following experiments further illustrate the beneficial effects of the compounds provided in the examples of the present invention, but this should not be understood as meaning that the compounds provided in the examples of the present invention only have the following beneficial effects.

[0219] Experimental Example 1 In vitro cytological activity of the compounds of the present invention

[0220] Test samples: some of the compounds of the present invention, their chemical names and structures are shown in the preparation examples.

[0221] The cell lines used in the following experiments are as follows:

[0222] OVCAR3: TP53-mutated human ovarian cancer cells

[0223] MDA-MB-157: TP53-mutated human breast cancer cells

[0224] Experimental method (CelltiterGlo assay)

[0225] 1. Cell Preparation

[0226] 1.1 Cell culture:

[0227] All cells were adherent cells. The culture medium for OVCAR3 cells was RPMI Medium 1640 + 20% FBS + 1% PS, and the culture medium for MDA-MB-157 cells was DMEM Medium + 10% FBS + 1% PS. The cells were tested in the logarithmic growth phase.

[0228] 1.2 Preparation of cell suspension:

[0229] Harvest cells in the logarithmic growth phase and count them using a platelet counter. Assess cell viability using trypan blue exclusion to ensure viability is above 90%. Adjust to the appropriate concentration and add 90 μL of the cell suspension to each well of a 96-well plate.

[0230] Table 1 Number of cells seeded

[0231] 2. Preparation of test compounds

[0232] 2.1 Prepare DMSO stock solution of the test compound. The concentration of the stock solution of the test compound is 10 mM.

[0233] 2.2 Preparation of test compound working stock solutions

[0234] The test compound stock solution was 10 mM and serially diluted 3-fold for a total of 9 concentrations. 2 μL of each DMSO-diluted compound was then added to 198 μL of culture medium to prepare the test compound working stock solution (compound concentration was 10 times the final concentration, with a maximum concentration of 100 μM).

[0235] 2.3 Compound treatment

[0236] 10 μL of compound working stock solution (10-fold dilution, final DMSO concentration of 0.1%) was added to each well of a 96-well plate seeded with cells.

[0237] The final concentrations of the test compounds were: 10 μM, 3.33 μM, 1.11 μM, 370 nM, 123 nM, 41.1 nM, 13.7 nM, 4.57 nM, 1.52 nM.

[0238] 2.4 Control well setting

[0239] Solvent control: 0.1% DMSO.

[0240] Blank control: culture medium

[0241] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 4 days.

[0242] 3. Detection

[0243] Thaw CTG reagent and equilibrate a 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Glo assay kit) to each well, shake on a shaker for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal using a multifunctional microplate reader.

[0244] 4. Data Processing

[0245] 1) Inhibition rate (%) = 1 - (test substance well reading + blank control well reading) / (DMSO solvent control well reading - blank control well reading) × 100%;

[0246] 2) Input GraphPad Prism to draw a graph and obtain the curve and IC 50 .

[0247] Experimental results and conclusions

[0248] Table 2 In vitro cytological activities of the compounds of the present invention (IC 50 ,nM)

[0249] A:IC 50 <100nM; B: 100nM≤IC 50<200nM; C: 200nM≤IC 50 <1 μM;

[0250] From the above, it can be seen 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 cancerous diseases with TP53 mutations.

[0251] Experimental Example 2 In vitro enzymatic activity of the compounds of the present invention

[0252] Test sample: The compound of the present invention, its structural formula and preparation method are shown in the preparation examples.

[0253] Experimental reagents:

[0254] Experimental methods:

[0255] 1. Compound dilution

[0256] (1) The compound of the present invention was prepared in DMSO to 10 mM as a test stock solution.

[0257] (2) The test stock solution was diluted 3-fold to 10 concentrations, with the highest concentration being 10 mM.

[0258] (3) The final concentrations of the test compounds were 10000 nM, 3333.3 nM, 1111.1 nM, 370.4 nM, 123.5 nM, 41.2 nM, 13.7 nM, 4.57 nM, 1.52 nM, and 0.51 nM.

[0259] 2. Enzyme reaction experiment

[0260] (1) Use Echo 650 to transfer 0.025 μL of compound dilution to each well of a 384-well assay plate, with each column containing 2 replicates.

[0261] (2) Add 2.5 μL of enzyme working solution to a 384-well assay plate and centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 10 minutes.

[0262] (3) Add 2.5 μL of ATP working solution and incubate at 25°C for 60 minutes.

[0263] (4) Add 4 μL of ADP-Glo ​​working solution and incubate at 25°C for 40 minutes.

[0264] (5) Add 8 μL of detection working solution and incubate at 25°C for 40 minutes.

[0265] 3. Result detection

[0266] (1) Read the chemiluminescence signal on the BMG HTS high-throughput drug screening multifunctional microplate reader.

[0267] (2) Collect data.

[0268] 4. Data Analysis

[0269] The inhibition rate (%inh) was calculated using the following formula:

[0270] Test compound inhibition rate (%inh) = 100*(ave High control-cpd well) / (ave High control-ave Low control)

[0271] Wherein, ave High control represents: the luminescent signal intensity of the positive control well without adding the compound;

[0272] Ave Low control indicates the luminescent signal intensity of the negative control well without enzyme addition;

[0273] Cpd well means: represents the luminescence signal intensity of the test compound;

[0274] IC calculation using XLfit 50 .

[0275] Experimental results:

[0276] Table 3 Inhibitory activity of the compounds of the present invention on KIF18A

[0277] It can be seen from the above experimental results that the compound of the present invention can effectively inhibit the activity of KIF18A and is an effective KIF18A inhibitor.

[0278] Experimental Example 3 Pharmacokinetics of the Compounds of the Invention in Mice

[0279] Test sample: Compound of the present invention, homemade, its chemical name and preparation method can be found in the preparation examples of each compound.

[0280] Test animals: CD1 mice, female, 6 mice / administration route / compound.

[0281] Preparation of test solution:

[0282] Preparation method of blank solvent (1): Weigh 20g HPC (hydroxypropyl cellulose), slowly add it to 500mL of stirred purified water, then add 1mL of Tween 80, stir until clear and transparent, adjust the volume to 1000mL, and stir evenly to obtain 2% HPC + 0.1% Tween 80.

[0283] IV (intravenous push) administration:

[0284] An appropriate amount of the compound of the present invention (e.g., 2.58 mg) was weighed, DMA (N,N-dimethylacetamide) (e.g., 489 μL) was added, and the solution was dissolved by ultrasonic vortexing. Kolliphor HS15 (polyethylene glycol-15-hydroxystearate) (e.g., 489 μL) was then added and vortexed to mix. Finally, DPBS (Dulcerative phosphate buffered saline) (e.g., 3.914 mL) was added and vortexed to prepare a 0.5 mg / mL clear solution, which was used as the IV dosing solution for the test compound.

[0285] PO (oral) administration:

[0286] An appropriate amount of the compound of the present invention (e.g., 10.16 mg) was weighed and placed in a tissue grinder. A blank solvent (1) (e.g., 3.102 mL) was added and ground uniformly at a speed of 1000 rpm to prepare a 3 mg / mL suspension solution, which was used as the PO administration solution for the test compound.

[0287] Experimental methods

[0288] The IV dose is 2.5 mg / kg, the administration concentration is 0.5 mg / mL, and the administration volume is 5 mL / kg.

[0289] The PO dose is 30 mg / kg, the dosing concentration is 3 mg / mL, and the dosing volume is 10 mL / kg.

[0290] Blood collection time points: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours after administration. Blood was collected according to the method shown in Table 4:

[0291] Table 4

[0292] At each time point, approximately 50 μL of whole blood was collected from the inner canthus of the eye and placed in an anticoagulant tube containing EDTA-K2 anticoagulant. The blood was centrifuged at 8000 rpm for 6 min at 4°C to obtain plasma samples, which were then frozen at -80°C until analysis.

[0293] Plasma sample analysis

[0294] The protein precipitation method was used: 20 μL of plasma sample was taken, 200 μL of internal standard (acetonitrile solution containing 200 ng / mL of tolbutamide) was added, and the sample was vortexed for 10 minutes, followed by centrifugation at 4000 rpm for 20 minutes. 100 μL of the supernatant was taken, and 100 μL of water was added. After vortexing for 3 minutes, the drug concentration in the plasma was analyzed by LC-MS / MS.

[0295] Experimental results and conclusions

[0296] The test results show that the compound of the present invention has good pharmacokinetic properties, a low clearance rate, and a high exposure and bioavailability. DETAILED DESCRIPTION

[0297] The technical solutions of the present invention will be described below in conjunction with specific embodiments. The embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0298] DMF: N,N-dimethylformamide EA: ethyl acetate PE: petroleum ether

[0299] DCM: dichloromethane THF: tetrahydrofuran DMA: N,N-dimethylacetamide

[0300] DIPEA: N,N-diisopropylethylamine DMSO: dimethyl sulfoxide DEAD: diethyl azodicarboxylate

[0301] NaH: Sodium hydride TFA: Trifluoroacetic acid SOCl2: Sulfonyl chloride

[0302] CuI: iodide Boc-NH2: tert-butyl carbamate

[0303] RuPhos Pd G3: methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II)

[0304] PdCl2(dppf): (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride

[0305] Example 1: Preparation of 4-((2-hydroxyethyl)sulfonyl)-N-(1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 1)

[0306] 1. Preparation of 6-chloro-1-propyl-1H-pyrazolo[3,4-b]pyridine (Int-1)

[0307] To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine (4.0 g, 26.0 mmol) in DMF (90 mL) was added NaH (1.6 g, 40.0 mmol) at 0°C and allowed to react for 30 minutes. Iodopropane (5.3 g, 31.1 mmol) was then added. The reaction was continued for 30 minutes. The system was quenched with water, and the organic phase was extracted with EA, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:4) to afford 3.8 g of the title compound in a 74.8% yield.

[0308] 2. Preparation of tert-butyl (1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (Int-2)

[0309] To a solution of compound Int-1 (800 mg, 4.1 mmol) in 1,4-dioxane (100 mL) were added Boc-NH2 (961 mg, 8.2 mmol), RuPhos Pd G3 (343 mg, 0.41 mmol), and cesium carbonate (4.0 g, 12.3 mmol). The mixture was reacted at 100°C under nitrogen for 16 hours. The reaction was quenched with water, and the organic phase was extracted with EA, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:9) to obtain 1.0 g of the title compound in an 88.5% yield.

[0310] 3. Preparation of 1-propyl-1H-pyrazolo[3,4-b]pyridin-6-amine (Int-3)

[0311] To a solution of compound Int-2 (1.0 g, 3.6 mmol) in DCM (15 mL) was added TFA (5 mL) at 25°C and allowed to react for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was diluted with DCM. The pH was adjusted to alkaline with saturated sodium bicarbonate. The organic phase was extracted with DCM, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:1) to obtain 500 mg of the title compound in a 78.4% yield.

[0312] 4. Preparation of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (Int-4)

[0313] To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (500 mg, 1.4 mmol) in DCM (8 mL) was added DMF (0.2 mL) at 25°C. SOCl2 (508 mg, 4.2 mmol) was then added at 0°C and the reaction continued for 30 minutes. Upon completion, the reaction solution was concentrated to dryness and used directly in the next step.

[0314] 5. Preparation of 4-iodo-N-(1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Int-5)

[0315] Potassium phosphate (297 mg, 1.4 mmol), DIPEA (1.1 g, 8.5 mmol), and compound Int-3 (247 mg, 1.4 mmol) were added to compound Int-4 (the crude product from the previous step) in DCM (10 mL) at 0°C, and the reaction was continued at 25°C for 2 hours. After completion of the reaction, the pH was adjusted to alkaline with saturated sodium bicarbonate. The organic phase was extracted with DCM, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:1) to obtain 360 mg of the title compound, with a two-step yield of 49.9%.

[0316] 6. Preparation of 4-((2-hydroxyethyl)sulfonyl)-N-(1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 1)

[0317] To compound Int-5 (202 mg, 0.39 mmol) in DMF (15 mL) were added CuI (74 mg, 0.39 mmol), N-methylglycine (69 mg, 0.78 mmol), potassium phosphate (414 mg, 2.0 mmol), and 2-hydroxyethane-1-sulfonamide (146 mg, 1.2 mmol). The mixture was then reacted at 100°C under nitrogen for 16 hours. After completion, the reaction was quenched with water, extracted with EA, concentrated, and purified on a silica gel column (EA:PE = 2:1) to obtain 136 mg of the title compound in a 67.7% yield.

[0318] Molecular formula: C 25 H 32 N6O4S molecular weight: 512.6 LC-MS (M / e): 513.2 (M+H + )

[0319] 1H-NMR (400MHz, DMSO-d6) δ: 13.68 (s, 1H), 10.2 (s, 1H), 8.27-8.22 (m, 2H), 8.13-8.07 (m, 2H), 7.32 (d, J = 2.0Hz, 1H), 7.18-7.15 (m, 1H), 4.95 (s ,1H),4.38-4.35(m,2H),3.77-3.76(m,2H),3.39-3.36(m,2H),3.04-3 .03(m,4H),1.99-1.82(m,6H),0.89-0.88(m,3H),0.43-0.0.41(m,4H).

[0320] Example 2: Preparation of 4-((2-hydroxyethyl)sulfonyl)-N-(4-methyl-1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 2)

[0321] 1. Preparation of (2,6-dichloro-4-methylpyridin-3-yl)methanol (Int-6)

[0322] Borane tetrahydrofuran solution (97.2 mL, 97.2 mmol) was added to a solution of 2,6-dichloro-4-methylnicotinic acid (5.0 g, 24.3 mmol) in THF (10 mL) at 0°C and allowed to react at 50°C for 16 hours. The reaction was quenched with water, and the organic phase was extracted with EA, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:2) to obtain 4.4 g of the title compound in a 94.4% yield.

[0323] 2. Preparation of 2,6-dichloro-4-methylnicotinaldehyde (Int-7)

[0324] To compound Int-6 (4.2 g, 21.9 mmol) in DCM (100 mL) was added pyridinium chlorochromate (14.2 g, 65.9 mmol), and the mixture was allowed to react at 25°C for 2 hours. The reaction solution was concentrated, and the residue was purified on a silica gel column (EA:PE = 1:3) to obtain 3.9 g of the title compound in a 93.8% yield.

[0325] 3. Preparation of 6-chloro-4-methyl-1H-pyrazolo[3,4-b]pyridine (Int-8)

[0326] To compound Int-7 (2.2 g, 11.6 mmol) in n-butanol (33 mL) was added hydrazine hydrate (1.7 g, 33.4 mmol) and the mixture was reacted at 125°C for 16 hours. The reaction solution was concentrated, and the residue was purified on a silica gel column (DCM:methanol = 20:1) to obtain 1.1 g of the title compound in a 56.7% yield.

[0327] 4. Preparation of 6-chloro-4-methyl-1-propyl-1H-pyrazolo[3,4-b]pyridine (Int-9)

[0328] To a solution of compound Int-8 (1.1 g, 6.6 mmol) in DMF (25 mL) was added NaH (396 mg, 9.9 mmol) at 0°C. The reaction was allowed to proceed for 30 min, followed by the addition of iodopropane (1.3 g, 7.6 mmol). The system was quenched with water, and the organic phase was extracted with EA and concentrated. The residue was purified on a silica gel column (EA:PE = 1:5) to afford 1.0 g of the title compound in a yield of 72.7%.

[0329] 5. Preparation of tert-butyl (4-methyl-1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (Int-10)

[0330] To a solution of compound Int-9 (1.0 g, 4.8 mmol) in 1,4-dioxane (40 mL) were added Boc-NH2 (1.1 g, 9.4 mmol), RuPhos Pd G3 (401 mg, 0.48 mmol), and cesium carbonate (4.7 g, 14.4 mmol). The mixture was reacted at 100°C under nitrogen for 3 hours. The reaction was quenched with water, and the organic phase was extracted with EA, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:9) to obtain 1.2 g of the title compound in an 86.6% yield.

[0331] 6. Preparation of 1-propyl-1H-pyrazolo[3,4-b]pyridin-6-amine (Int-11)

[0332] To a solution of compound Int-10 (1.2 g, 3.6 mmol) in DCM (24 mL) was added TFA (8 mL) at 25°C and allowed to react for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was diluted with DCM. The pH was adjusted to alkaline with saturated sodium bicarbonate. The organic phase was extracted with DCM, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:1) to obtain 600 mg of the title compound in a 76.3% yield.

[0333] 7. Preparation of 4-iodo-N-(4-methyl-1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Int-12)

[0334] Potassium phosphate (467 mg, 2.2 mmol), DIPEA (1.7 g, 13.2 mmol), and Int-11 (418 mg, 2.2 mmol) were added to a solution of Int-4 (2.2 mmol) in DCM (30 mL) at 0°C, and the reaction was continued at 25°C for 1 hour. After completion of the reaction, water was added, and the organic phase was extracted with DCM, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:9) to obtain 660 mg of the title compound in a 55.7% yield.

[0335] 8. Preparation of 4-((2-hydroxyethyl)sulfonyl)-N-(4-methyl-1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 2)

[0336] To compound Int-12 (300 mg, 0.57 mmol) in DMF (10 mL) were added CuI (108 mg, 0.57 mmol), N-methylglycine (101 mg, 1.1 mmol), potassium phosphate (605 mg, 2.8 mmol), and 2-hydroxyethane-1-sulfonamide (214 mg, 1.7 mmol). The mixture was then reacted at 100°C under nitrogen for 6 hours. After completion, the reaction was quenched with water, extracted with EA, concentrated, and purified on a silica gel column (EA:PE = 2:1) to obtain 100 mg of the title compound in a 33.5% yield.

[0337] Molecular formula: C 26 H 34 N6O4S molecular weight: 526.7 LC-MS (M / e): 527.2 (M+H + )

[0338] 1 H-NMR(400MHz,DMSO-d6)δ:13.53(s,1H),10.24(s,1H),8.14-8.07(m,3H),7.31(s,1H),7.178-7.15(m,1H),4.95(s,1H),4.38-4.32( m,2H),3.79-3.76(m,2H),3.39-3.33(m,2H),3.02-3.00(m,4H),2.61(s,3H),1.99-1.81(m,6H),0.85-0.70(m,3H),0.50-0.41(m,4H).

[0339] Example 3: Preparation of 4-((2-hydroxyethyl)sulfonamide)-N-(1-propyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 3)

[0340] 6-Chloro-1H-pyrrolo[2,3-b]pyridine and iodinated propane were used as raw materials, and referring to the preparation method of Example 1, 100 mg of 4-((2-hydroxyethyl)sulfonamide)-N-(1-propyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (Compound 3) was prepared in a yield of 50.3%.

[0341] Molecular formula: C 26 H 33 N5O4S molecular weight: 511.64 LC-MS (M / e): 512.31 (M+H + )

[0342] 1 H-NMR(400MHz, DMSO-d6)δ:13.24(s,1H),10.19(brs,1H),8.10~8.13(m,2H),7.95~7.99(m,1H),7.44(d,1H),7.30(s,1H),7.14~7.16( dd,1H),6.42(d,1H),4.98(brs,1H),4.18(t,2H),3.78(t,2H),3.37(t,2H),3.03(m,4H),1.81~1.99(m,4H),0.87(t,3H),0.42(m,4H).

[0343] Example 4: Preparation of 4-((2-hydroxyethyl)sulfonyl)-N-(4-methyl-1-propyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 4)

[0344] 1. Preparation of 4-bromo-1H-pyrrolo[2,3-b]pyridine oxide (Int-17)

[0345] To a 1L reaction flask, 400mL of DCM and 4-bromo-1H-pyrrolo[2,3-b]pyridine (20.0g, 111.7mmol) were added sequentially. Meta-chloroperbenzoic acid (34.6g, 167.6mmol) was added portionwise at 20°C and incubated at 20°C for 16 hours. After completion of the reaction, the system was concentrated under reduced pressure to a residual volume of 50mL, filtered, and the filter cake air-dried to obtain 20.0g of the title compound in a 91.7% yield.

[0346] 2. Preparation of 4-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine (Int-18)

[0347] To a 1-L reaction flask, 400 mL of DMF and compound Int-17 (20.0 g, 93.0 mmol) were added sequentially. Methanesulfonyl chloride (26.6 g, 232.5 mmol) was added dropwise at 50°C and allowed to react at 70°C for 2 hours. After completion, the reaction was cooled to 0°C and quenched with 200 mL of water. The pH was adjusted to 7 with 50% aqueous sodium hydroxide solution, and the mixture was filtered. The filter cake was purified on a silica gel column (EA:PE = 1:10) to obtain 6.0 g of the title compound in a 27.9% yield.

[0348] 3. Preparation of 4-bromo-6-chloro-1-propyl-1H-pyrrolo[2,3-b]pyridine (Int-19)

[0349] To a 1-L reaction flask, 50 mL of DMA and compound Int-18 (5.0 g, 21.6 mmol) were added sequentially. NaH (952 mg, 23.8 mmol) was added portionwise at 0°C, maintained at 0°C for 0.5 hour, and iodinated propane (4.0 g, 23.8 mmol) was added dropwise. The reaction was allowed to react at 20°C for 16 hours. Upon completion, the reaction solution was quenched by pouring into ice water, extracted with EA, and the organic phase was concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column (EA:PE = 1:10) to obtain 3.0 g of the title compound in a 50.8% yield.

[0350] 4. Preparation of 6-chloro-4-methyl-1-propyl-1H-pyrrolo[2,3-b]pyridine (Int-20)

[0351] To a 100 mL reaction flask, 30 mL of dioxane, compound Int-19 (3.0 g, 11.0 mmol), methylboronic acid (1.0 g, 16.5 mmol), PdCl2(dppf) (400 mg, 0.55 mmol), and potassium phosphate (7.0 g, 33.0 mmol) were added sequentially under nitrogen at 100°C for 2 hours. After completion, the reaction was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column (EA:PE = 1:10) to obtain 500 mg of the title compound in a 21.7% yield.

[0352] 5. Preparation of tert-butyl (4-methyl-1-propyl-1H-pyrrolo[2,3-b]pyridin-6-yl)carbamate (Int-21)

[0353] To a 100 mL reaction flask, 5 mL of dioxane, compound Int-20 (500 mg, 2.4 mmol), Boc-NH2 (562 mg, 4.8 mmol), RuPhos Pd G3 (100 mg, 0.16 mmol), and cesium carbonate (1.6 g, 4.8 mmol) were added sequentially. The mixture was reacted at 100°C under nitrogen for 1 hour. After completion, the reaction was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column (EA:PE = 1:20) to obtain 200 mg of the title compound in a 28.9% yield.

[0354] 6. Preparation of 4-methyl-1-propyl-1H-pyrrolo[2,3-b]pyridin-6-amine (Int-22)

[0355] To a 50 mL reaction flask, 5 mL of DCM and compound Int-21 (250 mg, 0.86 mmol) were added sequentially, followed by the dropwise addition of TFA (5 mL). The reaction was allowed to proceed at 20°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to dryness. The crude product was dissolved in 50 mL of DCM and adjusted to pH 8 with the addition of aqueous sodium bicarbonate. The organic phase was dried, filtered, and concentrated under reduced pressure to dryness to afford 100 mg of the title compound in a 61.3% yield.

[0356] 7. Preparation of 4-iodo-N-(4-methyl-1-propyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Int-23)

[0357] To a 50 mL reaction flask, 5 mL of DCM, compound Int-22 (100 mg, 0.53 mmol), compound Int-4 (500 mg, 1.33 mmol), and DIPEA (342 mg, 26.5 mmol) were added sequentially and allowed to react at 20°C for 1 hour. After completion, the reaction system was purified on a silica gel column (EA:PE = 1:10) to obtain 60 mg of the title compound in a 21.5% yield.

[0358] 8. Preparation of 4-((2-hydroxyethyl)sulfonyl)-N-(4-methyl-1-propyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 4)

[0359] To a 50 mL reaction flask, 2 mL of DMF, compound Int-23 (60 mg, 0.11 mmol), CuI (21 mg, 0.11 mmol), N-methylglycine (10 mg, 0.11 mmol), and potassium phosphate (70 mg, 0.33 mmol) were added sequentially. The mixture was reacted at 50°C for 5 minutes. 2-Hydroxyethane-1-sulfonamide (21 mg, 0.11 mmol) was then added and the mixture was reacted at 100°C for 1 hour. After completion, the reaction was quenched with water and extracted with EA. The organic phase was concentrated to dryness under reduced pressure. The crude product was purified by high-pressure preparative liquid chromatography to obtain 6 mg of the title compound in a 10.1% yield.

[0360] Molecular formula: C 27 H 35 N5O4S molecular weight: 525.67 LC-MS (M / e): 526.32 (M+H + )

[0361] 1 H-NMR (400MHz, DMSO-d6) δ: 11.54 (s, 1H), 8.10 ~ 8.13 (d, J = 8.4Hz, 1H), 8. 03(s,1H),7.28~7.32(m,1H),7.14(m,1H),7.0(m,1H),6.52(m,1H),4.24~ 4.28(t,2H),4.10~4.16(t,2H),3.34~3.36(t,2H),3.11~3.13(m,4H),2.6 7(s,3H),1.89~1.98(m,2H),1.46~1.58(m,4H),0.98(t,3H),0.42(m,4H).

[0362] Example 5: Preparation of 4-((2-hydroxyethyl)sulfonyl)-N-(1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 9)

[0363] 6-Chloro-1H-pyrazolo[3,4-b]pyridine and iodomethane were used as raw materials, and the preparation method of Example 1 was referred to to prepare 4-((2-hydroxyethyl)sulfonamide)-N-(1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 9) 18 mg in a yield of 12.4%.

[0364] Molecular formula: C 23 H 28 N6O4S molecular weight: 484.6 LC-MS (M / e): 485.0 (M+H + )

[0365] 1 H-NMR (400MHz, DMSO-d6) δ: 13.77 (s, 1H), 10.26 (s, 1H), 8.28-8.20 (m, 2H), 8.13-8.08 (m, 2H), 7.32 (d, J = 2.0Hz, 1H), 7.18-7. 15(m,1H),4.97(s,1H),4.01(s,3H),3.76-3.78(m,2H),3.40-3.37(m,2H),3.05-3.02(m,4H),1.99-1.84(m,4H),0.43(m,4H).

[0366] Example 6: Preparation of 4-((2-hydroxyethyl)sulfonyl)-N-(1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 10)

[0367] 6-Chloro-1H-pyrazolo[3,4-b]pyridine and 2-iodopropane were used as raw materials, and the preparation method according to Example 1 was referred to to prepare 44 mg of 4-((2-hydroxyethyl)sulfonyl)-N-(1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 10) in a yield of 29.6%.

[0368] Molecular formula: C 25 H 32 N6O4S molecular weight: 512.6 LC-MS (M / e): 513.0 (M+H + )

[0369] 1 H-NMR(400MHz,DMSO-d6)δ:13.73(s,1H),10.3(s,1H),8.23-8.27(m,2H),8.02-8.20(m,2H),7.31(s,1H),7.12-7.19(m,1H),5.05-5 .15(m,1H),4.96(s,1H),3.77(s,2H),3.39-3.36(m,2H),3.04(s,4H),1.75-1.90(m,4H),1.55(d,J=6.7Hz,6H),0.43-0.0.41(m,4H).

[0370] Example 7: Preparation of 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]benzamide (Compound 11)

[0371] 1. Preparation of Tetrahydro-2H-pyran-4-yl Methanesulfonate (Int-32)

[0372] Tetrahydro-2H-pyran-4-ol (4.0 g, 39 mmol) was dissolved in DCM (40 mL), and triethylamine (11.8 g, 117 mmol) was added. Methanesulfonyl chloride (4.9 g, 43 mmol) was added at 0°C. The mixture was reacted at 0°C for 1 hour, quenched with purified water, and washed once with water. The organic phase was concentrated to obtain 4.8 g of the title compound in a yield of 67.6%.

[0373] 2. Preparation of 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]benzamide (Compound 11)

[0374] 6-Chloro-1H-pyrazolo[3,4-b]pyridine and compound Int-32 were used as raw materials, and referring to the preparation method of Example 1, 40 mg of 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]benzamide (Compound 11) was prepared in a yield of 26.8%.

[0375] Molecular formula: C 27 H 34 N6O5S molecular weight: 554.7 LC-MS (M / e): 555.2 (M+H + )

[0376] 1H-NMR(400MHz,DMSO-d6)δ:13.52(s,1H),10.26(s,1H),8.27(m,2H),8.1 2-8.10(m,2H),7.32(m,1H),7.17-7.14(m,1H),4.95-4.92(m,2H),4.08-4 .06(m,2H),3.78-3.75(m,2H),3.57-3.54(m,2H),3.51(m,2H),3.03(m,4 H),2.33(m,2H),2.01-1.96(m,2H),1.80-1.45(m,4H),0.43-0.45(m,4H).

[0377] Example 8: Preparation of 4-(cyclopropylsulfonyl)-N-(1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 12)

[0378] To a solution of compound Int-5 (100 mg, 0.19 mmol) in DMSO (2 mL) were added CuI (4 mg, 0.021 mmol), L-proline (4 mg, 0.035 mmol), potassium carbonate (5 mg, 0.036 mmol), and sodium cyclopropylsulfinate (49 mg, 0.38 mmol). The mixture was then microwaved under nitrogen at 140°C for 1 hour. After completion, the reaction was quenched with water, extracted with EA, concentrated, and purified on a silica gel column (EA:PE = 1:2) to afford 45 mg of the title compound in a 47.0% yield.

[0379] Molecular formula: C 26 H 31 N5O3S molecular weight: 493.6 LC-MS (M / e): 494.2 (M+H + )

[0380] 1 H-NMR(400MHz,DMSO-d6)δ:13.43(s,1H),8.40-8.30(m,2H),8.29-8.20(m,1H),8.15(s,1H),7.92(s,1H),7.89-7.80(m,1H),4.45-4.35(m, 2H),3.20-3.3.12(m,4H),3.10-3.00(m,1H),2.05-1.85(m,2H),1.84- 1.74(m,3H),1.35-1.10(m,4H),0.95-0.80(m,4H),0.50-0.35(m,4H).

[0381] Example 9: Preparation of N-(3-fluoro-1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 13)

[0382] 1. Preparation of 6-chloro-3-fluoro-1-propyl-1H-pyrazolo[3,4-b]pyridine (Int-37)

[0383] Selectfluor reagent (9.8 g, 27.7 mmol) was added to 6-chloro-1H-pyrazolo[3,4-b]pyridine (1.8 g, 9.2 mmol) in acetonitrile (100 mL). The reaction was allowed to proceed at 80°C for 16 hours. The reaction was quenched with water, and the organic phase was extracted with EA, dried, and concentrated. The residue was purified on a silica gel column (DCM:PE = 3:1) to obtain 800 mg of the title compound in a 40.7% yield.

[0384] 2. Preparation of tert-butyl (3-fluoro-1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (Int-38)

[0385] Compound Int-37 (800 mg, 3.7 mmol) was reacted in 1,4-dioxane (30 mL), Boc-NH2 (867 mg, 7.4 mmol), RuPhos Pd G3 (310 mg, 0.37 mmol), and cesium carbonate (3.6 g, 11.0 mmol) at 100°C under nitrogen for 3 hours. The reaction was quenched with water, and the organic phase was extracted with EA, dried, and concentrated. The residue was purified on a silica gel column (DCM:PE = 2:3) to obtain 600 mg of the title compound in a 54.4% yield.

[0386] 3. Preparation of 3-fluoro-1-propyl-1H-pyrazolo[3,4-b]pyridin-6-amine (Int-39)

[0387] To a solution of compound Int-38 (600 mg, 2.0 mmol) in DCM (12 mL) was added TFA (4 mL) and allowed to react at 25°C for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was diluted with DCM. The pH was adjusted to alkaline with saturated sodium bicarbonate. The organic phase was extracted with DCM, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:3) to obtain 390 mg of the title compound in a 98.5% yield.

[0388] 4. Preparation of N-(3-fluoro-1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Int-40)

[0389] Potassium phosphate (255 mg, 1.2 mmol), DIPEA (930 mg, 7.2 mmol), and Int-39 (233 mg, 1.2 mmol) were added to a solution of compound Int-4 (1.2 mmol crude) in DCM (10 mL) at 0°C, and the reaction was continued at 60°C for 3 hours. After completion of the reaction, the pH was adjusted to alkaline with saturated sodium bicarbonate. The organic phase was extracted with DCM, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:9) to obtain 250 mg of the title compound in a 39.8% yield.

[0390] 5. Preparation of N-(3-fluoro-1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 13)

[0391] To compound Int-40 (110 mg, 0.219 mmol) in DMF (10 mL) were added CuI (40 mg, 0.21 mmol), N-methylglycine (37 mg, 0.42 mmol), potassium phosphate (223 mg, 1.1 mmol), and 2-hydroxyethane-1-sulfonamide (79 mg, 0.63 mmol). The mixture was then reacted at 100°C under nitrogen for 1 hour. After completion, the reaction was quenched with water, extracted with EA, concentrated, and purified on a silica gel column (EA:PE = 2:1) to obtain 30 mg of the title compound in a 27.4% yield.

[0392] Molecular formula: C 25 H 31 FN6O4S molecular weight: 530.6 LC-MS (M / e): 531.2 (M+H + )

[0393] 1 H-NMR(400MHz,DMSO-d6)δ:13.89(s,1H),10.2(s,1H),8.30-8.29(m,2H),8.13-8.11(m,1H),7.32(s,1H),7.18-7.15(m,1H),4.97(s,1H) ),4.33-4.27(m,2H),3.79-3.77(m,2H),3.39-3.35(m,2H),3.04-3.00(m,4H),1.95-1.65(m,6H),0.95-0.88(m,3H),0.50-0.41(m,4H).

[0394] Example 10: Preparation of N-(3-fluoro-1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 18)

[0395] Selecting 6-chloro-1H-pyrazolo[3,4-b]pyridine and iodinated isopropyl as starting materials, and referring to the preparation method of Example 9, N-(3-fluoro-1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl]benzamide was prepared.

[0396] Molecular formula: C 25 H 31 FN6O4S molecular weight: 530.21 LC-MS (M / e): 531.2 (M+H + )

[0397] 1 H-NMR(400MHz,DMSO-d6)δ:13.94(s,1H),10.3(m,1H),8.26(m,2H),8.12-8.10(m,1H),7.32(m,1H),7.18(m,1H),5.03(m,1H ),3.79-3.77(m,2H),3.55-3.53(m,2H),3.18-3.13(m,4H),2.03(m,1H),1.99-1.97(m,4H),1.55(m,6H),0.43-0.41(m,4H).

[0398] Example 11: N-(3-Fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 20)

[0399] Selecting 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine as the starting material, referring to the preparation method of Example 9, N-(3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl]benzamide was prepared.

[0400] Molecular formula: C 27 H 33FN6O5S molecular weight: 572.7 LC-MS (M / e): 573.2 (M+H + )

[0401] 1 H-NMR(400MHz,DMSO-d6)δ:13.72(s,1H),10.28(s,1H),8.33(m,2H),8.12-8.10( m,1H),7.33-7.32(m,1H),7.17-7.15(m,1H),4.98-4.96(m,1H),4.86-4.85(m,1H) ,4.07-4.04(m,2H),3.79-3.75(m,2H),3.53-3.51(m,2H),3.48(m,2H),3.03(m,4 H),2.19-2.17(m,2H),2.11-2.08(m,2H),1.78-1.45(m,4H),0.43-0.0.45(m,4H).

[0402] Example 12: Preparation of 4-(cyclopropylsulfonyl)-N-(1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 22)

[0403] 1. Preparation of ethyl 2-((4-((1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl]phenyl)sulfonyl)acetate (Int-50)

[0404] Compound Int-5 (200 mg, 0.39 mmol) was dissolved in DMSO (5 mL), and potassium metabisulfite (129 mg, 0.58 mmol), sodium formate (58 mg, 0.86 mmol), triphenylphosphine (16 mg, 0.06 mmol), 1,10-phenanthroline (11 mg, 0.06 mmol), tetrabutylammonium bromide (187 mg, 0.58 mmol) and palladium acetate (4 mg, 0.03 mmol) were added. Under nitrogen protection, the reaction was carried out at 70°C for 45 minutes. The temperature was lowered, and ethyl bromoacetate (97 mg, 0.58 mmol) was added. The reaction was allowed to react for 10 minutes. After completion of the reaction, the reaction was quenched with water, extracted with EA, and purified on a concentrated silica gel column (EA:PE = 55%) to give 150 mg of the target compound in a yield of 71.8%.

[0405] 2. Preparation of 4-((2-hydroxyethyl)sulfonyl)-N-(1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 22)

[0406] Lithium borohydride (19 mg, 0.83 mmol) was added to a THF (5 mL) solution containing compound Int-50 (150 mg, 0.28 mmol) at 25°C and allowed to react for 1 hour. After completion, the reaction was quenched with water, extracted with EA, and purified on a concentrated silica gel column (EA:PE = 60%). After EA slurrying, 30 mg of the title compound was obtained, yielding 20.8%.

[0407] Molecular formula: C 25 H 31 N5O4S molecular weight: 497.6 LC-MS (M / e): 498.0 (M+H+)

[0408] 1 H-NMR(400MHz,DMSO-d6)δ:13.47(s,1H),8.43-8.30(m,2H),8.24-8.21(m,1H),8.11(m,1H),7.96(m,1H),7.85-7.83(m,1H),4.95-4.93(m, 1H),4.39-4.36(m,2H),3.76-3.71(m,2H),3.59-3.56(m,2H),3.37-3. 14(m,4H),2.03-1.90(m,2H),1.78(m,4H),0.92(m,3H),0.456(m,4H).

[0409] Example 13: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 24)

[0410] 1. Preparation of 6-chloro-1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridine (Int-51)

[0411] 6-Chloro-1H-pyrazolo[3,4-b]pyridine (1.4 g, 9.3 mmol), 3,3-difluorocyclobutanol (1 g, 9.3 mmol), and triphenylphosphine (3.2 g, 12 mmol) were dissolved in THF. DEAD (2.4 g, 14 mmol) was added and the mixture was allowed to react at 25°C for 4 h. The reaction was quenched with water. The organic phase was extracted with EA, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:3) to obtain 750 mg of the title compound in a 33.4% yield.

[0412] 2. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 24)

[0413] The target compound was prepared by using compound Int-51 as the starting material and referring to the preparation method of Example 1.

[0414] Molecular formula: C 26 H 30 F2N6O4S molecular weight: 560.6 LC-MS (M / e): 561.0 (M+H + )

[0415] 1 H-NMR(400MHz,DMSO-d6)δ:13.85(s,1H),10.3(s,1H),8.05-8.35(m,4H),7.25-7.35(m,1H),7.10-7.20(m,1H),5 .22-5.32(m,1H),4.85-5.00(m,1H),3.77(s,4H),3.25(s,4H),3.04(s,4H),1.75-2.00(m,4H),0.40-0.50(m,4H).

[0416] Example 14: Preparation of 4-(cyclopropylsulfonyl)-N-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 25)

[0417] 6-Chloro-1H-pyrazolo[3,4-b]pyridine and 1,1-difluoro-2-iodoethane were used as raw materials, and the preparation method of Example 1 was referred to to prepare 4-(cyclopropylsulfonyl)-N-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide.

[0418] Molecular formula: C 25 H 27 F2N5O3S molecular weight: 515.6 LC-MS (M / e): 516.2 (M+H + )

[0419] 1 H-NMR(400MHz,DMSO-d6)δ:13.66(s,1H),8.37-8.25(m,4H),7.94(s,1H),7.85-7.83(m,1H),6.70-6.30(m,1H),4 .95-4.75(m,2H),3.30-3.20(m,4H),3.10-3.05(m,1H),1.95-1.75(m,4H),1.30-1.10(m,4H),0.42-0.41(m,4H).

[0420] Example 15: Preparation of 4-(cyclopropylsulfonyl)-N-(3-fluoro-1-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 26)

[0421] Compound Int-40 (60 mg, 0.11 mmol), sodium cyclopropanesulfinate (28 mg, 0.22 mmol), potassium carbonate (3 mg, 0.02 mmol), CuI (2 mg, 0.01 mmol), and L-proline (3 mg, 0.02 mmol) were added to a 2 mL DMSO solution. After nitrogen displacement, the mixture was microwaved at 140°C for 1 hour. After completion of the reaction, the mixture was quenched with water, extracted with EA, and concentrated. The crude product was then slurried with EA:PE (1:1) to afford 16.6 mg of the title compound, in a yield of 29.5%.

[0422] Molecular formula: C 26 H 30 FN5O3S molecular weight: 511.6 LC-MS (M / e): 512.1 (M+H + )

[0423] 1 H-NMR(400MHz,DMSO-d6)δ:13.60(s,1H),8.20-8.40(m,3H),7.94(s,1H),7.85-7.95(m,1H),4.27(s,2H ),3.16(s,4H),3.02-3.08(m,1H),1.60-1.80(m,6H),1.05-1.35(m,4H),0.88(t,3H),0.35-0.45(m,4H).

[0424] Example 16: Preparation of 4-(cyclopropylsulfonyl)-N-(3-propyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 27)

[0425] 1. Preparation of 6-chloro-3-nitro-N-propylpyridin-2-amine (Int-59)

[0426] 2,6-Dichloro-3-nitropyridine (5.0 g, 25.9 mmol) was dissolved in THF (50 mL), and propan-1-amine hydrochloride (4.95 g, 51.8 mmol) was added. DIPEA (13.4 g, 103.6 mmol) was added, and the mixture was reacted at 25°C for 16 hours. The concentrated residue was purified by column chromatography (EA / n-heptane = 10%) to obtain 5.0 g of the title compound in a yield of 74.6%.

[0427] 2. Preparation of 6-chloro-N2-propylpyridine-2,3-diamine (Int-60)

[0428] Compound Int-59 (4.5 g, 20.8 mmol) was dissolved in glacial acetic acid (45 mL), and iron powder (4.7 g, 83.2 mmol) was added. The reaction was allowed to proceed at 25°C for 18 hours. The reaction was completed. The mixture was concentrated to dryness, and saturated sodium bicarbonate solution was added to adjust the pH to 8. Extraction with EA was performed, and the mixture was concentrated to obtain 4.5 g of the crude target compound.

[0429] 3. Preparation of 5-chloro-3-propyl-3H-[1,2,3]triazolo[4,5-b]pyridine (Int-61)

[0430] Compound Int-60 (1.7 g, 9.1 mmol) was dissolved in acetic acid (15 mL), and sodium nitrite (1.3 g, 18.2 mmol) was added. The mixture was reacted at 25°C for 1 hour. Water was added and the reaction was continued at 25°C for 0.5 hour. The reaction was completed. Saturated sodium bicarbonate solution was added to quench the mixture, and the mixture was extracted twice with EA. The resulting mixture was concentrated to afford 1.6 g of the title compound in a 90.2% yield.

[0431] 4. Preparation of tert-butyl (3-propyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)carbamate (Int-62)

[0432] Compound Int-61 (2.2 g, 11.2 mmol) was dissolved in 1,4-dioxane (20 mL), and Boc-NH2 (2.6 g, 22.4 mmol) was added. RuPhos Pd G3 (920 mg, 1.1 mmol) and cesium carbonate (11.0 g, 33.6 mmol) were then added. The reaction was continued at 100°C under nitrogen for 3 hours until completion. The mixture was concentrated to dryness, quenched with saturated sodium bicarbonate solution, and extracted twice with EA. The residue was purified on a silica gel column (EA:PE = 40%) to obtain 1.8 g of the title compound in a 58.1% yield.

[0433] 5. Preparation of 3-propyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine (Int-63)

[0434] Compound Int-62 (1.8 g, 6.5 mmol) was dissolved in DCM (20 mL) and TFA (6 mL) was added. The mixture was reacted at 25°C for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure, the pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was extracted with EA, dried, and concentrated to afford the title compound (1.2 g crude product).

[0435] 6. Preparation of 4-iodo-N-(3-propyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Int-64)

[0436] Compound Int-4 (1.2 g) was dissolved in DCM (8 mL), and potassium phosphate (466 mg, 2.2 mmol), DIPEA (1.7 g, 13.2 mmol), and compound Int-63 (400 mg, 2.2 mmol) were added. The reaction was continued at 25°C for 4 hours until completion. The concentrated residue was purified on a silica gel column (EA:PE = 25%) to obtain 190 mg of the title compound, with a two-step yield of 17.3%.

[0437] 7. Preparation of 4-(cyclopropylsulfonyl)-N-(3-propyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0438] Compound Int-64 (190 mg, 0.32 mmol) was dissolved in DMSO (5 mL), and sodium cyclopropanesulfonate (94 mg, 0.74 mmol), potassium carbonate (10 mg, 0.074 mmol), CuI (7 mg, 0.037 mmol), and L-proline (9 mg, 0.074 mmol) were added. The mixture was microwaved at 140°C under nitrogen for 1 hour, and the reaction was complete. The mixture was quenched with saturated sodium bicarbonate solution and extracted with EA. The residue was concentrated and purified on a silica gel column (EA:PE = 47%). The mixture was slurried with EA, filtered, and dried to afford 60 mg of the title compound (33.0% yield).

[0439] Molecular formula: C 25 H 30 N6O3S molecular weight: 494.6 LC-MS (M / e): 495.2 (M+H + )

[0440] 1 H-NMR(400MHz,DMSO-d6)δ:13.62(s,1H),8.63-8.61(m,1H),8.46(m,1H),8.37(m,1H),7.94(m,1H),7.84-7.82(m,1H),4.61(m, 2H),3.15(m,4H),3.04(m,1H),2.04-1.98(m,2H),1.74(m,4H),1.27(m,2H),1.20-1.11(m,2H),0.92-0.89(m,3H),0.41(m,4H).

[0441] Example 17: Preparation of N-(1-cyclopropyl-3-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 28)

[0442] 6-Chloro-1H-pyrazolo[3,4-b]pyridine and cyclopropylboronic acid were used as raw materials, and the preparation method of Example 9 was referred to to prepare N-(1-cyclopropyl-3-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide. Molecular formula: C 25 H 28 FN5O4S molecular weight: 513.6 LC-MS (M / e): 514.0 (M+H + )

[0443] 1H-NMR (400MHz, DMSO-d6)δ:13.55(s,1H),8.30(s,3H),7.97(s,3H),7.80-7.85(m,1H),4.95(t,1H,J=5 .4Hz),3.70-3.75(m,2H),3.60-3.70(m,3H),3.15(s,4H),1.79(s,4H),1.10-1.40(m,4H),0.42(s,4H).

[0444] Example 18: Preparation of 4-((2-hydroxyethyl)sulfonamido)-N-(3-propyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 31)

[0445] Compound Int-64 (160 mg, 0.31 mmol) was dissolved in DMF (10 mL), and CuI (59 mg, 0.31 mmol), N-methylglycine (55 mg, 0.62 mmol), potassium phosphate (329 mg, 1.55 mmol), and 2-hydroxyethane-1-sulfonamide (116 mg, 0.93 mmol) were added. The mixture was reacted at 100°C under nitrogen for 3 hours. The reaction was completed. The mixture was quenched with saturated aqueous sodium bicarbonate solution, extracted with EA, concentrated, and purified on a silica gel column (EA:PE = 70%). The mixture was slurried with EA, filtered, and dried to obtain 15 mg of the title compound in a 9.4% yield.

[0446] Molecular formula: C 24 H 31 N7O4S molecular weight: 513.6 LC-MS (M / e): 514.2 (M+H + )

[0447] 1 H-NMR(400MHz,DMSO-d6)δ:13.98(s,1H),10.30(s,1H),8.59-8.57(m,1H),8.50(m,1H),8.14-8.12(m,1H),7.32(m,1H),7.17-7.15(m,1H ),5.03(m,1H),4.63-4.59(m,2H),3.77-3.76(m,2H),3.03(m,4H),2.04-2.00(m,4H),1.91-1.67(m,4H),0.93-0.89(m,3H),0.43(m,4H).

[0448] Example 19: Preparation of 4-((2-hydroxyethyl)sulfonyl)-N-(3-propyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 32)

[0449] 1. Preparation of ethyl 2-((4-((3-propyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate (Int-71)

[0450] Compound Int-64 (180 mg, 0.35 mmol) was dissolved in DMSO (10 mL) and potassium metabisulfite (118 mg, 0.53 mmol), sodium formate (52 mg, 0.77 mmol), triphenylphosphine (13 mg, 0.05 mmol), 1,10-phenanthroline (9 mg, 0.05 mmol), tetrabutylammonium bromide (171 mg, 0.53 mmol) and palladium acetate (7 mg, 0.03 mmol) were added in sequence. Under nitrogen protection, the reaction was carried out at 70 ° C for 45 minutes. The temperature was lowered and ethyl bromoacetate (89 mg, 0.53 mmol) was added to react for 10 minutes. After completion of the reaction, the reaction was quenched with water, extracted with EA, and purified on a concentrated silica gel column (EA: PE = 1:1) to obtain 80 mg of the target compound in a yield of 42.9%.

[0451] 2. Preparation of 4-((2-hydroxyethyl)sulfonyl)-N-(3-propyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0452] Lithium borohydride (10 mg, 0.45 mmol) was added to a THF (5 mL) solution containing compound Int-71 (80 mg, 0.15 mmol) at 25°C and allowed to react for 1 hour. After completion, the reaction was quenched with water, extracted with EA, and purified on a silica gel column (EA:PE = 3:1) to afford the crude product. After methanol slurrying, 27 mg of the title compound was obtained, yielding 36.1%.

[0453] Molecular formula: C 24 H 30 N6O4S molecular weight: 498.6 LC-MS (M / e): 499.0 (M+H + )

[0454] 1H-NMR(400MHz,DMSO-d6)δ:13.70(s,1H),8.62-8.68(m,1H),8.42-8.50(m,1H),8.20-8.30(m,1H),7.96(s,1H),7.82-7.90(m,1H),4.96(t,1H, J=5.4Hz),4.62(s,2H),3.70-3.80(m,2H),3.54-3.62(m,2H),3.15(s,4 H),1.90-2.10(m,2H),1.74(s,4H),0.91(t,3H,J=7.2Hz),0.41(s,4H).

[0455] Example 20: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 33)

[0456] 1. Preparation of ethyl 2-((4-((1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-ylphenyl)sulfonyl)acetate (Int-72)

[0457] Compound Int-54 (127 mg, 0.23 mmol) was dissolved in DMSO (5 mL) and potassium metabisulfite (77 mg, 0.35 mmol), sodium formate (34 mg, 0.50 mmol), triphenylphosphine (9 mg, 0.034 mmol), 1,10-phenanthroline (6 mg, 0.033 mmol), tetrabutylammonium bromide (111 mg, 0.34 mmol) and palladium acetate (4 mg, 0.018 mmol) were added in sequence. Under nitrogen protection, the reaction was carried out at 70 ° C for 45 minutes, and the temperature was lowered to 25 ° C. Ethyl bromoacetate (58 mg, 0.35 mmol) was added and the reaction was carried out for 15 minutes. After completion of the reaction, the reaction was quenched with water, extracted with EA, and purified on a concentrated silica gel column (EA:PE = 1:2) to obtain 60 mg of the target compound in a yield of 45.3%.

[0458] 2. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide

[0459] To a solution of compound Int-72 (60 mg, 0.10 mmol) in THF (4 mL) was added lithium borohydride (14 mg, 0.60 mmol) at 25°C and allowed to react for 1 hour. After completion, the reaction was quenched with water, extracted with EA, and purified on a silica gel column (EA:PE = 1:1) to afford 25 mg of the title compound in a 44.9% yield.

[0460] Molecular formula: C 26 H 29 F2N5O4S molecular weight: 545.6 LC-MS (M / e): 546.2 (M+H+)

[0461] 1 H-NMR (400MHz, DMSO-d6) δ: 13.66 (s, 1H), 8.40-8.20 (m, 4H), 7.97 (s, 1H), 7.84 (d, J = 8.4Hz, 1H), 5.40-5.20 (m, 1H), 4.96-4. 94(m,1H),3.82-3.70(m,2H),3.68-3.55(m,2H),3.30-3.10(m,4H),1.90-1.75(m,4H),1.40-1.20(m,4H),0.50-0.40(m,4H).

[0462] Example 21: Preparation of 4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0463] Compound Int-54 (100 mg, 0.18 mmol) was dissolved in DMSO (3 mL), and sodium cyclopropanesulfonate (46 mg, 0.36 mmol), potassium carbonate (6 mg, 0.04 mmol), CuI (4 mg, 0.02 mmol), and L-proline (5 mg, 0.04 mmol) were added. The mixture was microwaved at 140°C under nitrogen for 1 hour, and the reaction was complete. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EA. The residue was concentrated and purified on a silica gel column (EA:PE = 1:1) to obtain 20 mg of the title compound in a yield of 20.6%.

[0464] Molecular formula: C 27 H 29 F2N5O3S molecular weight: 541.6 LC-MS (M / e): 542.1 (M+H + )

[0465] 1H-NMR(400MHz,DMSO-d6)δ:13.62(s,1H),8.50-8.40(m,1H),8.30-8.40(m,2H),8.25-8.29(m,2H),7.95(s,1H),7.80-7.90(m,1H),5 .25-5.35(m,1H),3.45-3.50(m,2H),3.30-3.40(m,2H),3.16(s,4H),3.00-3.10(m,1H),1.99(s,4H),1.08-1.22(m,4H),0.45(s,4H).

[0466] Example 22: Preparation of 4-((2-hydroxyethyl)sulfonamido)-N-(1-(oxetane-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 35)

[0467] 6-Chloro-1H-pyrazolo[3,4-b]pyridine and oxetane-3-yl-4-methylbenzenesulfonate were selected as raw materials, and the preparation method of Example 7 was referred to to prepare 4-((2-hydroxyethyl)sulfonamido)-N-(1-(oxetane-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide.

[0468] Molecular formula: C 25 H 30 N6O5S molecular weight: 526.6 LC-MS (M / e): 527.2 (M+H + )

[0469] 1 H-NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.25(s,1H),8.31-8.25(m,2H) ,8.21(m,1H),8.10-8.08(m,1H),7.30(m,1H),7.16-7.14(m,1H),5.98-5.9 5(m,1H),5.20-5.16(m,2H),5.03-5.01(m,2H),3.76(m,2H),3.46-3.45(m, 2H),3.10-3.08(m,4H),1.90-1.62(m,4H),1.26(m,1H),0.43-0.46(m,4H).

[0470] Example 23: Preparation of 4-(cyclopropylsulfonyl)-N-(3-propyl-3H-imidazo[4,5-b]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 38)

[0471] Referring to the preparation method of Example 16, 8 mg of 4-(cyclopropylsulfonyl)-N-(3-propyl-3H-imidazo[4,5-b]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 38) was prepared in a yield of 4.2%.

[0472] Molecular formula: C 26 H 31 N5O3S molecular weight: 493.6 LC-MS (M / e): 494.2 (M+H + )

[0473] 1 H-NMR(400MHz,DMSO-d6)δ:13.24(s,1H),8.50-8.40(m,1H),8.37-8.27(m,2H),8.17(m,1H),7.91-7.84(m,1H),7.82(m,1H),4.23-4.20 (m,2H),3.14(m,4H),3.04-3.00(m,1H),1.99-1.96(m,2H),1.90-1.77(m,4H),1.23(m,2H),1.19-1.18(m,2H),0.94(m,3H),0.40(m,4H).

[0474] Example 24: Preparation of 4-((2-hydroxyethyl)sulfonamido)-N-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 55)

[0475] 6-Chloro-1H-pyrazolo[3,4-b]pyridine and 1-iodo-2-methoxyethane were used as raw materials, and the preparation method of Example 1 was referred to to prepare 4-((2-hydroxyethyl)sulfonamido)-N-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide.

[0476] Molecular formula: C 25 H 32 N6O5S molecular weight: 528.6 LC-MS (M / e): 529.0 (M+H + )

[0477] 1 H-NMR(400MHz,DMSO-d6)δ:13.69(s,1H),10.3(s,1H),8.15-8.20(m,2H),8.00-8.10(m,2H),7.30(s,1H),7.06-7.10(m,1H),4.99 -5.00(s,1H),4.50-4.60(m,2H),3.70-3.85(m,4H),3.30-3.40(m,2H),3.21(s,3H),3.02(s,4H),1.70-1.90(m,4H),0.35(s,4H).

[0478] Example 25: Preparation of N-(1-(2-(difluoromethoxy)ethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 56)

[0479] 1. Preparation of 1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyridine (Int-85)

[0480] To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine (1.3 g, 8.5 mmol) in DMF (50 mL) was added NaH (60%) (680 mg, 17.0 mmol) at 0°C and allowed to react for 30 minutes. (2-bromoethoxy)(tert-butyl)diphenylsilane (3.7 g, 10.2 mmol) was then added. The reaction was continued at 25°C for 5 hours. The system was quenched with water, and the organic phase was extracted with EA, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:10) to obtain 2.3 g of the title compound in a yield of 62.4%.

[0481] 2. Preparation of 2-(6-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)ethan-1-ol (Int-86)

[0482] To a solution of compound Int-85 (2.3 g, 5.3 mmol) in THF (20 mL) was added a 1 M solution of tetrabutylammonium fluoride in THF (15.9 mL, 15.9 mmol). The mixture was allowed to react at 25°C for 2 hours. The reaction was quenched with water, and the organic phase was extracted with EA, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:1) to afford 800 mg of the title compound in a 76.7% yield.

[0483] 3. Preparation of 6-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazolo[3,4-b]pyridine (Int-87)

[0484] To compound Int-86 (1.0 g, 5.1 mmol) in acetonitrile (30 mL) were added CuI (486 mg, 2.6 mmol) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.8 g, 10.1 mmol). The mixture was allowed to react at 50°C for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution. The organic phase was extracted with EA, dried, and concentrated. The residue was purified on a silica gel column (EA:PE = 1:5) to obtain 660 mg of the title compound in a 52.7% yield.

[0485] 4. Preparation of N-(1-(2-(difluoromethoxy)ethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0486] Int-87 was used as the raw material, and the preparation method of Example 1 was referred to prepare N-(1-(2-(difluoromethoxy)ethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide.

[0487] Molecular formula: C 25 H 30 F2N6O5S molecular weight: 564.6 LC-MS (M / e): 565.2 (M+H + )

[0488] 1 H-NMR(400MHz,DMSO-d6)δ:13.79(s,1H),10.29(s,1H),8.28-8.22(m,2H),8 .12-8.10(m,2H),7.33(s,1H),7.17(d,J=8.8Hz,1H),6.59(t,J=75.2Hz,1H) ,5.01-4.90(m,1H),4.65-4.63(m,2H),4.35-4.32(m,2H),3.78-3.74(m,2H) ,3.38-3.35(m,2H),3.15-3.00(m,4H),1.95-1.70(m,4H),0.42-0.41(m,4H).

[0489] In addition, the following compounds were prepared using the same or similar methods as in the above examples:

[0490] The KIF18A inhibitors and their applications provided by the present invention are described in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above examples is only intended to help understand the methods and central ideas of the present invention. It should be noted that, for those of ordinary skill in the art, several improvements and modifications may be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection of the claims of the present invention.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, in, X 1 、X 4 are independently selected from N or CR a ; X 2 、X 3 are independently selected from N or C; Ring A is selected from 5-12 membered cycloalkyl, 5-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, 5-12 membered bridged cyclyl or 5-12 membered bridged heterocyclyl; Each R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH2, -S(O)2-NH2 or -(L) optionally substituted with 1-4 substituents Q2 m -H, -(L) m -C 1-6 Alkyl, -(L) m -C 2-6 Alkenyl, -(L) m -C 2-6 Alkynyl, -(L) m -C 1-6 Alkoxy, di(C 1-6 Alkyl)amino, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -3-12 membered cycloalkyl, -(L) m -3-12 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -5-12 membered spirocyclic group, -(L) m -5-12 membered spiroheterocyclic group, -(L) m -5-12 membered bridged ring group, -(L) m -5-12 membered bridged heterocyclic group; Each Q1 and each Q2 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2- 6 alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, hydroxy 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 Alkylcarbonyl, C 1-6 Alkyloxycarbonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, C 1-6 Alkyl-OC 1-4 Alkylene, haloC 1-6 Alkyl-OC 1-4 Alkylene or 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl optionally substituted by 1-4 substituents q, wherein the substituents q 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; Each L is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, -NR c -、-S(O)(NR c )-、-CR a1 R b -; Each R a , each R a1 , each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkyl aminoacyl, C 1-6 Alkyl amido, C 1-6 Alkylsulfonylamino, C 1-6 Alkylaminosulfonyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -3-8 membered cycloalkyl or -(L) m -3-8 membered heterocyclic group; Each R c are independently selected from hydrogen, C 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; Each m and n are independently an integer from 0 to 6; p is selected from 0, 1, 2 or 3.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein: Ring A is selected from a 5-6 membered monocycloalkyl, a 5-6 membered monoheterocyclyl, an 8-10 membered fused cyclyl, an 8-10 membered fused heterocyclyl, a phenyl, a 5-6 membered monoheteroaryl, an 8-10 membered fused aryl or an 8-10 membered fused heteroaryl; preferably, Ring A is selected from a 5-6 membered monoheteroaryl, an 8-10 membered fused heterocyclyl or an 8-10 membered fused heteroaryl; Each R 1 、R 2 、R 3 、R 4 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro or -(L) optionally substituted with 1 to 4 substituents Q2 m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 alkyl; R 5 is selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro or -(L) optionally substituted with 1 to 4 substituents Q2 m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L) m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiro heterocyclic group; preferably, R 5 Selected from -(L) optionally substituted with 1 to 4 substituents Q2 m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -5-10 membered cycloalkyl, -(L) m -5-10 membered heterocyclic group, -(L) m -7-11 membered spirocyclic group, -(L) m -7-11 membered spiroheterocyclyl; Each L is independently selected from -S(O)2-, -NR c -、-CR a1 R b -; R 6 is selected from -S(O)2H, -C(O)H, -C(O)N(R c )2、-N(R c )S(O)2-C 1-6 Alkyl, -N(R c )-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1- 6-alkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -S(O)2N(R c )-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 group, -S(O)(NR c )-C 1-6 Alkyl, -S(O)(NR c )-3-6 membered cycloalkyl, -S(O)(NR c )-3-6 membered heterocyclic group, -N(R c )C(O)-C 1-6 Alkyl, -N(R c )C(O)-3-6 membered cycloalkyl, -N(R c )C(O)-3-6 membered heterocyclic group, -C(O)N(R c )-C 1-6 Alkyl, -C(O)N(R c )-3-6 membered cycloalkyl, -C(O)N(R c )-3-6 membered heterocyclic group, -C(O)-C 1-6 alkyl, -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocyclic group; preferably, R 6 is selected from -S(O)2H, -N(R c )S(O)2-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c )-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -S(O)2N(R c )-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 heterocyclyl; Each R a , each R a1 , each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 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, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or carboxyl C 1-6 alkyl; Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy; Each Q1 and each Q2 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-4 Alkyl-OC 1-3 Alkylene, haloC 1-4 Alkyl-OC 1-3 Alkylene or 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl optionally substituted by 1-3 substituents q; each q is independently selected from halogen, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy; Each m and n are independently an integer from 0 to 4; p is selected from 0 or 1.

3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein: Ring A is selected from cyclopentanyl, cyclohexanyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl or an 8-10 membered nitrogen-containing fused heterocyclic ring; Each R 1 、R 2 、R 3 、R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy; R 5 is selected from a 5-6 membered heterocyclyl or a 7-10 membered spiroheterocyclyl group optionally substituted by 1-3 substituents Q2; R 6 is selected from -S(O)2H, -N(R c )S(O)2-C 1-6 Alkyl, -N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2-C 1-6 alkyl; Each R a , each R a1 , each R b are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6 alkyl or halogenated C 1-6 alkoxy; Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy; Each Q1 and each Q2 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, haloC 1-3 Alkyl-OC 1-2 Alkylene or 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted by 1-3 substituents q; each q is independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy; n is selected from 0, 1 or 2; p is selected from 0 or 1.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein: Selected from the following structures: Each R 1 、R 2 、R 3 、R 4 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy; Each R a are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy; R 5 Selected from the following structures optionally substituted by 1-3 substituents Q2: R 6 Selected from the following structures: Each Q1 is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, haloC 1-3 Alkyl-OC 1-2 Alkylene or 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted by 1-3 substituents q; each q is independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1- 4 alkyl, halogenated C 1-4 alkoxy; Each Q2 is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy; n is selected from 0, 1 or 2.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, which has a structure represented by general formula (II), in, X 5 is selected from N or CH; t is selected from 0, 1 or 2; Ring A, X 1 、X 2 、X 3 、X 4 、R 1 、R 2 、R 3 、R 4 、R 6 , each Q1, each Q2, n, p are defined as described in any one of claims 1-4.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein: X 5 is N; Each R 1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy; R 2 、R 3 、R 4 are each independently hydrogen; R 6 Selected from the following structures: Selected from the following structures: Preferably, Selected from the following structures: Each Q1 is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, haloC 1-3 Alkyl-OC 1-2 Alkylene or 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted by 1-3 substituents q; each q is independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1- 4 alkyl, halogenated C 1-4 alkoxy; Each Q2 is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy; Each R a are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy; n is selected from 0, 1 or 2.

7. The compound according to claim 1, its pharmaceutically acceptable salt, ester or stereoisomer thereof, selected from the following compounds:

8. A pharmaceutical preparation comprising the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more pharmaceutically acceptable carriers and / or diluents; the pharmaceutical preparation is in any clinically or pharmaceutically acceptable dosage form.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, and one or more second therapeutically active agents; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or diluents.

10. Use of the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, ester or stereoisomer thereof, or the pharmaceutical preparation according to claim 8, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and / or preventing diseases mediated by KIF18A or related diseases; wherein, The KIF18A-mediated disease or related disease is selected from cancer or benign tumor; the cancer or benign tumor includes but is not limited to melanoma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, head and neck cancer, thyroid cancer, lung cancer, bronchial cancer, esophageal cancer, gastric cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, colon cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, bone cancer and blood tumor; the lung cancer includes but is not limited to small cell lung cancer and non-small cell lung cancer; the blood tumor includes but is not limited to leukemia, lymphoma, myeloma; the brain cancer includes but is not limited to glioma, neuroblastoma, astrocytoma, meningioma.

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